5-membered n-heterocyclic compounds with hypoglycemic and hypolipidemic activity

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

 

The technical field

The present invention relates to new nitrogen-containing 5-membered heterocyclic compound which has excellent hypoglycemic activity and hypolipidemic activity, which can be used as a means for prevention or treatment of diabetes, hyperlipidemia, decreased glucose tolerance, inflammatory diseases, arteriosclerosis and the like.

The present invention also relates to an agent for the prophylaxis or treatment of diabetes, hyperlipidemia, or reduced glucose tolerance, which comprises nitrogen-containing 5-membered heterocyclic compound.

The present invention also relates to the means regulating the function of retinoid-related receptor, or agent that increases insulin resistance, which includes a nitrogen-containing 5-membered heterocyclic compound.

Background of the invention

In JP-A 10-72434 described 2,4-substituted aniline derivative of the formula:

where R1represents alkyl, halogenated, alkoxy or the like; R2represents a hydrogen atom, alkyl, halogenated or the like;

R3represents alkyl, cycloalkyl, alkenyl or the like;

X represents oxygen, sulfur, NR5and the and single bond;

Q represents an azole or the like, and including the herbicide.

However, nothing was reported about the possibility of hypoglycemic activity and hypolipidemic activity of the specified derived.

Gamma receptor, activated by proliferation peroxisomes, (Rγ), member of the inter-core hormone superfamily of receptors, typical representatives of which are the receptors of steroid hormones and receptors, thyroid hormone, plays an important role as the primary regulator of the differentiation of adipose cells inducyruya their expression at early stages of differentiation of adipose cells. PPARγ form a dimer with ratinidine receptor X (RXR) upon binding with the ligand and attached to the appropriate website mesiniaga gene in the nucleus to direct control (activate) the efficiency of transcription. In recent years, some have suggested the possibility that 15-deoxy-Δ12.24prostaglandin J2, a metabolite of prostaglandin D2serves as the endogenous ligand of PPARγand it was shown that the class of insulin-resistant enhancers, typical representatives of thiazolidinedione derivatives inherent ligand activity against PPARγ and that their effectiveness proportional to their hypoglycemic activity or activity of stimulating the differentiation of adipose cells [Cel, vol.83, R (1995): the Journal of Biological Chemistry, vol.270, p.12953 (1995); Journal of Medicinal Chemistry, vol.39, p.655 (1996)]. In addition, in recent years it was shown that 1) PPARγ expressed in cultured origin cell liposarcomas person, the proliferation of which is invoked by adding a ligand of PPARγ [Proceedings of the National Academy of Sciences of the United States of America, vol. 94, p. 237 (1997)], 2) nonsteroidal anti-inflammatory drugs, typical representatives of which are indomethacin and fenoprofen have PPARγ ligand activity [the Journal of Biological Chemistry, vol.272, p.3406 (1997)], 3) PPARγ expressed at high levels in activated macrophages adding ligand along with a transcription of a gene involved in the inhibition of inflammation [Nature, vol.391, R (1998)], and 4) the ligands of PPARγ cupressinum production of inflammatory cytokines (TNFα, IL-lβ, IL-6) by monocytes [Nature, vol.391, R (1998)].

There is a need to develop new compounds that are used as tools for the prevention and treatment of diabetes, hyperlipidemia, decreased glucose tolerance, inflammatory diseases, atherosclerosis and the like, and having excellent pharmaceutical properties, such as the mild side effects and the like.

Description of the invention

The present invention relates (1) to the compound of the formula:

1represents a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted;

X represents a bond, an oxygen atom, a sulfur atom or a group of the formula: -CO-, -CS-, -CR4(OR5) - or-NR6-, where each R4and R6represents a hydrogen atom or a hydrocarbon group which may be substituted, R5represents a hydrogen atom or a protective group for hydroxyl group;

m represents an integer from 0 to 3;

Y represents an oxygen atom, a sulfur atom or a group of the formula: -SO-, -SO2-, -NR7-, -CONR7- or-NR7CO-, where R7represents a hydrogen atom or a hydrocarbon group which may be substituted;

ring a represents an aromatic ring which, in addition, may contain from 1 to 3 substituents;

n represents an integer from 1 to 8;

the ring is a nitrogen-containing 5-membered heterokonta, which, in addition, may be substituted by alkyl group;

X1represents a bond, an oxygen atom, a sulfur atom or a group of the formula: -SO-, -SO2-, -O-SO2- or-NR16-where R16represents a hydrogen atom or a hydrocarbon group which may be substituted;

R2represents a hydrogen atom, a hydrocarbon group, which may be the ü substituted, or heterocyclic group which may be substituted;

W represents a bond or divalently hydrocarbon residue containing from 1 to 20 carbon atoms;

R3represents a group of formula: -OR8(R8represents a hydrogen atom or a hydrocarbon group which may be substituted) or-NR9R10(each of R9and R10that can be either equal or different, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or acyl group which may be substituted; R9and R10can be combined with the formation of the ring);

provided that R1represents a heterocyclic group which may be substituted, or R2represents an aromatic hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted, if the ring a represents a benzene ring which may be substituted, and Y represents an oxygen atom, a sulfur atom, -NH - or-CONH-; or its salt;

(2) to the connection on one of the above (1), where X1is a bond and ring b is a nitrogen-containing 5-membered heterocyclic ring;

(3) to the connection on one of the above (1), where R1 represents a heterocyclic group, which may be substituted, or a cyclic hydrocarbon group which may be substituted;

(4) to the connection on one of the above (1), where R1represents a heterocyclic group which may be substituted;

(5) to the connection on one of the above (1), where X is a bond;

(6) the compound according to the above (1), where m is 1 or 2;

(7) the compound according to the above (1), where Y represents an oxygen atom;

(8) the compound according to the above (1), where the ring a represents a benzene ring or pyridine ring, each of which may also contain from 1 to 3 substituents;

(9) the compound according to the above (1), where n is an integer from 1 to 3;

(10) the compound according to the above (1), where X1represents a bond or an oxygen atom;

(11) the compound according to the above (1), where W is divalently hydrocarbon residue containing from 1 to 8 carbon atoms;

(12) to the connection on one of the above (1), where R3represents a group of formula: -OR8(R8represents a hydrogen atom or a hydrocarbon group which may be substituted);

(13) the compound according to the above (1), which is a

3-[3-ethoxy-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-1H-pyrazole-4-yl]propionic acid,

3-[3-this is the XI-1-[4-(2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid,

3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid,

3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propionic acid,

3-[1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-spirutal-4-yl]propionic acid, or

3-[1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propionic acid;

(14) to the prodrug compounds defined above in (1);

(15) the pharmaceutical composition containing the compound of the formula:

where R1represents a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted;

X represents a bond, an oxygen atom, a sulfur atom or a group of the formula: -CO-, -CS-, -CR4(OR5)- or-NR6-, where each R4and R6represents a hydrogen atom or a hydrocarbon group which may be substituted, R5represents a hydrogen atom or a protective group for hydroxyl group;

m represents an integer from 0 to 3;

Y represents an oxygen atom, a sulfur atom or a group of the formula: -SO-, -SO2-, -NR7-, -CONR7- or-NR7CO-, where R7represents a hydrogen atom or a hydrocarbon group which may be substituted;

ring a represents aromatizes the second ring, which, in addition, may contain from 1 to 3 substituents;

n represents an integer from 1 to 8;

the ring is a nitrogen-containing 5-membered heterokonta, which, in addition, may be substituted by alkyl group;

X1represents a bond, an oxygen atom, a sulfur atom or a group of the formula: -SO-, -SO2-, -O-SO2- or-NR16-where R16represents a hydrogen atom or a hydrocarbon group which may be substituted;

R2represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted;

W represents a bond or divalently hydrocarbon residue containing from 1 to 20 carbon atoms;

R3represents a group of formula: -OR8(R8represents a hydrogen atom or a hydrocarbon group which may be substituted) or-NR9R10(each of R9and R10that can be either equal or different, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or acyl group which may be substituted; R9and R10can be combined to form a ring); or its salt or its prodrug;

(16) the composition according to the above (15), where X 1is a bond and ring b is a nitrogen-containing 5-membered heterocyclic ring;

(17) to the agent for the prophylaxis or treatment of diabetes containing the compound of the formula (II)or its salt or its prodrug;

(18) to the agent for the prophylaxis or treatment of hyperlipidemia, containing the compound of the formula (II)or its salt or its prodrug;

(19) to the agent for the prevention or treatment reduced glucose tolerance, containing the compound of the formula (II)or its salt or its prodrug;

(20) by means of regulating the function of retinoid-related receptor containing the compound of the formula (II)or its salt or its prodrug;

(21) means on one of the above (20), which is a ligand for the proliferation of activated receptors in peroxisomes;

(22) means on one of the above (20), which is a ligand retinoid X receptor;

(23) means that increase insulin resistance, which comprises a compound of the formula (II)or its salt or its prodrug;

(24) to a method of preventing or treating diabetes in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of the compounds of formula (II)or its salt or its prodrug;

(25) the way PR is the prevention or treatment of hyperlipidemia in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of the compounds of formula (II)or its salt or its prodrug;

(26) the method of prevention or treatment reduced glucose tolerance in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of the compounds of formula (II)or its salt or its prodrug;

(27) the method of regulating functions of retinoid-related receptor in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of the compounds of formula (II)or its salt or its prodrug;

(28) to the use of compounds of formula (II)or its salt or its prodrug, for the production of a pharmaceutical preparation for the prevention or treatment of diabetes;

(29) to the use of compounds of formula (II)or its salt or its prodrug, for the production of a pharmaceutical preparation for the prophylaxis or treatment of hyperlipidemia;

(30) to the use of compounds of formula (II)or its salt or its prodrug, for the production of a pharmaceutical preparation for the prevention or treatment reduced glucose tolerance;

and

(31) to the use of compounds of formula (II)or its salt or its prodrug, for the production of cf is DSTV, regulating the function of retinoid-related receptor.

(1) the Definition of R1

(1-1) the Definition of “hydrocarbon group” for R1

Examples of the hydrocarbon group in the “hydrocarbon group which may be substituted” for R1in formulas (I) and (II) are aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, alicyclic-aliphatic hydrocarbon group, an aromatic-aliphatic hydrocarbon groups and aromatic hydrocarbon groups. The number of carbon atoms in these hydrocarbon groups preferably ranges from 1 to 14.

Aliphatic hydrocarbon group, preferably represent an aliphatic hydrocarbon group containing from 1 to 8 carbon atoms. Examples of aliphatic hydrocarbon groups include saturated aliphatic hydrocarbon groups containing from 1 to 8 carbon atoms (for example, alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, heptyl and octyl; and unsaturated aliphatic hydrocarbon group containing from 2 to 8 carbon atoms (for example, alkeline group containing from 2 to 8 carbon atoms, akadeemiline group containing from 4 to 8 carbon atoms, alkenylacyl group sod is rashie from 2 to 8 carbon atoms, akadeemiline group containing from 4 to 8 carbon atoms, such as ethynyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl, ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl.

Alicyclic hydrocarbon group, preferably represent an alicyclic hydrocarbon group containing from 3 to 7 carbon atoms. Examples of the alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups containing 3 to 7 carbon atoms (for example, cycloalkyl group), such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; and unsaturated alicyclic hydrocarbon groups containing 5 to 7 carbon atoms (for example, cycloalkenyl group, cycloalkenyl group), such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadiene.

Examples of the alicyclic-aliphatic hydrocarbon groups are groups formed by binding the above is s alicyclic hydrocarbon groups and aliphatic hydrocarbon groups (for example, cycloalkyl-alkyl groups, cycloalkenyl-alkyl groups), with, preferably, alicyclic-aliphatic hydrocarbon groups containing from 4 to 9 carbon atoms. Examples of the alicyclic-aliphatic hydrocarbon groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentylmethyl, 3-cyclopentylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylmethyl, cycloheptylmethyl and cycloheptylmethyl.

Aromatic-aliphatic hydrocarbon groups, preferable are aromatic-aliphatic hydrocarbon group containing from 7 to 13 carbon atoms (for example, kalkilya group containing from 7 to 13 carbon atoms, arylalkyl group containing from 8 to 13 carbon atoms). Examples of the aromatic-aliphatic hydrocarbon groups include phenylalkyl containing from 7 to 9 carbon atoms, such as benzyl, phenethyl, 1-phenylethyl, 1-phenylpropyl, 2-phenylpropyl and 3-phenylpropyl; naphthylethylene group containing from 11 to 13 carbon atoms, such as α-naphthylmethyl, β-naphtalate, β-naphthylmethyl and β-naphtalate; phenylalkylamine group containing from 8 to 10 carbon atoms, such as styryl; and naphthylethylene group containing from 12 to 13 atoms of carbon is a, such as 2-(2-naphthylvinyl).

Aromatic hydrocarbon group, preferably represents an aromatic hydrocarbon group containing from 6 to 14 carbon atoms (for example, aryl groups). Examples of aromatic hydrocarbon groups include phenyl, naphthyl, antril, tenantry, acenaphthylene and biphenylyl, preference is given to phenyl, 1-naphthyl, 2-naphthyl and the like.

From the above hydrocarbon groups, cyclic hydrocarbon groups, such as the alicyclic hydrocarbon groups and aromatic hydrocarbon groups are preferred. Preferred hydrocarbon groups are aromatic hydrocarbon groups containing from 6 to 14 carbon atoms, preference is given to phenyl, naphthyl and the like.

(1-2) the Definition of “heterocyclic group” for R1

Examples of the heterocyclic group in the “heterocyclic group which may be substituted” for R1in formulas (I) and (II) serve a 5-7 membered monocyclic heterocyclic group containing as constituents of the ring atoms besides carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, or a condensed heterocyclic group. Examples of the condensed heterocyclic groups include groups which, formed by condensation of such a 5-7 membered monocyclic heterocyclic groups with 6-membered ring containing 1 to 2 nitrogen atoms, benzene ring or 5-membered ring containing 1 sulfur atom.

In particular, examples of the heterocyclic group include aromatic heterocyclic groups such as 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, isoxazolyl, isothiazole, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl, 1,3,4-thiadiazole-2-yl, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl, 1,2,3-triazole-1-yl, 1,2,3-triazole-2-yl, 1,2,3-triazole-4-yl, tetrazol-1-yl, tetrazol-5-yl, 2-chinolin, 3-chinolin, 4-chinolin, 2-chinadoll, 4-chinadoll, 2-Minoxidil, 2-benzoxazolyl, 2-benzothiazolyl, benzimidazole-1-yl, benzimidazole-2-yl, indol-1-yl, indol-3-yl, 1H-indazol-3-yl, 1H-pyrrolo[2,3-b]pyrazin-2-yl, 1H-pyrrolo[2,3-b]pyridine-6-yl, 1H-imidazo[4,5-b]pyridine-2-yl, 1H-imidazo[4,5-C]pyridine-2-yl, 1H-imidazo[4,5-b]pyrazin-2-yl and benzotriazol-1-yl; and non-aromatic heterocyclic groups such as 1-pyrrolidinyl, piperidino, morpholino, thiomorpholine, 1-Pieper is sinil, hexamethylenimine-1-yl, oxazolidin-3-yl, thiazolidin-3-yl, imidazolidin-3-yl, 2-Oxymetazoline-1-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxoimidazolidin-3-yl, 2,4-dioxothiazolidine-3-yl, 1-oxo-phthalazine-2-yl and 2-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl.

Heterocyclic groups are preferably aromatic heterocyclic groups, and, more preferably, 5 - or 6-membered aromatic heterocyclic groups which may be condensed with a benzene ring (preferably, fullam, teinila, pyridium, pyrimidinium, pyrazinium, pyrazolyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl). Especially preferred are furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, thiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, chinosol and the like.

(1-3) the Definition of “Deputy” for R1

Each of the hydrocarbon group and heterocyclic group for R1in formulas (I) and (II) may contain from 1 to 5, preferably from 1 to 3, substituents at substitutable position. Examples of the substituents include halogen atoms, nitrogen atoms”, “aliphatic hydrocarbon group which may be substituted”, “alicyclic hydrocarbon group which may be substituted”, “aromatic hydrocarbon group, which may be zames the us, “aromatic heterocyclic group which may be substituted”, the “non-aromatic heterocyclic group which may be substituted”, the “acyl group which may be substituted”, the “amino group which may be substituted”, the “hydroxy-group which may be substituted”, “Tilney group which may be substituted”, and “carboxyl group which may be etherification or aminirovanie”.

Examples of halogen atoms include fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

Examples of aliphatic hydrocarbon groups in the expression “aliphatic hydrocarbon group which may be substituted” are aliphatic hydrocarbon group with a straight or branched chain, containing from 1 to 15 carbon atoms, such as alkyl groups, alkeline group and alkyline group.

Preferred examples of alkyl groups include alkyl groups containing from 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2-ethylbutyl, heptyl, octyl, nonyl and decyl.

Preferred examples alkenyl groups include alkeneamine group containing from 2 to 10 carbon atoms such as these is Il, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, 1-heptenyl and 1-octanol.

Preferred examples etkinlik groups include alkyline group containing from 2 to 10 carbon atoms, such as ethinyl, 1-PROPYNYL, 2-PROPYNYL, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-heptenyl and 1-octenyl.

Examples of substituents in the expression “aliphatic hydrocarbon group which may be substituted” include cycloalkyl group containing from 3 to 10 carbon atoms, aryl groups containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl), aromatic heterocyclic groups (for example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl), non-aromatic heterocyclic group (for example, tetrahydrofuryl, morpholino, thiomorpholine, piperidine, pyrrolidine, piperazinil), kalkilya group containing from 7 to 9 carbon atoms, amino groups, amino groups, mono - or disubstituted by alkyl groups containing from 1 to 4 carbon atoms, or acyl groups containing from 2 to 8 carbon atoms (for example, alcoholnye group), amidinopropane, acyl group containing from 2 to 8 atoms in the of Lerida (for example, alcoholnye group), karbamoilnuyu group, karbamoilnuyu group, mono - or disubstituted by alkyl group containing from 1 to 4 carbon atoms, sulfamoyl group, sulfamoyl group, mono - or disubstituted by alkyl groups containing from 1 to 4 carbon atoms, carboxyl group, alkoxycarbonyl group containing from 2 to 8 carbon atoms, a hydroxy-group, alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkenylacyl containing from 2 to 5 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), cycloalkylcarbonyl containing from 3 to 7 carbon atoms, aralkylated containing from 7 to 9 carbon atoms, alloctype containing from 6 to 14 carbon atoms (for example, phenyloxy, naphthyloxy), Tilney group, ancilliary containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), arkitip, containing from 7 to 9 carbon atoms, aristocraty containing from 6 to 14 carbon atoms (for example, phenylthio, naphthylthio), alphagroup, cyano, azide group, a nitrogroup, nitrosolobus and halogen atoms (e.g. fluorine, chlorine, bromine, iodine). The number of Deputy is th same, for example, from 1 to 3.

Examples of the alicyclic hydrocarbon groups in terms of the “alicyclic hydrocarbon group which may be substituted” are saturated or unsaturated alicyclic hydrocarbon groups containing from 3 to 12 carbon atoms, such as cycloalkyl group, cycloalkenyl group and cycloalkenyl group.

Preferred examples cycloalkyl groups include cycloalkyl group containing from 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.1]nonyl and bicyclo[4.3.1]decyl.

Preferred examples cycloalkenyl groups include cycloalkenyl group containing from 3 to 10 carbon atoms, such as 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl.

Preferred examples cycloalkenyl groups include cycloalkenyl group containing from 4 to 10 carbon atoms, such as 2,4-cyclopentadiene-1-yl, 2,4-cyclohexadiene-1-yl and 2,5-cyclohexadiene-1-yl.

Preferred examples of aromatic hydrocarbon groups in the expression “aromatic hydrocarbon group which may be substituted” include an aromatic hydrocarbon group, with the holding from 6 to 14 carbon atoms (for example, aryl group such as phenyl, naphthyl, antril, tenantry, acenaphthylene and biphenylyl, preference is given to phenyl, 1-naphthyl, 2-naphthyl and the like.

Preferred examples of the aromatic heterocyclic groups in the expression “aromatic heterocyclic group which may be substituted” include a 5-7-membered monocyclic aromatic heterocyclic group containing as constituents of the ring atoms besides carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, such as furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazane, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl; and bicyclic or tricyclic condensed aromatic heterocyclic group containing from 3 to 13 carbon atoms and having as constituents of the ring atoms in addition to carbon atoms, from 1 to 5 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, such as benzofuranyl, isobenzofuranyl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazole, benzimidazole, benzoxazole, benzothiazole, 1H-benzotriazolyl, hinely, Itoh nail, hennell, chinadoll, honokalani, phthalazine, naphthylidine, purinol, pteridinyl, carb was Salil, α-Carbonell, β-Carbonell, γ-Carbonell, acridines, phenoxazines, phenothiazines, phenazines, phenoxathiin, thianthrene, indolizinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl and 1,2,4-triazolo[4,3-b]pyridazinyl.

Preferred examples of non-aromatic heterocyclic groups in the expression “non-aromatic heterocyclic group which may be substituted” include non-aromatic heterocyclic groups containing from 2 to 10 carbon atoms and having as constituents of the ring atoms besides carbon atoms, 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms, such as oxiranyl, azetidine, oxetane, titanyl, pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, thiomorpholine, piperazinil, pyrrolidinyl, piperidino, morpholino, thiomorpholine.

Examples of substituents in the above expressions, “alicyclic hydrocarbon group which may be substituted”, “aromatic hydrocarbon group which may be substituted”, “aromatic heterocyclic group which may be substituted” and “neuroma the practical heterocyclic group, which may be substituted” include alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkeline group containing from 2 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), cycloalkyl group containing from 3 to 10 carbon atoms, aryl groups containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl), an aromatic heterocyclic group (for example, thienyl, furyl, pyridyl, oxazolyl, thiazolyl), non-aromatic heterocyclic group (for example, tetrahydrofuryl, morpholino, thiomorpholine, piperidine, pyrrolidine, piperazinil), kalkilya group containing from 7 to 9 carbon atoms, amino group, amino group, mono - or disubstituted by alkyl groups containing from 1 to 4 carbon atoms, or acyl groups containing from 2 to 8 carbon atoms (for example, alcoholnye group), amidinopropane, acyl group containing from 2 to 8 carbon atoms (for example, alcoholnye group), karbamoilnuyu group, carbamoyl group, mono - or disubstituted by alkyl groups containing from 1 to 4 carbon atoms, sulfamoyl group, sulfamoyl group, mono - or disubstituted by alkyl groups containing from 1 to 4 atoms ug is erode, carboxyl group, alkoxycarbonyl group containing from 2 to 8 carbon atoms, a hydroxy-group, alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkenylacyl containing from 2 to 5 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), cycloalkylcarbonyl containing from 3 to 7 carbon atoms, aralkylated containing from 7 to 9 carbon atoms, alloctype containing from 6 to 14 carbon atoms (for example, phenyloxy, naphthyloxy), Tilney group, ancilliary containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), arkitip containing from 7 to 9 carbon atoms, aristocraty containing from 6 to 14 carbon atoms (for example, phenylthio, naphthylthio), alphagroup, cyano, asiagraph, a nitrogroup, nitrosolobus and halogen atoms (e.g. fluorine, chlorine, bromine, iodine). The number of substituents is, for example, from 1 to 3.

Examples of acyl groups in the expression “acyl group which may be substituted” are acyl groups containing from 1 to 13 carbon atoms, especially formyl, and groups of formula: -COR11, -SO2R11, -SOR11or RHO3R11the 12where each R11and R12that can be either equal or different, represents a hydrocarbon group or aromatic heterocyclic group.

Examples of the hydrocarbon group for R11or R12are hydrocarbon groups mentioned for R1. Especially preferred are alkyl groups containing from 1 to 10 carbon atoms, cycloalkyl group containing from 3 to 10 carbon atoms, alkeline group containing from 2 to 10 carbon atoms, cycloalkenyl group containing from 3 to 10 carbon atoms, and aryl groups containing from 6 to 12 carbon atoms.

Examples of the aromatic heterocyclic group for R11or R12are aromatic heterocyclic groups mentioned above for R1. Especially preferred are thienyl, furyl, pyridyl and the like.

Preferred examples of acyl groups include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cyclohexylcarbonyl, crotonyl, 2-cyclohexanecarbonyl, benzoyl, nicotinoyl and isonicotinoyl.

The indicated acyl group may have 1 to 3 substituents at substitutable positions. Examples of such substituents include the C 1-6alkyl group which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, iodine), C1-6alkoxygroup, which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino.

The expression “amino group which may be substituted” are examples of the amino group which may be mono - or disubstituted by alkyl groups containing from 1 to 10 carbon atoms, cycloalkyl groups containing from 3 to 10 carbon atoms, alkenylamine groups containing from 2 to 10 carbon atoms, cycloalkenyl groups containing from 3 to 10 carbon atoms, acyl groups containing from 1 to 13 carbon atoms, or aryl groups containing from 6 to 12 carbon atoms.

Examples of acyl groups are the same acyl groups described above, and preferable are alcoholnye group containing from 2 to 10 carbon atoms, arylcarbamoyl group containing from 7 to 13 carbon atoms, and the like.

Examples of substituted amino groups include methylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino, diallylamine, cyclohexylamino, acetylamino, propionamido, benzoylamine, phenylamino and N-methyl-N-phenylamino.

In the expression is a hydroxy-group, which may be substituted” an example is the hydroxy-group which may be substituted by alkyl groups containing from 1 to 10 carbon atoms, alkenylamine groups containing from 2 to 10 carbon atoms, Uralkalij groups containing 7 to 10 carbon atoms, acyl groups containing from 1 to 13 carbon atoms, or aryl groups containing from 6 to 12 carbon atoms, each of these groups may be substituted.

Examples of substituents which may be of such alkyl groups containing from 1 to 10 carbon atoms”, “alkenyl groups containing from 2 to 10 carbon atoms”, “Uralkalij groups containing 7 to 10 carbon atoms”, “acyl group containing from 1 to 13 carbon atoms and aryl groups containing from 6 to 12 carbon atoms”include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkoxygroup, which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), hydroxy, nitro and amino. The number of substituents is for example 1 or 2.

Examples of the substituted hydroxy-group include alkoxygroup, alkenylacyl, aralkylated, alloctype and alloctype, each of these groups may be substituted.

Preferred examples of alkoxygroup include alkoxygroup containing from 1 to 10 carbon atoms, such kamataki, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentylamine, neopentylene, hexyloxy, heptyloxy, nonyloxy, CYCLOBUTANE, cyclopentyloxy, cyclohexyloxy.

Preferred examples of alkenylacyl include alkenylacyl containing from 2 to 10 carbon atoms, such as allyloxy, krotylov, 2-pentyloxy, 3 hexenoate, 2-cyclopentyloxy and 2 cyclohexyloxy.

Preferred examples of aralkylated include aralkylated containing 7 to 10 carbon atoms, such as phenyl-C1-4alkyloxyaryl (for example, benzyloxy, penetrate).

Preferred examples of acyloxy include alloctype containing from 2 to 13 carbon atoms, more preferred alkanoyloxy containing from 2 to 4 carbon atoms (for example, atomic charges, propionyloxy, butyryloxy, isobutyryloxy).

Preferred examples of aryloxy include alloctype containing from 6 to 14 carbon atoms, such as phenoxy, naphthyloxy.

The above alkoxygroup, alkenylacyl, aralkylated, alloctype and alloctype may contain 1 or 2 substituent in positions that can be substituted. Examples of such substituents include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkoxy PPI, which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), hydroxy, nitro and amino. For example, examples of the substituted alloctype include 4-chlorphenoxy and 2 methoxyphenoxy.

Example Tilney group which may be substituted, is Tolna group which may be substituted by alkyl groups containing from 1 to 10 carbon atoms, cycloalkyl groups containing 3 to 10 carbon atoms, Uralkalij groups containing 7 to 10 carbon atoms, acyl groups containing 2 to 13 carbon atoms, aryl groups containing 6 to 14 carbon atoms, heteroaryl groups and the like.

Examples of substituted tylnej groups include ancilliary, cycloalkylation, arkitip, alltihopa, aristocraty and heteroanalogues.

Preferred examples of alkylthio include ancilliary containing from 1 to 10 carbon atoms, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutyric, sec-butylthio, tert-butylthio, pentylthio, isopentyl, neopentyl, hexylthio, Reptilia, Nonito.

Preferred examples of cycloalkenyl include cycloalkylation containing from 3 to 10 carbon atoms, such as cyclobutyl, cyclopentyl, cyclohexylthio.

Preferred examples of aralkyl is AGroup include arkitip, containing 7 to 10 carbon atoms, such as phenyl-C1-4allylthiourea (for example, benzylthio, penetito).

Preferred examples of alltop include alltihopa containing from 2 to 13 carbon atoms, more preferred alcoholtoprol containing from 2 to 4 carbon atoms (for example, acetylthio, propositio, butylthio, isobutyrate).

Preferred examples of aricioglu include aristocraty containing from 6 to 14 carbon atoms, such as phenylthio, naphthylthio.

Preferred examples of heteroaromatics include 2-pyridylthio, 3 pyridylthio, 2-imidazoline and 1,2,4-triazole-5-ylthio.

Examples of the esterified carboxyl groups in the carboxyl groups, which can be tarifitsirovana serve alkoxycarbonyl group containing from 2 to 5 carbon atoms (for example, methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl), aracelikarsaalyna group containing from 8 to 10 carbon atoms (for example, benzyloxycarbonyl), and aryloxyalkyl group containing from 7 to 15 carbon atoms (for example, phenoxycarbonyl, p-tolylacetylene), which may be substituted by 1 or 2 alkyl groups containing from 1 to 3 carbon atoms.

Examples emitirovannykh carboxyl groups in the carboxyl groups, which can be amidino the Ana, serve a group of the formula: -CON(R13) (R14), where each R13and R14that can be either equal or different, represents a hydrogen atom, a hydrocarbon group which may be substituted, or a heterocyclic group which may be substituted.

Examples of the hydrocarbon group in the “hydrocarbon group which may be substituted” for R13and R14here are aliphatic hydrocarbon groups, alicyclic hydrocarbon groups and aromatic hydrocarbon groups mentioned as examples of the hydrocarbon group in the “hydrocarbon group which may be substituted” for R1. In addition, examples of the heterocyclic group in the “heterocyclic group which may be substituted” for R13and R14are heterocyclic groups mentioned as examples of the heterocyclic group in the “heterocyclic group which may be substituted” for R1. These hydrocarbon groups and heterocyclic groups may contain from 1 to 3 substituents in positions that can be substituted. Examples of such substituents include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkyl group which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkoxygroup the dust, which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino.

Substituents of the hydrocarbon group and heterocyclic group for R1in formulas (I) and (II), preferably, are:

1) an alkyl group containing from 1 to 10 (preferably from 1 to 4) carbon atoms which may have from 1 to 3 substituents selected from the group including alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino;

2) cycloalkyl group containing from 3 to 10 (preferably 3 to 7) carbon atoms which may have from 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine)atoms halogen (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino;

3) an aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrazinyl and the like), which may have from 1 to substituents, selected from the group comprising alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino;

4) aryl group containing from 6 to 14 carbon atoms (preferably phenyl, naphthyl and the like)which may have 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino; and the like. The number of substituents is, for example, from 1 to 3, preferably 1 or 2.

The substituents are preferably alkyl groups containing from 1 to 4 carbon atoms, furyl, thienyl, phenyl, naphthyl and the like.

(1-4) Preferred examples of R1

In formulas (I) and (II), R1preferably represents heterocyclic the forge group, which may be substituted, or a cyclic hydrocarbon group which may be substituted. More preferably, R1represents a heterocyclic group which may be substituted. The heterocyclic group here, preferably, is a 5 - or 6-membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl), which may be condensed with a benzene ring. Especially preferred are furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, oxadiazolyl, benzoxazolyl, benzothiazolyl, hinely, pyrazolyl and the like.

Preferred examples of the substituents that can be vysheukazannoe heterocyclic group or a cyclic hydrocarbon group include:

1) furyl, thienyl, pyridyl, pyrazinyl, phenyl or naphthyl, each of which may have 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (for example, FPO is, chlorine, bromine, iodine), nitro, hydroxy and amino;

2) an alkyl group containing from 1 to 4 carbon atoms or cycloalkyl group containing from 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group comprising alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino. The number of substituents is for example 1 or 2.

Particularly preferably, R1represents pyridyl, oxazolyl, thiazolyl, triazolyl or pyrazolyl, each of which may have 1 to 2 substituents selected from the group comprising alkyl groups containing from 1 to 3 carbon atoms, cycloalkyl group containing from 3 to 7 carbon atoms, furyl, thienyl, pyridyl, phenyl and naphthyl.

(2) the Definition of X

In formulas (I) and (II), X represents a bond, an oxygen atom, a sulfur atom or a group of the formula: -CO-, -CS-, -CR4(OR5)- or-NR6-, where each R4and R6represents a hydrogen atom or a hydrocarbon group which may be substituted, R5represents a hydrogen atom or a protective group for hydroxyl group; and preferably represents a bond, -CR4(OR5)- or-NR6-where characters who have the same values as indicated above, more preferably represents a bond or-NR6-where the symbols have the same meanings as described above. Particularly preferably, X represents a bond.

Examples of the “hydrocarbon group which may be substituted” for R4and R6here are the “hydrocarbon group which may be substituted”mentioned above. Preferably, the mentioned “hydrocarbon group which may be substituted” are alkyl groups containing from 1 to 4 carbon atoms which may be substituted, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl.

These alkyl groups can have from 1 to 3 substituents in positions that can be substituted. Examples of such substituents include halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 4 carbon atoms (e.g. methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy), hydroxy, nitro, amino and acyl groups containing from 1 to 4 carbon atoms (for example, alcoholnye group containing from 1 to 4 carbon atoms, such as formyl, acetyl and propionyl).

R4and R6preferably represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms.

Examples of protective gr the PP for the hydroxyl group in the R 5include C1-6alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, C7-10kalkilya group (e.g., benzyl), formyl, C1-6alkylcarboxylic (for example, acetyl, propionyl), benzoyl, C7-10aralkyl-carbonyl group (e.g., benzylcarbamoyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl) and C2-6alkeneamine group (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkyl groups (e.g. methyl, ethyl, propyl), C1-6alkoxygroup (for example, methoxy, ethoxy, propoxy), nitro or the like.

(3) Determine m and Y

In formulas (I) and (II), m represents an integer from 0 to 3, preferably an integer from 1 to 3 and, more preferably, 1 or 2.

In formulas (I) and (II), Y represents an oxygen atom, a sulfur atom or a group of the formula: -SO-, SO2-, -NR7-, -CONR7- or-NR7CO-, where R7represents a hydrogen atom or a hydrocarbon group which may be substituted and preferably represents an oxygen atom, a sulfur atom, -NR7- or-NR7CO-, where the symbol has the same meaning as above.

Examples of “carbohydrate is adnych groups, which may be substituted” for R7here are the above examples of the “hydrocarbon group which may be substituted” for R4and R6. Preferably, R7represents a hydrogen atom. Particularly preferably, Y represents an oxygen atom.

(4) the denition of the ring And

In formulas (I) and (II), examples of the “aromatic ring” in the expression “aromatic ring which, in addition, may have from 1 to 3 substituents for rings And serve as a benzene ring, a condensed aromatic hydrocarbon ring, 5 - or 6-membered aromatic heterocycles and condensed aromatic heterocycles.

Examples of the “condensed aromatic hydrocarbon rings include here a condensed aromatic hydrocarbon ring containing from 9 to 14 carbon atoms.

Especially can be specified naphthalene, inden, fluorene, anthracene and the like.

Examples of “5 - or 6-membered aromatic heterotopic” include 5 - or 6-membered aromatic heterokonta containing, besides carbon atoms, 1 to 3 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom.

Especially can be specified thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazol, oxazol, isoxazol, pyridine, pyrazin, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3, 4-oxadiazole,1,2,4-thiadiazole, 1,3,4-thiadiazole, furazan and the like.

Examples of the “condensed aromatic heterotopic include 9-14-membered (preferably 9-10-membered) condensed aromatic heterokonta containing, besides carbon atoms, 1 to 4 heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom. Especially can be specified benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzisothiazole, oil[2,3-b]thiophene, isoquinoline, quinoline, indole, cinoxacin, phenanthridine, phenothiazines, phenoxazin, phthalazine, naphthiridine, hinzelin, cinnoline, carbazole, β-carbolin, acridine, fenesin, phthalimide and the like.

“Aromatic ring”preferably represents a benzene ring, a condensed aromatic hydrocarbon ring containing from 9 to 14 carbon atoms (preferably, naphthalene and the like), 5-6-membered aromatic heterokonta (preferably, pyridine, isoxazol, and the like) or the like.

Examples of “substituents” in the “aromatic ring which, in addition, may have from 1 to 3 substituents for ring a include aliphatic hydrocarbon group (preferably an alkyl group)which may be substituted, a hydroxy-group, which may be substituted, halogen atoms, acyl group which may be substituted, nitro group and an amino group, which may be substituted. All these substituents are the same as mentioned above as examples of substituents for R1. These substituents preferably are alkyl groups containing from 1 to 4 carbon atoms, a hydroxy-group, alkoxygroup containing from 1 to 4 carbon atoms, aralkylated containing 7 to 10 carbon atoms (preferably benzyloxy), or halogen atoms.

Ring And preferably represents a benzene ring or pyridine ring, each of which, in addition, may contain from 1 to 3 substituents, more preferably a benzene ring or pyridine ring, each of which, in addition, may contain from 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 4 carbon atoms, a hydroxy-group, alkoxygroup containing from 1 to 4 carbon atoms, aralkylated containing 7 to 10 carbon atoms, and halogen atoms. Particularly preferably, the ring a represents a benzene ring.

(5) Definition n

In formulas (I) and (II), n represents an integer from 1 to 8, preferably an integer from 1 to 3.

(6) determination of the ring

In formulas (I) and (II), examples of the “nitrogen-containing 5-membered heterokonta” in the “nitrogen-containing 5-membered heteroclite to the e, in addition, there may be a substituted alkyl group” for ring are 5-membered heterokonta that contain as constituents of the ring atoms in addition to carbon atoms, at least 1 nitrogen atom, and which, moreover, can have from 1 to 3 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom.

Preferred examples of the nitrogen-containing 5-membered heterokonta include 5-membered aromatic heterokonta, such as pyrrole, pyrazole, imidazole, thiazole, isothiazol, oxazol, isoxazol, 1,2,4-triazole, 1,2,3-triazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, furazan, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole and tetrazole; and 5-membered nonaromatic heterokonta, such as pyrrolidine, imidazolidine and pyrazolidine. The nitrogen-containing 5-membered heterokonta preferably represent a 5-membered aromatic heterokonta that as constituents of the ring atoms in addition to carbon atoms, contains at least 1 nitrogen atom, and which, furthermore, may contain 1 heteroatom selected from oxygen atom, sulfur atom and nitrogen atom, such as pyrrole, pyrazole, imidazole, thiazole, isothiazol, oxazol and isoxazol. Especially preferred are pyrrole, pyrazole, imidazole and the like.

Examples of “alkyl group” in the “nitrogen-containing 5-membered heteroclite that, in addition, may be substituted alkyl group are alkyl groups containing from 1 to 4 carbon atoms. Especially may be mentioned methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, preference is given to stands and ethyl.

The ring preferably is a pyrrole, pyrazole or imidazole, each of which may also be substituted by alkyl group containing from 1 to 4 carbon atoms. Particularly preferably, the ring is a pyrazole.

(7) the Definition of X1

In formulas (I) and (II) X1represents a bond, an oxygen atom, a sulfur atom or a group of the formula: -SO-, -SO2-, -O-SO2- or-NR16-where R16represents a hydrogen atom or a hydrocarbon group which may be substituted.

Examples of the “hydrocarbon group which may be substituted” for R16serve as the “hydrocarbon group which may be substituted”mentioned above as examples for R4and R6.

Preferably, X1represents a bond or an oxygen atom.

(8) the Definition of R2

In formulas (I) and (II), examples of the expression “hydrocarbon group which may be substituted” and “heterocyclic group which may be substituted” for R2accordingly serve as the “hydrocarbon group that may be substituted” and “heterocyclic group, which may be substituted”mentioned as examples for R1.

(8-1) when X1in formulas (I) and (II) represents the relationship

The hydrocarbon group in the “hydrocarbon group which may be substituted” for R2preferably represents an aliphatic hydrocarbon group containing from 1 to 8 carbon atoms (preferably an alkyl group), or aromatic hydrocarbon group containing from 6 to 14 carbon atoms, and more preferably, an aromatic hydrocarbon group containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl).

Heterocyclic group in the “heterocyclic group which may be substituted” for R2preferably represents a 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl).

The substituents in the above-mentioned “hydrocarbon group which may be substituted” and “heterocyclic group which may be substituted”is preferably represent: 1) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 2) an alkyl group containing from 1 to 4 carbon atoms (e.g. methyl, trifluoromethyl, propyl, isopropyl), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 3) alkoxygroup containing from 1 to 4 atoms carbon (e.g. the measures methoxy, triptoreline), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 4) aralkylated containing 7 to 10 carbon atoms (e.g. benzyloxy), 5) alloctype containing from 6 to 14 carbon atoms (for example, phenoxy), 6) aromatic heterocyclic group (e.g., furyl, thienyl) or the like. The number of substituents is, for example, from 1 to 3.

R2preferably represents 1) aromatic uglevodorodnye group containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl)which may be substituted, or 2) a 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl), which can be overridden.

More preferably, R2represents 1) an aromatic hydrocarbon group containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl), or 2) a 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl). Especially preferred are phenyl, furyl, thienyl and the like.

(8-2) when X1in formulas (I) and (II) represents an oxygen atom, a sulfur atom or a group of the formula: -SO-, -SO2-, -O-SO2- or-NR16-where the symbol has the same meaning as above.

The hydrocarbon group in the “hydrocarbon group that can in order to be substituted for R 2preferably represents an aliphatic hydrocarbon group containing from 1 to 8 carbon atoms (preferably, alkyl group (e.g. methyl, ethyl, propyl, isopropyl)), aromatic-aliphatic hydrocarbon group containing from 7 to 13 carbon atoms (preferably, aracelio group (e.g., benzyl)), an aromatic hydrocarbon group containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl).

Heterocyclic group in the “heterocyclic group which may be substituted” for R2preferably represents a 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl).

The substituents in the above-mentioned “hydrocarbon group which may be substituted” and “heterocyclic group which may be substituted”is preferably represent 1) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 2) an alkyl group containing from 1 to 4 carbon atoms (e.g. methyl, ethyl, trifluoromethyl), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 3) aralkylated containing from 1 to 10 carbon atoms (for example, benzyloxy), 4) [5 - or 6-membered aromatic heterocyclic group (e.g. pyridyl, oxazolyl, thiazolyl, triazolyl), which may have 1 or 2 of replacing the Titel, selected from alkyl groups containing from 1 to 3 carbon atoms, cycloalkyl group containing from 3 to 7 carbon atoms (e.g. cyclohexyl), furyl, thienyl, phenyl and naphthyl]-alkoxygroup containing from 1 to 6 carbon atoms (e.g. methoxy, ethoxy), 5) an aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl), 6) alloctype containing from 6 to 14 carbon atoms (for example, phenoxy), 7) alkoxygroup containing from 1 to 4 carbon atoms (e.g., methoxy, ethoxy, triptoreline), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) or the like. The number of substituents is, for example, from 1 to 3.

R2preferably represents an aliphatic hydrocarbon group containing from 1 to 8 carbon atoms (preferably an alkyl group (e.g. methyl, ethyl, propyl, isopropyl), which may be substituted, an aromatic-aliphatic hydrocarbon group containing from 7 to 13 carbon atoms (preferably, aracelio group (e.g. benzyl), which may be substituted, or a heterocyclic group (preferably 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl), which may be substituted.

More predpochtitelno, R2represents aliphatic hydrocarbons is one group, containing from 1 to 8 carbon atoms (preferably an alkyl group (e.g. methyl, ethyl, propyl, isopropyl), or aromatic aliphatic hydrocarbon group containing from 7 to 13 carbon atoms (preferably aracelio group (e.g., benzyl)).

(9) Determination of W

In formulas (I) and (II), examples of “devalentino hydrocarbon residue containing from 1 to 20 carbon atoms” for W are “divalent acyclic hydrocarbon residues”, “divalent cyclic hydrocarbon residues and divalent group obtained by combining 1 or more “divalentin neilcicierega uglevodorodnykh residues” 1 or more “divalentin tilmicosin hydrocarbon residue”.

Examples of “divalent acyclic hydrocarbon residues include here alkylene containing from 1 to 20 carbon atoms, Alcanena containing from 2 to 20 carbon atoms, and akinyemi containing from 2 to 20 carbon atoms.

Examples of “divalent tilmicosin hydrocarbon residues include divalent group obtained by removing two randomly selected hydrogen atoms of cycloalkanes containing from 5 to 20 carbon atoms, cycloalkanes containing from 5 to 20 carbon atoms, or aromatic hydrocarbons containing from 6 to 20 carbon atoms (for example, benzene, naphthalene, is ndana, anthracene). In particular, there may be mentioned 1,2-cyclopentyl, 1,3-cyclopentyl, 1,2-cyclohexyl, 1,3-cyclohexyl, 1,4-cyclohexyl, 1,2-cycloheptadiene, 1,3-cycloheptadiene, 1,4-cycloheptene, 3-cyclohexen-1,4-ilen, 3-cyclohexen-1,2-ilen, 2,5-cyclohexadiene-1,4-ilen, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene, 1,4-naftilan, 1,6-naftilan, 2, 6-naftilan, 2, 7-naftilan, 1,5-Ingenier, 2,5-Ingenier and the like.

Compounds in which W in the formula (I) and (II) is divalently hydrocarbon residue containing from 1 to 20 carbon atoms, has a greater hypoglycemic and hypolipidemic activities than those in which W represents a bond. Thus, it is preferable that W was divalently hydrocarbon residue containing from 1 to 20 carbon atoms. More preferably, W represents the “divalently hydrocarbon residue containing from 1 to 8 carbon atoms, preference is given:

(1) C1-8alkylene (for example, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -(CH2)7-, -(CH2)8-, -CH(CH3)-, -C(CH3)2-, -(CH(CH3))2-, -(CH2)2C(CH3)2-, -(CH2)3C(CH3)2-);

(2) C2-8Alcanena (for example, -CH=CH-, -CH2-CH=CH-, -C(sub> 3)2-CH=CH-, -CH2-CH=CH-CH2-, -CH2-CH2-CH=CH-, -CH=CH-CH=-, -CH=CH-CH2-CH2-CH2-); or

(3) C2-8akinlana (for example,

Particularly preferably, W represents-CH2-,

-(CH2)2-, -(CH2)3-, -(CH2)4-, -CH=CH -, or the like.

(10) the Definition of R3

In formulas (I) and (II), R3represents a group of formula: -OR8(R8represents a hydrogen atom or a hydrocarbon group which may be substituted) or-NR9R10(each of R9and R10that can be either equal or different, represents a hydrogen atom, a hydrocarbon group which may be substituted, a heterocyclic group which may be substituted, or acyl group which may be substituted;

R9and R10can be combined with the formation of rings).

Examples of the “hydrocarbon group which may be substituted” for R8serve as the “hydrocarbon group which may be substituted”mentioned as an example for R1.

Mentioned “hydrocarbon group which may be substituted”preferably represents an alkyl group containing from 1 to carbon atoms”, “aryl group storagemojo from 6 to 10 carbon atoms which may have from 1 to 3 substituents, selected from alkyl groups containing from 1 to 4 carbon atoms, and halogen atoms (e.g. fluorine, chlorine, bromine, iodine), or the like. Examples of “alkyl groups containing from 1 to 4 carbon atoms” include methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, tert-butyl and the like, preference is given to stands and ethyl. As the “halogen atom” preferred is chlorine. Examples of “aryl group containing from 6 to 10 carbon atoms include phenyl and naphthyl, preferably phenyl.

Examples of the “hydrocarbon group which may be substituted” and “heterocyclic group which may be substituted” for R9and R10appropriately serve as the “hydrocarbon group which may be substituted” and “heterocyclic group which may be substituted”mentioned as examples for R1.

An example of “acyl group which may be substituted” for R9and R10serves as the “acyl group which may be substituted”indicated as examples of the substituent R1.

Examples of rings formed by R9and R10bound together, include a 5-7-membered cyclic amino group, preferably 1-pyrrolidinyl, 1-piperidinyl, 1-hexameta animinal, 4 morpholino, 4-thiomorpholine and the like.

R9and R10preferably represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms (e.g. methyl, ethyl).

R3preferably represents a group of formula: -OR8(the symbol has the same meaning as above and R8preferably represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms (e.g. methyl, ethyl).

(11) the Preferred connection

Preferred examples of the compounds of formulas (I) and (II) include compounds shown below.

(A) Compounds in which R1represents 5 - or 6-membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl), which may be condensed with a benzene ring and may have 1 or 2 substituent selected from the

1) furil, teinila, pyridyl, pyrazinyl, phenyl or naphthyl, each of which may contain from 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 6 carbon atoms which may be the substituted from 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino; and

2) alkyl groups containing from 1 to 4 carbon atoms, or cycloalkyl groups containing from 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group comprising alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino;

X represents a bond or-NR6-where R6represents a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

m is 1 or 2;

Y represents an oxygen atom, a sulfur atom, -NH -, or-NHCO-;

ring a represents a benzene ring, a condensed aromatic hydrocarbon ring containing from 9 to 14 carbon atoms (preferably, naphthalene and the like), or 5 - or 6-membered aromatic heterocycle (preferably pyridine, isoxazol, and the like), each of these rings, in addition, may also contain from 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 4 carbon atoms, a hydroxy-group, alkoxygroup containing from 1 to 4 carbon atoms, containing aralkylated from 7 to 10 carbon atoms and halogen atoms;

n is an integer from 1 to 3;

the ring represents a 5-membered aromatic heterokonta that as constituents of the ring atoms in addition to carbon atoms, contains at least 1 nitrogen atom, and which additionally may contain 1 heteroatom selected from oxygen atom, sulfur atom and nitrogen atom (e.g., pyrrole, pyrazole, imidazole, thiazole, isothiazol, oxazol, isoxazol), which, in addition, may be substituted by alkyl group containing from 1 to 4 carbon atoms;

X1represents a bond;

R2represents an aliphatic hydrocarbon group containing from 1 to 8 carbon atoms (preferably an alkyl group), an aromatic hydrocarbon group containing from 6 to 14 carbon atoms (e.g. phenyl, naphthyl), or a 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl), each of which may be substituted by 1 to 3 substituents selected from the group consisting of 1) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 2) alkyl groups containing from 1 to 4 carbon atoms (e.g. methyl, trifluoromethyl, propyl, isopropyl), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 3) alkoxygroup containing from 1 to 4 carbon atoms (e.g. methoxy, triptoreline)that mo is ut to be substituted by 1 to 3 halogen atoms (for example, fluorine, chlorine, bromine, iodine), 4) aralkylated containing 7 to 10 carbon atoms (e.g. benzyloxy), 5) alloctype containing from 6 to 14 carbon atoms (for example, phenoxy), and 6) an aromatic heterocyclic group (e.g., furyl, thienyl);

W represents C1-8alkylene, C2-8albaniles or C2-8akinyan;

R3represents-OR8(R8represents a hydrogen atom, the “alkyl group containing from 1 to 4 carbon atoms or aryl group containing from 6 to 10 carbon atoms which may have from 1 to 3 substituents, selected from alkyl groups containing from 1 to 4 carbon atoms, and halogen atoms (e.g. fluorine, chlorine, bromine, iodine)), or-NR9R10(each of R9and R10that can be either equal or different and represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms).

(C) Compounds in which

R1represents 5 - or 6-membered aromatic heterocyclic group (preferably furyl, thienyl, pyridyl, pyrimidinyl, pyrazinyl, oxazolyl, thiazolyl, triazolyl, oxadiazolyl, pyrazolyl), which may be condensed with a benzene ring and may contain 1 or 2 substituents selected from

1) furil, teinila, pyridyl, pyrazinyl, phenyl is or naphthyl, each of which may contain from 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino; and

2) an alkyl group containing from 1 to 4 carbon atoms or cycloalkyl group containing from 3 to 7 carbon atoms, each of which may have 1 to 3 substituents selected from the group comprising alkoxygroup containing from 1 to 6 carbon atoms which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), halogen atoms (e.g. fluorine, chlorine, bromine, iodine), nitro, hydroxy and amino;

X represents a bond or-NR6-where R6is a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms;

m is 1 or 2;

Y represents an oxygen atom, a sulfur atom, -NH -, or-NHCO-;

ring a represents a benzene ring, a condensed aromatic hydrocarbon ring containing from 9 to 14 carbon atoms (preferably, naphthalene and the like)or a 5 - or 6-membered aromatic heterokonta (preferably, pyridine, isoxazol, and the like), each of these rings, in addition, may contain from 1 to 3 substituents selected from the group comprising alkyl groups containing from 1 to 4 carbon atoms, a hydroxy-group, alkoxygroup containing from 1 to 4 carbon atoms, aralkylated containing 7 to 10 carbon atoms, and halogen atoms;

n is an integer from 1 to 3;

the ring is a “5-membered aromatic heterokonta that as constituents of the ring atoms in addition to carbon atoms, contains at least 1 nitrogen atom, and which additionally may contain 1 heteroatom selected from oxygen atom, sulfur atom and nitrogen atom (e.g., pyrrole, pyrazole, imidazole, thiazole, isothiazol, oxazol, isoxazol), which, in addition, may be substituted by alkyl group containing from 1 to 4 carbon atoms;

X1represents a bond;

R2represents an aliphatic hydrocarbon group containing from 1 to 8 carbon atoms (preferably, alkyl group (e.g. methyl, ethyl, propyl, isopropyl)), aromatic-aliphatic hydrocarbon group containing from 7 to 13 carbon atoms (preferably, aracelio group (e.g. benzyl), or 5 - or 6-membered aromatic heterocyclic group (e.g., furyl, thienyl, pyrid the l), each of which may be substituted by 1 to 3 substituents selected from the group comprising (1) halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 2) an alkyl group containing from 1 to 4 carbon atoms (e.g. methyl, ethyl, trifluoromethyl), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), 3) aralkylated containing 7 to 10 carbon atoms (e.g. benzyloxy), 4) [5 - or 6-membered aromatic heterocyclic group (e.g. pyridyl, oxazolyl, thiazolyl, triazolyl), which may have 1 or 2 substituent selected from alkyl groups containing from 1 to 3 carbon atoms, cycloalkyl groups containing from 3 to 7 carbon atoms (e.g. cyclohexyl), furyl, thienyl, phenyl and naphthyl]-alkoxygroup containing from 1 to 6 carbon atoms (e.g. methoxy, ethoxy), 5) an aromatic heterocyclic group (e.g., furyl, thienyl, pyridyl), 6) alloctype containing from 6 to 14 carbon atoms (for example, phenoxy), and 7) alkoxygroup containing from 1 to 4 carbon atoms (e.g. methoxy, ethoxy, triptoreline), which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine);

W represents C1-8alkylene, C2-8albaniles or C2-8akinyan;

R3represents-OR8(R8PR is dstanley a hydrogen atom, “alkyl group containing from 1 to 4 carbon atoms or aryl group containing from 6 to 10 carbon atoms which may have from 1 to 3 substituents, selected from alkyl groups containing from 1 to 4 carbon atoms, and halogen atoms (e.g. fluorine, chlorine, bromine, iodine)), or-NR9R10(each of R9and R10that can be either identical or different, represent a hydrogen atom or an alkyl group containing from 1 to 4 carbon atoms).

(12) Salt

Salt of the compounds of formula (I) or (II) (hereinafter also indicated as the compound (I) or (II), respectively), preferably represents a pharmacologically acceptable salt, and examples include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids and salts with basic and acidic amino acids.

Preferred examples of salts with inorganic bases include alkali metal salts, such as salts of sodium and potassium salts; salts of alkaline earth metals such as calcium salts and magnesium salts; aluminum salts and ammonium salts.

Preferred examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, ,N-dibenziletilendiaminom and the like.

Preferred examples of salts with inorganic acids include salts with hydrochloric acid, Hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.

Preferred examples of salts with organic acids include salts with formic acid, acetic acid, triperoxonane acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid and the like.

Preferred examples of salts with basic amino acids include salts with arginine, lysine, ornithine and the like.

Preferred examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid and the like.

The above salt, sodium salt, potassium salt, hydrochloride and the like are preferred.

(13) Prodrugs, and the like

Prodrugs of compound (II) refer to the connection that can be converted into the compound (II) when the enzyme reaction under the action of gastric juice or the like under physiological conditions in vivo, namely, to the connection that can be converted into the compound (II) when the enzyme oxidation recovery the hydrolysis or the like, or compound that can be converted into the compound (II) during the hydrolysis or the like under the action of gastric juice or the like. Examples of prodrugs of compound (II) include compounds that are formed during the acylation, alkylation or phosphorylation of the amino group of compound (II) (for example, compounds that are formed when alzarouni, alanalanalana, intramyocardially, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylamino, tetrahydrofurfurylamine, pyrrolidinylcarbonyl, pivaloyloxymethyl or tert-bottling amino group of compound (II)); compounds that are formed during the acylation, alkylation, phosphorylation or boronovanii hydroxyl group of compound (II) (for example, compounds that are formed during the acetylation, palmitoylation, propanolamine, pihlajasaari, succinylcholine, omarileaman, alanalanalana or dimethylaminoethylacrylate hydroxyl group of compound (II)); and compounds that are formed during the esterification or amidation of carboxyl group of compound (II) (for example, compounds that are formed when utilaterial, phenylacetate, karboksimetilcellyulozih, dimethylaminoethylacrylate, pivaloyloxymethyl, etox is carbamidomethylation, feliciaeriksen, (5-methyl-2-oxo-1,3-dioxolan-4-yl)metaliterature, cyclohexanecarbonitrile or methylaminopropane carboxyl group of compound (II)). These compounds can be obtained from compound (II) by methods known in this field.

Under physiological conditions, the prodrug of compound (II) may be capable of converting the compound (II), as described in “lyakuhin No Kaihatsu (Development of Drugs)”, vol.7, Molecular Designing, published by Hirokawa Shoten, 1990, p.163-198.

Examples of prodrugs of compound (I) are those prodrugs, which are presented for the compound (II).

In addition, compound (I) and the compound (II) can be in the state of isotopes (for example,3H14C,35S125I).

Moreover, the compound (I) and the compound (II) may be anhydrides or hydrates.

(14) the Pharmaceutical composition

The compound (I) and (II) and their salts (hereinafter also indicated as “compound of the present invention”) are non-toxic and can be used as a tool for the prevention or treatment of various diseases mentioned below, in mammals (e.g. humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys) as such or in the form of pharmaceutical compositions obtained by mixing with a pharmacologically acceptable carrier and that is similar.

Examples of pharmacologically acceptable carriers there are various organic or inorganic substances-media, usually used as substances of pharmaceutical preparations, and for solid preparations are used as excipients, lubricants, binding agents, and baking powder; and to obtain a liquid preparations are used as solvents, solubilization, suspendida agents, agents capable isotonicity, buffers, soothing agents and the like. In addition, if necessary, can also be used with other additives to pharmaceutical preparations, such as antiseptics, antioxidants, colorants and sweeteners.

Preferred examples of the excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinising starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, Arabian gum, dextrin, pullulan, bright engineered silica, synthetic aluminum silicate and magnesium metasilicate aluminate.

Preferred examples of lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.

Preferred examples of binding agents include gelatinising starch, sucrose, gelatin, Arabian is amedi, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, saccharose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hypromellose and polyvinylpyrrolidone.

Preferred examples of disintegrating agents include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, sodium to croscarmellose, sodium carboximetilkrahmal, light anhydride silicon and nitrosamino hydroxypropylcellulose.

Preferred examples of the solvent include water for injection, physiological saline, ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil and cottonseed oil.

Preferred examples of solubilization include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trilaminate, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate and sodium acetate.

Preferred examples suspendida agents include surfactants such as steartrimonium, sodium lauryl sulfate, lauramidopropyl acid, lecithin, benzalkonium chloride, chloride benzene and monetarily glycerin; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium CT is Oxymetazoline, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and Polysorbate, and polyoxyethylene-polymerized castor oil.

Preferred examples of agents that support isotonicity include sodium chloride, glycerin, D-mannitol, D-sorbitol and glucose.

Preferred examples of the buffers include buffer solutions of fosfatos, acetates, carbonates, citrates and the like.

Preferred examples of soothing agents include benzyl alcohol.

Preferred examples of the antiseptics include esters of p-oksibenzoynoy acid, chlorbutanol, benzyl alcohol, finitely alcohol, along with dehydroacetic acid and sorbic acid.

Preferred examples of the antioxidant include sulfites and ascorbate.

Preferred examples of the dyes include food dyes such as water-soluble food dyes based resin (for example, red food dye # 2 and # 3, yellow food dye No. 4 and 5, blue food dye No. 1 and 2), water-insoluble dyes colorful lacquer (for example, aluminum salts, of the above water-soluble food dyes based resin) and natural dyes (for example, β-carotene, chlorophyll, oxide red).

Preferred examples of the sweeteners include saccharin sodium, Dikili glycereth the NAT, aspartame and Peconic Kapiolani.

(15) Dosage forms

Examples of dosage forms of pharmaceutical compositions include oral preparations such as tablets, capsules (including soft capsules and microcapsules), granules, powders, syrups, emulsions and suspensions; and neironalny preparations such as injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection), drugs for external use (for example, drugs for insertion into the nose, preparations for application to the skin, ointments), suppositories (e.g. rectal suppositories, vaginal suppositories), pillule, drips and drugs slow release. These drugs are also safe to take either orally or neironalna.

The pharmaceutical composition may be obtained by conventional methods used in the field of pharmaceutical production technologies, for example, by methods described in the Japanese Pharmacopoeia. Here and hereinafter described in detail special methods for such products.

Oral drugs, for example, is obtained by adding to the active substance excipient (for example, lactose, sucrose, starch, D-mannitol), baking powder (e.g., calcium carboxymethylcellulose), binding agent (for example, gelatinise of grahm is l, Arabian gum, carboxymethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone) or lubricants (e.g. talc, magnesium stearate, polyethylene glycol 6000), compression molding the resulting mixture, and then, if necessary, coating methods known in this field, using the basis of the cover for receiving a sweet film, Intercollege coating or coatings for sustained release.

Examples of the substrate surface include sugar-based coating, water soluble film based coating, intersolubility film based coatings based on film coatings for impaired release.

Used sugar basis for coverage. In addition, the combination can be used alone, or two or more substances selected from talc, precipitated calcium carbonate, gelatin, Arabic gum, pullulan, Carnauba wax and the like.

Examples of water-soluble film of the basics of coatings include cellulose polymers such as hydroxypropylcellulose, hypromellose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose; synthetic polymers, such as polyvinylacetal diethylaminoacetate, copolymer E aminoalkylsilane [Eudragit E (registered trademark), Rhom Pharma] and polyvinylpyrrolidone; polysaccharides, t is the cue as, pullulan.

Examples of bases intersolubility film coatings include cellulose polymers such as phthalate of hydroxypropylmethylcellulose, acetylsuccinate hydroxypropylmethylcellulose, karboksimetiltselljuloza, phthalate of acetosella; polymers of acrylic acid such as a copolymer L, methacrylic acid [Eudragit L (registered trademark), Rhom Pharma], the copolymer LD, methacrylic acid [Eudragit L-30D55 (registered trademark), Rhom Pharma), a copolymer S, methacrylic acid [Eudragit S (registered trademark), Rhom Pharma]; natural substances such as shellac and the like.

Examples of the basics of film coating for sustained release include cellulose polymers such as ethylcellulose; polymers of acrylic acid such as a copolymer RS aminoalkylsilane [Eudragit RS (registered trademark), Rhom Pharma] and copolymer suspension of ethyl acrylate-methyl methacrylate [Eudragit NE (registered trademark), Rhom Pharma].

Two or more of the above basic coverage can be used in a mixture with a suitable ratio. As the coating can be used a protective agent, such as titanium oxide, red iron oxide.

The injection is obtained by dissolving, suspendresume or emulsification of the active substance in an aqueous solvent (for example, distiller the Anna water, saline solution, ringer's solution) or an oily solvent (e.g., vegetable oil such as olive oil, sesame oil, cottonseed oil, corn oil, propylene glycol), together with a dispersing agent (e.g., Polysorbate 80, polyoxyethylene-polymerized castor oil 60, polyethylene glycol, carboxymethylcellulose, sodium alginate), a preservative (e.g. methylparaben, propyl paraben, benzyl alcohol, chlorobutanol, phenol), an agent that supports isotonicity (for example, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like. If desirable, can be used additives such as solubilization (e.g., sodium salicylate, sodium acetate), stabilizers (for example, albumin human serum), soothing agents (e.g., benzyl alcohol).

(16) Agents

The connection according to the present invention can be used as an agent that increases insulin resistance, an agent that regulates the function of retinoid-related receptor, a ligand-activated proliferation peroxisome receptor and the ligand of retinoid X receptor and the like. The term “agent regulating function” refers here to both the agonist and the antagonist. Agent, a regulatory function, can be a partial agonist, or partial antagonist is istom.

The compound of the present invention possesses hypoglycemic activity, hypolipidemic activity, activity that increases resistance to insulin, activity, increasing sensitivity to insulin, and activity, regulating the function of retinoid-related receptor. The term “retinoid-related receptor”, as used here, refers to nuclear receptors and transcription is the DNA-binding factor, a ligand which is a signaling molecule, such as oil-soluble vitamins, and the like, and may be either Monomeric receptor or homodimer receptor or heterodimeric receptor.

Examples of Monomeric receptor here include retinoid receptor (hereinafter, also denoted by the abbreviation ROR) α (GenBank Accession No. L14611), RORβ (GenBank Accession No. L14160), RORγ (GenBank Accession No. U16997); Rev-erb α (GenBank Accession No. M24898), Rev-erb β (GenBank Accession No. L31785); ERRα (GenBank Accession No. X51416), ERRβ (GenBank Accession No. X51417); Ftz-FIα (GenBank Accession No. S65876), Ftz-FIβ (GenBank Accession No. M81385); TIx (GenBank Accession No. S77482); GCNF (GenBank Accession No. U14666).

Examples homodimeric receptor include homodimer formed by the retinoid X receptor (hereinafter, also denoted by the abbreviation RX R) α (GenBank Accession No. X52733), RXRβ (GenBank Accession No. M84820), RXRγ (GenBank Accession No. U 38480); COUPα (GenBank Accession No. X12795), COUPβ (GenBank Accession No. M64497), COUPγ (GenBak Accession No. X12794); TR2α (GenBank Accession No. M29960), TR2β (GenBank Accession No. L27586); or HNF4α (GenBank Accession No. X76930), HNF4γ (GenBank Accession No. Z49826) and the like.

Examples of heterodimeric receptor include heterodimer, which are formed above the retinoid X receptor (RXRα, RXRβ or RXTγ) and one receptor selected from a retinoid receptor A (hereinafter, also denoted by the abbreviation RAR) α (GenBank Accession No. X00614), RARβ (GenBank Accession No. Y00291), RARγ (GenBank Accession No. M24857); receptor thyroid hormone (hereinafter, also denoted by the abbreviation TR) α (GenBank Accession No. M24748), TRβ (GenBank Accession No. M26747); vitamin D receptor (VDR) (GenBank Accession No. J03258); activated proliferation peroxisome receptor (hereinafter, also denoted by abreviaturas PPAR) α (GenBank Accession No. L02932), PPARβ (PPARδ) (GenBank Accession No. U10375), PPARγ (GenBank Accession No. L40904); LXRα (GenBank Accession No. U22662), LXRβ (GenBank Accession No. U14534); FXR (GenBank Accession No. U18374); MB67 (GenBank Accession No. L29263); ONR (GenBank Accession No. X75163); and NURα (GenBank Accession No. L13740) NURβ (GenBank Accession No. X75918) and NURγ (GenBank Accession No. U12767).

Among all the above-mentioned retinoid-related receptor compound of the present invention has excellent ligand activity, in particular, to the retinoid X receptors (RXRα, RXRβ, RXRγ) and activated proliferation receptors in peroxisomes (PPARα, PPARβ (PPARδ), PPARγ).

In addition, connection of the giving of the present invention has excellent ligand activity to active proliferation receptors in peroxisomes, in the form heterodimeric receptor formed of retinoid receptor X and proliferation of activated receptor peroxisomes, and preferably in the form heterodimeric receptor formed by RXRα and PPARγ.

Accordingly, the ligand retinoid-related receptor of the present invention mainly can be used as a ligand for activated proliferation peroxisome receptor, or a ligand for retinoid receptors X.

The compound of the present invention, especially one that has divalent hydrocarbon residues containing from 1 to 20 carbon atoms (especially alkylene, such as, methylene) W, may, preferably, be used as an agonist of PPARγ or a partial agonist of PPARγ.

Along with this, the connection of the present invention, especially one that represents the relationship in W, may, preferably, be used as an antagonist of PPARγ or a partial antagonist of PPARγ.

(17) Target diseases

The compound of the present invention and the pharmaceutical composition of the present invention can be used, for example, as an agent for the prophylaxis or treatment of diabetes (e.g., diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes); an agent for the prophylaxis or treatment of hyperlipidemia (in the example, hypertriglyceride, hypercholesterolemia, decreased blood high-density lipoprotein, hyperlipemia after eating); as a means to enhance insulin sensitivity; as a means to increase resistance to insulin; as a tool for prevention and treatment reduced glucose tolerance (IGT) and as a means to prevent the development of diabetes with reduced glucose tolerance.

With regard to diagnostic criteria of diabetes mellitus, new diagnostic criteria were reported by the Japanese Association of diabetologists in 1998.

According to this report, diabetes is a condition in which the level of fasting blood glucose (glucose concentration in venous plasma) is not less than 126 mg/DL, 2-hour value (glucose concentration in venous plasma) in the test for tolerance to 75 g of glucose, accepted oral (75 g OGTT)is not less than 200 mg/DL or glucose level in the blood is not on an empty stomach (glucose concentration in venous plasma) is not less than 200 mg/DL. In addition, a condition in which the values of blood glucose does not reach the above values for diabetes, but that is not a “condition in which the level of fasting blood glucose (glucose concentration in venous plasma) of less than 110 mg/DL or 2-hour value (the concentration of CH the goats in venous plasma) in the test for tolerance to 75 g glucose, accepted oral (75 g OGTT)is less than 140 mg/DL” (normal value), is called a “border state”.

In addition, concerning the diagnostic criteria for diabetes, new diagnostic criteria were reported ADA (American Association of diabetologists) in 1997 and who 1998.

According to these reports, diabetes is a condition in which the level of fasting blood glucose (glucose concentration in venous plasma) is not less than 126 mg/DL and 2-hour value (glucose concentration in venous plasma) in the test for tolerance to 75 g of glucose, accepted oral, is not less than 200 mg/DL.

In addition, according to the above messages, reduced glucose tolerance is a condition in which the level of fasting blood glucose (glucose concentration in venous plasma) is not less than 126 mg/DL and 2-hour value (glucose concentration in venous plasma) in the test for tolerance to 75 g of glucose, accepted oral, is not less than 140 mg/DL but less than 200 mg/DL. In addition, according to the ADA, a condition in which the level of fasting blood glucose (glucose concentration in venous plasma) is not less than 110 mg/DL but less than 126 mg/DL is called IFG (reduced fasting glucose). On the other hand, according to the who, the state of the IFG (below the Naya glucose on an empty stomach) such in which the 2-hour value (glucose concentration in venous plasma) in the test for tolerance to 75 g of glucose, accepted oral, is less than 140 mg/DL is called IFG (reduced fasting glucose).

The compound of the present invention and the pharmaceutical composition according to the present invention can be used as a means of prevention or treatment of diabetes, borderline States, reduced glucose tolerance, IFG (reduced fasting glucose) and IFG (reduced fasting glucose), which is defined above the new diagnostic criteria.

In addition, the compound of the present invention and the pharmaceutical composition of the present invention can also be used to prevent crossing the border States, reduced glucose tolerance, IFG (reduced fasting glucose) or IFG (reduced fasting glucose in diabetes mellitus.

The compound of the present invention and the pharmaceutical composition of the present invention can also be used for prevention or treatment of complications of diabetes (e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathies, osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infection, urinary tract infections, infections of the gastro-Ki is echnolo tract, soft tissue infection of the skin, infections of the lower extremities), diabetic gangrene, xerostomia, hearing loss, cerebral-vascular diseases, disorders of peripheral blood circulation, and the like), obesity, osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, cachexia in diseases of the blood, endocrinopathic cachexia, infectious cachexia, cachexia due to acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary, renal diseases (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, terminal renal disease), muscular dystrophy, myocardial infarction, angina, cerebral-vascular diseases (for example, cerebral infarction, apoplexy of the brain), syndrome of resistance to insulin, syndrome X, hyperinsulinemia, hyperinsulinemia caused by sensory disorders, malignant tumors (e.g., leukemia, breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., chronic rheumatoid arthritis, spondylitis deformans, osteoar is Rita, lumbago, gout, postoperative or traumatic inflammation, tumor remission, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including steatohepatitis, non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory colitis, ulcerative colitis), syndrome of visceral obesity and the like.

The compound of the present invention and the pharmaceutical composition of the present invention have activity in reducing total cholesterol and increase antiarteriosclerotic index [(HDL cholesterol/total cholesterol)X100] and, thus, can be used as a means for prevention or treatment of arteriosclerosis (for example, ateriosclerosis) and the like.

Also the connection of the present invention and the pharmaceutical composition of the present invention can be used to reduce pain, nausea, vomiting, or dysphoria in the epigastrium that accompanies ulcers of the gastrointestinal tract, acute or chronic gastritis, dyskinesia or cholecystitis.

In addition, the compound of the present invention and the pharmaceutical composition of the present invention can control (increase or decrease) of appetite and food intake and, therefore, can be used as a treatment for low weight and pathological aversion to food (qi is ophobia) (subjects, suffering from low weight or cibophobia, with the introduction of the tool, the weight increased) or as a treatment for obesity.

The compound of the present invention and the pharmaceutical composition of the present invention can also be used as a means for prevention or treatment induced TNF inflammatory diseases. Caused by TNF-α inflammatory diseases involve inflammatory diseases that occur in the presence of TNF-α and can be treated by inhibiting the activity of TNF-α. Examples of such inflammatory diseases include complications of diabetes (e.g., retinopathy, neropathy, neuropathy, macroangioapthy), rheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, postoperative or traumatic inflammation, remission of the tumor, neuralgia, pharyngolaryngitis, cystitis, hepatitis, pneumonia, damage of the gastric mucosa (including damages the lining of the stomach caused by aspirin), and the like.

The compound of the present invention and the pharmaceutical composition of the present invention possess apoptotic inhibitory activity and can be used as a means for prevention or treatment of diseases caused by increased apoptosis. Examples of diseases caused by increased apoptosis include viral is e disease (e.g., AIDS, instant hepatitis), neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, retinitis pigmentosa, spinal cerebellar degeneration), myelodysplasia (e.g., aplastic anemia), ischemic diseases (e.g. myocardial infarction, stroke), hepatitis (e.g., alcoholic hepatitis, hepatitis b, hepatitis C), diseases of the joints (for example, osteoarthrit), atherosclerosis and the like.

The compound of the present invention and the pharmaceutical composition of the present invention can be used to reduce visceral obesity, inhibiting the formation of visceral obesity, to improve glucose metabolism, improvement of lipid metabolism, improve resistance to insulin, for inhibiting the production of oxidized LDL, metabolism of lipoproteins metabolism of the coronary arteries for prevention or treatment of cardiovascular complications, for the prevention or treatment of complications of heart failure, lowering blood remnant, for the prevention or treatment of anovulation, prophylaxis or treatment of hirsutism, for the prevention or treatment of hyperandrogenism and the like.

The compound of the present invention and the pharmaceutical composition of the present invention can be used to re-what about the prevention and inhibition of the development of various diseases, above (for example, cardiovascular diseases such as myocardial infarction or the like).

The compound of the present invention and the pharmaceutical composition of the present invention can be used in combination with midazolam, ketoconazole and the like.

Although the dosage of the compounds of the present invention and pharmaceutical compositions of the present invention vary depending on the entity to which they are administered, route of administration, target disease, clinical condition, and the like, it is desirable that the active ingredient, i.e. the compound of the present invention, was administered the standard dosing of, for example, an adult patient suffering from diabetes from about 0.01 to 100 mg/kg body weight, preferably from 0.05 to 10 mg/kg body weight, more preferably from 0.1 to 2 mg/kg of body weight, on introduction, 1-3 times per day, oral.

(18) Concomitant drug use

The compound of the present invention can be used in combination with drugs such as therapeutic agent for diabetes, a therapeutic agent for the management of complications in diabetes, antihyperlipidemic agent, a hypotensive agent, an anti-obesity, diuretic, a chemotherapeutic agent, immunotherapeutic the economic means, therapeutic agent for osteoporosis, anti-dementia agent, which improves the erection, therapeutic remedy for incontinence or pollakiuria and the like (hereinafter denoted by the abbreviation of the concomitant drug). In this case, the timing of the introduction of the compound of the present invention and the concomitant drug is not limited. The subject can be administered simultaneously or sequentially. The dose of the concomitant drug can be appropriately selected based on the clinically used dose. The proportion of compounds of the present invention and the concomitant drug can be appropriately selected in accordance with the entity to which injected a drug, route of administration, target disease, clinical condition, combination, and other factors. In the case where the actor, who injected a drug is, for example, people associated with the drug can be used in amounts of from 0.01 to 100 parts by weight relative parts by weight of the compounds of the present invention.

Examples of therapeutic agents for diabetes include insulin preparations (e.g., animal insulin preparations extracted from the pancreas of the ox Il the pig; preparations of human insulin synthesized by means of genetic engineering using Escherichia coli or yeast), tools that increase resistance to insulin (e.g., pioglitazone hydrochloride, troglitazone, rosiglitazone or its maleate, GI-262570, JTT-501, MCC-555, YM-440, KRP-297, CS-011, FK-614), inhibitors α-glucosidase (e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g., phenformin, Metformin, buformin), drugs that enhance insulin secretion [the sulfonylurea (e.g., tolbutamide, glibenclamide, gliclazide, hlorpropamid, tolazamide, acetohexamide, glimepiride, glimepiride, glipizide, glybuzole), Repaglinide, sinapinic, nateglinide, mitiglinide or their hydrate calcium salts, GLP-1)], the agonist of amerina (for example, pramlintide), inhibitors phosphoribosyltransferase (for example, vanadium acid)inhibitors dipeptidylpeptidase IV (for example, NVP-DPP-278, RT-100, R/98), β 3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB226552, AJ-9677, BMS-196085, AZ40140), inhibitors of gluconeogenesis (e.g., glycogen phosphorylase inhibitors, inhibitors of glucose-6-phosphate, glucagon antagonists, inhibitors of SGLT (sodium co-Transporter glucose) (e.g., T-1095).

Examples of therapeutic agent for the complications of diabetes include inhibitors alsoreported (for example, tolrestat, epalrestat, zenarestat, zopolrestat, minalrestat, fidarestat, SNK-860, CT-112), it is atroficheskie factors (for example, NGF, NT-3, BDNF), inhibitors of the RCC (e.g., LY-333531), AGE inhibitors (e.g., ALT946, pimagedine, paroxetin, N-phenacylthiazolium bromide (ALT766), EXO-226), pagetitle active oxygen (e.g., thioctic acid), cerebral vasodilators (e.g., tapered, meksiletin).

Examples of the antihyperlipidemic tools include compounds statin, which inhibit cholesterol synthesis (e.g., tseriwastatina, pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin, itavastatin or their salts (e.g. sodium salt)), inhibitors stvalentines or connection fibrate (for example, bezafibrat, clofibrate, simfibrate, clinofibrate)having activity to reduce triglycerides.

Examples of antihypertensive drugs include angiotensin converting enzyme inhibitors (e.g. captopril, enalapril, delapril), antagonists of angiotensin II (e.g., losartan, candesartan cilexetil, losartan, eprosartan, valsartan, telmisartan, irbesartan, tasosartan), calcium antagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine, nicardipine), clonidine.

Examples of anti-obesity include anti-obesity drugs acting on the Central nervous system (for example, dexfenfluramin, fenfluramine, phentermine, sibutramine, amfepramone, dexamfetamine, mazindol, phenylpropanolamine, clobenzorex), inhibit the market pancreatic lipase (for example, orlistat), β3 agonists (e.g., CL-316243, SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140), anorexicskin peptides (e.g., leptin, CNTF (ciliary neurotrophic factor)), cholecystokinin agonists (e.g., lintitript, FPL-15849).

Examples of the diuretics include xanthine derivatives (e.g., teobrom and sodium salicylate, teobrom and calcium salicylate), drugs thiazide (for example, atiase, cyclopenthiazide, trichlormethiazide, hydrochlorothiazide, hydroflumethiazide, benzylhydroxylamine, panflutes, polythiazide, methyclothiazide), drugs antialdosterone (e.g., spironolactone, triamterene), inhibitors carbonatehydroxide (e.g., acetazolamide), drugs chlorobenzenesulfonamide (e.g., chlorthalidone, mefruside, indapamide), azosemide, isosorbide, ethacrynic acid, piretanide, bumetanide, furosemide.

Examples of chemotherapeutic agents include alkylate petrol sredstva (e.g., cyclophosphamide, ifosamide), metabolic antagonists (e.g., methotrexate, 5-fluorouracil), antitumor antibiotics (e.g., mitomycin, adriamycin), antitumor agents of vegetable origin (for example, vincristine, vindesine, Taxol), cisplatin, carbapenem, etoposide. Among them, preferred are derivatives of 5-fluorouracil, such as furtulon and neo-furtulon.

Examples immunotherapeutics the th tools include components, obtained from microorganisms or bacteria (for example, derivatives of muramyldipeptide, picibanil), polysaccharides with immunostimulatory activity (e.g., lentinan, sizofiran, christenings), cytokines obtained by genetic engineering methods (e.g., interferons, interleukins (IL)), colony stimulating means (e.g., granulocyte-colony stimulating factor, erythropoietin) and the like. Among them, preferred are IL-1, IL-2, IL-12, and the like.

Examples of therapeutic agents for osteoporosis include alfacalcidol, calcitriol, alkaloid, calcitonin salmon, estriol, ipriflavone, pamidronate disodium, alendronate hydrate of sodium, encadrant disodium.

Examples of anti-dementia include taken, donepezil, rivastigmine, galantamine.

Examples of tools that improves erections include apomorphine, sildenafil citrate.

Examples of therapeutic agent for incontinence or pollakiuria include flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride.

In combination with the compound of the present invention can be used, in addition, the means, the effect of which is to improve cachexia has been confirmed in animal models or clinically, namely cyclo-oxygenase inhibitors (eg, indomethacin) (Cancer Research, vol.49, pp.5935-5939, 1989), proizvodi the e progesterone (for example, megestrol acetate) (Journal of Clinical Oncology, vol.12, pp.213-225, 1994), glucocorticoids (e.g. dexamethasone), drug metoclopramide, a drug tetrahydrocannabinol (the links above are applicable to both), agents, improving fat metabolism (e.g., eicosapentanoic acid) (British Journal of Cancer, vol.68, pp.314-318, 1993), growth hormones, IGF-1 and antibodies to factor TNF-αinducing cachexia, LIF, IL-6 or oncostatin M

Concomitant drug is a drug is insulin, the means strengthening resistance to insulin, the inhibitor α-glucosidase, biguanid tool that enhance insulin secretion (preferably a sulfonylurea) and the like.

The above-mentioned concomitant drugs can be used in the form of a mixture of two or more components with a suitable ratio. In the case of using two or more concomitant drugs, preferred combinations include the following combinations:

1) a means of enhancing insulin resistance, and insulin product;

2) a means of enhancing insulin resistance, and a means of enhancing insulin secretion (preferably a sulfonylurea);

3) a means of enhancing insulin resistance, and the inhibitor α-glucosidase;

4) a means of enhancing insulin resistance, and biguanide;

5)tool, intensifying insulin resistance, insulin product and biguanide;

6) a means of enhancing insulin resistance, insulin product and means of enhancing insulin secretion (preferably a sulfonylurea);

7) a means of enhancing insulin resistance, insulin product and inhibitor α-glucosidase;

8) means that increase insulin resistance, a means of enhancing insulin secretion (preferably a sulfonylurea), and biguanide;

9) means that increase insulin resistance, a means of enhancing insulin secretion (preferably a sulfonylurea) and inhibitor α-glucosidase; and

10) means that increase insulin resistance, biguanide and inhibitor α-glucosidase.

If the compound or pharmaceutical composition of the present invention are used in combination with a concomitant drug, the quantity of each drug can be reduced within a safe area, taking into account their side effects. In particular, the dose means that increase insulin resistance, means of enhancing insulin secretion (preferably a sulfonylurea) and biguanide, can be reduced compared with the standard dose. Thus, a side effect that may be caused by the medium is you can be safely prevented. In addition, the dose of drug for treatment of complications of diabetes, the remedy against hyperlipemia and antihypertensives can be reduced, whereby it may be effectively prevented a side effect that can cause these tools.

(19) the Method of obtaining

Hereinafter is described a method for obtaining compounds of the present invention. As the compound (I) included in the compound (II)described a method of producing compound (II).

The compound (II) can be obtained by methods known in this field, for example, any manner of methods A-F and way N, described below, or from methods similar to these.

[Method]

where Z represents a hydroxy-group, a halogen atom or a group of the formula: OSO2R15where R15represents an alkyl group containing from 1 to 4 carbon atoms, or aryl group containing from 6 to 10 carbon atoms which may be substituted by an alkyl group containing from 1 to 4 carbon atoms; other symbols have the same meaning as described above.

Examples of alkyl groups containing from 1 to 4 carbon atoms, in the expression “alkyl group containing from 1 to 4 carbon atoms and aryl group containing from 6 to 10 carbon atoms which may be substituted by an alkyl group is Oh, containing from 1 to 4 carbon atoms for R15here are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl, are preferred stands.

Examples of aryl groups containing from 6 to 10 carbon atoms, in the expression “aryl group containing from 6 to 10 carbon atoms which may be substituted by an alkyl group containing from 1 to 4 carbon atoms for R15serve as phenyl and naphthyl, preferably phenyl.

In this method, the compound (II) are obtained by reacting compound (III) and compound (IV).

If Z is a hydroxy-group, this interaction is carried out by a method known in this field, for example, by the method described in Synthesis, page I (1981) or in the same way. Namely, this interaction is usually carried out in the presence of organic phosphorus compounds and electrophilic agent in a solvent which does not affect the interaction.

Examples of the organic phosphorus compounds include triphenylphosphine and tributylphosphine.

Examples of electrophilic agent include diethylazodicarboxylate, diisopropylsalicylic and azodicarbonamide.

The amount of organic phosphorus compounds and electrophilic agent, preferably, is from about 1 to about 5 molar equivalents relative to connected the I (IV).

Examples of the solvent which does not affect the interaction include ethers, such as diethyl ether, tetrahydrofuran and dioxane; halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene, toluene and xylene; amides such as N,N-dimethylformamide; and sulfoxidov, such as dimethylsulfoxide. These solvents can be used in the form of a mixture with the corresponding value.

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

If Z represents a halogen atom or a group of the formula: OSO2R15this interaction is conducted in the usual way in the presence of a base in a solvent that does not affect the interaction.

Examples of the base include alkali metal salts, such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethylamine, N,N-dimethylaniline and 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium.

The number of these used bases, preferably, is from about 1 to about 5 molar what's equivalents relative to the compound (IV).

Examples of the solvent which does not affect the interaction, include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ketones, such as acetone and 2-butanone;

halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N-dimethylformamide; and sulfoxidov, such as dimethylsulfoxide. These solvents can be used in a mixture at an appropriate ratio.

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

The compound (II)obtained in this way can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (III) and compound (IV)used as starting products in the way As described above, are known compounds. The compound (III), where Z is a hydroxy-group, for example, described in EP-A 710659. In addition, the compound (III) described in EP-A 629624 (JP-7(1995)-53555), WO 98/03505 and the like. Also, the compound (III) can be floor is constrained ways, similar to those described in these patent publications.

On the other hand, the compound (IV) is described in, for example, Journal of Heterocyclic Chemistry, vol. 24, p 1669 (1987); Journal of Organic Chemistry, vol. 62, p. 2649 (1997); Bioorganic & Medicinal Chemistry Letters, vol. 6, p. 1047 (1996), and the like. In addition, the compound (IV) can also be obtained by methods similar to those described in these publications.

The compound of formula (II), where R3is a OR8and W represents-CH=CH - or -(CH2)2[compound (II-2) or (II-3), respectively] can also be obtained by the method described below.

[Method]

where the symbols have the same meanings as above.

(Stage 1)

This interaction is carried out in the usual way in the presence of a reducing agent in a solvent which does not affect the interaction.

Examples of the reducing agent include sodium borohydride, lithium borohydride, alumoweld lithium and diisobutylaluminium.

The amount of reducing agent, preferably, is from about 0.5 to about 10 molar equivalents relative to compound (II-1).

Examples of the solvent which does not affect the interaction, include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; ethers, such as then it is carbonated shall return, dioxane and diethyl ether; water and alcohols, such as methanol, ethanol and isopropanol. These solvents can be used in a mixture at an appropriate ratio.

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

The compound (V)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (II-1), which is used as starting product in stage 1 of the method described above can be obtained, for example, by the method As described above. In addition, the compound (II-1) can also be obtained by the method described, for example, Journal of Heterocyclic Chemistry, vol. 24, R (1987); Journal of Organic Chemistry, vol.62, p.2649 (1997); Bioorganic & Medicinal Chemistry Letters, vol.6, p.1047 (1996), and the like, or a similar method.

(Stage 2)

This interaction is carried out in the usual way in the presence of an oxidant in a solvent which does not affect the interaction.

Examples of the oxidizing agent include metal oxidants such as dioxide, magnesium chlorproma pyridine, pyridine dichromate and ACS is on ruthenium.

The amount of oxidizing agent, preferably, is from about 1 to about 10 molar equivalents relative to the compound (V).

Examples of the solvent which does not affect the interaction, include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; and halogenated hydrocarbons such as chloroform and dichloromethane. These solvents can be used in a mixture at an appropriate ratio.

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

In addition, the compound (VI) can also be obtained by adding a reaction reagent, such as a complex of sulfur trioxide-pyridine or oxalyl chloride, to the compound (V) in dimethyl sulfoxide or in a solvent mixture of dimethyl sulfoxide and halogenated hydrocarbons, such as chloroform or dichloromethane, and interaction with organic base such as triethylamine or N-methylmorpholine.

The number of the reaction reagent, preferably, is from about 1 to about 10 molar equivalents relative to the compound (V).

The amount of organic base, preferably extending t is from about 1 to about 10 molar equivalents relative to the compound (V).

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

The compound (VI)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

(Stage 3)

In this interaction, the compound (II-2) is obtained by reacting organic phosphorus reagent and compound (VI).

This interaction is carried out in the usual way in the presence of a base in a solvent that does not affect the interaction.

Examples of the organic phosphorus reagent include metiltiofosfonata, ethyldichlorosilane and ethyldimethylammonium.

The amount used of the organic phosphorus reagent, preferably, is from about 1 to about 10 molar equivalents relative to the compound (VI).

Examples of the base include alkali metal salts, such as potassium hydroxide, sodium hydroxide, sodium bicarbonate and potassium carbonate; amines such as pyridine, triethylamine, N.N-dimethylaniline and 1,8-diazabicyclo[5.4.0]undec-7-ene; metal hydrides such as potassium hydride and sodium hydride; and alkoxides of alkali metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium.

The number of such bases, preferably, is from about 1 to about 5 molar equivalents relative to the compound (VI).

Examples of the solvent which does not affect the interaction, include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N-dimethylformamide; and sulfoxide such as dimethylsulfoxide. These solvents can be used in a mixture at an appropriate ratio.

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

The compound (II-2)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

(Stage 4)

This interaction is carried out in the usual way in atomsphere hydrogen or in the presence of a hydrogen source (e.g., formic acid) and meta is symbolic of the catalyst in the solvent, which does not affect the interaction.

Examples of the metal catalyst include catalysts based on transition metals, such as palladium on charcoal, palladium black, palladium oxide, Raney Nickel and the catalyst of Wilkinson.

The number of these used catalysts based on transition metals, preferably represents from about 0.01 to about 10 molar equivalents relative to compound (II-2).

Examples of the solvent which does not affect the interaction, include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as tetrahydrofuran, dioxane and diethyl ether; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N-dimethylformamide; and an alcohol such as methanol, ethanol and isopropanol. These solvents can be used in a mixture at an appropriate ratio.

The reaction temperature is usually from about -50 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

The compound (II-3)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, repeat rim dissolution and chromatography.

where Y' represents an oxygen atom, a sulfur atom or a group of the formula-NR7-where R7has the same meaning as described above;

other symbols have the same meanings as above.

In this method, the compound (II-4) is produced by interaction of the compound (VII) and compound (VIII). This interaction is carried out in the same way as the interaction of the compound (III) and compound (IV) in method A.

The compound (II-4)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (VII)used as starting product in the way described above, is a known compound and is described, for example, in Chemical and Pharmaceutical Bulletin, vol. 34, p. 2840 (1986); Journal of Medicinal Chemistry, vol. 35, p. 2617 (1992); WO 98/03505 and the like. In addition, the compound (VII) can be obtained in a manner analogous to the methods described in these publications.

where the symbols have the same meanings as above.

In this method, the compound (II-6) obtained by hydrolysis of compound (II-5).

This hydrolysis reaction is conducted in the usual way in the presence of the iSlate or grounds in hydrated solvent.

Examples of the acid include hydrochloric acid, sulfuric acid, acetic acid and Hydrobromic acid.

Examples of the base include carbonates of alkali metals such as potassium carbonate and sodium carbonate; alkoxides of alkali metals such as sodium methoxide; and hydroxides of alkali metals such as potassium hydroxide, sodium hydroxide and lithium hydroxide.

The amount of acid or base is usually in excess relative to the compound (II-5). Preferably, the amount of acid used is from about 2 to about 50 equivalents relative to compound (II-5) and the amount used of the base is usually from about 1.2 to about 5 equivalents relative to compound (II-5).

Examples of hydrated solvent include a solvent mixture of water and one or more solvents selected from alcohols such as methanol and ethanol; ethers, such as tetrahydrofuran, dioxane and diethyl ether;

dimethyl sulfoxide and acetone.

The reaction temperature is usually from about -20 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.1 to about 20 hours.

The compound (II-6)thus obtained can be isolated and purified by known methods of separation and the cleaning for example, concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (II-5), which is used as starting product in method D described above, is obtained by using, for example, methods a-C, described above.

The compound (II-7), containing NR9R10for R3in the formula (II)can also be obtained by method E described below.

where the symbols have the same meanings as above.

In this method, the compound (II-7) is obtained by amidation of the compound (II-6). This interaction is carried out by a method known in this field, for example, a method where the compound (II-6) and compound (IX) is directly condensed by a condensing agent (for example, dicyclohexylcarbodiimide), by the way, where the reactive derivative of compound (II-6) and compound (IX) is subjected to interact appropriately, or the like. Examples of the reactive derivative of compound (II-6) are acid anhydrides, halides (acid chlorides, acid bromides), imidazoline or mixture of halides (for example, anhydrides with methoxycarbonyl acid, ethoxycarbonyl acid or isobutoxide acid).

If using the tsya gelegenheid, for example, the interaction is carried out in the presence of a base in a solvent that does not affect the interaction.

Examples of the base include triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogen carbonate, sodium carbonate and potassium carbonate.

Examples of the solvent which does not affect the interaction include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran, dioxane and diethyl ether; ethyl acetate and water.

These solvents can be used in a mixture at an appropriate ratio.

The amount used of the compound (IX) is from 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (II-6).

The reaction temperature is usually from -30 to 100°C.

Interaction time is usually from 0.5 to 20 hours.

Additionally, if you use a mixture of halides, the compound (II-6) and ether hydrochloric acid (for example, methylcarbonate, ethylchloride, isobutylparaben) is subjected to interaction in the presence of a base (e.g. triethylamine, N-methylmorpholine, N,N-dimethylaniline, sodium hydrogen carbonate, sodium carbonate, potassium carbonate) and, optionally subjected to interaction with the compounds is of (IX).

The amount used of the compound (IX) is usually from 0.1 to 10 molar equivalents, preferably 0.3 to 3 molar equivalents, relative to compound (II-6).

The reaction temperature is usually from -30 to 100°C.

Interaction time is usually from 0.5 to 20 hours.

The compound (II-7)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (II-6), which is used as starting product in method E described above can be obtained, for example, methods A-D, described above.

where X2represents an oxygen atom, a sulfur atom or a group of the formula: -NR16-where R16has the same values as above;

Z1represents a hydroxy-group, a halogen atom or a group of the formula: OSO2R17where R17represents an alkyl group containing from 1 to 4 carbon atoms, or aryl group containing from 6 to 10 carbon atoms which may be substituted by an alkyl group containing from 1 to 4 carbon atoms; other symbols have the same meanings as above.

An example is mi alkyl group, containing from 1 to 4 carbon atoms and aryl groups containing from 6 to 10 carbon atoms which may be substituted by an alkyl group containing from 1 to 4 carbon atoms for R17are these examples for R15above.

In this method, the compound (II-9) is produced by interaction of the compound (II-8) and compound (XI). This interaction is carried out in the same way as the interaction of the compound (III) and compound (IV) in method A.

The compound (II-9)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (II-8), which is used as starting product in method F described above can also be obtained, for example, by the method described in Bioorganic & Medicinal Chemistry Letters, vol.6, p.1047 (1996), and the like, or in a similar way. In addition, the compound (II-8) can also be obtained by methods a-E described above.

The compound (VIII)used as starting product in the method, can be obtained, for example, by the method G described above.

where the symbols have the same meanings as above.

Atvsamala carried out in the same way, as the interaction of the compound (III) and compound (IV) in method A.

The condensation reaction can be carried out with a protected-Y H group of the compound (X), this group may be unprotected after the reaction. Protective groups which can be used include benzyl group, methoxymethyl group and a silyl group (for example, trimethylsilyloxy group, tert-butyldimethylsilyloxy group).

The compound (II-10)containing IT for R3and containing-CH2- for W in the formula (II)can also be obtained by way N., described below.

[Method N]

where the symbols have the same meanings as above.

(Stage 5)

The compound (XII) can be obtained by the interaction of the compounds (VI) and p-toluensulfonate in the presence of a base, such as tert-piperonyl potassium, sodium hydride and lithium hydride, in a solvent which does not affect the interaction, and then carrying out the alcoholysis.

The number of p-toluensulfonate, preferably, is from about 0.5 to about 10 molar equivalents, relative to compound (VI).

The amount of base, preferably, is from about 0.5 to about 20 molar equivalents, relative to compound (VI).

Examples of alcohols used in the alcoholysis include methane is l, ethanol, propanol, butanol and isopropanol.

Examples of the solvent which does not affect the interaction, include aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform and dichloromethane; ethers, such as tetrahydrofuran, dioxane, diethyl ether, 1,2-dimethoxyethane. These solvents can be used in a mixture at an appropriate ratio.

The reaction temperature typically ranges from about -100 to about 150°preferably from about -80 to about 100°C.

Interaction time is usually from about 0.5 to about 20 hours.

The compound (XII)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under reduced pressure, extraction with solvent, crystallization, recrystallization, re-dissolution and chromatography.

The compound (VI)used as starting product in stage 5 of method H, described above, can be obtained, for example, stage 2 of the method described above.

(Stage 6)

In this method, compound (II-10) obtained by hydrolysis of compound (XII).

This hydrolytic interaction carried out in the usual way in the presence of acid or base in hydrated solvent.

When the minimum level of the acid include hydrochloric acid, sulfuric acid, acetic acid and Hydrobromic acid.

Examples of the base include carbonates of alkali metals such as potassium carbonate and sodium carbonate; alkoxides of alkali metals such as sodium methoxide; and hydroxides of alkali metals such as potassium hydroxide, sodium hydroxide and lithium hydroxide.

The amount of acid or base is usually in excess relative to the compound (XII). Preferably, the amount of acid used is from about 2 to about 50 equivalents relative to the compound (XII) and the amount of base is from about 1.2 to about 5 equivalents relative to the compound (XII).

Examples of hydrated solvents include solvent mixture of water and one or more solvents selected from alcohols such as methanol and ethanol; ethers such as tetrahydrofuran, dioxane and diethyl ether;

dimethyl sulfoxide and acetone.

The reaction temperature is usually from about -20 to about 150°preferably from about -10 to about 100°C.

Interaction time is usually from about 0.1 to about 20 hours.

The compound (II-10)thus obtained can be isolated and purified by known methods of separation and purification such as concentration, concentration under pony is hinnon pressure, extraction solvent, crystallization, recrystallization, re-dissolution and chromatography.

If the original product includes amino, carboxy, hydroxy or carbonyl as Deputy in separate reactions described above, these groups may have a protective group commonly used in chemistry of peptides and presented here in other areas. The desired compound can be obtained by removing the protective group after the interaction, if necessary.

Examples of protective groups for amino include formyl, C1-6acylcarnitine group (for example, acetyl, propionyl), C1-6alkoxycarbonyl group (for example, methoxycarbonyl, etoxycarbonyl, tert-butoxycarbonyl), benzoyl, C7-10aralkylamines group (for example, benzylcarbamoyl), C7-14aracelikarsaalyna group (for example, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), trityl, phthaloyl, N,N-dimethylaminomethylene, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl) and C2-6alkeneamine group (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6CNS groups (for example, methoxy, ethoxy, propoxy), nitro or the like.

Examples of protective g the SCP for carboxy include C 1-6alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), C7-11kalkilya group (e.g., benzyl), phenyl, trityl, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl) and C2-6alkeneamine group (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkoxygroup (for example, methoxy, ethoxy, propoxy), nitro or the like.

Examples of protective groups for hydroxy include C1-6alkyl groups (e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, trityl, C7-10kalkilya group (e.g., benzyl), formyl, C1-6acylcarnitine group (for example, acetyl, propionyl), benzoyl, C7-10aralkylamines group (for example, benzylcarbamoyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, silyl group (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilane, tert-butyldimethylsilyl, tert-butyldimethylsilyl) and C2-6alkeneamine group (e.g., 1-allyl). These groups may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), C1-6alkyl groups (e.g. methyl, ethyl, propyl), C1-6alkoxygroup (for example, methoxy, ethoxy, propoxy), nitro, or that p is such.

Examples of protective groups for carbonyl include cyclic acetylene group (for example, 1,3-dioxane) and acyclic acetylene group (for example, di-C1-6alkylenediamine group).

In addition, these protective groups can be removed by methods known in this field, for example, a method described in Protective Groups in Organic Synthesis, published by John Wiley and Sons (1980). For example, you can use the methods using acid, base, ultraviolet rays, hydrazine, phenylhydrazine, N-methyldithiocarbamate sodium, tetrabutylammonium fluoride, palladium acetate, halide trialkylsilyl (for example, iodide of trimethylsilyl, bromide of trimethylsilyl) or the like, a reduction method and the like.

If the compound (II) contains an optical isomer, stereoisomer, isomer, or the isomer of rotation, these isomers are also included in compound (II) and each can be obtained as a separate substance izvestnim in this field by the method of synthesis or secretion. For example, if the compound (II) contains an optical isomer, an optical isomer separated from these compounds are also included in the compounds (II).

The optical isomers can be obtained by a method known in this field. More specifically, optical isomers receive the usual way, using optically active about eroticne products of synthesis or optically resolved racemic final product.

Examples of optical methods of separation known in this area include, as a way of fractional recrystallization, the way chiral column chromatography and diastereomeric method.

1) the Method of fractional recrystallization

The way in which salt is formed between the racemate and optically active compound [for example, (+)-mandelic acid, (-)-mandelic acid, (+)-tartaric acid, (-)-tartaric acid, (+)-1-phenethylamine, (-)-1-phenethylamine, cinchonine, (-)-cinchonidine, brucine], this salt is separated by fractional recrystallization and the like, and if desired, is subjected to the neutralization process of obtaining a free optical isomer.

2) the Way chiral column chromatography

A method in which a racemate or its salt is applied to the column for separation of optical isomers (chiral column). If, for example, liquid chromatography, optical isomers are separated by drawing on a chiral column such as ENANTIO-OVM (manufactured by Tosoh Corporation) or a series of CHIRAL manufactured by DAICEL CHEMICAL IND., a mixture of optical isomers and processing water, various buffers (e.g. phosphate buffer), organic solvent (e.g. ethanol, methanol, isopropanol, acetonitrile, triperoxonane acid, diethylamino) or mixtures of these solvents. If, for example, gas HRO is ecografia, for the separation of optical isomers used chiral column such as CP-Chirasil-DeX ST (manufactured by GL Science).

3) Diastereomeric way

The way in which racemic mixture of optically active reagent chemically interact with obtaining diastereomeric mixture, which is then subjected to conventional separation (e.g., fractional recrystallization, chromatography) with the release of certain substances that enter into a chemical reaction, such as acid hydrolysis, with the Department group of the optically active reagent, thereby obtaining the desired optical isomer. For example, if the compound (I) include hydroxy or primary or secondary amino group in its molecule, the specified connection, optically active organic acid (e.g., MTR [α-methoxy-α-(trifluoromethyl)phenylacetic acid], (-)-metacercaria acid) and the like can be subjected to the condensation reaction with the release of the diastereoisomer ester or amide, respectively. On the other hand, if the compound (I) includes a carboxyl group, this compound and an optically active amine or alcohol reagent may be subjected to the condensation reaction with the release of the diastereoisomer amide or ester, respectively. The diastereoisomer, separated thereby is converted into an optical isomer of the original with the unity, exposing his reaction, acid hydrolysis or basic hydrolysis.

The BEST EMBODIMENT of the INVENTION

The present invention is hereinafter described in more detail using the following examples, tests, reference examples, examples, and examples of the preparation, but it is not limited. In addition, the symbol % in the reference examples and examples described below, indicates the percentage by weight, unless otherwise stated. Room temperature means a temperature of from 1 to 30°C.

Abbreviations bases, amino acids and other abbreviations used in this detailed description, based on abbreviations specified by the Commission IUPAC-IUB biochemical nomenclature or abbreviations commonly used in the fields related to this. Some examples are given below. If the optical isomer may be present in the amino acid, it is an L-configuration, unless otherwise specified.

The number of sequences in the sequence listed in this detailed description, shown in the respective sequences.

[Sequence ID:1]

Shows the basic sequence of primer PAG-U used in reference example 1.

[Sequence ID:2]

Shows the basic sequence of primer PAG-L, used in the reference example 1.

[Sequence ID:3]

Shows the basic sequence of primer XRA-U used in reference example 2.

[Sequence ID:4]

Shows the basic sequence of primer XRA-L used in reference example 2.

[Sequence ID:5]

Shows the basic sequence of primer PPRE-U used in reference example 4.

[Sequence ID:6]

Shows the basic sequence of primer PPRE-L used in reference example 4.

[Sequence ID:7]

Shows the basic sequence of primer TK-U used in reference example 4.

[Sequence ID number:8]

Shows the basic sequence of primer TK-L used in reference example 4.

The test example 1

Hypoglycemic and hypolipidemic activity in mice

Test compounds were mixed with powdered feed (CE-2, Clea Japan) with a concentration of 0.01% (compounds of examples 12, 30, 89, 186), 0,005% (connection examples 7, 80, 82, 181, 182, 184, 256, 262, 283), 0,001% (connection examples 9, 104, 110, 155, 156, 160, 167, 169, 172, 174, 176, 189) or 0.0003% (compounds of examples 38, 40, 44) and unlimited gave mice CCCAY(ages 9-12 weeks old, 5 mice per group), a model of obesity and diabetes mellitus type 2, for four days. During this period unrestricted giving is whether the water. The blood was collected from orbital venous plexus and enzymatically determined the levels of glucose and triglycerides isolated from blood plasma using L type Wako Glu2 (Wako Pure Chemical Industries, Ltd.) or L type Wako TG·H (Wako Pure Chemical Industries, Ltd.), respectively. The results are shown in table 1.

In the table the value of each of the treated groups are presented as percent reduction compared with uncultivated group.

Table 1
Test the connection (example)Hypoglycemic activity (%)Hypolipidemic activity(%)
75460
94870
124663
305477
384469
404166
444774
804222
825058
894870
1044342
1105070
1554956
1564580
1605457
1674860
1694839
1724262
1744052
1764066
1815663
1823412
1845682
1865778
1894475
2565716
2624561
2835278

These results show that the compounds of the present invention have a strong hypoglycemic and hypolipidemic activities. Thus, it was proved that the compounds can be used as a means for the prevention or treatment of diabetes, hyperlipidemia (especially hypertriglyceridemia), reduced glucose tolerance and the like.

The test example 2

Activity to reduce total cholesterol and activity to increase antiarteriosclerotic ind the KSA plasma in mice

Test compounds were mixed with powdered feed (CE-2, Clea Japan) with a concentration of 0.01% (compounds of examples 12, 30, 89), 0,005% (connection examples 38, 40, 44, 181, 184, 262, 283) or 0.001% (compounds of examples 9, 156, 167, 172, 174, 176, 189) and unlimited gave mice ADCY(ages 9-12 weeks old, 5 mice per group), a model of obesity and diabetes mellitus type 2, for four days. During this period, unlimited water is given. The blood was collected from orbital venous plexus, and separated plasma. Determined the levels of total cholesterol, using L type Wako Cholesterol (Wako Pure Chemical Industries, Ltd.). The precipitating reagent for Ares containing lipoprotein, was added in part of the plasma for deposition of non-HDL lipoprotein and formed in the supernatant was determined cholesterol (HDL cholesterol). Using these cholesterol levels, expected antiarteriosclerotic index of plasma [ (HDL cholesterol/total cholesterol) X 100]. The results are shown in table 2.

In the table “activity for the reduction of total cholesterol (%)” is presented as a percentage reduction (%) total cholesterol in the treated group, provided that the total cholesterol in uncultivated group is taken as 100%. “Activity to increase antiarteriosclerotic index of plasma (%)” is presented as the percentage increase (%) antiarteriosclerotic index of plasma in treated gr is PPI, provided that antiarteriosclerotic index of plasma in uncultivated group is taken as 100%.

Table 2
Test the connection (example)Activity reduction in total cholesterol (%)Activity to increase antiarteriosclerotic index of plasma (%)
91612
121524
302716
382421
401922
442321
89815
1562015
167199
1722011
1741910
1762311
1812521
1842717
1892120
262229
2832419

These results show the t, the compounds of the present invention have high activity for the reduction of total cholesterol and activity to increase antiarteriosclerotic index of plasma. Thus, it was proved that the compounds can be used as a means for the prevention or treatment of arteriosclerosis, improving the profile of plasma lipoproteins in hypercholesterolemia and/or Hypo-NDL-cholesterolemia.

The test example 3

(Ligand activity of heterodimer PPARγ-RXRα)

In the environment WE F12 (available from NISSUI SEIYAKU)containing 10% fetal bovine serum (produced by Life Technologies, Inc., USA), counted cells PPARγ:RXRα:4ERPP/CHO-Kl obtained in reference example 5, described below, was then inoculable in 96-well white plate (produced by Corning Costar Corporation, USA) with a density of 2 X 104cells/well and cultured in an incubator containing gaseous CO2at 37°With during the night.

After washing the 96-well white plates PBS (phosphate saline buffer), was added 90 μl of environment WE F12 containing 0.1% fetal bovine serum albumin (BSA), which do not contain fatty acids, and 10 μl of test compounds, and cultured in CO2gas incubator at 37 °C for 48 hours. After removal of the medium, was added 40 μl PIKKAGENE 7,5 (available from Wako Pure Chemical Industries, Ltd.). After stirring ODA is delali luciferase activity, using the Lumistar (available from BMG Labtechnologies GmbH, Germany).

The multiplicity of induction was calculated based on the luciferase activity of each test compound, taking luciferase activity unhandled group 1. Concentrations of the tested compounds and the ratio of induction were analyzed using PRISM 2,01 (available from GraphPad Software Inc. USA) to calculate the values of EC50effective concentrations of the tested compounds at 50% from maximum frequency induction. The results are presented in table 3.

Table 3
Test the connection,

(example)
EC50

(nm)

7the 3.8
82,7
91.5
12320
30the 9.7
3838
4057
4413
802,5
821,4
890,23
1001,8
1042,0
1103,5
25653
26233
283 0,22

These results show that the compounds of the present invention have a strong ligand activity heterodimer PPARγ-RXRα.

Reference example 1

(Cloning of the gene of PPARγ person)

Gene PPARγ human cloned using as template for PCR analysis cDNA hearts (available from Toyobo Co., Ltd., trade name: QUICK-Clone cDNA)using the primer set shown below which was obtained in accordance with the base sequence of a gene of PPARγpresented in Greene et al. (Gene Expr., 1995, Vol. 4 (4-5), SCR-299).

PAG-U: 5'-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3' (sequence ID number: 1)

PAG-L: 5'-GGG GTC GAC CAG GAC TCT CTG HUNDRED GTA CAA GTC-3' (sequence ID number: 2)

PCR was performed by hot start method using AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.). First received the mixture of the solutions for the bottom layer, mixing 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mm dNTP solution, and 2.5 μl of 12.5 μm each of the primer solution and 10 μl of sterile distilled water. To obtain the solution of the upper layer, mixing 1 µl of the cDNA of the human heart (1 ng/ml) as a template, 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mm dNTP solution, and 0.5 μl of TaKaRa LA Taq DNA polymerase (produced by TAKARA SHUZO CO., LTD.) and 24.5 μl of sterile distilled water.

In the solution of the lower layer, described above, was added one AmpliWax PCR Gem 100 (produced TAKRA SHUZO CO., LTD.) and they were heated to 70°C for 5 minutes, then cooled on ice for 5 minutes. Then the solution of the upper layer was added to the mixture to obtain a reaction mixture for PCR. The tube containing the reaction mixture, was installed in the fuser (available from Perkin Elmer, USA) and treated at 95°C for 2 minutes. After repeating the cycle at 95 C for 15 seconds and at 68 °for 2 additional minutes 35 times, the tube was treated with 72°C for 8 minutes.

Thus obtained PCR product was subjected to electrophoresis on agarose gel (1%)gel received a 1.4 kb DNA fragment containing the gene of PPARγand then inserted into the vector RT Blue-T (manufactured by TAKARA SHUZO CO., LTD.) to obtain plasmid pTBT-hPPARγ.

Reference example 2

(Cloning of the gene RXRα person)

Gene RXRα human cloned using as template for PCR analysis cDNA kidney (available from Toyobo Co., Ltd., brand name: QUICK-Clone cDNA)using the primer set shown below which was obtained in accordance with the base sequence of a gene RXRαpresented in Mangelsdorf, D. J. et al (Nature, 1990, Vol.345 (6272), str-229).

XRA-U: 5'-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3' (sequence ID number: 3)

XRA-L: 5'-CCC CTC GAG HUNDRED AGT CAT TTG GTG CGG CGC CTC-3' (sequence ID number: 4)

PCR was performed by hot start method using AmpliWax PCR Gem 100 (produced TAARA SHUZO CO., LTD.). First received the solution of the lower layer mixing 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mm dNTP solution, and 2.5 μl of 12.5 μm each solution for primer and 10 μl of sterile distilled water. To obtain the solution of the upper layer was mixed 1 ál kidney cDNA (1 ng/ml) as a template, 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mm dNTP solution, and 0.5 μl of TaKaRa LA Taq DNA polymerase (produced by TAKARA SHUZO CO., LTD.) and 24.5 μl of sterile distilled water.

In the solution of the lower layer, described above, was added one AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.) and they were heated to 70°C for 5 minutes, then cooled on ice for 5 minutes. Then the solution of the upper layer was added to the mixture to obtain a reaction mixture for PCR. The tube containing the reaction mixture, was installed in the fuser (available Per-kin Elmer, USA) and treated at 95°C for 2 minutes. After repeating the cycle at 95°C for 15 seconds and at 68°for 2 additional minutes 35 times, the tube was treated with 72°C for 8 minutes.

Thus obtained PCR product was subjected to electrophoresis on agarose gel (1%) and gel received a 1.4 kb DNA fragment containing the gene RXRαand then inserted into the vector RT Blue-T (manufactured by TAKARA SHUZO CO., LTD.) to obtain plasmid pTBT-hRXRα.

Reference example 3

(Creation of plasmids for the expression of PPARγ human RXRα)/p>

Ligated to 7.8 kb fragment FspI-NotI plasmids pVgRXR (available from Invitrogen, USA) and 0.9 kb fragment FspI-NotI containing RXR geneα plasmid pTBT-hRXRαobtained in reference example 2, with the formation of plasmid pVgRXR2. Then pVgRXR2cut BstXI and processed TANK polymerase (produced by TAKARA SHUZO CO., LTD.) to obtain blunt ends. Then cut with Kpnl getting a 6.5 kb DNA fragment.

On the other hand, plasmid RTT-Farrarγobtained in reference example 1, cut Sal I and then treated TANK polymerase (produced by TAKARA SHUZO CO., LTD.) to obtain blunt ends. Then cut with Kpnl getting a 1.4 kb DNA fragment containing the gene of PPARγ man.

Both DNA fragment ligated to create plasmid pVgRXR2-hPPARγ.

Reference example 4

(Creation of reporter plasmids)

Using the following 5'-terminal phosphorylated synthetic DNA, obtained DNA fragment containing the PPAR-responsible element (PPRE) acyl-COA oxidase.

PPRE-U: 5'-pTCGACAGGGGACCAGGACAAAGGTCACGTTCgggag-3' (sequence ID number: 5)

PPRE-L: 5'-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCccctg-3' (sequence ID number: 6)

First PPRE-U and PPRE-L were annealed and inserted into the Sal website I plasmid pBlue Script SK+. Defining the basic sequence of the inserted fragment were selected plasmid pBSS-PPRE4, in which 4 PPRE were legirovanyh in a tandem repeat.

Cloned HSV thymidine kinase minimal is robotomy plot (TK promoter), using the vector pRL-TK (available from Promega, USA) as template for PCR analysis using primer listed below, which were obtained in accordance with the main sequence of the promoter region timidinkinaza presented Luckow, et al. (Nucleic Acids Res., 1987, Vol.15 (13), R).

TK-U: 5'-CCCAGATCTCCCCAGCGTCTTGTCATTG-3'(sequence ID number: 7)

TK-L: 5'-TCACCATGGTCAAGCTTTTAAGCGGGTC-3' (sequence ID number: 8)

PCR reaction was performed by hot start method using AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.). First received the solution of the lower layer mixing 2 μl of 10 × LA PCR buffer, 3 μl of 2.5 mm dNTP solution, and 2.5 μl of 12.5 μm each of the primer solution and 10 μl of sterile distilled water. To obtain a mixture of the upper layer was mixed 1 ál vector pRL-TK (available from Promega, USA) as a template, 3 μl of 10 × LA PCR buffer, 1 μl of 2.5 mm dNTP solution, and 0.5 μl of TaKaRa LA Taq DNA polymerase (produced by TAKARA SHUZO CO., LTD.) and 24.5 μl of sterile distilled water.

In the solution of the lower layer, described above, was added one AmpliWax PCR Gem 100 (produced by TAKARA SHUZO CO., LTD.) and they were heated to 70°C for 5 minutes, then cooled on ice for 5 minutes. Then the solution of the upper layer was added to the mixture to obtain a reaction mixture for PCR. The tube containing the reaction mixture, was installed in the fuser (available from Perkin Elmer, USA) and treated at 95°t the value of 2 minutes. After repeating the cycle at 95°C for 15 seconds and at 68°for 2 additional minutes 35 times, the tube was treated with 72°C for 8 minutes.

Thus obtained PCR product was subjected to electrophoresis on agarose gel (1%) and the gel was received 140 b DNA fragment containing the TK-promoter, and then inserted into the vector RT Blue-T (manufactured by TAKARA SHUZO CO., LTD.). Thus obtained plasmid was cut with the enzymes Qg1 II and Nco I to obtain a fragment containing the TK promoter, which is ligated with a fragment Bgl II-Nco I plasmids pGL3-Basic vector (available from Promega, USA) to obtain the plasmid pGL3-TK.

Thus obtained a 4.9 kb fragment Nhe I Xho I plasmid pGL3-TK ligated with 200 b fragment Nhe I Xho I plasmid pBSS-PPRE4 with the formation of plasmid pGL3-4ERPP-TK.

Thus obtained plasmid pGL3-4ERPP-TK cut BamHI (produced by TAKARA SHUZO CO., LTD.) and then processed TANK polymerase (produced by TAKARA SHUZO CO., LTD.) with the formation of blunt ends, and thus, the DNA fragment.

On the other hand, pGFP-Cl (available from Toyobo Co., Ltd.) cut Bsu36I (NEB) and then processed TANK polymerase (produced by TAKARA SHUZO CO., LTD.) with the formation of blunt ends, and thus, a 1.6 kb DNA fragment.

Both DNA fragment ligated with the receipt of reporter plasmid pGL3-4ERPP-TK peo.

Reference example 5

(The introduction of plasmids, PPARγ man and RXRαand reporter plasmids into cells Cho-K1, and the creation of expressed cells).

After cells Cho-K1, cultured in 750 ml-OIC flask for tissue culture (produced by Corning Costar Corporation, USA)containing environment WE F12 (available from NISSUI SEIYAKU) with the addition of 10% fetal bovine serum (produced by Life Technologies, Inc., USA)were cleaned by treatment with 0.5 g/l trypsin - 0.2 g/l EDTA (ethylenediaminetetraacetic acid) (available from Life Technologies, Inc., USA), cells were washed in PBS (phosphate saline buffer) (available from Life Technologies, Inc., USA), centrifuged (1000 rpm, 5 minutes) and then suspended in PBS. Then introduced DNA into the cells under the conditions shown below using GENE PULSER (manufactured by Bio-Rad Laboratories, USA).

Namely, in a cuvette with a 0.4 cm gap was added 8 X 106cells and 10 μg of plasmid pVgRXR2-hPPARγobtained in reference example 3, and 10 μg of reporter plasmid pGL3-4ERPP-TC peo obtained in reference example 4 were subjected to electroporation with an electric voltage of 0.25 kV and resistance 960 F. The cells are then transferred to the environment WE F12 containing 10% fetal bovine serum, and were konturirovany within 24 hours, the cells are then again scraped and centrifuged, and then suspended in the environment WE F12 containing 10% fetal bovine serum, with the addition of 500 μg/ml GENETICIN (available from Life Technologies, Inc., USA) and 250 μg/ml ZEOCI (available from Invitrogen, USA), and diluted to a density of 104cells/ml, inocula in 96-well plate (produced by Corning Costar Corporation, USA), which were cultured in the CO2gas incubator at 37°thus, getting the transformant resistant to GENETICIN and ZEOCIN.

Then, after the thus obtained transformed cell line was cultured in 24-hole plate (produced by Corning Costar Corporation, USA)was carried out selection of cell lines with the expression and induction of luciferase, i.e. cells PPARγ:RXRα: 4ERPP/CHO-K1, by adding 10 μm pioglitazone hydrochloride.

Reference example 6

Alumoweld lithium (2,53 g) was added to a solution of methyl 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (21,52 g) in tetrahydrofuran (100 ml) at 0°and the mixture was stirred at room temperature for one hour. In the reaction mixture was added decahydrate sodium sulfate (30,00 g) and hexane (100 ml), the mixture was stirred at room temperature for one hour. Then the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), received [1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]methanol (19,68 g, yield: 98%) as colorless crystals. It was recrystallized from ethyl acetate-hexane. The point is as melting point: 122-123° C.

Reference example 7

A mixture of [1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]methanol (19,00 g), activated manganese dioxide (41,19 g) and tetrahydrofuran (300 ml) was stirred at room temperature overnight. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (18,56 g, yield: 98%) as colorless crystals. It was recrystallized from ethyl acetate-hexane. Melting point: 100-101°C.

Reference example 8

A mixture of ethyl (E)-3-[1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (19,50 g), 5% palladium on coal (20,00 g) and tetrahydrofuran (200 ml) was stirred overnight at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (14,92 g, yield: 96%) as an oily substance.

NMR (Dl3) δ: 1.20(3H, t, J=7.0 Hz), 2.44-2.58(2H, m), 2.88-3.02(2H, m), 4.08(2H, q, J=7.0 Hz), 4.93(2H, s), 6.46-6.54(1H, m), 6.66-6.84(3H, m), 7.02-7.12(2H, m), 7.14-7.44(5H, m).

Reference example 9

Almogi the reed lithium (232 mg) was added to a mixture of methyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenylpyrrole-3-carboxylate (2,92 g), diethyl ether (50 ml) and tetrahydrofuran (25 ml) at 0°and the mixture was stirred at 0°C for 3 hours. Then the reaction mixture was added water, the precipitate was removed by filtration. The filtrate was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio), received [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]methanol (2.37 g, yield: 86%) as a colorless amorphous substance.

NMR (Dl3)δ: 2.43(3H, s), 4.64(2H, s), 4.99(4H, similar to C), 6.73-6.77(1H, m), 6.80-6.83(1H, m), 7.04(2H, d, J=8.6 Hz), 7.12-7.56(10H, m), 7.98-8.04(2H, m).

Reference example 10

A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]methanol (3.98 g), activated manganese dioxide (8.00 g) and toluene (50 ml) was stirred at 80° C for 10 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio) was obtained 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenylpyrrole-3-carbaldehyde (2.85 g, yield: 72%) as colorless crystals. Their recrystallized from ethyl acetate, the-hexane. Melting point: 117-118°C.

Reference example 11

Alumoweld lithium (305 mg) was added to a solution of methyl 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-errorcorrection (1.78 g) in tetrahydrofuran (40 ml) at 0°and the mixture was stirred at room temperature for 6 hours. Then the reaction mixture was added water, the precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), received [1-[4-[2-[N-methyl-N-(2-pyridyl)amino]-ethoxy]benzyl]-4-phenyl-3-pyrrolyl]methanol (1.45 g, yield: 87%) as an oily substance.

NMR (Dl3) δ: 1.35-1.5(1H, m), 3.15(3H, s), 3.99(2H, t, J=5.5 Hz), 4.18(2H. t, J=5.5 Hz), 4.63(2H, d, J=4.5 Hz), 4.96(2H, s), 6.45-6.6(2H, m), 6.73(1H, d, J=2.5 Hz), 6.79(1H, d, J=2.5 Hz), 6.87(2H, d, J=9.0 Hz), 7.12(2H, d, J=9.0 Hz), 7.15-7.6(6N, m), 8.1-8.2(1H, m,).

Reference example 12

A mixture of [1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]methanol (1.45 g), activated manganese dioxide (4.0 g) and tetrahydrofuran (60 ml) was stirred at room temperature for 3 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl] -4-phenylpyrrole-3-carbaldehyde (1.40 g, yield: 97%) as an oily substance.

NMR (Dl3)δ: 3.15(3H, s), 3.99(2H, t, J=Hz), 4.19(2H, t, J=5.5 Hz), 5.02(2H, s), 6.45-6.6(2H, m), 6.73(1H, d, J=2.0 Hz), 6.90(2H, d, J=8.5 Hz), 7.15(2H, d, J=8.5 Hz), 7.2-7.5(7H, m), 8.1-8.2(1H, m), 9.84(1H,s).

Reference example 13

Alumoweld lithium (0,258 g) was added to a solution of methyl 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carboxylate (totaling 3.04 g) in tetrahydrofuran (30 ml) at 0°and the mixture was stirred at room temperature for one hour. In the reaction mixture was added decahydrate sodium sulfate (2,19 g) and hexane (30 ml) and the mixture was stirred at room temperature for 30 minutes. Then the precipitate was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to yield [1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]methanol (2,54 g, yield: 89%). It was recrystallized from ethyl acetate-hexane. Melting point: 116-117°C.

Reference example 14

A mixture of [1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]-methanol (2,39 g), activated manganese dioxide (4,80 g) and tetrahydrofuran (50 ml) was stirred at room temperature for one hour. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to yield 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carbaldehyde (2.24 g, yield: 94%). It was recrystallized from tetrahydrofuran-hexane. Melting point: 140-141°C.

Reference note the R 15

A mixture of ethyl (E)-3-[1-(6-benzyloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl] propenoate (1,46 g), 5% palladium on coal (1.5 g), ethanol (15 ml) and tetrahydrofuran (15 ml) was stirred for 4 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (1.08 g, yield: 90%) as an oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.2 Hz), 2.53(2H, t, J=Hz), 2.97(2H, t, J=7.6 Hz), 4.07(2H, q, J=7.2 Hz), 5.10(2H, s), 5.57(1H,users), 6.55(1H, d, J=2.4 Hz), 6.76(1H, d, J=2.4 Hz), 7.07-7.45(8H, m), 7.54(1H, s), 7.60-7.71(2H, m).

Reference example 16

Alumoweld lithium (0.25 g) was added to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-pyrrole-3-carboxylate (2,40 g) in tetrahydrofuran (30 ml) at 0°and the mixture was stirred at 0°C for 30 minutes. Then the reaction mixture was added decahydrate sodium sulfate (2,13 g) and hexane (30 ml), the mixture was stirred at room temperature for 30 minutes. Then the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), received[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-3-pyrrolyl]methanol (2,09 g, yield: 95%) as an oily substance.

NMR (Dl3)δ: 2.44(3H, s), 4.55(2H, s), 4.99(4H, s), 6.88(1H, d, J=2.2 Hz), 6.94-7.22(6N, m), 7.36-7.69(5H, m), 7.96-8.08(2H, m), 8.46-8.53(1H, m).

Reference example 17

A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-3-pyrrolyl]methanol (2,01 g), activated manganese dioxide (5,09 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-4-(2-pyridyl)pyrrole-3-carbaldehyde (1,71 g, yield: 85%) as an oily substance.

NMR (Dl3)δ: 2.44(3H, s), 5.00(2H, s), 5.06(2H, s), 6.96-7.28(6N, m), 7.38-7.49(4H, m), 7.62-7.74(1H, m), 7.79-7.86(1H, m), 7.96-8.08(2H, m), 8.54-8.60(1H, m), 10.16(1H, s).

Reference example 18

Chloride methanesulfonyl (5,03 ml) was slowly added to a mixture of 3,5-dimensionsdimensions alcohol (16.0 g), triethylamine (9,06 ml) and tetrahydrofuran (200 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained colorless crystals Sobir is whether filtering with access 3,5-dibenzylethylenediamine (22,20 g, yield: 91%). Their recrystallized from ethyl acetate-hexane. Melting point: 85-86°C.

Reference example 19

Alumoweld lithium (1.97 g) was added to a solution of methyl 1-(3, 5-dibenzalacetone)-4-phenyl-3-errorcorrection (26,2 g) in tetrahydrofuran (250 ml) at 0°and the mixture was stirred at room temperature for one hour. In the reaction mixture was added decahydrate sodium sulfate (16.1 g) and hexane (250 ml), the mixture was stirred at room temperature for 30 minutes. Then the precipitate was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to yield [1-(3,5-dibenzalacetone)-4-phenyl-3-pyrrolyl]methanol (24,20 g, yield: 98%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 115-116°C.

Reference example 20

A mixture of [1-(3,5-dibenzalacetone)-4-phenyl-3-pyrrolyl]-methanol (23,8 g), activated manganese dioxide (50,00 g) and tetrahydrofuran (200 ml) was stirred at room temperature for two hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to yield 1-(3,5-dibenzalacetone)-4-phenylpyrrole-3-carbaldehyde (23,10 g, yield: 97%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 117-118°C.

Reference example 21

A mixture of ethyl (E)-3-[1-(3,5-is benzyloxybenzyl)-4-phenyl-3-pyrrolyl] propenoate (19,0 g), 5% palladium on coal (40,0 g), ethanol (200 ml) and tetrahydrofuran (200 ml) was stirred for 4 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (3:2, volume ratio)was obtained ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (12,10 g, yield: 95%) as an oily substance.

NMR (Dl3) δ: 1.13(3H, t, J=7.2 Hz), 2.49(2H, t, J=7.4 Hz), 2.93(2H, t, J=7.4 Hz), 4.01(2H, q, J=7.2 Hz), 4.77(2H, s), 6.09(2H, d, J=2.2 Hz), 6.24(1H, t, J=2.2 Hz), 6.33(2H, s), 6.42(1H. d, J=2.4 Hz), 6.65(1H, d, J=2.4 Hz), 7.14-7.37(5H, m).

Reference example 22

Alumoweld lithium (884 mg) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (being 9.61 g) in tetrahydrofuran (50 ml) at 0°and the mixture was stirred at 0°C for one hour. After adding water, the reaction mixture was stirred at room temperature for one hour. Then the precipitate was removed by filtration, the filtrate was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained crystals were collected by filtration to yield [1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]methanol (23,10 g, yield: 97%). Their recrystallized from ethyl is Zetta-hexane. Melting point: 88-89°C.

Reference example 23

Thionyl chloride (1,83 ml) was added dropwise to a solution of [1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]methanol (8,43 g) in toluene (100 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was dissolved in tetrahydrofuran (30 ml) and this solution was added to a mixture of diethylmalonate (18,3 g), sodium hydride (60%, in oil, of 3.65 g) and tetrahydrofuran (100 ml) at 0°C. the Above mixture was stirred at 0°C for one hour and then at room temperature for 6 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), received diethyl 2-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]methylmalonate (9,50 g, yield: 81%) as a colorless oily substance.

NMR (Dl3) δ: 1.15(6N, t, J=Hz), 3.21(2H, d, J=Hz), 3.52(1H, t, J=8.0 Hz), 4.08(4H, q, J=Hz), 5.06(2H, s), 5.21(2H,s), 6.94(2H, the, J=Hz), 7.15-7.47(11N, m), 7.60-7.47(11N, m), 7.60-7.66(2H, m).

Reference example 24

A mixture of methyl 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), 5% palladium on coal (1,00 g) and tetrahydrofuran (10 ml) was stirred for 18 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio)was obtained methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (325 mg, yield: 80%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 87-88°C.

Reference example 25

Chloride methanesulfonyl (3,37 g) was added dropwise to a mixture of 2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]Ethan-1-ol (7.0 g), triethylamine (2,97 g) and ethyl acetate (300 ml) at 0°and the mixture was stirred for 3 hours at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid and then saturated aqueous sodium chloride, then dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to yield 2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]ethylmethanesulfonate (8.44 grams yield: 96%). Their recrystallized from ethyl acetate-hexane. Melting point: 66-67°C.

Reference example 26

A mixture of 4-[4-(3,5-dimethyl-1H-pyrazole-1-ylmethyl)-phenoxymethyl]-5-methyl-2-phenyloxazole (1,62 g), phosphorus oxychloride (1,00 g) and N.N-dimethylformamide (20 ml) was stirred for 5 days at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride, then dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carbaldehyde (950 mg, yield: 55%) as an oily substance.

NMR (Dl3)δ: 2.43(3H, s), 2.47(6N, s), 4.97(2H, s), 5.18(2H, s), 6.98 (2H, d, J=9 Hz), 7.10(2H, d, J=9 Hz), 7.4-7.5(3H, m), 7.95-8.05(2H, m), 9.92(1H, s).

Reference example 27

Alumoweld lithium (262 mg) was added to a solution of methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (3.50 g) in diethyl ether (50 ml) at 0°and the mixture was stirred at 0°C for one hour. After adding water, the reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer prom is Wali saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (3:2, volume ratio)was obtained 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propan-1-ol (3.04 from g, yield: 92%) as a colorless oily substance.

NMR (Dl3) δ: 1.72-1.87(2H, m), 2.44(3H, s), 2.65-2.74(2H, m), 3.63(2H, t, J=Hz), 4.99(2H, s), 5.25(2H, s), 7.00(2H, d, J=8.8 Hz), 7.17-7.46(M, m), 7.62-7.68(2H, m), 7.98-8.04(2H, m).

Reference example 28

Chloride methanesulfonyl (of 0.625 ml) was added to a mixture of 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propan-1-ol (2,98 g), triethylamine (1,74 ml) and ethyl acetate (50 ml) at 0°and the mixture was stirred for 30 minutes. The reaction mixture was washed with water and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. Then the precipitate was dissolved in acetone (50 ml), was added sodium iodide (1.86 g) and the solution was stirred at 50°C for 3 hours. Then the solvent was removed under reduced pressure, extracted with acetic ether, the precipitate was dissolved in water. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated to obtain 1-iodide-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propane (of 3.60 g, yield: 98%) in the form b is izvetnogo oily substance.

NMR (Dl3) δ: 1.96-2.08(2H, m), 2.44(3H, s), 2.69-2.77(2H, m), 3.15(2H, t, J=Hz), 4.99(2H, s), 5.25(2H, s), 7.01(2H, d, J=8.8 Hz), 7.19-7.48(M, m), 7.60-7.66(2H, m), 7.98-8.04(2H, m).

Reference example 29

A mixture of 1-iodide-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-phenyl-1H-pyrazole-4-yl]propane (1,75 g), sodium cyanide (291 mg) and dimethyl sulfoxide (5 ml) was stirred at 60 °C for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgS04) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio)was obtained 4-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]butyronitrile (1,34 g, yield: 92%) as a colorless oily substance.

NMR (Dl3)δ: 1.76-1.92(2H, m), 2.28(2H, t, J=7.0 Hz), 2.44(3H, s), 2.78(2H, t, J=Hz), 4.99(2H, s), 5.25(2H, s), 7.01(2H, d, J=Hz), 7.19-7.47 (M, t), 7.58-7.64 (2H, t), 7.98-8.04(2H, t).

Reference example 30

Sodium hydride (60%in oil, 476 mg) was added to a solution of diethylmalonate (2.37 g) in tetrahydrofuran (50 ml) at 0°and the mixture was stirred for 30 minutes. A solution of 1-iodide-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propane (1.75 g) in tetrahydrofuran (15 ml) was added dropwise to the above mixture and stirred at room the temperature for 13 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), received diethyl 2-[3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propyl]malonate (1.63 g, yield: 88%) as a colorless oily substance.

NMR (Dl3)δ: 1.23(6N, t, J=7.1 Hz), 1.50-1.65 (2H, m), 1.86-1.98(2H, m), 2.43(3H, s), 2.63(2H, t, J=7.7 Hz), 3.29(1H, t, J=Hz), 4.15(4H, q, J=Hz), 4.99(2H, s), 5.24(2H, s), 7.00(2H, d, J=8.8 Hz), 7.17-7.47(M, m), 7.59-7.65(2H, m), 7.98-8.04(2H, m).

Reference example 31

Alumoweld lithium (2,03 g) was added to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-carboxylate (40,00 g) in tetrahydrofuran (150 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was added water, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained crystals were collected by filtration to yield [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)be the ZIL]-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-yl]methanol (35,91 g, yield: 95%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 157-158°C.

Reference example 32

A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3- [4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-yl]methanol (27,02 g), activated manganese dioxide (52,29 g), chloroform (50 ml) and tetrahydrofuran (300 ml) was stirred at room temperature for 3 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3- [4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-carbaldehyde (25,69 g, yield: 95%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 155-156°C.

Reference example 33

Alumoweld lithium (0,98 g) was added to a solution of ethyl 1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl) -5-methyl-4-oxazolidinone] benzyloxy] -1H-pyrazole-4-carboxylate (19,16 g) in tetrahydrofuran (75 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was added water, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained crystals were collected fil the radio with the release of [1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2- (2-furyl)-5-methyl-4-oxazolidinone]benzyloxy]-1H-pyrazole-4-yl]methanol (17,25 g, yield: 96%). Their recrystallized from ethyl acetate-hexane. Melting point: 80-81°C.

Reference example 34

A mixture of [1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyloxy]-1H-pyrazole-4-yl]methanol (16,59 g), activated manganese dioxide (35,19 g) and tetrahydrofuran (100 ml) was stirred at room temperature for 3 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield 1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyloxy]-1H-pyrazole-4-carbaldehyde (14,73 g, yield: 89%). Their recrystallized from ethyl acetate-hexane. Melting point: 109-110°C.

Reference example 35

Alumoweld lithium (0,58 g) was added to a solution of methyl 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carboxylate(9,02 g) in tetrahydrofuran (50 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was added water, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya ethylacetate the-hexane (1:1, the volumetric ratio), received [3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]methanol (8,20 g, yield: 97%). It was recrystallized from ethyl acetate-hexane. Melting point: 98-99°C.

Reference example 36

A mixture of ethyl 3-oxohexanoate (15,80 g) and N.N-dimethylformamidine (17.9 g) was boiled under reflux for 2.5 hours and the reaction mixture was concentrated under reduced pressure. Then the precipitate was dissolved in ethanol (200 ml) and was degirolami, added benzylidenemalonate (22,0 g) and the solution boiled under reflux for 2 hours in nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed with water, and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:9, volume ratio)was obtained ethyl 1-benzyl-5-propyl-1H-pyrazole-4-carboxylate (22,81 g, yield: 84%) as a colorless oily substance.

NMR (Dl3)δ: 0.92(3H, t, J=7.2 Hz), 1.34(3H, t, J=7.2 Hz), 1.39-1.59(2H, m), 2.84-2.92(2H, m), 4.28(2H, q, J=Hz), 5.32(2H, s), 7.08-7.13(2H, m), 7.26-7.34(3H, m), 7.92(1H, s).

Reference example 37

Alumoweld lithium (2.58 g) was added to a solution of ethyl 1-benzyl-5-propyl-1H-pyrazole-4-carboxylate 18,50 g) in tetrahydrofuran (300 ml) at 0° C and the mixture was stirred at room temperature for one hour. In the reaction mixture was added decahydrate sodium sulfate (21,88 g) and hexane (100 ml) and the mixture was stirred at room temperature for 30 minutes. Then the precipitate was removed by filtration, the filtrate was concentrated to obtain (1-benzyl-5-propyl-1H-pyrazole-4-yl)methanol (14,99 g, yield: 96%) as a colorless oily substance.

NMR (Dl3)δ: 0.90(3H, t, J=Hz), 1.38-1.57(2H, m), 2.59(2H, t, J=7.6 Hz),4.52 (2H, s), 5.29(2H, s), 7.06-7.11(2H, m), 7.21-7.36(3H, m), 7.51(1H, s).

Reference example 38

A mixture of (1-benzyl-5-propyl-1H-pyrazole-4-yl)methanol (14,99 g), activated manganese dioxide (30.0 g) and tetrahydrofuran (300 ml) was stirred at room temperature for 3 days. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained 1-benzyl-5-propyl-1H-pyrazole-4-carbaldehyde (10,69 g, yield: 72%) as a colorless oily substance.

NMR (Dl3) δ: 0.93(3H, t, J=Hz), 1.43-1.58(2H, m), 2.89(2H, t, J=8.0 Hz), 5.33(2H, s), 7.11-7.16(2H, m), 7.26-7.37(3H, m), 7.96(1H, s), 9.88(1H, s).

Reference example 39

Sodium hydride (60%in oil, 2.25 g) was added to a mixture of 1-benzyl-5-propyl-1H-pyrazole-4-carbaldehyde (12,60 g), ethyl diethylphosphonoacetate (10,69 g) and N,N-dimethylfuran the IDA (150 ml) at 0° C and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water and then saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl (E)-3-(1-benzyl-5-propyl-1H-pyrazole-4-yl)propenoate (11,90 g, yield: 85%) as a colorless oily substance.

NMR (Dl3) δ: 0.90(3H, t, J=Hz), 1.32(3H, t, J=7.2 Hz), 1.36-1.60(2H, m), 2.65(2H, t, J=7.6 Hz), 4.24 (2H, q, J=7.2 Hz), 5.30(2H, s), 6.17(1H, d, J=15.6 Hz), 7.07-7.12(2H, m), 7.26-7.37(3H, m), 7.50(1H, d, J=15.6 Hz), 7.77(1H, s).

Reference example 40

A mixture of ethyl (E)-3-(1-benzyl-5-propyl-1H-pyrazole-4-yl)-propenoate (6,00 g), 5% palladium on coal (12.0 g), formic acid (50 ml) and ethanol (100 ml) was boiled under reflux for 16 hours. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-(3-what ropyl-1H-pyrazole-4-yl)propionate (3,45 g, yield: 82%) as a colorless oily substance.

NMR (Dl3) δ: 0.97(3H, t, J=7.2 Hz), 1.25(3H, t, J=7.2 Hz), 1.56-1.76(2H, m), 2.50-2.79(6N, m), 4.13(2H, q, J=Hz), 7.34(1H, s).

Reference example 41

A mixture of ethylbenzylamine (20,0 g) and dimethylacetal N.N-dimethylformamide (18,59 g) was boiled under reflux for 1.5 hours and the reaction mixture was concentrated under reduced pressure. Then the precipitate was dissolved in ethanol (200 ml) and was degirolami, added benzylidenemalonate (22,25 g) and the solution boiled under reflux for 2 hours in nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and then saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:6, volume ratio)was obtained ethyl 1-benzyl-5-phenyl-1H-pyrazole-4-carboxylate (20,9 g, yield: 66%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 78-79°C.

Reference example 42

Alumoweld lithium (2.50 g) was added to a solution of ethyl 1-benzyl-5-phenyl-1H-pyrazole-4-carboxylate (20.2 g) in tetrahydrofuran (300 ml) at 0°and the mixture was stirred at room temperature for one hour. In the reactions is nnow the mixture was added decahydrate sodium sulfate (21,23 g) and hexane (100 ml), the mixture was stirred at room temperature for one hour. Then the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), received (1-benzyl-5-phenyl-1H-pyrazole-4-yl)methanol (17,4 g, yield: 100%) as a colorless oily substance.

NMR (Dl3) δ: 4.46(2H, s), 5.25(2H, s), 6.99-7.04 (2H, m), 7.23-7.32 (5H, m), 7.41-7.45(3H, m), 7.69(1H, s).

Reference example 43

A mixture of (1-benzyl-5-phenyl-1H-pyrazole-4-yl)methanol (9,76 g), activated manganese dioxide (20,0 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 12 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7.30 g, yield: 75%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 99-100°C.

Reference example 44

Sodium hydride (60%in oil, 1.28 g) was added to a mixture of 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (7,00 g), ethyl diethylphosphonoacetate (6,59 g) and N,N-dimethylformamide (100 ml) at 0°and the mixture was stirred at room temperature for 2.5 days. Reaction the second mixture was poured into ice water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl (E)-3-(1-benzyl-5-phenyl-1H-pyrazole-4-yl)propenoate (6,30 g, yield: 71%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 62-63°C.

Reference example 45

A mixture of ethyl (E)-3-(1-benzyl-5-phenyl-1H-pyrazole-4-yl)-propanoate (300 mg), 5% palladium on coal (600 mg), formic acid (3 ml) and ethanol (10 ml) was boiled under reflux for 2 hours. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio)was obtained ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (120 mg, yield: 55%) as a colorless oily substance.

NMR (Dl3)δ: 1.23(3H, t, J=7.2 Hz), 2.58(2H, t, J=7.6 Hz), 2.98(2H, t, J=Hz), 4.12(2H, q, J=Hz), 7.38-7.58(6N, m).

Reference example 46

Alumoweld lithium (1,93 g) was added to Astor ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (15,00 g) in tetrahydrofuran (150 ml) at 0° C and the mixture was stirred at room temperature for one hour. In the reaction mixture was added decahydrate sodium sulfate (21,03 g) and hexane (100 ml) and the mixture was stirred at room temperature for one hour. Then the precipitate was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield [3-methyl-1-(2-pyridyl)-1H-pyrazole-4-yl]methanol (11,38 g). Their recrystallized from acetone-hexane. Melting point: 116-117°C.

Reference example 47

Sodium hydride (60%, in oil, of 0.80 g) was added to a solution of [3-methyl-1-(2-pyridyl)-1H-pyrazole-4-yl]methanol (3,20 g) in N,N-dimethylformamide (50 ml) at 0°and the mixture was stirred at room temperature for one hour. In the reaction mixture was added 4-forbindelse (2 ml) and the mixture was stirred over night at 50°C. the Reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained 4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzaldehyde (4.26 deaths g, yield: 86%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 84-85°C.

With Ilony example 48

Sodium borohydride (0.25 g) was added to a mixture of 4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzaldehyde (3.50 g), methanol (5 ml) and tetrahydrofuran (25 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was concentrated under reduced pressure, to the precipitate was added diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained 4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]-benzyl alcohol (3,41 g, yield: 97%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 83-84°C.

Reference example 49

Sodium hydride (60%in oil, 180 mg) was added to a mixture of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (1,00 g), benzyl 4-chloromethylbenzene (1,17 g) and N.N-dimethylformamide (10 ml) at 0°and the mixture was stirred for 2.5 days at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column with Seeley what aelem and from the faction, elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained benzyl 4-[4-(3-ethoxy-3-oxo-1-propyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoate (1.68 g, yield: 88%) as a colorless oily substance.

NMR (Dl3) δ: 1.18(3H, t, J=7.0 Hz), 2.53(2H, t, J=7.6 Hz), 2.96(2H, t, J=Hz), 4.07(2H, q, J=Hz), 5.35(4H, s), 7.25-7.46(11N, m), 7.60-7.66(2H, m), 8.02-8.07(2H, m).

Reference example 50

A mixture of benzyl 4-[4-(3-ethoxy-3-oxo-1-propyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoate (1,67 g), 5% palladium on coal (2.00 g) and ethanol (50 ml) was stirred for 5 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield 4-[4-(3-ethoxy-3-oxo-1-propyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoate (1.08 g, yield: 79%). Their recrystallized from ethyl acetate-hexane. Melting point: 97-98°C.

Reference example 51

Sodium hydride (60%in oil, 850 mg) was added to a mixture of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (4,69 g), benzyl 3-chloromethylbenzene (5.50 g) and N,N-dimethylformamide (50 ml) at 0°and the mixture was stirred for 2.5 days at room temperature. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography n is a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 5% palladium on coal (12.0 g) and ethanol (200 ml) was stirred for 5 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield 3-[4-(3-ethoxy-3-oxo-1-propyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoate (to 2.41 g, yield: 33%). Their recrystallized from ethyl acetate-hexane. Melting point: 101-102°C.

Reference example 52

Thionyl chloride (4.35 g) was added dropwise to a solution of (1-benzyl-5-phenyl-1H-pyrazole-4-yl)methanol (8.06 g) in toluene (100 ml) at 0°and the mixture was stirred at room temperature for one hour and then boiled under reflux for ten minutes. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8,31 g, yield: 96%) as a colorless oily the substances.

NMR (Dl3)δ: 4.44(2H, s), 5.23(2H, s), 6.99-7.04 (2H, m), 7.22-7.36 (5H, m), 7.42-7.47(3H, m), 7.72(1H, s).

Reference example 53

A mixture of 1-benzyl-4-chloromethyl-5-phenyl-1H-pyrazole (8,31 g), potassium cyanide (2,87 g) and N,N-dimethylformamide (100 ml) was stirred for 15 hours at 90°C, poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), received (1-benzyl-5-phenyl-1H-pyrazole-4-yl)acetonitrile (3.50 g, yield: 44%) as a colorless oily substance.

NMR (Dl3)δ: 3.45(2H, s), 5.21(2H, s), 6.97-7.02 (2H, m), 7.19-7.30 (5H, m), 7.43-7.50(3H, m), 7.67(1H, s).

Reference example 54

A mixture of (1-benzyl-5-phenyl-1H-pyrazole-4-yl)acetonitrile (3.50 g), 4 N. of an aqueous solution of potassium hydroxide (16 ml) and ethanol (50 ml) was boiled under reflux for 4 hours. The reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with etiracetam. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain (1-benzyl-5-phenyl-1H-pyrazole-4-yl)acetic acid (3,70 g, yield: 99%) as a colorless oily substance.

NMR (Dl3)δ: 3.42(2H, s), 5.22(2H, s) 6.97-7.02 (2H, m), 7.22-7.26 (5H, m), 7.40-7.44(3H, m), 7.65(1H, s).

Sslsocket example 55

A mixture of (1-benzyl-5-phenyl-1H-pyrazole-4-yl)acetic acid (3,70 g), concentrated sulfuric acid (0.5 ml) and ethanol (200 ml) was boiled under reflux for 5 hours. The reaction mixture was podslushivaet saturated aqueous sodium bicarbonate and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:6, volume ratio)was obtained ethyl (1-benzyl-5-phenyl-1H-pyrazole-4-yl)acetate (3,62 g, yield: 89%) as an oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7.2 Hz), 3.38(2H, s), 4.11(2H, q, J=Hz), 5.21(2H, s), 6. 98-7 .03 (2H, m), 7.21-7.28(5H, m), 7.37-7.44(3H, m), 7.63(1H, s).

Reference example 56

A mixture of ethyl (1-benzyl-5-phenyl-1H-pyrazole-4-yl)acetate (3,60 g), 5% palladium on coal (7,00 g), formic acid (40 ml) and ethanol (150 ml) was boiled under reflux for 2 hours. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain ethyl (3-phenyl-1H-pyrazole-4-yl)acetate (2,33 g, in the course: 90%) as a colorless oily substance.

NMR (Dl3)δ: 1.23(3H, t, J=7.2 Hz), 3.61(2H, s), 4.15(2H, q, J=1.2 Hz), 7.36-7.64(6N, m).

Reference example 57

A mixture of ethyl (1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazole-4-yl)acetate (800 mg), 5% palladium on coal (1.50 g), tetrahydrofuran (20 ml) and ethanol (30 ml) was stirred for 3 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl [1-[2-(4-hydroxyphenyl)ethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (400 mg, yield: 63%) as an oily substance.

NMR (Dl3)δ: 1.23(3H, t, J=Hz), 3.11(2H, t, J=7.2 Hz), 3.57(2H, s), 4.13(2H, q, J=7.0 Hz), 4.29(2H, t, J=7.2 Hz), 5.36(1H, user. s), 6.69-6.74(2H, m), 6.93-6.98(2H, m), 7.26-7.45(4H, m), 7.58-7.62(2H, m).

Reference example 58

Alumoweld lithium (323 mg) was added to a mixture of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carboxylate (3.55 g), diethyl ether (25 ml) and tetrahydrofuran (25 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into an aqueous solution of sodium hydroxide and was extracted with diethyl ether. A layer of diethyl ether was washed with water and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. Polucen the e crystals were filtered to obtain [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]methanol (2,93 g, yield: 92%). Their recrystallized from ethyl acetate-hexane. Melting point: 100-101°C.

Reference example 59

A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]methanol (2,82 g), activated manganese dioxide (6,00 g) and tetrahydrofuran (50 ml) was stirred at room temperature for 2 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carbaldehyde (2,63 g, yield: 94%) as a colorless oily substance.

NMR (Dl3)δ: 2.44(3H, s), 5.00(2H, s), 5.27(2H, s), 7.03(2H, d, J=8.8 Hz), 7.24(2H, d, J=8.8 Hz), 7.40-7.48(3H, m),7.97-8.04(3H, m), 9.82(1H, s).

Reference example 60

Sodium hydride 60%in oil, 880 mg, was added to a mixture of 3,5-dimethylpyrazole (2,11 g) and tetrahydrofuran (50 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was added 4-(4-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazol (6,28 g), the mixture was boiled under reflux for 24 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. the STATCOM was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole (5.49 g, yield: 74%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 86-87°C.

Reference example 61

A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (11,53 g), benzylbromide (18 ml), potassium carbonate (21,12 g) and N,N-dimethylformamide (300 ml) was stirred for 5 hours at 80°C. the Reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (13,52 g, yield: 95%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 71-72°C.

Reference example 62

Alumoweld lithium (6,64 g) was added to a solution of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-carboxylate (58,90 g) in tetrahydrofuran (500 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. Then the reaction mixture was poured into water and the precipitate was removed by filtration, the filtrate extra is Aravali with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya-acetic acid ethyl ester was obtained (1-benzyl-3-benzyloxy-1H-pyrazole-4-yl)methanol (45,30 g, yield: 88%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 79-80°C.

Reference example 63

A mixture of (1-benzyl-3-benzyloxy-1H-pyrazole-4-yl)methanol (14,70 g), activated manganese dioxide (30,00 g) and tetrahydrofuran (200 ml) was stirred at room temperature for 2 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (13,10 g, yield: 90%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 85-86°C.

Reference example 64

Sodium hydride 60%in oil, of 1.94 g, was added to a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12,90 g), ethyl diethylphosphonoacetate (9,60 ml) and N,N-dimethylformamide (200 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid and then saturated aqueous chlorine is Yes sodium, dried (MgSO4) and then concentrated. The obtained crystals were collected by filtration to yield ethyl (E)-3-(1-benzyl-3-benzyloxy-1H-pyrazole-4-yl)propenoate (14,50 g, yield: 91%). Their recrystallized from ethyl acetate-hexane. Melting point: 88-89°C.

Reference example 65

A mixture of ethyl (E)-3-(1-benzyl-3-benzyloxy-1H-pyrazole-4-yl)propenoate (14,30 g), 5% palladium on coal (28,00 g), ethanol (150 ml) and tetrahydrofuran (150 ml) was stirred at room temperature for 3 hours in hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazole-4-yl)propionate (9,01 g, yield: 83%). Their recrystallized from ethyl acetate-hexane. Melting point: 75-76°C.

Reference example 66

Sodium hydride 60%in oil, 1.28 g, was added to a solution of ethyl 3-(1-benzyl-3-hydroxy-1H-pyrazole-4-yl)propionate (8,78 g) in N, N-dimethylformamide (100 ml) at 0°and the mixture was stirred for 30 minutes. In the reaction mixture was added Iodate (2,82 ml) and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer washed with 1 N. hydrochloric acid and then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to x is matography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:5, volume ratio)was obtained ethyl 3-(1-benzyl-3-ethoxy-1H-pyrazole-4-yl)propionate (8,80 g, yield: 91%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.2 Hz), 1.37(3H, t, J=7.0 Hz), 2.48-2.55(2H, m), 2.62-2.70(2H, m), 4.09(2H, q, J=7.2 Hz), 4.22(2H, q, J=7.0 Hz), 5.07(2H, s), 6.96(1H, s), 7.13-7.18(2H, m), 7.26-7.37(3H, m).

Reference example 67

A mixture of ethyl 3-(1-benzyl-3-ethoxy-1H-pyrazole-4-yl)propionate (21,20 g), 5% palladium on coal (40,00 g), ethanol (200 ml) and formic acid (100 ml) was boiled under reflux for one hour. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (10,70 g, yield: 72%) as a colorless oily substance.

NMR (Dl3)δ: 1.24 (3H, t, J=7.2 Hz), 1.39 (3H, t, J=7.0 Hz), 2.51-2.59 (2H, m), 2.66-2.74 (2H, m), 4.12 (2H, q, J=7.2 Hz), 4.24 (2H, q, J=7.0 Hz), 7.18 (1H, s), 9.15 (1H, s).

Reference example 68

A mixture of ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazole-4-yl]propionate (5.32 g), 5% palladium on coal (3,45 g) and tetrahydrofur the Ana (100 ml) was stirred for 3 hours at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (of 3.56 g, yield: 86%) as a colorless oily substance.

NMR (Dl3)δ: 1.22 (3H, t, J=7.4 Hz), 1.35 (3H, t, J=7.4 Hz), 2.44-2.72 (4H, m), 4.03-4.29 (4H, m), 4.96(2H, s), 6.58-6.68(2H, m), 6.90-7.03(3H, m).

Reference example 69

Alumoweld lithium (1.52 g) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-carboxylate (11,00 g) in tetrahydrofuran (200 ml) at 0°and the mixture was stirred at room temperature for one hour. Then the reaction mixture was added water, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained crystals were collected by filtration to yield [1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-yl]methanol (7,11 g, yield: 70%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 128-129°C.

Reference example 70

A mixture of [1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-yl]methanol (6,84 g), activated manganese dioxide (14,00 g) and is of tetrahydrofuran (70 ml) was stirred at room temperature for one hour. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-carbaldehyde (6.50 g, yield: 95%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 138-139°C.

Reference example 71

A mixture of ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-yl]propenoate (6,61 g), 5% palladium on coal (13,00 g), ethanol (150 ml) and tetrahydrofuran (150 ml) was stirred for one hour at room temperature in hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration to yield ethyl 3-[1-(4-hydroxybenzyl)-3-hydroxy-1H-pyrazole-4-yl]propionate (2,98 g, yield: 89%). Their recrystallized from ethyl acetate-hexane. Melting point: 143-144°C.

Reference example 72

Sodium hydride (60%, in oil, of 2.40 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolidinone (9,46 g) in N,N-dimethylformamide (50 ml) at 0°and was stirred for 15 minutes. To the mixture was added a solution of methyl 2-chloro-4-pyridinecarboxylic (8,58 g) in tetrahydrofuran (50 ml). After stirring at room temperature for 1 hour, the reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous RA is tworoom sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain methyl 2-(5-methyl-2-phenyl-4-oxazolidinone)-4-pyridinecarboxylic (2190 mg, yield 14%) as colorless crystals from the fraction, buervenich with ethyl acetate-hexane (1:3, volume ratio). Their recrystallized from ethyl acetate-hexane. Melting point: 106-107°C.

Reference example 73

Alumoweld lithium (228 mg) was added to a solution of methyl 2-(5-methyl-2-phenyl-4-oxazolidinone)-4-pyridinecarboxylic (1,95 g) in tetrahydrofuran (20 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (1,93 g) and stirred at room temperature for 30 minutes. The precipitate was removed by filtration, the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain 2-(5-methyl-2-phenyl-4-oxazolidinone)-4-pyridinemethanol (1,37 g, yield 77%). Their recrystallized from ethyl acetate-hexane. Melting point: 100-101°C.

Reference example 74

A mixture of 2-(5-methyl-2-phenyl-4-oxazolidinone)-4-pyridinemethanol (1.19 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was concentrated, the mixture was added saturated aqueous sodium bicarbonate solution and was extracted with ethylacetate is. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (680 mg, yield 54%) as colorless crystals from the fraction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio). Their recrystallized from ethyl acetate-hexane. Melting point: 104-105°C.

Reference example 75

A mixture of methyl 5-hydroxy-3-pyridinecarboxylic (9,84 g), 4-chloromethyl-5-methyl-2-phenyloxazole (13,40 g), potassium carbonate (8.90 g) and N,N-dimethylformamide (100 ml) was stirred at 80°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), methyl 5-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridinecarboxylic (12,42 g, yield 59%) as pale yellow crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 119-120°C.

Reference example 76

Alumoweld lithium (1,02 g) was added to a solution of methyl 5-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridinecarboxylic (10,70 g) tet is hydrofuran (100 ml) at 0° C and was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (8,93 g) and stirred at room temperature for 30 minutes. The precipitate was removed by filtration and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain 5-(5-methyl-2 phenyl-4-oxazolidinone)-3-pyridinemethanol (8,93 g, yield 91%). Their recrystallized from ethyl acetate-hexane. Melting point: 111-112°C.

Reference example 77

A mixture of 5-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridinemethanol (1,33 g) and thionyl chloride (4 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was concentrated, the mixture was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with tetrahydrofuran-hexane (1:1, volume ratio), 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolidinone) pyridine (911 mg, yield 64%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 98-99°C.

Reference example 78

Sodium borohydride (0,378 g) was added to a mixture of 4-methoxy-3-(5-methyl-2-phenyl-4-is catholicmatch)benzaldehyde (3,23 g), tetrahydrofuran (15 ml) and methanol (15 ml) at room temperature and was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried with anhydrous sulfate Magina and concentrated to obtain crystals of 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl alcohol. Their recrystallized from tetrahydrofuran-hexane to obtain pale yellow plate crystals (3,22 g, 99%). Melting point: 144-145°C.

Reference example 79

A mixture of 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl alcohol (3,22 g), thionyl chloride (0,73 ml) and toluene (50 ml) was boiled under reflux for 1 hour. Then the reaction mixture was concentrated, added to a mixture of saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain 4-(5-chloromethyl-2-methoxyphenoxy)-5-methyl-2-phenyloxazole (2,59 g, 75%yield) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 129-130°C.

Reference example 80

Sodium borohydride (378 mg) slowly obavljale in a mixture of 3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzaldehyde (3,37 g), tetrahydrofuran (50 ml) and methanol (50 ml) at room temperature and was stirred for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 3-ethoxy-4- (5-methyl-2-phenyl-4-oxazolidinone)-benzyl alcohol (3.28 g, yield 97%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 130-131°C.

Reference example 81

Thionyl chloride (0,73 ml) was slowly added to a mixture of 3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl alcohol (3,05 g), tetrahydrofuran (25 ml) and toluene (50 ml) at room temperature and was stirred at 80°C for 30 minutes. After cooling, the reaction mixture was poured into aqueous saturated sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, dried (MgSO4) and concentrated to obtain 4-(4-chloromethyl-2-ethoxyphenoxy)-5-methyl-2-phenyloxazole (2,94 g, yield 91%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 138-139°C.

Reference example 82

Sodium hydride (60%in oil, 1.40 g) was added to a solution of methyl 3-hydroxyethoxy-5-carboxylate (5,01 g) in N,N-dime Informatica (70 ml) at 0° C and was stirred for 15 minutes. To the mixture was added 4-chloromethyl-5-methyl-2-phenyloxazol (7,26 g). After stirring at 60°C for 2 hours, the reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain methyl 3-(5-methyl-2-phenyl-4-oxazolidinone)-5-isoxazolecarboxylic (of 7.96 g, yield 72%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 123-124°C.

Reference example 83

Diisobutylaluminum (1.0 M solution in tetrahydrofuran, 60 ml) was slowly added to a solution of methyl 3-(5-methyl-2-phenyl-4-oxazolidinone)-5-isooxazolyl (7,86 g) in tetrahydrofuran (150 ml) at 0°and was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 3-(5-methyl-2-phenyl-4-oxazolidinone)-5-isoxazolidinone (5,93 g, yield 86%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 99-100°C.

Reference example 84

Thionylchloride the (0,80 ml) was slowly added to a solution of 3-(5-methyl-2-phenyl-4-oxazolidinone)-5-isooxazolyl (2.86 g) in toluene (50 ml) at room temperature and was stirred for 30 minutes while boiling under reflux. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolidinone)-isoxazol (2.70 g, yield 89%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 105-106°C.

Reference example 85

Sodium borohydride (620 mg) was added to a mixture of 4-[2-[1-oxo-2(1H)-Paladini]ethoxy]benzaldehyde (4,90 g), methanol (20 ml) and tetrahydrofuran (20 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added diluted hydrochloric acid and the obtained colorless crystals were collected by filtration to obtain 4-[2-[1-oxo-2-(1H)-Paladini]ethoxy]benzyl alcohol (4,53 g, yield 92%). Their recrystallized from acetone-hexane. Melting point: 142-143°C.

Reference example 86

Sodium borohydride (600 mg) was added to a mixture of 3-[2-[1-oxo-2(1H)-Paladini]ethoxy]benzaldehyde (5,00 g), methanol (30 ml) and tetrahydrofuran (30 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added diluted hydrochloric acid and the obtained colorless crystals were collected by filtration to obtain 3-[2-[1-oxo-2(1H)-taladine]ethoxy]benzyl alcohol (4,80 g, yield 95%). Their recrystallized from ethyl acetate-hexane. Melting point: 133-134°C.

Reference example 87

Thionyl chloride (1 ml) was slowly added to a solution of 4-[2-[1-oxo-2(1H)Paladini]ethoxy]benzyl alcohol (3.80 g) in toluene (40 ml) at room temperature and was stirred at 90°C for 30 minutes. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated to obtain 2-[2-(4-chloromethylene)ethyl]-1(2H)-phthalazinone (3,62 g, yield 95%) as a colorless oily substance.

NMR (Dl3)δ: 4.37-4.47(2H, m), 4.54(2H, s), 4.60-4.70(2H, m), 6.86-6.96(2H, m), 7.24-7.34(2H, m), 7.66-7.86(3H, m), 8.19(1H, s), 8.40-8.48(1H, m).

Reference example 88

Thionyl chloride (1.3 ml) was slowly added to a solution of 3-[2-[1-oxo-2(1H)-Paladini]ethoxy]benzyl alcohol (4.59 g) in toluene (30 ml) at room temperature and was stirred at 90°C for 30 minutes. After cooling, the reaction mixture was poured into saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 2-[2-(3-chloromethylene)ethyl]-1(2H)-phthalazinone (4,39 g, yield 95%) as a colourless what about the oily substance.

NMR (Dl3)δ: 4.40-4.48(2H, m), 4.51(2H, s), 4.62-4.70(2H, m), 6.84-7.00(3H, m), 7.18-7.26(1H, m), 7.64-7.88(3H, m), 8.19(1H, s), 8.40-8.50(1H, m).

Reference example 89

Sodium hydride (60%, in oil, of 1.80 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolidinone (8,51 g) in tetrahydrofuran (100 ml) at 0°and was stirred at room temperature for 15 minutes. A solution of methyl 6-chloro-2-pyridinecarboxylic (7,72 g) in tetrahydrofuran (75 ml) was added to the mixture. After stirring at 40°C for 5 hours, the reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain methyl 6-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridinecarboxylic (7,41 g, 51%yield) as yellow crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 97-98°C.

Reference example 90

Alumoweld lithium (759 mg) was added to a solution of methyl 6-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridinecarboxylic (of 6.49 g) in tetrahydrofuran (60 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (6,44 g) and stirred at room temperature for 30 minutes. The residue was removed by filtration and the filtrate was concentrated. The mixture of residue and thionyl chloride (20 ml) was stirred at whom atoi temperature for 1 hour. The reaction mixture was concentrated, added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain 2-chloromethyl-6-(5-methyl-2-phenyl-4-oxazolidinone)-pyridine (2,74 g, yield 44%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 85-86°C.

Reference example 91

Alumoweld lithium (2,43 g) was added to a solution of methyl 6-phenyl-3-pyridinecarboxylic (14,00 g) in tetrahydrofuran (200 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (22,50 g) and stirred at room temperature for 30 minutes. The precipitate was removed by filtration and the filtrate was concentrated to obtain 6-phenyl-3-pyridinemethanol (11,63 g, yield 96%) as a pale yellow oily substance.

NMR (Dl3)δ: 1.91(1H, users), 4.78(2H, d, J=5.6 Hz), 7.34-7.54(3H, m), 7.70-7.84(2H, m), 7.93-8.04(2H, m), 8.64-8.71(1H, m).

Reference example 92

Thionyl chloride (10 ml) was slowly added to a solution of 6-phenyl-3-pyridinemethanol (11,60 g) in toluene (100 ml) at room temperature and was stirred at 100°C for 1 hour. After cooling, the reaction mixture was pouring out and into saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 5-chloromethyl-2-phenylpyridine (11,49 g, yield 89%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 95-96°C.

Reference example 93

Sodium hydride 60%in oil, 2,88 g, was added to a mixture of 2-(2-furyl)-5-methyl-4-oxazolidinone (10,80 g), methyl 2-chloro-4-pyridinecarboxylic (10.30 g), tetrahydrofuran (100 ml) and N,N-dimethylformamide (100 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 2-[2-(2-furyl)-5-methyl-4-oxazolidinone]-4-pyridinecarboxylic (2.86 g, yield 15%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 80-81°C.

Reference example 94

Alumoweld lithium (304 mg) was added to a solution of ethyl 2-[2-(2-furyl)-5-methyl-4-oxazolidinone]-4-pyridinecarboxylic (2,63 g) in tetrahydrofuran (30 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (2.58 g) ipermediali at room temperature for 30 minutes. The precipitate was removed by filtration and the filtrate was concentrated. A mixture of the residue, thionyl chloride (10 ml) and toluene (5 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was concentrated, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), 4-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]pyridine (1020 mg, yield 42%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 107-108°C.

Reference example 95

Sodium hydride 60%in oil, 2.00 g, was added to a mixture of 5-chloroimidazo[1,2-a]pyridine-2-ylmethanol (8,77 g), methyl 2-chloro-4-pyridinecarboxylic (8,24 g) and N,N-dimethylformamide (150 ml) at 0°and the mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya by tetrahydrofuran, methyl-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridinecarboxylic (2,78 g, yield 18%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 157-158°C.

Reference example 96

Diisobutylaluminum (1.0 M solution in tetrahydrofuran, 30 ml) was added to a solution of methyl 2-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridinecarboxylic (of 3.97 g) in tetrahydrofuran (150 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (12.2 g) and stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain 2-(5-chloroimidazo[1,2-a] pyridine-2-ylethoxy)-4-pyridinemethanol (3.12 g, yield 86%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 143-144°C.

Reference example 97

A mixture of 2-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridinemethanol (2,90 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was concentrated, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with receiving from FR the functions, elyuirovaniya a tetrahydrofuran (THF), 5-chloro-2-(4-chloromethyl-2-pyridyloxy)imidazo[1,2A]pyridine (2,63 g, yield 85%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 118-119°C.

Reference example 98

Sodium hydride 60%in oil, 2,88 g, was added to a solution of methyl 5-hydroxy-3-pyridinecarboxylic (10,00 g) and N-phenyltrichlorosilane (24,00 g) in tetrahydrofuran (200 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio), methyl 5-tripterocalyx-3-pyridinecarboxylic (18,06 g, yield 97%) as a colorless oily substance.

NMR (Dl3)δ: 4.01 (3H, s), 8.23(1H, DD, J=1.4, 2.6 Hz), 8.77(1H, d, J=2.6 Hz), 9.26(1H, d, J=1.4 Hz).

Reference example 99

A mixture of methyl 5-tripterocalyx-3-pyridinecarboxylic (18,00 g), phenylboronic acid (7,88 g), tetrakis(triphenylphosphine)palladium (3,01 g), sodium carbonate (13,51 g), ethanol (80 ml), water (80 ml) and toluene (500 ml) was boiled OBR is Tim fridge overnight in an argon atmosphere. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 5-phenyl-3-pyridinecarboxylic (8,63 g, yield 60%) as a colorless oily substance from the fraction, elyuirovaniya with ethyl acetate.

NMR (Dl3)δ: 1.44(3H, t, J=6.8 Hz), 4.46(2H, q, J=6.8 Hz), 7.42-7.70(5H, m), 8.44-8.56(1H, m), 9.00(1H, d, J=2.2 Hz), 9.20(1H, d, J=1.8 Hz).

Reference example 100

Alumoweld lithium (1.45 g) was added to a solution of ethyl 5-phenyl-3-pyridinecarboxylic (at 8.60 g) in tetrahydrofuran (100 ml) at 0°and was stirred at room temperature for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (13,40 g) and stirred at room temperature for 30 minutes. The precipitate was removed by filtration and the filtrate was concentrated. The obtained colorless crystals were collected by filtration to obtain 5-phenyl-3-pyridinemethanol (4,82 g, yield 69%). Their recrystallized from ethyl acetate-hexane. Melting point: 71-72°C.

Reference example 101

A mixture of 5-phenyl-3-pyridinemethanol (4,50 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hour. Then the reaction mixture was concentrated, the mixture was added saturated aqueous solution of bicarbonate of soda which I and were extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya-tetrahydrofuran, 3-chloromethyl-5-phenylpyridine (4,28 g, yield 86%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 75-76°C.

Reference example 102

A mixture of methyl 3-hydroxyethoxy-5-carboxylate (5,01 g)of the hydrochloride of 2-chloromethylpyridine (8,99 g), potassium carbonate (14,50 g) and N,N-dimethylformamide (100 ml) was stirred at 60°C for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain methyl 3-(2-chinaillon)-5-isoxazolecarboxylic (7.78 g, yield 78%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 133-134°C.

Reference example 103

Diisobutylaluminum (1.0 M solution of tetrahydrofuran, 60 ml) was slowly added to a solution of methyl 3- (2-chinaillon)-5-isoxazolecarboxylic (7,39 g) in tetrahydrofuran (150 ml) at 0°and was stirred at room temperature for 30 minutes. The reaction mixture is alibali in diluted Solano acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 3-(2-chinaillon)-5-isoxazolidinone (4,95 g, yield 74%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 111-112°C.

Reference example 104

A mixture of 3-(2-chinaillon)-5-isoxazolidinone (1.54 g) and thionyl chloride (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 2-(5-chloromethyl-3-isoxazolidinone)quinoline (1,61 g, yield 98%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 126-127°C.

Reference example 105

Tert-butyl lithium (1.7 M solution of pentane, 15 ml) was slowly added to a solution of 5-chloro-2-phenylpyridine (4,70 g) in tetrahydrofuran (50 ml) at -78°C in nitrogen atmosphere and was stirred for 1 hour. While the temperature was raised to room temperature, the mixture was slowly added N,N-dimethylformamide (2.3 ml) and was stirred for 1 hour. After adding diluted hydrochloric is islote the mixture was stirred at room temperature for 30 minutes. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. In the mixture of residual tetrahydrofuran (50 ml) and methanol (50 ml) was slowly added sodium borohydride (946 mg)at room temperature and was stirred for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:6, volume ratio), 3-chloro-6-phenyl-2-pyridinemethanol (2.35 g, yield 43%) as light yellow crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 69-70°C.

Schlocky example 106

A mixture of 3-chloro-6-phenyl-2-pyridinemethanol (2.20 g), 5% palladium on coal (1.10 g), triethylamine (1.4 ml), methanol (20 ml) and tetrahydrofuran (20 ml) was stirred at room temperature in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:5, volume ratio), 6-phenyl-2-is iriternational (1,76 g, yield 95%) as a colorless oily substance.

NMR (Dl3)δ: 4.20(1H, t, J=3.8 Hz), 4.82(2H, d, J=3.8 Hz), 7.16(1H, DD, J=0.8, 7.6 Hz), 7.38-7.54(3H, m), 7.64(1H, DD, J=0.8, 7.6 Hz), 7.76(1H, t, J=7.6 Hz), 7.99-8.05(2H, m).

Reference example 107

A mixture of 3-chloro-6-phenyl-2-pyridinemethanol (2.20 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 3-chloro-2-chloromethyl-5-phenylpyridine (2.25 g, yield 94%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 74-75°C.

Reference example 108

A mixture of 6-phenyl-2-pyridinemethanol (1,76 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:5, about the lending ratio), 2-chloromethyl-5-phenylpyridine (1,91 g, yield 99%) as a colorless oily substance.

NMR (Dl3)δ: 4.75(2H, s), 7.36-7.52 (4H, m), 7.64(1H, DD, J=1.0, 7.6 Hz), 7.77(1H, t, J=7.6 Hz), 7.96-8.02(2H, m).

Reference example 109

Sodium hydride (60%in oil, 1.40 g) was added to a solution of 2-phenyl-4-triazolylmethyl (6,69 g) and methyl 6-chloro-3-pyridinecarboxylic (6,01 g) in N,N-dimethylformamide (100 ml) at 0°and the mixture was stirred for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. Into a solution of the residue in tetrahydrofuran (150 ml) was added alumoweld lithium (1,33 g) at 0°and was stirred at room temperature for 10 minutes. In the reaction mixture was added decahydrate sodium sulfate (11.3 g) and was stirred for 30 minutes at room temperature. The precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya by tetrahydrofuran, 6-(2-phenyl-4-thiazoleacetate)-3-pyridinemethanol (of 5.81 g, yield 56%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 134-135°C.

Reference example 110

Sodium hydride 60%in oil, 1,58 g, was added to a solution of 2-kinalimutan (6,29 g) and met the l 6-chloro-3-pyridinecarboxylic (of 6.78 g) in N,N-dimethylformamide (100 ml) at 0° C and the mixture was stirred for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. Alumoweld lithium (1.50 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0°and was stirred at room temperature for 10 minutes. In the reaction mixture was added decahydrate sodium sulfate (12.7 g) and stirred at room temperature for 1 hour. The precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate. Their recrystallized from ethyl acetate-hexane, 2-(2-chinaillon)-5-pyridinemethanol (5.31g, yield 50%) as colorless crystals. Melting point: 124-125°C.

Reference example 111

A mixture of 6-(2-chinaillon)-3-pyridinemethanol (2.66 g) and thionyl chloride (10 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with the floor is the group of fractions, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), 2-(5-chloromethyl-2-pyridyloxy)quinoline (2.50 g, yield 88%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 118-119°C.

Reference example 112

A mixture of 6-(2-phenyl-4-thiazoleacetate)-3-pyridinemethanol (2,98 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya-ethyl acetate, 5-chloromethyl-2-(2-phenyl-4-thiazoleacetate)pyridine (2,40 g, yield 76%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 117-118°C.

Reference example 113

A mixture of 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylmethanol (3.00 g), thionyl chloride (2.5 ml) and toluene (50 ml) was stirred at 70°C for 2 hours. The reaction mixture was concentrated under reduced pressure, to the precipitate was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated is one solution of sodium chloride, dried (gSO4) and concentrated to obtain 4-chloromethyl-3-methyl-1-(2-pyridyl)-1H-pyrazole (3,10 g, yield 94%) as a colorless oily substance.

NMR (Dl3)δ: 2.44(3H, s), 4.58(2H, s), 7.46-7.60(1H, m), 8.18-8.42(2H, m), 8.50-8.60(1H, m), 9.43(1H, s).

Reference example 114

A mixture of 2-methyl-5-(5-methyl-2-phenyl-4-oxazolidinone)-pyridine (18,04 g), 3-chloroperbenzoic acid (18,85 g) and tetrahydrofuran (100 ml) was stirred at room temperature overnight and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya a tetrahydrofuran, a colorless oily substance. A solution of the obtained colorless oily substance in acetic anhydride (100 ml) was slowly added acetic anhydride (200 ml)was heated at 130°C, stirred for 2 hours and concentrated. The residue was dissolved in ethyl acetate and washed in a saturated aqueous solution of sodium bicarbonate, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), [5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]acetate (18,09 g, yield 83%) as a colorless oily substance.

NMR (Dl3)δ: 2.13(3H, s), 2.45(3H, s), 5.05(2H, s) 5.16 (2H, s), 7.26-7.50(5H, m), 7.94-8.05(2H, m), 8.38-8.43(1H, m).

Reference example 115

A mixture of [5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]acetate and (18,00 g), 1 N. aqueous sodium hydroxide solution (75 ml) and methanol (100 ml) was stirred at room temperature for 3 hours and concentrated. The residue was dissolved in ethyl acetate and washed with water, saturated aqueous sodium chloride. The organic layer was dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridinemethanol (14,29 g, yield 91%). Their recrystallized from ethyl acetate-hexane. Melting point: 125-126°C.

Reference example 116

Sodium borohydride (835 mg), was added to a solution of 6-(5-methyl-2-phenyl-4-oxazolidinone)nicotinanilide (13,0 g) in tetrahydrofuran (150 ml)/methanol (10 ml) at 0°C. After stirring for 30 minutes the reaction mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated to obtain crystals of 6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridinemethanol. Their recrystallized from acetone-isopropyl ether to obtain colorless prismatic crystals (12.4 g, yield 95%). Melting point: 121-122°C.

Reference example 117

Tianello the ID (5,39 g) was added to a mixture of 6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridinemethanol (12.2 g) and toluene (200 ml) and stirred at room temperature for 1 hour. In the reaction mixture were added ice water and neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (11.7 g, yield 90%) as colorless crystals. Their recrystallized from ethyl acetate-hexane to obtain colorless prismatic crystals. Melting point: 86-87°C.

Reference example 118

Sodium borohydride (410 mg) was added to a mixture of 6-[2-(2-furyl)-5-methyl-4-oxazolidinone]nicotinanilide (3,10 g), tetrahydrofuran (50 ml) and ethanol (50 ml) at room temperature and was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated to obtain 6-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-pyridinemethanol (2.86 g, yield 92%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 120-121°C.

Reference example 119

A mixture of 6-[2-(2-furyl)-5-methyl-4-o is catholicmatch]-3-pyridinemethanol (1,87 g) and thionyl chloride (15 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolidinone]pyridine (1,41 g, 71%yield) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 95-96°C.

Reference example 120

Alumoweld lithium (1,33 g) was added to a solution of ethyl 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-carboxylate (15.1 g) in tetrahydrofuran (300 ml) at 0°and was stirred at room temperature for 1 hour. In the reaction mixture was added decahydrate sodium sulfate (of 12.26 g) and hexane (100 ml) and stirred at room temperature for 1 hour. Then the precipitate was removed by filtration, the filtrate was concentrated to obtain 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-ylmethanol (12.9 g, yield 95%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 112-113°C.

Reference example 121

A mixture of 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl) - Rev. ethanol (11,7 g), activated manganese dioxide (20,0 g) and tetrahydrofuran (150 ml) was stirred at room temperature for 2 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-carbaldehyde (10,9 g, yield 94%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 97-98°C.

Reference example 122

A mixture of 5-hydroxy-2-methylpyridine (8,46 g), 4-chloromethyl-5-methyl-2-phenyloxazole (15,20 g), potassium carbonate (15,98 g) and N,N-dimethylformamide (200 ml) was stirred at 80°C for 3 hours, poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with tetrahydrofuran-hexane (1:1, volume ratio), 2-methyl-5-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (19,68 g, yield 96%) as light yellow crystals. Their recrystallized from acetone-hexane. Melting point: 103-104°C.

Reference example 123

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (2,02 g), 1,2-dibromethane (20 ml), potassium carbonate (1.68 g) and N,N-dimethylformamide (20 ml) was stirred at 90°C for 24 hours. The reaction mixture howled the Wali in the water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio), ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (1530 mg, yield 58%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.0 Hz), 2.46-2.58(2H, m), 2.88-3.00(2H, m), 3.59-3.70(2H, m), 4.08(2H, q, J=7.0 Hz), 4.24-4.35(2H, m), 5.24(2H, s), 6.84-6.94(2H, m), 7.16-7.52(6N, m), 7.58-7.68(2H, m).

Reference example 124

A solution of p-toluensulfonate (12.3 g) in dimethoxyethane (60 ml) was added to a mixture of tert-butoxide potassium (13.5 g) and dimethoxyethane (60 ml) at -78°and the resulting product was stirred for 5 minutes. To the mixture was added a solution of 1-benzyl-5-phenyl-1H-pyrazole-4-carbaldehyde (13,0 g) dimethoxyethane (60 ml). After stirring at the same temerature within 1 hour, the mixture was stirred 1, increasing the temperature. To the mixture was added methanol (180 ml) and boiled under reflux for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatographia column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), a colorless oily substance. A mixture of the obtained colorless oily substance, 4 N. aqueous sodium hydroxide solution (100 ml), tetrahydrofuran (100 ml) and ethanol (100 ml) was boiled under reflux for 3 days. After cooling, the mixture was neutralized with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. A mixture of the residue, ethyl iodide (6.5 ml), potassium carbonate (14.9 g) and N,N-dimethylformamide (150 ml) was stirred at room temperature for 3 hours, the Reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), a colorless oily substance. A mixture of the obtained oily substance, 5% palladium on coal (30.0 g), formic acid (80 ml) and ethanol (160 ml) was boiled under reflux for 1 hour. After cooling palladium on coal was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with saturated waters is the first sodium bicarbonate solution, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-phenyl-1H-pyrazole-4-ilaclama (4,65 g, yield 34%) as a colorless oily substance.

NMR (Dl3)δ: 1.23(3H, t, J=Hz), 3.61(2H, s), 4.14(2H, q, J=7.0 Hz), 7.32-7.47(3H, m), 7.51-7.59(3H, m), 11.38(1H, user. C).

Reference example 125

Alumoweld lithium (300 mg) was sequentially added to a solution of ethyl 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carboxylate (1.56 g) in tetrahydrofuran (70 ml) at 0°and was stirred for 2 hours. In the reaction mixture was added decahydrate sodium sulfate (3,40 g) and the precipitate was filtered. The filtrate was concentrated and the residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya acetone-hexane (2:3, volume ratio), 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-ylmethanol (1.27 g, yield 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.60(1H, t, J=Hz), 2.48(3H, s), 4.68(2H, d, J=5.5 Hz), 5.26(2H, s), 5.30(2H, s), 6.82(1H, d, J=8.5 Hz), 7.25-7.5 (7H, m), 7.56(1H, DD, J=8.5, 2 Hz), 7.7-7.8(2H, m), 7.95-8.05(1H, m,), 8.15(1H, d, J=2 Hz).

Reference example 126

A mixture of 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyrid metil]-3-phenyl-1H-pyrazole-4-ylmethanol (1,25 d), activated manganese dioxide (3.00 g) and ethyl acetate (80 ml) was stirred at room temperature for 3 hours. Then manganese dioxide was separated by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carbaldehyde (1.20 g, yield 96%) as a colorless oily substance.

NMR (Dl3)δ: 2.48(3H, s), 5.30(2H, s), 5.31(2H, s), 6.85(1H, d, J=8.5 Hz), 7.4-7.6(7H, m), 7.59(1H, DD, J=8.5, 2.5 Hz), 7.65-7.8(2H, m), 7.97(1H, s), 8.0-8.05(2H, m), 8.21(1H, d, J=2 Hz), 9.93(1H, s).

Reference example 127

A solution of p-toluensulfonate (is 3.08 g) in dimethoxyethane (15 ml) was added to a mixture of tert-butoxide potassium (3,37 g) and dimethoxyethane (15 ml) at -78°and the resulting product was stirred for 5 minutes. To the mixture was added a solution of 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-carbaldehyde (5,80 g) dimethoxyethane (30 ml). After stirring at the same temperature and the mixture was stirred for 1 hour, increasing the temperature. To the mixture was added methanol (45 ml) and boiled under reflux for 1 hour. After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. An ethyl acetate layer industry is Ali saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-ylacetonitrile (4.52 g, yield 76%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 86-87°C.

Reference example 128

A mixture of ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (21,50 g), 5% palladium on coal (10,43 g) and tetrahydrofuran (300 ml) was stirred overnight in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated to obtain ethyl 3 hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (13,35 g, yield 96%) as colorless crystals. Their recrystallized from acetone-hexane. Melting point: 117-118°C.

Reference example 129

Alumoweld lithium (205 mg) was sequentially added into a solution of methyl 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenylpyrrole-3-carboxylate (1.30 grams) in tetrahydrofuran (40 ml) at 0°and the resulting product was stirred for 3 hours. In the reaction mixture was added decahydrate sodium sulfate (2,80 g) and the precipitate was removed by filtration. The filtrate was concentrated and the residue was subjected to chromatography on a column of silica gel with getting of f the shares, elyuirovaniya with ethyl acetate-hexane (3:2, volume ratio), [1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]methanol (1,15 g, yield 94%) as a colorless oily substance.

NMR (Dl3)δ: 2.48(3H, s), 4.63(2H, users), 4.98(2H, s), 5.30 (2H, s), 6.7-6.85(2H, m), 7.2-7.55(10H, m), 7.95-8.1 (3H, m).

Reference example 130

A mixture of [1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]methanol (1,15 g), activated manganese dioxide (2.30 g) and ethyl acetate (80 ml) was stirred at room temperature for 2 hours. Then the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenylpyrrole-carbaldehyde (1.06 g, yield 93%) as a colorless oily substance.

NMR (Dl3)δ: 2.48(3H, s), 5.04(2H, s), 5.31(2H, s), 6.75 (1H,d, J=2 Hz), 6.84(1H, d, J=8.5 Hz), 7.25-7.5 (10H, m), 7.95-8.15(3H, m), 9.86(1H, s).

Reference example 131

A mixture of ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propenoate (12,13 g), 5% palladium on coal (10,22 g) and tetrahydrofuran (100 ml) was stirred for 5 hours in an atmosphere of hydrogen. Then palladium on coal was removed by filtration, the filtrate was concentrated to obtain ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (9,52 g, yield 98%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=Hz),2.48-2.58(2H, m), is 2.88-3.00(2H, m), 4.08(2H, q, J=7.2 Hz), 5.19(2H, s), 6.62-6.74(2H, m), 6.98-7.10(2H, m), 7.18-7.45(4H, m), 7.56-7.66(2H, m).

Reference example 132

A mixture of ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl]propenoate (10.0 g), 5% palladium on coal (20,0 g), ethanol (100 ml) and tetrahydrofuran (100 ml) was stirred for 1 hour in a hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated to obtain ethyl 3-[3-(4-forfinal)-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]-propionate (7,15 g, yield 88%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.6 Hz), 2,90(2H, t, J=7.6 Hz), 4.08(2H, q, J=7.2 Hz), 5.15(2H, s), 6.57(2H, d, J=8.4 Hz), 6.97(2H, d, J=8.4 Hz), 7.07(2H, t, J=8.8 Hz), 7.24(1H, s), 7.56(2H, DD, J=5.4, 8.8 Hz), 7.59(1H, s).

Reference example 133

A mixture of 5-phenyl-2-pyridylmethylamine (3,68 g), 1 N. aqueous sodium hydroxide solution (30 ml), tetrahydrofuran (30 ml) and methanol (300 ml) was stirred at room temperature for 3 hours and concentrated. The residue was dissolved in ethyl acetate, and then the solution was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The remainder in the form of colorless crystals were collected by filtration to obtain 5-phenyl-2-pyridinemethanol (2,84 g, yield 95%). Their recrystallized from ethyl acetate-hexane. Melting point: 86-87°C.

Reference example 134

A mixture of 5-phenyl-2-pyrid is methanol (1.98 g), thionyl chloride (1.6 ml) and toluene (30 ml) was stirred at 70°C for 2 hours. After the reaction mixture was concentrated, to the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. A mixture of the residue, 4-hydroxybenzoato alcohol (1,37 g), potassium carbonate (3,18 g) and N,N-dimethylformamide (50 ml) was stirred at 80°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), 4-(5-phenyl-2-pyridyloxy)benzyl alcohol (2,69 g, yield 86%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 159-160°C.

Reference example 135

Sodium borohydride (0.36 g) was added to a mixture of 4-(2-phenyl-4-oxazolidinone)benzaldehyde (2.65 g) and methanol (50 ml) under cooling with ice and stirred at room temperature for 1 hour. In the reaction mixture was added diluted hydrochloric acid and ice water, extracted with ethyl acetate. An ethyl acetate layer washed is whether saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 4-(2-phenyl-4-oxazolidinone)benzyl alcohol (2,43 g, yield 91%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 141-142°C.

Reference example 136

A mixture of 4-(2-phenyl-4-oxazolidinone)benzyl alcohol (2,39 g), thionyl chloride (0,69 ml) and toluene (50 ml) was stirred at 40°C overnight and then the reaction mixture was concentrated. To the residue was added saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), 4-(4-chloromethylphenoxyacetic)-2-phenyloxazole (2,34 g, yield 92%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 129-130°C.

Reference example 137

Alumoweld lithium (320 mg) was sequentially added into a solution of methyl 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (of 4.00 g) in tetrahydrofuran (30 ml) at 0°and was stirred for 2 hours. In the reaction mixture was added dehydrate sodium sulfate (2,95 g) and the precipitate was separated by filtration. The filtrate conc is listed and the residue was subjected to chromatography on a column of silica gel to obtain [3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]methanol (3,56 g, yield 97%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 103-104°C.

Reference example 138

A mixture of [3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]methanol (2.85 g), activated manganese dioxide (8,42 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight. Then manganese dioxide was separated by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbaldehyde (2,61 g, yield 92%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 129-130°C.

Reference example 139

A mixture of 4-(2-bromoethoxy)benzaldehyde (equal to 4.97 g), 1(2H)-phthalazinone (3,27 g), potassium carbonate (6.20 g) and N,N-dimethylformamide (50 ml) was stirred at 80°C for 5 hours. After cooling, the reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 4-[2-[1-oxo-2-(1H)-phthalazine]ethoxy]benzaldehyde (are 5.36 g, yield 84%) as colorless crystals. Their recrystallized from ethyl acetate-hexane melting Point: 126-127° C.

Reference example 140

A mixture of 3-(2-bromoethoxy)benzaldehyde (6,00 g), 1(2H)-phthalazinone (4,21 g), potassium carbonate (7,24 g) and N,N-dimethylformamide (40 ml) was stirred at 80°C for 5 hours. After cooling, the reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 3-[2-[1-oxo-2(1H)-phthalazine]ethoxy]benzaldehyde (6,94 g, yield 90%) as colorless crystals. Their recrystallized from acetone-hexane. Melting point: 110-111°C.

Reference example 141

A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (to 7.59 g), 2-chloropyridine (5 ml), sodium hydride (60%in oil, 2,32 g) and N,N-dimethylformamide (150 ml) was stirred at 180°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:9, volume ratio), ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (8,31 g, yield 73%). This substance was recrystallized from ethyl acetate-hexane. Melting point: 79-80°C.

Reference example 142

Sodium borohydride (0.45 g) was added to a mixture of 4-(2-phenyl-thiazoleacetate)benzaldehyde (6,35 g), tetrahydrofuran (30 ml) and methanol (20 ml) under cooling with ice and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with diluted hydrochloric acid and water to form a precipitate, which was collected by filtration and then dried with air to obtain crystals of 4-(2-phenyl-4-thiazoleacetate)benzyl alcohol (USD 5.76 g, yield 90%). Their recrystallized from ethyl acetate-hexane to obtain colorless needle-like crystals. Melting point: 145-146°C.

Reference example 143

A solution of thionyl chloride (1.5 ml) in toluene (5 ml) was added to a mixture of 4-(2-phenyl-4-thiazoleacetate)benzyl alcohol (4.35 g), tetrahydrofuran (50 ml) and toluene (50 ml) under cooling with ice and stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and the solution washed with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain colorless crystals of 4-(4-chloromethylphenoxyacetic)-2-phenylthiazole (4,10 g, yield 89%). Melting point: 98-99°C.

Referential example 144

A mixture of 4-chloromethyl-5-methyl-2-phenylthiazole (of 5.40 g), 4-hydroxybenzaldehyde (2.91 in g), anhydrous potassium carbonate (4,95 g) and N,N-dimethylformamide (50 ml) was stirred at 8° C for 3 hours. The reaction mixture was poured into water, the precipitated solid precipitate was collected by filtration and dried with air to obtain crystals of 4-(5-methyl-2-phenyl-4-thiazoleacetate) benzaldehyde (6.85 g, yield 93%). Their recrystallized from ethyl acetate-hexane to obtain colorless prismatic crystals. Melting point: 118-119°C.

Reference example 145

Sodium borohydride (0,38 g) was added to a mixture of 4-(5-methyl-2-phenyl-4-thiazoleacetate)benzaldehyde (6,00 g), tetrahydrofuran (30 ml) and methanol (20 ml) under cooling with ice and stirred at room temperature for 30 minutes. The reaction mixture was neutralized with diluted hydrochloric acid and water polucheniem precipitate, which was collected by filtration and dried with air to obtain crystals of 4-(5-methyl-2-phenyl-4-thiazoleacetate)benzyl alcohol (of 5.68 g, yield 94%). Their recrystallized from ethyl acetate-hexane to obtain colorless prismatic crystals. Melting point: 94-95°C.

Reference example 146

A solution of thionyl chloride (1.5 ml) in toluene (5 ml) was added to a mixture of 4-(5-methyl-2-phenyl-4-thiazoleacetate)benzyl alcohol (4,50 g), tetrahydrofuran (50 ml) and toluene (50 ml) under cooling with ice and stirred at room temperature for 2 hours. The reaction mixture was concentrated. The residue was dissolved in ethyl acetate and washed with saturated waters is the first sodium bicarbonate solution, then saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated to obtain colorless crystals of 4-(4-chloromethylphenoxyacetic)-5-methyl-2-phenylthiazole (4,50 g, yield 94%). Melting point: 100-101°C.

Reference example 147

A mixture of 4-chloromethyl-2-phenylthiazole (at 8.60 g), sodium acetate (10.1 g) and N,N-dimethylformamide (80 ml) was stirred at 80°C for 6 hours. After cooling, the reaction solution was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The mixture of residue 4 N. aqueous sodium hydroxide solution (25 ml), tetrahydrofuran (50 ml) and methanol (50 ml) was stirred at room temperature for 5 minutes, poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), 2-phenyl-4-triazolylmethyl (7,05 g, yield 90%) as colorless crystals. Their recrystallized from hexane. Melting point: 71-72°C.

Reference example 148

A mixture of the hydrochloride of 2-chloromethylpyridine (21,4 g), sodium acetate (32,8 g) and N,N-dim is teleformula (200 ml) was stirred at 60° With during the night. After cooling, the reaction solution was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. A mixture of the residue, 4 N. aqueous sodium hydroxide solution (50 ml), tetrahydrofuran (100 ml) and methanol (100 ml) was stirred at room temperature for 1 hour, poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), 2-kinalimutan (14.0 g, yield 88%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 68-69°C.

Reference example 149

Sodium hydride 60%in oil, 5,01 g, was added to a solution of 5-hydroxy-2-methylpyridine (12,45 g) and N-phenyltrichlorosilane (40,80 g) in tetrahydrofuran (500 ml) at 0°and was stirred at room temperature for 1 hour and concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried (MgSO4) and concentrated. The residue was subjected to chromatography on a number of the NECS with silica gel to obtain from the faction, elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio), 6-methyl-3-pyridyl triftoratsetata (23,10 g, yield 84%) as a colorless oily substance.

NMR (Dl3)δ: 2.61 (3H, s), 7.27(1H, d, J=8.4 Hz), 7.52(1H, DD, J=2.8, 8.4 Hz), 8.47(1H, d, J=2.8 Hz).

Reference example 150

A mixture of 6-methyl-3-pyridylmethylamine (23,00 g), phenylboronic acid (11,83 g), tetrakis-(triphenylphosphine)palladium (5,00 g), sodium carbonate (22,43 g), ethanol (100 ml), water (100 ml) and toluene (500 ml) was boiled under reflux overnight in an argon atmosphere. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya-ethyl acetate, 2-methyl-5-phenylpyridine (15,24 g, yield 94%) as a colorless oily substance.

NMR (Dl3)δ: 2.61(3H, s), 7.23(1H, d, J=8.0 Hz), 7.32-7.63(5H, m), 7.78(1H, DD, J=2.6, Hz), 8.73(1H, d, J=2.6 Hz).

Reference example 151

A mixture of 2-methyl-5-phenylpyridine (3.00 g), 3-chloroperbenzoic acid (4,79 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya by tetrahydrofuran, b is izvetnogo oily substance. A solution of the obtained colorless oily substance in acetic anhydride (50 ml) was slowly added acetic anhydride (50 ml)was heated at 130°C, stirred for 2 h and concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate, saturated aqueous sodium chloride, and then dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), 5-phenyl-2-pyridylmethylamine (3,68 g, yield 92%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 71-72°C.

Reference example 152

A solution of p-toluensulfonate (10.3 g) in dimethoxyethane (50 ml) was added to a mixture of tert-butoxide potassium (11.2 g) and dimethoxyethane (50 ml) at -78°and the mixture was stirred for 5 minutes. To the mixture was added a solution of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (14.6 g) in dimethoxyethane (50 ml). After stirring at the same temperature for 1 hour, the mixture was stirred for 1 hour, increasing the temperature. To the mixture was added methanol (150 ml) and boiled under reflux for 1 hour. After cooling, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl what cetecom. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), 1-benzyl-3-benzyloxy-1H-pyrazole-4-ylacetonitrile (13.1 g, yield 86%) as a colorless oily substance.

NMR (Dl3)δ: 3.42(2H, s), 5.11(2H, s), 5.24(2H, s), 7.18-7.24(3H, m), 7.27-7.47(8H, m).

Reference example 153

A mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-ylacetonitrile (13,0 g), 4 N. aqueous sodium hydroxide solution (100 ml), tetrahydrofuran (100 ml) and ethanol (100 ml) was boiled under reflux for 3 days. After cooling, the mixture was neutralized with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. A mixture of the residue, ethyl iodide (5.2 ml), potassium carbonate (11.9 g) and N,N-dimethylformamide (100 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-GE the dignity (1:2, the volumetric ratio), ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-ilaclama (14.9 g, yield 99%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=Hz), 3.39(2H, s), 4.12(2H, q, J=7.2 Hz), 5.12(2H, s), 5.24(2H, s), 7.17-7.26(3H, m), 7.28-7.49(8H, m).

Reference example 154

A mixture of ethyl 1-benzyl-3-benzyloxy-1H-pyrazole-4-ilaclama (14.9 g), 5% palladium on coal (15.0 g), tetrahydrofuran (150 ml) and ethanol (150 ml) was stirred for 2 hours in hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated to obtain ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-ilaclama (9,76 g, yield 88%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 156-157°C.

Reference example 155

Sodium hydride 60%in oil, 1.20 g, was added to a solution of ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-ilaclama (7,81 g) in N,N-dimethylformamide (100 ml) at 0°and was stirred at room temperature for 15 minutes. To the mixture was added ethyl iodide (2,40 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane the (1:3, the volumetric ratio), ethyl 1-benzyl-3-ethoxy-1H-pyrazole-4-ilaclama (7,52 g, yield 87%) as a colorless oily substance.

NMR (Dl3)δ: 1.25(3H, t, J=Hz), 1.35(3H, t, J=Hz), 3.36(2H, s), 4.14(2H, q, J=Hz), 4.23(2H, q, J=Hz), 5.10(2H, s), 7.16-7.38(6N, m).

Reference example 156

A mixture of ethyl 1-benzyl-3-ethoxy-1H-pyrazole-4-ilaclama (7.50 g), 5% palladium on coal (15.0 g), formic acid (50 ml) and ethanol (100 ml) was boiled under reflux for 1 hour. After cooling palladium on coal was removed by filtration and the filtrate was concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-ethoxy-1H-pyrazole-4-ilaclama (2,79 g, yield 54%) as a colorless oily substance.

NMR (Dl3)δ: 1.27(3H, t, J=7.2 Hz), 1.38(3H, t, J=7.0 Hz), 3.41(2H, s), 4.14(2H, q, J=Hz), 4.25(2H, q, J=Hz), 7.38(1H, s), 9.38(1H, user. C).

Reference example 157

Alumoweld lithium (1100 mg) was gradually added to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (14,39 g) in tetrahydrofuran (50 ml) at 0°and was stirred for 30 minutes. In the reaction Mas added decahydrate sodium sulfate (12,14 g) and the precipitate was removed by filtration. The filtrate was concentrated and the residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methanol (12,20 g, yield: 93%) as a pale yellow oily substance.

NMR (Dl3)δ: 2.44(3H,s), 4.69(2H, d, J=5.4 Hz), 4.99(2H, s), 5.24(2H, s), 6.96-7.13(3H, m), 7.20-7.34(4H, m), 7.38-7.48(4H, m), 7.96-8.06(2H, m).

Reference example 158

A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methanol (12,15 g), activated manganese dioxide (37,03 g) and tetrahydrofuran (200 ml) was stirred at room temperature overnight. Then the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (11,68 g, yield: 96%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 136~137°C.

Reference example 159

Alumoweld lithium (540 mg) was gradually added to a solution of ethyl 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (7,10 g) in tetrahydrofuran (50 ml) at 0°and was stirred for 30 minutes. In the reaction mixture was added decahydrate sodium sulfate (4,33 g) and the precipitate was removed by filtration. The filtrate was concentrated and the OS is atok was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), [1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methanol (of 6.31 g, yield: 96%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 147-148°C.

Reference example 160

A mixture of [1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methanol (5,57 g), activated manganese dioxide (16,11 g) and tetrahydrofuran (100 ml) was stirred at room temperature overnight. Then the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (5,39 g, yield: 98%) as colorless crystals. Their recrystallized from acetone-hexane. Melting point: 115-116°C.

Reference example 161

A solution of p-toluensulfonate (0.95 g) in dimethoxyethane (10 ml) was added to a mixture of tert-butoxide potassium (1.01 g) and dimethoxyethane (10 ml) at -78°and the mixture was stirred for 5 minutes. To the mixture was added a solution of 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (2,01 g) dimethoxyethane (20 ml)and then stirred at the same temperature for 1 hour and at room temperature for 1 hour. To the mixture was added methanol (40 ml) and were boiled under reflux in accordance with the s 1 hour. After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]acetonitrile (1,69 g, yield: 78%) as a colorless oily substance.

NMR (Dl3)δ: 2.44(3H, s), 3.69(2H, s), 4.99(2H, s), 5.24(2H, s), 6.96-7.48 (11N, m), 7.95-8.08(2H, m).

Reference example 162

A mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (5,02 g), diethylmalonate (2,12 g), piperidine (0.35 ml), benzoic acid (0.27 g) and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on silica gel to obtain a colorless oily substance from the fraction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio). In the mixture of the obtained colorless oily substance, ethanol (20 ml) and tetrahydrofur is on (20 ml) was added sodium borohydride (170 mg) at 0° C and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), diethyl [1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methylmalonate (between 6.08 g, yield: 92%) as a pale yellow oily substance.

NMR (Dl3)δ: 1.14-1.35(6N, m), 2.44(3H, s), 3.24(2H, d, J=7.6 Hz), 3.61 (1H, t, J=7.6 Hz), 4.05-4.18(4H, m), 4.98(2H, s), 5.20(2H, s), 6.92-7.34 (8H, m), 7.38-7.48(3H, m), 7.96-8.06(2H, m).

Reference example 163

A mixture of 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (3,70 g), diethylmalonate (1.56 g), piperidine (0.25 ml), benzoic acid (0.20 g) and toluene (50 ml) was subjected to azeotropic the de-hydration for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), a colorless oily what about the substance. In the mixture of the obtained colorless oily substance, ethanol (30 ml) and tetrahydrofuran (30 ml) was added sodium borohydride (150 mg) at 0°and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), diethyl [1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methylmalonate (4.09 g, yield: 84%) as an oily yellow substance.

NMR (Dl3)δ: 1.18(6N, t, J=7.0 Hz), 3.24(2H, d, J=7.6 Hz), 3.62(1H, t, J=7.6 Hz), 4.12(4H, q, J=7.0 Hz), 5.20(2H, s), 5.26(2H, s), 6.94-7.04(2H, m), 7.09(1H, DD, J=3.6, 5.2 Hz), 7.15-7.36(6N, m), 7.40-7.48(3H, m), 7.90-7.99(2H, m).

Reference example 164

Alumoweld lithium (210 mg) portions was added to a solution of ethyl 1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (2,73 g) in tetrahydrofuran (50 ml) at 0°and was stirred for 30 minutes. Then the reaction mixture was added decahydrate sodium sulfate (1.80 g) and the precipitate was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, erwerbende is an ethyl acetate-hexane (1:1, the volumetric ratio), [1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methanol (2,33 g, yield: 94%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 155~156°C.

Reference example 165

A mixture of [1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methanol (2,03 g), activated manganese dioxide (6,00 g) and tetrahydrofuran (50 ml) was stirred at room temperature overnight. Then the manganese dioxide was removed by filtration, the filtrate was concentrated to obtain 1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1,74 g, yield: 86%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 153~154°C.

Reference example 166

A mixture of 1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.60 g), diethylmalonate (0,69 g), piperidine (0,12 ml), benzoic acid (0.09 g) and toluene (50 ml) was subjected to azeotropic dehydration for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio is osenia), colorless oily substance. In the mixture of the obtained colorless oily substance, ethanol (20 ml) and tetrahydrofuran (20 ml) was added sodium borohydride (105 mg) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), diethyl [1-[4-(2-phenyl-4-oxazolyl-methoxy)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methylmalonate (1,76 g, yield: 83%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(6N, t, J=7.0 Hz), 3.24(2H, d, J=7.8 Hz), 3.61(1H, J=7.8 Hz), 4.11(2H, q, J=7.0 Hz), 4.12(2H, q, J=7.2 Hz), 5.07(2H, d, J=1.0 Hz), 5.20(2H, s), 6.95-7.01 (2H, m), 7.0(1H, DD, J=5.0. 3.6 Hz), 7.17-7.32 (5H, m), 7.42-7.50(3H, m), 7.73(1H, J=1.0 Hz), 8.02-8.08 (2H, m).

Reference example 167

A mixture of 2-acetylthiophene (50,75 g), sodium hydride 60%in oil, 16,33 g and diethylmalonate (500 ml) was stirred at 80°C for 1 hour. In the reaction mixture was added water and the aqueous layer was neutralized with diluted hydrochloric acid. After stirring at room temperature for 30 minutes, the reaction mixture was extracted with ethyl acetate. An ethyl acetate layer industry is Ali saturated aqueous sodium chloride, dried (gSO4) and concentrated. The mixture of sludge and N,N-dimethylformamide-dimethylacetal (52,46 g) was boiled under reflux for 1.5 hours. The reaction mixture was concentrated and the residue was dissolved in ethanol (500 ml). To the solution was added hydrazinehydrate (20,09 g) and boiled under reflux for 3 hours. The reaction mixture was concentrated and to the residue was added saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to obtain ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (73,22 g, yield: 82%). Their recrystallized from ethyl acetate-hexane. Melting point: 123-124°C.

Example 1.

Sodium hydride 60%in oil, 2.55 g, was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (of 11.61 g), 4-benzyloxybenzaldehyde (15,23 g) and N,N-dimethylformamide (100 ml) at 0°and the mixture was stirred for one hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume the second ratio), received methyl 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carboxylate (22,16 g, yield: 97%). This substance was recrystallized from ethyl acetate-hexane. Melting point: 97-98°C.

Example 2.

Sodium hydride 60%in oil, of 2.13 g) was added to a mixture of 1-(4-benzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (18,00 g), ethyl diethylphosphonoacetate (12,09 g) and N,N-dimethylformamide (150 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl (E)-3-[1-(4-benzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (20,16 g, yield: 94%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 111-112°C.

Example 3.

Sodium hydride 60%in oil, 298 mg) was added to a mixture of methyl 4-phenylpyrrole-3-carboxylate (1.50 g), 4-(4-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazole (2,34 g) and N.N-dimethylformamide (15 ml) at 0°and the mixture was stirred for one hour. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. Ethylacetate the layer was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained methyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenylpyrrole-3-carboxylate (3.12 g, yield: 88%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 115-116°C.

Example 4.

Sodium hydride (60%in oil, 222 mg) was added to a mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenylpyrrole-3-carbaldehyde (2.37 g), ethyl diethylphosphonoacetate (1.1 ml) and tetrahydrofuran (30 ml) at 0°and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]- 4-phenyl-3-pyrrolyl]propenoate (2,13 g, yield: 78%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 120-121°C.

Example 5.

A mixture of ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-4-Fe the Il-3-pyrrolyl]propenoate (600 mg), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 60°C for 3 hours, was added 1 N. hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained crystals were collected by filtration to yield (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]propanolol acid (521 mg, yield: 92%). Their recrystallized from ethyl acetate-hexane. Melting point: 154-155°C.

Example 6.

A mixture of ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-4-phenyl-3-pyrrolyl]propenoate (700 mg), 5% palladium on coal (1,00 g) and tetrahydrofuran (15 ml) was stirred for one hour at room temperature in hydrogen atmosphere. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:7, volume ratio)was obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]propionate (618 mg, yield: 88%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.1 Hz), 2.43(3H, s), 2.47-2.56(2H, m), 2.91-3.00(2H, m), 4.08(2H, q, J=7.1 Hz), 4.95(2H, s), 4.98(2H, s), 6.51(1H, d, J=2.2 Hz), 6.71(1H, d, J=2.2 Hz), 6.98(2H, d, J=8.8 Hz), 7.10-7.47 (YOON, m), 7.97-8.04(2H, m).

Example 7.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (531 mg), monohydrate of lithium hydroxide (128 mg), tetrahydrofuran (6 ml), ethanol (4 ml) and water (4 ml) was stirred at room temperature for 2 hours and acidified by adding 1 N. hydrochloric acid, and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (451 mg, yield: 90%). Their recrystallized from ethyl acetate-hexane. Melting point: 124-125°C.

Example 8.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl] propionate (1.01 g), 4-chloromethyl-2-(2-furyl)-5-methoxazole (0.75 g), potassium carbonate (0,63 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained oily substance. The mixture obtained maslanik the CSOs substances, 1 N. aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyl]-4-phenyl-3-pyrrolyl]propionic acid (1,02 g, yield: 73%). Their recrystallized from ethyl acetate-hexane. Melting point: 86-87°C.

Example 9.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (1,30 g), 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (0.95 g), potassium carbonate (1.20 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (10 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours,and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolidinone]-benzyl]-4-phenyl-3-pyrrolyl]propionic acid (1,43 g, yield: 77%). Their recrystallized from ethyl acetate-hexane. Melting point: 117-118°C.

Example 10.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (1.55 g), benzylbromide (0.7 ml), potassium carbonate (0,92 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio), obtained oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[1-(4-benzyloxybenzyl-4-phenyl-3-pyrrolyl]propionic acid (1,53 g, yield: 84%). Their recrystallized from ethyl acetate-hexane. Melting point: 130-131°C.

Example 11.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl] propionate (1.31 g), hydrochloride 2-picolylamine (0.73 g), potassium carbonate (0,69 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water to the residue was neutralized by addition of 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(2-pyridyloxy)benzyl]-3-pyrrolyl]propionic acid (1.06 g, yield: 69%). Their recrystallized from ethanol-water. Melting point: 109-110°C.

Example 12.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl] propionate (1.35 g), hydrochloride 3-peak is lillolita (0,76 g), potassium carbonate (0.85 grams) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), obtained oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (8 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was neutralized by addition of 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(3-pyridyl-methoxy)benzyl]-3-pyrrolyl]propionic acid (0,76 g, yield: 48%). Their recrystallized from ethanol-water. Melting point: 131-132°C.

Example 13.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (1.10 g), 4-picolylamine hydrochloride (0,60 g), potassium carbonate (0.88 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer is washed with a saturated aqueous solution of sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), obtained oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was neutralized by addition of 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(4-pyridyl-methoxy)benzyl]-3-pyrrolyl]propionic acid (0,98 g, yield: 75%). Their recrystallized from acetone-hexane. Melting point: 124-125°C.

Example 14.

A solution of 40% of diethylazodicarboxylate in toluene (5,66 g) dropwise slowly added to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (2,84 g), 2-(5-methyl-2-phenyl-4-oxazolyl)ethanol (2,48 g), triphenylphosphine (of 3.31 g) and tetrahydrofuran (25 ml) at room temperature. Then the above solution was stirred at room temperature for 2 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume with the compared), got oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (15 ml), tetrahydrofuran (15 ml) and ethanol (15 ml) was stirred at room temperature for 3 hours and the organic solvent was removed under reduced pressure. After adding water, the residue was acidified by adding 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-benzyl]-4-phenyl-3-pyrrolyl]propionic acid (2,72 g, yield: 57%). Their recrystallized from ethanol-water. Melting point: 147-148°C.

Example 15.

Sodium hydride 60%in oil, 60,0 mg, was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 2-(4-chloromethyl-2-thiazolyl)pyrazin (349 mg) and stirred at room temperature for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[4-phenyl-1-[4-[2-(2-pyridinyl)-4-thiazoline is XI]benzyl]-3-pyrrolyl]propionate (629 mg, yield: 80%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=Hz), 2.52(2H, t, J=Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.96(2H, s), 5.28(2H, s), 6.51(1H, d, J=2.4 Hz), 6.72(1H, d, J=2.4 Hz), 6.99(2H, d, J=8.8 Hz), 7.16(2H, d, J=8.8 Hz), 7.19-7.42(5H, m), 7.50(1H, s), 8.56(1H, DD, J=2.4, 1.6 Hz), 8.61(1H, d, J=2.4 Hz), 9.43(1H, d, J=1.6 Hz).

Example 16.

A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-3-pyrrolyl]propionate (629 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-3-pyrrolyl]propionic acid (523 mg, yield: 88%) as colorless crystals. Their recrystallized from ethanol. Melting point: 137-138°C.

Example 17.

A solution of 40% of diethylazodicarboxylate in toluene (1.04 g) dropwise slowly added to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (699 mg), 3-furanmethanol (0,172 ml), triphenylphosphine (577 mg) and tetrahydrofuran (20 ml) at room temperature. After the solution was stirred at room temperature overnight, the reactions the config solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[1-[4-(3-FuelMAX)benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 45%) as an oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.0 Hz), 2.51(2H, t, J=Hz), 2.94(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.0 Hz), 4.91(2H, s), 4.94(2H, s), 6.48(1H, d, J=1.8 Hz), 6.50(1H, d, J=2.6 Hz), 6.71(1H, d, J=2.6 Hz), 6.92(2H, d, J=8.8 Hz), 7.12(2H, d, J=8.8 Hz), 7.16-7.43(5H, m), 7.49(1H, d, J=1.8 Hz).

Example 18.

A mixture of ethyl 3-[1-[4-(3-FuelMAX)benzyl]-4-phenyl-3-pyrrolyl]propionate (382 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(3-FuelMAX)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (257 mg, yield: 72%). Their recrystallized from ethanol-hexane. Melting point: 110-111°C.

Example 19.

A solution of 40% of diethylazodicarboxylate in toluene (1,74 g) dropwise slowly added to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), 2-thiophenemethyl (0,237 ml), triphenylphosphine (984 mg) and t is trihydrogen (20 ml) at room temperature. After the solution was stirred over night at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[1-[4-(2-teenrotica)benzyl]-4-phenyl-3-pyrrolyl]propionate (620 mg, yield: 56%) as an oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.3 Hz), 2.51(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.94(2H, s). 5.20(2H, s), 6.50(1H, d, J=2.2 Hz), 6.70(1H, d, J=2.2 Hz), 6.90-7.02(3H, m), 7.14-7.25(4H, m), 7.30-7.41(5H, m).

Example 20.

A mixture of ethyl 3-[4-phenyl-1-[4-(2-teenrotica)benzyl]-3-pyrrolyl]propionate (620 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 7 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(2-teenrotica)benzyl]-3-pyrrolyl]propionic acid (272 mg, yield: 47%). Their recrystallized from ethyl acetate-hexane. Melting point: 127-128°C.

Example 21.

A solution of 40% of diethylazodicarboxylate in toluene (1,74 g) dropwise slowly added to a mixture of the mentioned 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), 3-thiophenemethyl (0,236 ml), triphenylphosphine (984 mg) and tetrahydrofuran (20 ml) at room temperature. Then the solution was stirred over night at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[1-[4-(3-teenrotica)benzyl]-4-phenyl-3-pyrrolyl]propionate (629 mg, yield: 56%) as an oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.2 Hz), 2.51(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.0 Hz), 4.93(2H, s), 5.05(2H, s), 6.50(1H, d, J=2.2 Hz), 6.71(1H, d, J=Hz), 6.92(2H, d, J=8.8 Hz), 7.08-7.22(4H, m), 7.31-7.41(6N, m).

Example 22.

A mixture of ethyl 3-[4-phenyl-1-[4-(3-teenrotica)benzyl]-3-pyrrolyl]propionate (624 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 5 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(3-teenrotica) benzyl]-3-pyrrolyl]propionic acid (421 mg, yield: 72%). Their recrystallized from ethyl acetate-hexane. Melting point: 118-119°C.

Example 2.

A solution of 40% of diethylazodicarboxylate in toluene (1,74 g) dropwise slowly added to a mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (873 mg), furfuryl alcohol (0,216 ml), triphenylphosphine (984 mg) and tetrahydrofuran (20 ml) at room temperature. Then the solution was stirred over night at room temperature, the reaction solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[1-[4-(2-FuelMAX)benzyl]-4-phenyl-3-pyrrolyl]propionate (624 mg, yield: 58%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.94(2H, s), 4.99(2H, s), 6.38(1H, DD,J=3.2, 1.4 Hz), 6.43(1H, d, J=3.2 Hz). 6.50(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 6.95(2H, d, J=8.8 Hz), 7.10-7.45(8H, m).

Example 24.

A mixture of ethyl 3-[1-[4-(2-FuelMAX)benzyl]-4-phenyl-3-pyrrolyl]propionate (624 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the C fraction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained 3-[1-[4-(2-FuelMAX)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (386 mg, yield: 66%) as an oily substance.

NMR (Dl3)δ: 2.58(2H, t, J=7.8 Hz), 2.96(2H, t, J=7.8 Hz), 4.94(2H, s), 4.98(2H, s), 6.37(1H, DD, J=3.4, 1.8 Hz), 6.42(1H, d, J=3.4 Hz), 6.52(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 6.94(2H, d, J=8.8 Hz), 7.12(2H, d, J=8.8 Hz), 7.19-7.44(8H, m).

Example 25.

Sodium hydride 60%in oil, 60,0 mg, was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°C and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 3-chloromethyl-2-methylpyridine (212 mg) and stirred at room temperature for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[1-[4-(2-methyl-3-pyridyloxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (581 mg, yield: 85%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 2.52(2H, t, J=7.8 Hz), 2.59(3H, s), 2.96(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.0 Hz), 4.96(2H, s), 5.03(2H, s), 6.51(1H, d, J=2.6 Hz), 6.72(1H, d, J=2.6 Hz), 6.72(1H, d, J=2.6 Hz), 6.94(2H, d, J=8.8 is C), 7.11-7.42(8H, m), 7.71(1H, DD, J=7.8, 1.8 Hz), 8.48(1H, DD, J=4.8, 1.8 Hz).

Example 26.

A mixture of ethyl 3-[1-[4-(2-methyl-3-pyridyloxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (568 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 4 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(2-methyl-3-pyridyl-methoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (465 mg, yield: 87%). Their recrystallized from ethyl acetate-hexane. Melting point: 158-159°C.

Example 27.

Sodium hydride 60%in oil, 60,0 mg, was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-5-methyl-2-phenylthiazol (336 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the C fraction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (690 mg, yield: 86%) as an oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.2 Hz), 2.51(2H, t, J=7.8 Hz), 2.52(3H, s), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.94(2H, s), 5.15(2H, s), 6.50(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 7.00(2H, d, J=8.8 Hz), 7.13(2H, d, J=8.8 Hz), 7.16-7.25(1H, m), 7.29-7.46(7H, m), 7.86-7.91(2H, m).

Example 28.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-thiazolyl-methoxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (671 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (495 mg, yield: 78%). Their recrystallized from ethyl acetate-hexane. Melting point: 157-158°C.

Example 29.

Sodium hydride 60%in oil, 60,0 mg, was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 m the chickpeas. To the mixture was added 4-chloromethyl-2-phenylthiazole (315 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-pyrrolyl]propionate (717 mg, yield: 91%) as an oily substance.

NMR (Dl3)δ: of 1.20(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.95(2H, s), 5.25(2H, s), 6.51(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 6.98(2H, d, J=8.8 Hz), 7.13(2H, d, 0=8.8 Hz), 7.18-7.25 (1H, m), 7.30-7.49(8H, m), 7.91-7.99(2H, m).

Example 30.

A mixture of ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-thiazolyl-methoxy)benzyl]-3-pyrrolyl]propionate (706 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 6 hours, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-pyrrolyl]-impregnated the new acid (619 mg, yield: 93%). Their recrystallized from ethanol-hexane. Melting point: 111-112°C.

Example 31.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-(2-pyridyl)thiazole (316 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazoleacetate)benzyl]-3-pyrrolyl]propionate (590 mg, yield: 75%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 81-82°C.

Example 32.

A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazoleacetate) benzyl]-3-pyrrolyl]propionate (471 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight and added to a mixture of 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed on Ishenim aqueous solution of sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-pyridyl)-4-thiazoleacetate)benzyl]-3-pyrrolyl]propionic acid (408 mg, yield: 91%). Their recrystallized from ethanol-hexane. Melting point: 117-118°C.

Example 33.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added chloromethyl-2-(4-pyridyl)thiazole (316 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:1, volume ratio)was obtained ethyl 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazoleacetate)benzyl]-3-pyrrolyl]propionate (867 mg, yield: 89%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 2.51(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.95(2H, s), 5.27(2H, s), 6.51(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 6.98(2H, d, J=8.8 Hz), 7.14(2H, d, J=8.8 Hz), 7.18-7.26(1H, m), 7.29-7.41(4H, m), 7.45(1H, s), 7.81(2H, DD, J=4.8, 1.4 Hz), 8.71(2H, DD, J=4.8, 1.4 Hz).

Prima is 34.

A mixture of ethyl 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazoleacetate)benzyl]-3-pyrrolyl]propionate (864 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(4-pyridyl)-4-thiazoleacetate)benzyl]-3-pyrrolyl]propionic acid (771 mg, yield: 94%). Their recrystallized from ethanol. Melting point: 149-150°C.

Example 35.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 2-(3-chloromethylene)pyrazin (307 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume sootnoshenie is), was obtained ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg, yield: 83%) as an oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.94(2H, s), 5.15(2H, s), 6.51(1H, d, J=2.2 Hz), 6.71(1H, d, J=2.2 Hz), 6.96(2H, d, J=8.8 Hz), 7.13(2H, d, J=8.8 Hz), 7.18-7.41 (5H, m), 7.49-7.56(2H, m), 7.92-8.00(1H, m), 8.10(1H, s), 8.52(1H, d, J=2.6 Hz), 8.64(1H, DD, J=2.6, 1.4 Hz), 9.04(1H, d, J=1.4 Hz).

Example 36.

A mixture of ethyl 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionate (647 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-[3-(2-pyrazinyl)benzyloxy]benzyl]-3-pyrrolyl]propionic acid (470 mg, yield: 77%). Their recrystallized from ethyl acetate-hexane. Melting point: 91-92°C.

Example 37.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-(2-FSD is l)thiazole (299 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[1-[4-[2-(2-furyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (643 mg, yield: 84%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 2.52(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.0 Hz), 4.95(2H, s), 5.23(2H, s), 6.52-6.55(2H, m), 6.71(1H, d, J=2.2 Hz), 6.96(2H, d, J=8.8 Hz), 7.01(1H, d, J=2.2 Hz), 7.13(2H, d, J=8.8 Hz), 7.16-7.41(6N, m), 7.51(1H, DD, J=1.8, 0.6 Hz).

Example 38.

A mixture of ethyl 3-[1-[4-[2-(2-furyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (641 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 5 hours, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (485 mg, yield: 78%). Their recrystallized from ethanol-hexane. Melting point: 114-115#x000B0; C.

Example 39.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-(2-thienyl)thiazole (324 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazoleacetate]benzyl]-3-pyrrolyl]propionate (590 mg, yield: 74%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 2.52(2H, t, J=Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.0 Hz), 4.94(2H, s), 5.22(2H, s), 6.51(1H, d, J=2.2 Hz), 6.70(1H, d, J=2.2 Hz), 6.96(2H, d, J=8.8 Hz), 7.03-7.40 (10H, m), 7.52(1H, DD, J=3.6, 1.0 Hz).

Example 40.

A mixture of ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolyl-methoxy]benzyl]-3-pyrrolyl]propionate (582 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate SL the St was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazoleacetate]benzyl]3-pyrrolyl]propionic acid (421 mg, yield: 76%). Their recrystallized from ethyl acetate-hexane. Melting point: 106-107°C.

Example 41.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (349 mg), hydrochloride 4-chloromethyl-2-methylthiazole (276 mg), potassium carbonate (276 mg) and N,N-dimethylformamide (5 ml) was stirred at 90°C for 6 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-[4-(2-methyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (373 mg, yield: 81%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.73(3H, s), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.94(2H, s), 5.15(2H, s), 6.50(1H, d, J=2.2 Hz), 6.71(1H, d, J=2.2 Hz), 6.95(2H, d, J=8.8 Hz), 7.12(2H, d, J=8.8 Hz), 7.14-7.41 (6N, m).

Example 42.

A mixture of ethyl 3-[1-[4-(2-methyl-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (368 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) paramesh the Wali at room temperature for 4 hours, to the mixture was added 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(2-methyl-4-thiazolyl-methoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (251 mg, yield: 73%). Their recrystallized from ethanol-hexane. Melting point: 113-114°C.

Example 43.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-phenyloxazol (290 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl-3-[4-phenyl-1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-pyrrolyl]propionate (550 mg, yield: 72%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 2.52(2H, t, J=Hz). 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.95(2H, s), 5.07(2H), 6.51(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 6.97(2H, d, J=8.8 Hz), 7.01-7.50 (10H, m), 7.73(1H, s), 8.01-8.10(2H, m).

Example 44.

A mixture of ethyl 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolyl-methoxy]benzyl]-3-pyrrolyl]propionate (532 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-(2-phenyl-4-oxazolidinone]benzyl]-3-pyrrolyl]propionic acid (428 mg, yield: 85%). Their recrystallized from ethanol-hexane. Melting point: 139-140°C.

Example 45.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-(3-pyridyl)thiazole (316 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography n is a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazoleacetate]benzyl]-3-pyrrolyl]propionate (657 mg, yield: 84%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.96(2H, s), 5.27(2H, s), 6.51(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 6.99(2H, d, J=8.6 Hz), 7.02-7.42(M, m), 8.24(1H, DDD, J=8.2, 2.0, 1.2 Hz), 8.66(1H, DD, J=4.8, 1.2 Hz), 9.17(1H, d, J=2.0 Hz).

Example 46.

A mixture of ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazoleacetate]benzyl]-3-pyrrolyl]propionate (655 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 6 hours, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazoleacetate]benzyl]-3-pyrrolyl]propionic acid (537 mg, yield: 92%). Their recrystallized from ethanol. Melting point: 118-119°C.

Example 47.

Thionyl chloride (830 mg) was added dropwise to a solution of 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl alcohol (1.50 g) in toluene (40 ml) at 0°C. After stirring at room temperature for 2 hours, the reaction mixture to which has centriole. The residue and methyl 4-phenylpyrrole-3-carboxylate (1.40 g) was dissolved in N,N-dimethylformamide (40 ml). Sodium hydride (60%in oil, 465 mg) was added to the solution at 0°and was stirred at room temperature for 3 days. The reaction mixture was poured into a saturated aqueous solution of sodium chloride and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, then dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained methyl 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenylpyrrole-3-carboxylate (1.80 g, yield: 70%) as an oily substance.

NMR (Dl3)δ: 3.15(3H, s), 3.70(3H, s), 3.99(2H, t, J=5.0 Hz), 4.19(2H, t, J=5.0 Hz), 4.97(2H, s), 6.5-B.6(2H, m), 6.64(1H, d, J=2.5 Hz), 6.88(2H, d, J=Hz), 7.13(2H, d, J=8.5 Hz), 7.2-7.55(7H, m), 8.1-8.2(1H, m).

Example 48.

Sodium hydride (60%in oil, 200.0 mg) was added to a solution of 1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-pyrrole-3-carbaldehyde (1.35 g) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (30 ml) at 0°C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, then neutralized using 2 N. hydrochloric acid, and was extracted with ethyl acetate. An ethyl acetate layer was washed water is th, then saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya acetone-hexane (1:2, volume ratio)was obtained ethyl (E)-3-[1-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propenoate (1.35 g, yield: 85%) as an oily substance.

NMR (Dl3)δ: 1.26(3H, t, J=7 Hz), 3.16(3H. s), 3.95-4.25(6N, m), 4.98(2H, s), 6.05(1H, d, J=16 Hz), 6.5-6.6(2H, m), 6.69(1H, d, J=2.5 Hz), 6.88(2H, d, J=9 Hz), 7.03(1H, d, J=2.5 Hz), 7.14(2H, d, J=9 Hz), 7.2-7.55 (6N, m), 7.69(2H, d, J=16 Hz), 8.1-8.2(1H, m).

Example 49.

Catalytic hydrogenation of a mixture of ethyl (E) 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]-propanoate (1,32 g), 5% palladium on coal (1.0 g), tetrahydrofuran (40 ml) and ethanol (40 ml) was carried out at ordinary temperature and ordinary pressure. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was dissolved in a mixture solvent of tetrahydrofuran (10 ml) and ethanol (10 ml), then the solution was added 1 N. aqueous sodium hydroxide solution (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was poured into water, then neutralized 1 N. hydrochloric acid (10 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. the received colorless crystals were collected by filtration to yield 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (900 mg, yield: 72%). Their recrystallized from acetone-ethyl acetate. Melting point: 110-111°C.

Example 50.

3-Phenoxybenzaldehyde (11,32 g) and ethyl 3-phenyl-1H-pyrazole-4-carboxylate (11,30 g) was dissolved in N,N-dimethylformamide (100 ml). Sodium hydride (60%in oil, 2,49 g) was added to the solution at 0°and the solution was stirred at room temperature for 20 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained oily substance. A mixture of the obtained oily substance, potassium hydroxide (8.53 g) and ethanol (150 ml) was boiled under reflux for 5 hours. Then the reaction solvent was removed under reduced pressure, adding water to the mixture, then the mixture was acidified with 1 N. hydrochloric acid. The obtained colorless crystals were collected by filtration to yield 1-(3-phenoxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylic acid (14,83 g, yield: 77%). Their recrystallized from acetone-hexane. Melting point: 148-149°C.

Example 51.

Sodium hydride (60%in oil, 0.36 g) was added to a mixture of methyl 4-Fe is espiral-3-carboxylate (1.81 in), 6-benzyloxy-2-chloromethylketone (2,54 g) and N,N-dimethylformamide (35 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with tetrahydrofuran-hexane (1:2, volume ratio)was obtained methyl 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carboxylate (3,20 g, yield: 80%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 109-110°C.

Example 52.

Sodium hydride (60%in oil, 0.20 g) was added to a mixture of ethyl diethylphosphonoacetate (0,992 ml) and tetrahydrofuran (20 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. To the mixture was slowly added a solution of 1-(6-benzyloxy-2-naphthylmethyl)-4-phenylpyrrole-3-carbaldehyde (2,09 g) in tetrahydrofuran (20 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield ethyl (E)-3-[1-(6-b is siloxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propenoate (1.65 g, yield: 68%). Their recrystallized from ethyl acetate-hexane. Melting point: 119-120°C.

Example 53.

Sodium hydride (60%in oil, to 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]-propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 4-chloromethyl-5-methyl-2-phenyloxazol (207 mg) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (304 mg, yield: 59%) as an oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.0 Hz), 2.47(3H, s), 2.52(2H, t, J=7.8 Hz), 2.97(2H, t, J=7.8 Hz), 4.06(2H, q, J=7.0 Hz), 5.11(2H, s), 5.13(2H, s), 6.56(1H, d, J=2.2 Hz), 6.77(1H, d, J=2.2 Hz), 7.15-7.48(11N, m), 7.56(1H, s), 7.71(2H, d, J=8.8 Hz), 7.99-8.06(2H, m).

Example 54.

A mixture of ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (304 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room the temperature for 7 hours, to the mixture was added hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]-propionic acid (243 mg, yield: 84%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 122-123°C.

Example 55.

Sodium hydride (60%in oil, to 36.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]-propionate (360 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To this mixture was added 2-tormentilla (0,119 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[1-[6-(2-forbindelse)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (404 mg, yield: 88%) as an oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.96(2H, t, J=7.8 Hz), 4.06(2H, q,J=7.2 Hz), 5.12(2H. s), 5.24(2H, s), 6.55(1H, d, J=2.4 Hz), 6.76(1H, d, J=2.4 Hz), 7.06-7.43(11N, m), 7.51-7.59(2H, m), 7.68-7.75(2H, m).

Example 56.

A mixture of ethyl 3-[1-[6-(2-forbindelse)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (401 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 7 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[6-(2-forbindelse)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionic acid (289 mg, yield: 76%). Their recrystallized from ethanol-hexane. Melting point: 143-144°C.

Example 57.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]-propionate (599 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 3-picolylamine (230 mg) and stirred at room temperature for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column with what silicagel and from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[4-phenyl-1-[6-(3-pyridyloxy)-2-naphthylmethyl]-3-pyrrolyl]propionate (647 mg, yield: 88%) as an oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.0 Hz), 2.52(2H, t, J=Hz), 2.97(2H, t, J=7.6 Hz), 4.06(2H, q, J=7.0 Hz), 5.13(2H, s), 5.19(2H, s), 6.56(1H, d, J=2.6 Hz), 6.76(1H, d, J=2.6 Hz), 7.16-7.43(M, m), 7.57(1H, s), 7.68-7.84(3H, m), 8.60(1H, d, J=4. 4 Hz), 8.74(1H, s).

Example 58.

A mixture of ethyl 3-[4-phenyl-1-[6-(3-pyridyloxy)-2-naphthylmethyl]-3-pyrrolyl]propionate (638 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[4-phenyl-1-[6-(3-pyridyloxy)-2-naphthylmethyl]-3-pyrrolyl]propionic acid (508 mg, yield: 84%). Their recrystallized from ethanol. Melting point: 158-159°C.

Example 59.

Sodium hydride (60%in oil, 80.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]-propionate (799 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 3-chloromethyl-2-metylene is in (283 mg) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-[6-(2-methyl-3-pyridyloxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (959 mg, yield: 95%) as an oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.2 Hz), 2.52(2H, t, J=Hz), 2.63(3H, s), 2.97(2H, t, J=7.8 Hz), 4.07(2H, q, J=Hz), 5.13(2H, s), 5.15(2H, s), 6.56(1H, d, J=2.6 Hz), 6.77(1H, d, J=2.6 Hz), 7.14-7.48(N, m), 7.57(1H, s), 7.69-7.79(3H, m), 8.49(1H, DD, J=4.8, 1.8 Hz).

Example 60.

A mixture of ethyl 3-[1-[6-(2-methyl-3-pyridyloxy)-2-naphthylmethyl] -4-phenyl-3-pyrrolyl]propionate (959 mg), 1 N. aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature overnight, the mixture was added 1 N. hydrochloric acid (4 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[6-(2-methyl-3-pyridyloxy) -2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionic acid (750 mg, yield: 83%). Their recrystallized from ethanol. Melting point: 163-164°C.

P the emer 61.

Sodium hydride (60%, in oil and 0.22 g) was added to a mixture of ethyl 4-(2-pyridyl)pyrrole-3-carboxylate (1.10 g), 4-(4-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazole (1,83 g) and N,N-dimethylformamide (25 ml) at 0°and the mixture was stirred for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with tetrahydrofuran-hexane (1:1, volume ratio)was obtained ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)pyrrole-3-carboxylate (2,43 g, yield: 97%) as an oily substance.

NMR (Dl3)δ: 1.28(3H, t, J=7.2 Hz), 2.44(3H, s). 4.22(2H, q, J=7.2 Hz), 4.99(2H, s), 5.02(2H, s), 6.94-7.24(6N, m), 7.35-7.48(4H, m), 7.60-7.72(1H, m), 7.84-7.92(1H, m), 7.96-8.08(2H, m), 8.51-8.58(1H, m).

Example 62.

Sodium hydride (60%in oil, 0.17 g) was added to a mixture of ethyl diethylphosphonoacetate (1,00 g) and N,N-dimethylformamide (5 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. To the mixture was slowly added a solution of 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenylpyrrole-3-carbaldehyde (1.65 g) in N,N-dimethylformamide (10 ml) and stirred at room temperature for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. E. hilarity layer was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1 volume ratio)was obtained ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propenoate (1,83 g, yield: 96%) as an oily substance.

NMR (Dl3)δ: 1.29(3H, t, J=7.2 Hz), 2.44(3H, s), 4.21(2H, q, J=7.2 Hz), 4.99(2H, s), 5.02(2H, s), 6.14(1H, d, J=16.0 Hz), 6.94-7.24(7H, m), 7.34-7.52 (4H, m), 7.58-7.72 (1H, m), 7.86-8.16(3H, m), 8.58-8.66(1H, m).

Example 63.

A mixture of ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propenoate (1,80 g), 5% palladium on coal (2,32 g) and tetrahydrofuran (30 ml) was stirred overnight in a hydrogen atmosphere at room temperature. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propionate (1,61 g, yield: 89%) as an oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 2.43(3H, s), 2.56-2.66 (2H, m), 3.04-3.16(2H. m), 4.09(2H, q, J=7.0 Hz), 4.96(2H, s), 4.98(2H, s), 6.51 (1H, d, J=2.6 Hz), 6.92-7.18 (6N, m), 7.34-7.66(5H, m), 7.94-8.04(2H, m), 8.50-8.56(1H, m).

Example 64.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-4-(2-pyridyl)-3-Pierre is a Lil]propionate (1,46 g), 1 N. aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature for 5 hours, the mixture was added 1 N. hydrochloric acid (6 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-(2-pyridyl)-3-pyrrolyl]propionic acid (1.20 g, yield: 87%). Their recrystallized from N.N-dimethylformamide-water. Melting point: 155-156°C.

Example 65.

Sodium hydride (60%in oil, 2.20 g) was added to a mixture of methyl-4-phenylpyrrole-3-carboxylate (11,10 g), 3,5-dibenzylethylenediamine (21,9 g) and N,N-dimethylformamide (200 ml) at 0°and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with tetrahydrofuran-hexane (1:2, volume ratio)was obtained methyl 1-(3, 5-dibenzalacetone)-4-phenylpyrrole-3-carboxylate (26,4 g, yield: 95%) as an oily substance.

NMR (Dl3)δ: 3.2(3H, s), 4.95(2H, s), 4.99(4H, s). 6.41(1H, d, J=2.6 Hz), 6.56(1H, t, J=2.2 Hz), 6.64(1H, d, J=2.6 Hz), 7.21-7.42(15 NM, m), 7.44-7.50(2H, m).

Example 66.

Sodium hydride (60%in oil, 2,11 g) was added to a mixture of ethyl diethylphosphonoacetate (10.5 ml) and tetrahydrofuran (150 ml) at 0°and was stirred at room temperature for 30 minutes. To the mixture was slowly added a solution of 1-(3,5-dibenzalacetone)-4-phenylpyrrole-3-carbaldehyde (22.7 g) in tetrahydrofuran (20 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the obtained ethyl (E)-3[1-(3, 5-dibenzalacetone)-4-phenyl-3-pyrrolyl]propenoate (21,9 g, yield: 84%). This substance was recrystallized from ethyl acetate-hexane. Melting point: 98-99°C.

Example 67.

After a mixture of ethyl (E)-3-[1-(3, 5-dibenzalacetone)-4-phenyl-3-pyrrolyl]propenoate (544 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred overnight at 50°C, the mixture was added 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. Received the s colorless crystals were filtered and received E-3-[1-(3,5-dibenzalacetone)-4-phenyl-3-pyrrolyl]-propanolol acid (479 mg, yield: 93%). Their recrystallized from ethanol. Melting point: 182-183°C.

Example 68.

Sodium hydride (60%in oil, 0.54 g) was added to a solution of ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (4,93 g) in N,N-dimethylformamide (50 ml) at 0°and the solution was stirred at room temperature for 15 minutes. To the solution was added 2-(4-chloromethyl-2-thiazolyl)pyrazin (2.86 g) and stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the obtained ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenylpyrrole]-propionate (2.00 g, yield: 27%) as colorless crystals. Their recrystallized from tetrahydrofuran-hexane. Melting point: 156-157°C.

Example 69.

A mixture of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate] benzyl]-4-phenylpyrrole]propionate (324 mg), 1 N. aqueous sodium hydroxide solution (1.5 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at 50°C for 2 hours, the mixture was added 1 N. hydrochloric acid (1.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO 4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-pyrrolyl]propionic acid (277 mg, yield: 90%). Their recrystallized from ethanol-hexane. Melting point: 206-207°C.

Example 70.

Sodium hydride (60%, in oil, of 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]-benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N,N-dimethylformamide (5 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added logmean (0,0523 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (361 mg, yield: 93%) as an oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.96(2H, t, J=7.8 Hz), 3.77(3H, s), 4.09(2H, q, J=7.2 Hz), 4.95(2H, s), 5.23(2H, s), 6.36(1H, s), 6.43(1H, s), 6.52(1H, t, J=2.2 Hz), 6.53(1H, d, J=2.2 Hz), 6.73(1H, d, J=2.2 Hz), 7.16-7.42(5H, m), 7.48(1H, s), 8.56(1H, DD, J=2.6, 1.4 Hz), 8.61(1 is, D. J=2.6 Hz), 9.43(1H, d, J=1.4 Hz).

Example 71.

A mixture of ethyl 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (361 mg), 1 N. aqueous sodium hydroxide solution (1.5 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for 4 hours, the mixture was added 1 N. hydrochloric acid (1.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[3-methoxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]4-phenyl-3-pyrrolyl]propionic acid (338 mg, yield: 99%). Their recrystallized from ethanol-hexane. Melting point: 111-112°C.

Example 72.

Sodium hydride (60%, in oil, of 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]-benzyl]-4-phenyl-3-pyrrolyl]propionate (378 mg) in N.N-dimethylformamide (5 ml) at 0°and was stirred at room temperature for 15 minutes. To the mixture was added Iodate (0,0672 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of forces is by Kagel and from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (385 mg, yield: 97%) as an oily substance.

NMR (Dl3) δ: 1.20(3H, t, J=7.2 Hz), 1.39(3H, t, J=7.0 Hz), 2.52(2H, t, J=7.8 Hz), 2.96(2H, t, J=7.8 Hz), 3.98(2H, q, J=7.0 Hz), 4.09(2H, q, J=7.2 Hz), 4.94(2H, s), 5.23(2H, s), 6.35(1H. s), 6.42(1H, s), 6.50-6.53(2H, m), 6.73(1H, d, J=2.6 Hz), 7.16-7.42(5H. m), 7.48(1H, s), 8.56(1H, DD, J=2.4, 1.2 Hz), 8.61 (1H, d, J=2.4 Hz), 9.42(1H, d, J=1.2 Hz).

Example 73.

A mixture of ethyl 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (370 mg), 1 N. aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred over night while boiling under reflux and the mixture was then added 1 N. hydrochloric acid (6 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[3-ethoxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionic acid (210 mg, yield: 60%). Their recrystallized from ethanol. Melting point: 97-98°C.

Example 74.

Sodium hydride (60%, in oil, of 28.0 mg) was added to a solution of ethyl 3-[1-[3-hydroxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]-benzyl]-4-phenyl-3-pyrrolyl]propionate (378 m is) in N,N-dimethylformamide (5 ml) at 0° C and the mixture was stirred at room temperature for 15 minutes. To the mixture was added benzylbromide (0.10 ml) and stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]-benzyl]-4-phenyl-3-pyrrolyl]-propionate (419 mg, yield: 95%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 126-127°C.

Example 75.

A mixture of ethyl 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-pyrrolyl]propionate (347 mg), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred over night while boiling under reflux and then the mixture was added 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[3-benzyloxy-5-[2-(2-pyrazinyl)-4-thiazoleacetate]benzyl]-4-phenyl-3-PI is roll]-propionic acid (274 mg, yield: 83%). Their recrystallized from ethanol-hexane. Melting point: 109-110°C.

Example 76.

Sodium hydride (60%in oil, 1.85 g) was added to a mixture of 4-benzyloxybenzaldehyde (10.8 g), ethyl 3-phenyl-1H-pyrazole-4-carboxylate (10.0 g) and N,N-dimethylformamide (50 ml) at 0°and the mixture was stirred for 1.5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (15.3 g, yield: 80%). Their recrystallized from ethyl acetate-diisopropyl ether. Melting point: 102-103°C.

Example 77.

A mixture of diethyl 2-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-ylmethyl]malonate (9,41 g), 4 N. of an aqueous solution of potassium hydroxide (30 ml) and ethanol (30 ml) was boiled under reflux for 1 hour. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate.

An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The residue was dissolved in pyridine (20 ml) and stirred at 110°C for 2 hours. After removal of the solvent under reduced pressure, the residue was extracted with ethyl acetate, the m An ethyl acetate layer was washed with diluted hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained crystals were collected by filtration to yield 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]-propionic acid (7,52 g, yield: 99%). Their recrystallized from ethyl acetate-hexane. Melting point: 147-148°C.

Example 78.

A mixture of 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionic acid (7.01 g), iodomethane (2,12 ml), potassium carbonate (4,70 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 48 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained methyl 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (6,51 g, yield: 90%) as an oily substance.

NMR (Dl3)δ: 2.48-2.57(2H, m), 2.90-2.98(2H, m), 3.61(3H, s), 5.06(2H, s), 5.23(2H, s), 6.95(2H, d, J=8.8 Hz), 7.17-7.46(11N, m), 7.59-7.66(2H, m).

Example 79.

A mixture of 4-chloromethyl-2-(2-furyl)-5-methoxazole (312 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7) - Rev. l) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (5:6, volume ratio)was obtained methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]- 3-phenyl-1H-pyrazole-4-yl]propionate (687 mg, yield: 87%) as an oily substance.

NMR (Dl3)δ: 2.42(3H, s), 2.49-2.58(2H, m), 2.90-2.99(2H, m), 3.61(3H, s), 4.98(2H, s), 5.24(2H, s), 6.51-6.54 (1H, m), 6.94-7.02(3H, m), 7.18-7.46(6N, m), 7.52-7.55 (1H, m), 7.60-7.66(1H, m).

Example 80.

A mixture of methyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (610 mg), monohydrate of lithium hydroxide (154 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3,7 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. Colorless crystals were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (583 mg, yield: 98%). Their recrystallized from ethyl acetate-hexane. Melting point: 152-153°C.

Example 81.

CME is ü 4-chloromethyl-5-methyl-2-(2-thienyl)oxazole (338 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio)was obtained methyl 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolidinone]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (715 mg, yield: 88%) as a colorless oily substance.

NMR (Dl3)δ: 2.41(3H, s), 2.49-2.58(2H, m), 2.90-2.99(2H, m), 3.61(3H, s), 4.96(2H, s), 5.24(2H, s), 6.98(2H, d, J=8.8 Hz), 7.06-7.12(1H, m), 7.17-7.46(7H, m), 7.60-7.66(3H, m).

Example 82.

A mixture of methyl 3-[1-[4-[5-methyl-2-(2-thienyl)-4-oxazolidinone]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (633 mg), monohydrate of lithium hydroxide (155 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3,7 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[5-methyl-2-(2-t is enyl)-4-oxazolidinone]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (581 mg, yield: 95%). Their recrystallized from ethyl acetate-hexane. Melting point: 159-160°C.

Example 83.

Diethylazodicarboxylate (40% in toluene, 753 mg) dropwise slowly added to a mixture of methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), [5-methyl-2-(4-pyridyl)-4-oxazolyl]methanol (274 mg), triphenylphosphine (414 mg) and tetrahydrofuran (7 ml) at room temperature. After stirring at room temperature for 4 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (3:1, volume ratio), obtained oily substance. A mixture of the obtained oily substance, monohydrate of lithium hydroxide (181 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (4.3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[5-methyl-2-(4-pyridyl)-4-oxazolidinone]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (470 mg, yield: 68%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 154-155°C.

Prima is 84.

A mixture of 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (307 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained methyl 3-[3-phenyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (651 mg, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 2.49-2.57 (2H, m), 2.90-2.99 (2H, m), 3.61(3H, s), 5.25(4H, s), 7.04(2H, d, J=8.8 Hz), 7.18-7.66(11N, m), 8.13-8.19(2H, m).

Example 85.

A mixture of methyl 3-[3-phenyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (560 mg), monohydrate of lithium hydroxide (139 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3.4 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield the m 3-[3-phenyl-1-[4-(5-phenyl-1,2,4-oxadiazol-3-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (529 mg, yield: 97%). Their recrystallized from ethyl acetate-hexane. Melting point: 166-167°C.

Example 86.

Diethylazodicarboxylate (40% in toluene, of 1.00 g) is added dropwise slowly added to a mixture of methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), (2,5-dimethyl-4-oxazolyl]methanol (275 mg), triphenylphosphine (585 mg) and tetrahydrofuran (10 ml) at room temperature. Then the mixture was stirred at room temperature for 8 hours, the reaction solvent was removed under reduced pressure. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (6:5, volume ratio)was obtained methyl 3-[1-[4-(2, 5-dimethyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (288 mg, yield: 44%) as an oily substance.

NMR (Dl3)δ: 2.31(3H, s), 2.41(3H, s), 2.49-2.58 (2H, m), 2.90-2.99(2H, m), 3.62(3H, s), 4.86(2H, s), 5.24(2H, s), 6.97(2H, d, J=8.8 Hz), 7.18-7.47(6N, m), 7.59-7.66(2H, m).

Example 87.

A mixture of methyl 3-[1-[4-(2,5-dimethyl-4-oxazolidinone)-benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (254 mg), monohydrate of lithium hydroxide (69,9 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (1.7 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO ), then concentrated to yield 3-[1-[4-(2, 5-dimethyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]-propionic acid (243 mg, yield: 99%) in the form of a non-crystalline substance.

NMR (Dl3)δ: 2.30(3H, s), 2.41(3H, s), 2.54(2H, t, J=7.4 Hz), 2.92(2H, t, J=7.4 Hz), 4.85(2H, s), 5.21(2H, s), 6.94(2H, d, J=8.4 Hz), 7.15-7.47(6N, m), 7.61(2H, d, J=7.0 Hz).

Example 88.

A mixture of 3-chloromethyl-5-methyl-2-phenyloxazole (324 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (397 mg) and N,N-dimethylformamide (7 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (657 mg, yield: 90%) as a colorless oily substance.

NMR (Dl3)δ: 2.43(3H,s), 2.49-2.58(2H, m), 2.95(2H, t, J=Hz), 3.61(3H, s), 4.99(2H, s), 5.24(2H, s), 7.00(2H, d, J=8.8 Hz), 7.18-7.47(M, m), 7.60-7.66(2H, m), 7.98-8.04(2H, m).

Example 89.

A mixture of methyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (640 mg), monohydrate of lithium hydroxide (363 mg), tetrahydrofuran ( ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (9 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]-propionic acid (592 mg, yield: 97%). Their recrystallized from ethyl acetate-hexane. Melting point: 179-180°C.

Example 90.

In thionyl chloride (1 ml) was added 4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl alcohol (400 mg) at 0°and was stirred at room temperature for 1 hour. Then thionyl chloride was removed under reduced pressure, the residue was dissolved in ethyl acetate and sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (gSO4), then concentrated. In the mixture the residue was added sodium hydride (60%in oil, 60 mg), ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (320 mg) and N,N-dimethylformamide (20 ml) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO 4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (340 mg, yield: 50%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.2 Hz), 2.39(3H,s), 2.52(2H, t, J=7.7 Hz), 2.94(2H, t, J=7.7 Hz), 4.07(2H, q, J=7.2 Hz), 4.97(2H, s), 5.24(2H, s), 6.94-6.99(2H, m), 7.11-7.45 (7H, m), 7.61-7.65(2H, m,), 7.74-7.82 (1H, m), 7.91 (1H, d, J=8.4 Hz), 8.36-8.39(1H, m), 8.53(1H, s).

Example 91.

A mixture of the hydrochloride of 3-picolylamine (148 mg), methyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (300 mg), potassium carbonate (357 mg) and N,N-dimethylformamide (5 ml) was stirred at 50°C for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate, was obtained colorless oily substance. A mixture of the obtained oily substance, monohydrate of lithium hydroxide (108 mg), tetrahydrofuran (6 ml), water (4 ml) and methanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2.6 ml) and was extracted with atilas what tatom. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[3-phenyl-1-[4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (279 mg, yield: 78%). Their recrystallized from acetone-hexane. Melting point: 112-113°C.

Example 92.

A mixture of ethyl 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (1,79 g), potassium hydroxide (0.75 g) and ethanol (30 ml) was boiled under reflux for 5 hours. After the solvent was removed under reduced pressure, the reaction mixture was added water, then the mixture was acidified using 1 N. hydrochloric acid. The obtained crystals were collected by filtration to yield 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylic acid (1,36 g, yield: 82%). Their recrystallized from acetone-hexane. Melting point: 152-153°C.

Example 93.

A mixture of 4-chloromethyl-5-methyl-2-phenyloxazole (2,42 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (3,40 g), potassium carbonate (of 2.51 g) and N,N-dimethylformamide (50 ml) was stirred overnight at 80°C. the Reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (1.78 g) and ethane is La (50 ml) was boiled under reflux for 5 hours. Then the reaction solvent was removed under reduced pressure, the reaction mixture was added water, then the mixture was acidified using 1 N. hydrochloric acid. The obtained crystals were collected by filtration to yield 1-[4-(5-methyl-2 phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-carboxylic acid (3,66 g, yield: 75%). Their recrystallized from acetone-hexane. Melting point: 165-166°C.

Example 94.

A mixture of 4-chloromethyl-2-phenylthiazole (1.19 g), ethyl 1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-carboxylate (1.65 g), potassium carbonate (1.18 g) and N,N-dimethylformamide (25 ml) was stirred overnight at 80°C. the Reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. A mixture of the residue, potassium hydroxide (0,93 g) and ethanol (50 ml) was boiled under reflux for 5 hours. Then the reaction solvent was removed under reduced pressure, the reaction mixture was added water, then the mixture was acidified using 1 N. hydrochloric acid. The obtained crystals were collected by filtration to yield 3-phenyl-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-1H-pyrazole-4-carboxylic acid (1,82 g, yield: 76%). Their recrystallized from acetone-hexane. Melting point: 119-120°C.

Example 95.

Thionyl chloride (1 ml) was added dropwise to a solution of [1-[4-(5-methyl-2-f the Nile-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl] methanol (3,01 g) in toluene (50 ml) at 0° C and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate. The solution was washed with water, then saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was dissolved in N,N-dimethylformamide (50 ml). Then the solution was added tianity sodium (0,82 g) at 0°C, the solution was stirred overnight at 70°C. the Reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (gSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), received a non-crystalline substance. The mixture obtained non-crystalline substances, 4 N. of an aqueous solution of potassium hydroxide (10 ml) and ethanol (20 ml) was boiled under reflux overnight. After the solvent was removed, added water to the mixture, then the mixture was acidified using 1 N. hydrochloric acid. The obtained crystals were collected by filtration to yield [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]acetate (2.38 g, yield: 74%). Their recrystallized from ethyl acetate-hexane. Melting point: 156-157°C.

Example 96

A mixture of 4-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]butyronitrile (1.27 g), 4 N. of an aqueous solution of potassium hydroxide (5 ml) and ethanol (10 ml) was boiled under reflux for 18 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 4-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]butane acid (709 mg, yield: 54%). Their recrystallized from ethyl acetate-hexane. Melting point: 118-119°C.

Example 97.

A mixture of diethyl 2-[3-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]propyl]-malonate (1.56 g), 4 N. of an aqueous solution of potassium hydroxide (5 ml) and ethanol (10 ml) was boiled under reflux for 30 minutes. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The mixture of residue and pyridine (10 ml) was stirred at 100°C for 2 hours. After the solvent was removed under reduced pressure, the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed izbavlenii hydrochloric acid, then saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 5-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-phenyl-1H-pyrazole-4-yl]pentanol acid (857 mg, yield: 65%). Their recrystallized from ethyl acetate-hexane. Melting point: 109-110°C.

Example 98.

Tetrakis(triphenylphosphine)palladium (120 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (1.20 g), 4-triftormetilfullerenov acid (0,46 g), 2 N. of an aqueous solution of sodium carbonate (2.6 ml), ethanol (3 ml) and toluene (50 ml). This mixture was boiled under reflux in an argon atmosphere for 13 hours. In the reaction mixture was added ethyl acetate, and the mixture was washed with a saturated aqueous solution of sodium chloride, dried (gSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid and extragear the Vali with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(4-triptoreline)-1H-pyrazole-4-yl]propionic acid (250 mg, yield: 22%). Their recrystallized from ethyl acetate-hexane. Melting point:

149-150°C.

Example 99.

Tetrakis(triphenylphosphine)palladium (130 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (1.31 g), 4-ftorhinolonovy acid (0.31 g), 2 N. aqueous sodium carbonate solution (2.9 ml), ethanol (3 ml) and toluene (50 ml). This mixture was boiled under reflux in an argon atmosphere for 13 hours. This reaction mixture was added ethyl acetate, and the mixture was washed with a saturated aqueous solution of sodium chloride, dried (gSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[3-(4-forfinal)-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (540 mg, yield 45%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 93-94°C.

Example 100.

A mixture of ethyl 3-[3-(4-ftoh the Nile)-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (500 mg), 1 N. aqueous sodium hydroxide solution (2 ml), ethanol (3 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[3-(4-forfinal)-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-1H-pyrazole-4-yl]propionic acid (330 mg, yield: 69%). Their recrystallized from ethyl acetate-hexane. Melting point: 139-140°C.

Example 101.

Tetrakis(triphenylphosphine)palladium (790 mg) was added to a mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (2.00 g), 4-methoxyphenylacetic acid (0,77 g), 2 N. aqueous sodium carbonate solution (5.0 ml), ethanol (5 ml) and toluene (100 ml). This mixture was boiled under reflux in an argon atmosphere for 13 hours. In the reaction mixture were added ethyl acetate and washed with saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxaz is lilimecocci)benzyl]-1H-pyrazole-4-yl]-propionate (450 mg, yield: 24%) as an oily substance.

NMR (Dl3)δ: 1,19(3H, t, J=7.0 Hz), 2,44(3H,c), of 2.51(2H, t, J=7.5 Hz), of 2.92(2H, t, J=7.5 Hz), of 3.84(3H, s)4,08(2H, q, J=7.0 Hz), 4,99(2H, s), with 5.22(2H, s), 6,93-7,02 (4H, m), 7,16-7,26(3H, m), 7,52-to 7.59(2H, m), 7,99-of 8.04(2H, m).

Example 102.

A mixture of ethyl 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (450 mg), 1 N. aqueous sodium hydroxide solution (2 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified using 1 N. hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[3-(4-methoxyphenyl)-1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (350 mg, yield: 81%). Their recrystallized from ethyl acetate-hexane. Melting point: 137-138°C.

Example 103.

Tetrakis(triphenylphosphine)palladium (990 mg) was added to a mixture of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone)-benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (2.50 g), 4-triftormetilfullerenov acid (1.23 g), 2 N. of an aqueous solution of sodium carbonate (6.5 ml), ethanol (7 ml) and toluene (100 ml). This mixture was boiled under reflux in an argon atmosphere for 13 hours is. This reaction mixture was added ethyl acetate and washed with saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone)benzyl]-3-(4-triptoreline)-1H-pyrazole-4-yl]propionic acid (680 mg, yield: 29%). Their recrystallized from ethyl acetate-hexane. Melting point: 92-93°C.

Example 104.

Tetrakis(triphenylphosphine)palladium (878 mg) was added to a mixture of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone)-benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (2,22 g), 4-ftorpolimernoj acid (798 mg), 2 N. aqueous sodium carbonate (10 ml), ethanol (10 ml) and toluene (30 ml). This mixture was heated with reverse hall is dildocam in argon atmosphere for 13 hours. This reaction mixture was added ethyl acetate and washed with saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[3-(4-forfinal)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]-propionate (350 mg, yield: 17%) as a colorless oily substance.

NMR (Dl3)δ: 1,19(3H, t, J=7.2 Hz), 2,42(3H,c), of 2.51(2H, t, J=7,6 Hz), only 2.91(2H, t, J=7,6 Hz), 4,08(2H, q, J=7.2 Hz), to 4.98(2H, s), with 5.22(2H, s), 6,53(1H, DD, J=3,4, 1.8 Hz), of 6.96-7,01(3H, m), 7,05-of 7.23(5H, m), 1, 53-7,63(2H, m).

Example 105.

A mixture of ethyl 3-[3-(4-forfinal)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (350 mg), 1 N. aqueous sodium hydroxide solution (2 ml), ethanol (4 ml) and tetrahydrofuran (4 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. The obtained colorless crystals were collected by filtration to yield 3- [3-(4-forfinal)-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (150 mg, yield: 45%). Their recrystallized from ethyl acetate-hexane. Point p is Alenia: 125-126° C.

Example 106.

A mixture of 4-(4-chloromethylene)methyl-5-methyl-2-phenyloxazole (7,13 g), ethyl 3-isopropyl-1H-pyrazole-4-carboxylate (6,17 g), potassium carbonate (4.72 in g) and N,N-dimethylformamide (70 ml) was stirred at 80°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4), then concentrated. A mixture of the residue, potassium hydroxide (4.83 g) and ethanol (150 ml) was boiled under reflux for 5 hours. Then the reaction solvent was removed under reduced pressure, the mixture was added water, then the mixture was acidified with diluted hydrochloric acid. The obtained crystals were collected by filtration to yield 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-carboxylic acid (is 11.39 g, yield: 78%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 194-195°C.

Example 107.

A mixture of 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-carboxylic acid (of 10.09 g), iodomethane (2 ml), potassium carbonate (4.83 g) and N,N-dimethylformamide (50 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. Estato is subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained methyl 3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carboxylate (9.80 g, yield: 94%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 90-91°C.

Example 108.

Methanesulfonamide was added dropwise to a mixture of [3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]methanol (2,02 g), triethylamine (0.8 ml) and ethyl acetate (30 ml) at 0°and was stirred at room temperature for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was dissolved in tetrahydrofuran (20 ml). This solution was added dropwise at 0°it received a separate solution of tetrahydrofuran (30 ml) of sodium diethylmalonate, using diethylmalonate (2.35 g) and sodium hydride (60%in oil, 0.55 g). The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was dissolved in ethanol (50 ml), then the solution was added 1 N. aqueous sodium hydroxide solution (15 ml) and stirred at 60°for 2 is aces. Then the reaction solvent was removed under reduced pressure, adding water to the mixture and acidified with diluted hydrochloric acid. Then the obtained crystals were filtered and washed with water, the crystals were dissolved in pyridine (50 ml) and stirred at 120°C for 2 hours. Then the pyridine was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed with diluted hydrochloric acid, then saturated aqueous sodium chloride and dried (MgSO4), then concentrated. The obtained crystals were collected by filtration to yield 3-[3-isopropyl-1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (1.23 g, yield: 55%). Their recrystallized from ethyl acetate-hexane. Melting point: 97-98°C.

Example 109.

Sodium hydride (60%in oil, 110 mg) was added to a mixture of 4-[(4-chloromethylene)methyl]-5-methyl-2-phenyloxazole (910 mg), ethyl 3-(3-propyl-1H-pyrazole-4-yl)propionate (500 mg) and N,N-dimethylformamide (10 ml) and was stirred for 12 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-propyl-1H-pyrazole-4-yl]propionate (620 mg, in the progress: 53%) as a colorless oily substance.

NMR (Dl3)δ: of 0.97(3H, t, J=7.2 Hz), to 1.21(3H, t, J=7.2 Hz), 1,60-1,75(2H, m), 2,43(3H, s), 2,45 at 2.59(4H, m), 2,66 is 2.75(2H, m), 4,10(2H, q, J=7.2 Hz), to 4.98(2H, s), 5,14(2H, s), 6,94? 7.04 baby mortality(3H, m), 7,11-7,16(2H, m), 7,42 was 7.45(3H, m), 7,98-of 8.04 (2H, m).

Example 110.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-propyl-1H-pyrazole-4-yl]propionate (610 mg), 1 N. aqueous sodium hydroxide solution (2.6 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained crystals were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-propyl-1H-pyrazole-4-yl]propionic acid (480 mg, yield: 80%). Their recrystallized from ethyl acetate-hexane. Melting point: 153-154°C.

Example 111.

Using chromatography on a column of silica gel of fractions, elyuirovaniya after elution of the compound of example 109 was obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-5-propyl-1H-pyrazole-4-yl]propionate (240 mg, yield: 21%) as a colorless oily substance.

NMR (Dl3)δ: to 0.89(3H, t, J=7.2 Hz), 1,24(3H, t, J=7.2 Hz), of 1.35 to 1.47(2H, m), 2,42(3H, s), 2,43-of 2.58(4H, m), 2,67 is 2.75(2H, m), of 4.13(2H, q, J=7.2 Hz), 4,96(2H, s), 5,20(2H, s), 6,91-7,06(4H, m), 7,33(1H, s), 7,41-,45(3H, m), 7,98-8,03(2H, m).

Example 112.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-5-propyl-1H-pyrazole-4-yl]propionate (210 mg), 1 N. aqueous sodium hydroxide solution (1 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained crystals were collected by filtration to yield 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-5-propyl-1H-pyrazole-4-yl]propionic acid (170 mg, yield: 85%). Their recrystallized from ethyl acetate-hexane. Melting point: 158-159°C.

Example 113.

A mixture of ethyl 3-[1-[4-[3-methyl-1-(2-pyridyl)-)-4-ylethoxy]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (340 mg), 1 N. aqueous sodium hydroxide solution (1.5 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 1 hour. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The obtained crystals were collected by filtration to yield 3-[1-[4-(3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-3-phenyl)-4-yl]propionic what Islami (320 mg, yield: 88%). Their recrystallized from ethyl acetate-hexane. Melting point: 131-132°C.

Example 114.

Sodium hydride (60%in oil, 200 mg) was added to a solution of N.N-dimethylformamide (15 ml), ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (1.04 g) at 0°and was stirred for 30 minutes at 0°C. In the reaction mixture were added 4-[2-(4-chloromethylene)ethyl]-5-methyl-2-phenyloxazol (1,43 g) and stirred at room temperature over night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained oily substance. The mixture obtained substances, 1 N. aqueous sodium hydroxide solution (4 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred for 2 hours at room temperature. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgS4), then concentrated. The obtained crystals were collected by filtration to yield 3-[1-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (930 mg, output is: 71%). Their recrystallized from acetone-hexane. Melting point: 142-143°C.

Example 115.

Sodium hydride (60%in oil, 170 mg) was added to a solution of N.N-dimethylformamide (50 ml) of ethyl 3-(3-phenyl-1H-pyrazole-4-yl) propionate (890 mg) at 0°and the mixture was stirred at 0°C for 30 minutes. In the reaction mixture was added 2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]ethylmethanesulfonate (2,79 g) and stirred at 90°C for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the obtained ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-ethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (1.19 g, yield: 62%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 81-82°C.

Example 116

A mixture of ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)phenyl]ethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (900 mg), 1 N. aqueous sodium hydroxide solution (3.4 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated aqueous solution of chloride on the matter, dried (gSO4), then concentrated. The obtained crystals were collected by filtration to yield 3-[1-[2-[4- (5-methyl-2-phenyl-4-oxazolidinone)-phenyl]ethyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (860 mg, yield: 91%). Their recrystallized from ethyl acetate-hexane. Melting point: 85-86°C.

Example 117.

Thionyl chloride (0,31 ml) was added dropwise into a solution of toluene (30 ml), 4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy] -benzyl alcohol (900 mg) at 0°C. the Reaction mixture was stirred at room temperature for 2 hours, then concentrated. The residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate, then saturated aqueous sodium chloride and dried (MgSO4), then concentrated. The residue and ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (860 mg) was dissolved in N,N-dimethylformamide (15 ml). To the solution was added sodium hydride (60%in oil, 100 mg) and then stirred at room temperature for 12 hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride and dried (MgSO4), then concentrated. The residue was subjected to chromatography on a column of silica gel and the obtained ethyl 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-3-phenyl-1H-feast of the evil-4-yl]-propionate (0.75 g, yield: 68%) as a colorless oily substance.

NMR (Dl3)δ: of 1.17(3H, t, J=7.0 Hz), 2,46-of 2.54(2H, m), 2,89-of 2.97(2H, m), and 3.16(3H, s)to 3.99(2H, t, J=5.4 Hz), 4,06(2H, q, J=7.0 Hz), 4,19(2H, t, J=5.4 Hz), to 5.21(2H, s), 6,51-6,59(2H, m), 6,83-6,89(2N, m), 7,15-7,51(7H, m), to 7.59-to 7.64(2H, m), 8,13-8,17(1H, m).

Example 118.

A mixture of ethyl 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]-benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (750 mg), 1 N. aqueous sodium hydroxide solution (3 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for one hour. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate.

An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (610 mg, yield: 90%). Their recrystallized from ethyl acetate-hexane. Melting point: 110-111°C.

Example 119.

2-Chloromethyl-6-(2-forbindelse)naphthalene (540 mg) and ethyl 3-(3-phenyl-1H-pyrazole-4-yl]propionate (390 mg) was dissolved in N,N-dimethylformamide (10 ml). To the solution was added sodium hydride (60%in oil, 70 mg) at 0°and was stirred at room temperature for two hours. The reaction mixture was poured into a saturated aqueous solution of sodium chloride and was extracted with ethyl acetate, the m An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[1-[6-(2-forbindelse)-2-naphthylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (0,58 g, yield: 72%) as a colorless oily substance.

NMR (Dl3)δ: to 1.14(3H, t, J=7.0 Hz), 2,47-of 2.50 (2H, m), 2.91 in are 2.98(2H, m), Android 4.04(2H, q, J=7.0 Hz), 5.25(2H,s), 7,06-to 7.77(M, m).

Example 120.

A mixture of ethyl 3-[1-[6-(2-forbindelse-2-naphthylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (580 mg), 1 N. aqueous sodium hydroxide solution (2.2 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for two hours. The reaction mixture was acidified with diluted hydrochloric acid and the obtained colorless crystals were collected by filtration and obtained 3-[1-[6-(2-forbindelse)-2-naphthylmethyl]-3-phenyl-1H-pyrazole-4-yl]-propionic acid (450 mg, yield: 85%). Their recrystallized from ethanol. Melting point: 152-153°C.

Example 121.

A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (500 mg), 4-triphtalocyaninine (250 mg), 1-hydroxybenzotriazole (210 mg), WSC (270 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. P is a promotional mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (3:1, volume ratio)was obtained ethyl 3-[3-phenyl-1-[4-(4-trifluoromethyl-benzylaminocarbonyl)benzyl]-1H-pyrazole-4-yl)propionate (550 mg, yield: 77%) as a colorless amorphous substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.0 Hz), 2.47(3H, s), 2.53(2H, t, J=7.6 Hz), 2.95(2H, t, J=7.6 Hz), 4.07(2H, q, J=7.0 Hz), 4.52(2H, d, J=5.2 Hz), 5.33(2H, s), 6.83(1H, users), 7.24-7.47(M, m), 7.60-7.65(2H, m), 7.76-7.81(2H, m), 7.96-8.01(2H, m).

Example 122.

A mixture of ethyl 3-[3-phenyl-1-[4-(4-triftoratsetilatsetonom)benzyl]-1H-pyrazole-4-yl]propionate (680 mg), 1 N. aqueous sodium hydroxide solution (1.7 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for two hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-phenyl-1-[4-(4-triftoratsetilatsetonom)benzyl]-1H-pyrazole-4-yl]propionic acid (620 mg, yield: 94%). Their recrystallized from ethyl is the Etat-hexane. Melting point: 151-152°C.

Example 123.

A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (500 mg), (5-methyl-2-phenyl-4-oxazolyl)methylamine (260 mg), monohydrate of 1-hydroxybenzotriazole (210 mg), WSC (270 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 13 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained yellow crystals were collected by filtration and obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinedione)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (600 mg, yield: 87%). Their recrystallized from ethyl acetate-hexane. Melting point: 190-191°C.

Example 124.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinedione)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (550 mg), 1 N. aqueous sodium hydroxide solution (1.3 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for two hours. The reaction mixture was acidified with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. Received Chris is Alla was collected by filtration and obtained 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinedione)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (500 mg, yield: 96%). Their recrystallized from acetone-methanol. Melting point: 177-178°C.

Example 125.

A mixture of 3-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (700 mg), 4-triphtalocyaninine (390 mg), 1-hydroxybenzotriazole (340 mg), WSC (430 mg) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 18 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya acetone-hexane (1:2, volume ratio)was obtained ethyl 3-[3-phenyl-1-[3-(4-triftoratsetilatsetonom)benzyl]-1H-pyrazole-4-yl]-propionate (900 mg, yield: 91%) as an oily substance.

NMR (Dl3)δ: 1.13(3H, t, J=7 Hz), 2.52(2H, t, J=7.3 Hz), 2.96(2H, t, J=7.3 Hz), 3.98(2H, q, J=7 Hz), 4.68(2H, d, J=6 Hz), 5.35(2H, s), 6.80(1H, users), 7.25-7.65(13H, m), 7.7-7.8(1H, m).

Example 126.

A mixture of ethyl 3-[3-phenyl-1-[3-(4-trifloromethyl-aminocarbonyl)benzyl]-1H-pyrazole-4-yl]propionate (870 mg), 1 N. aqueous sodium hydroxide solution (2 ml), ethanol (6 ml) and tetrahydrofuran (4 ml) was stirred at room temperature for one hour. The reaction mixture was poured into water, then the mixture was added 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer washed is whether water, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-phenyl-1-[3-(4-triftoratsetilatsetonom)benzyl]-1H-pyrazole-4-yl]-propionic acid (730 mg, yield: 89%). Their recrystallized from acetone-isopropyl ether. Melting point: 165-166°C.

Example 127.

A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (300 mg), 2-picolylamine (95 mg), monohydrate of 1-hydroxybenzotriazole (130 mg), WSC (170 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-methanol (50:1, volume ratio)was obtained ethyl 3-[3-phenyl-1-[3-(2-picolylamine)benzyl]-1H-pyrazole-4-yl]propionate (200 mg, yield: 54%) as a colorless oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.2 Hz), 2.53(2H, t, J=7.6 Hz), 2.96(2H, t, J=7.6 Hz), 4.06(2H, q, J=7.2 Hz), 4.76(2H, J=4.8 Hz), 5.36(2H, s), 7.18-7.49(7H,m), 7.61-7.84(6N,m), 8.53(1H, m, J=4.0 Hz).

Example 128.

A mixture of ethyl 3-[3-phenyl-1-[3-(2-picolylamine)-benzyl]-1H-pyrazole-4-yl]propionate (180 mg), 1 N. aqueous sodium hydroxide solution (0,77 ml), ethanol (1 ml) is tetrahydrofuran (1 ml) was stirred at room temperature for one hour. In the reaction mixture were added 1 N. hydrochloric acid (0,77 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-phenyl-1- [3-(2-picolylamine)benzyl]-1H-pyrazole-4-yl]propionic acid (120 mg, yield: 71%). Their recrystallized from ethyl acetate-hexane. Melting point: 83-85°C (decomposition).

Example 129.

A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (400 mg), 2-aminopyridine (120 mg), monohydrate of 1-hydroxybenzotriazole (200 mg), WSC (250 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then with saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (5:1, volume ratio)was obtained ethyl 3-[3-phenyl-1-[3-(2-pyridylmethyl)benzyl]-1H-pyrazole-4-yl]propionate (200 mg, yield: 40%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.0 Hz), 2.54(2H, t, J=7.4 Hz), 2.97(2H, t, J=7.4 Hz), 4.08(2H, q, J=7.0 Hz), .37(2H, s), 7.05-7.12(1H, m), 7.26-7.86(11N, m), 8.30-8.39(2H, m), 8.56(1H, users).

Example 130.

A mixture of ethyl 3-[3-phenyl-1-[3-(2-pyridylmethyl)-benzyl]-1H-pyrazole-4-yl]propionate (200 mg), 1 N. aqueous sodium hydroxide solution (0,88 ml), ethanol (1 ml) and tetrahydrofuran (1 ml) was stirred at room temperature for one hour. In the reaction mixture were added 1 N. hydrochloric acid (0,88 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-phenyl-1-[3-(2-pyridylmethyl)benzyl]-1H-pyrazole-4-yl]propionic acid (110 mg, yield: 58%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 187-188°C.

Example 131.

A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (400 mg), 2-(2-pyridyl)ethylamine (170 mg), monohydrate of 1-hydroxybenzotriazole (200 mg), WSC (250 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 2.5 days. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica the LEM and from the faction, elyuirovaniya with ethyl acetate-methanol (50:1, volume ratio)was obtained ethyl 3-[3-phenyl-1-[3-[2-(2-pyridyl) ethylaminomethyl)benzyl]-1H-pyrazole-4-yl]propionate (460 mg, yield: 87%) as a colorless oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.0 Hz), 2.52(2H, t, J=7.6 Hz), 2.95(2H, t, J=7.6 Hz), 3.08(2H, t, J=6.0 Hz), 3.85(2H, q, J=6.0 Hz), 4.06(2H, q, J=7.0 Hz), 5.33(2H, s), 7.07-7.72(13H, m), 8.49(1H, d, J=4.0 Hz).

Example 132.

A mixture of ethyl 3-[3-phenyl-1-[3-[2-(2-pyridyl) ethylaminomethyl]benzyl]-1H-pyrazole-4-yl]propionate (450 mg), 1 N. aqueous sodium hydroxide solution (2 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. In the reaction mixture is then added 1 N. hydrochloric acid (2 ml), the reaction mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-phenyl-1-[3-[2-(2-pyridyl)ethylaminomethyl]-benzyl]-1H-pyrazole-4-yl]propionic acid (400 mg, yield: 95%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 166-167°C.

Example 133.

A mixture of 4-[4-(2-ethoxycarbonylethyl)-3-phenyl-1H-pyrazole-1-ylmethyl]benzoic acid (400 mg), 3-aminopyridine (160 mg), monohydrate of 1-hydroxybenzotriazole (200 mg), WSC (250 mg) and N,N-dimethylformamide (10 ml) was stirred at on the th temperature for 2.5 days. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-methanol (50:1, volume ratio)was obtained ethyl 3-[3-phenyl-1-[3-(3-pyridylamino-carbonyl)benzyl]-1H-pyrazole-4-yl]propionate (280 mg, yield: 56%) as colorless crystals. Melting point: 111-112°C.

Example 134.

A mixture of ethyl 3-[3-phenyl-1-[3-(3-pyridylmethyl)-benzyl]-1H-pyrazole-4-yl]propionate (230 mg), 1 N. aqueous sodium hydroxide solution (1.2 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. Then the reaction mixture was added 1 N. hydrochloric acid (1.2 ml), the reaction mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-phenyl-1-[3-(3-pyridylmethyl)benzyl]-1H-pyrazole-4-yl]propionic acid (190 mg, yield: 86%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 131-132°C.

Example 135.

In a mixture of 2-(4-benzyloxyphenyl)ethanol (119 g), triethylamine (700 mg) and ethyl acetate (30 ml) was added dropwise methanesulfonanilide (790 mg) at 0°and the mixture was stirred at room temperature for two hours. The reaction mixture was washed with water, saturated aqueous sodium bicarbonate, 1 N. hydrochloric acid, then with saturated sodium chloride solution, dried (gSO4) and concentrated. In the mixture of the residue, ethyl (3-phenyl-1H-pyrazole-4-yl)acetate (1.0 g) and N,N-dimethylformamide (50 ml), sodium hydride (60%in oil, 190 mg) was added at 0°and the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya diethyl ether-hexane (2:3, volume ratio)was obtained ethyl [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (0.45 g, yield: 24%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7.0 Hz), 3.15(2H, t, J=7.4 Hz), 3.57(2H, s), 4.13(2H, q, J=7.0 Hz), 4.31(2H, t, J=7.4 Hz), 5.05(2H, s), 6.87-6.92(2H, m), 7.02-7.07(2H, m), 7.31-7.47 (M, m), 7.58-7.64(2H, m).

Example 136.

To a solution of ethyl 1-[2-(4-hydroxyphenyl)ethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (400 mg) in N,N-dimethylformamide (10 ml), was added sodium hydride (60%, by weight of the e, 50 mg) at 0°and the solution was stirred at room temperature for 30 minutes. To this solution was added 4-chloromethyl-5-methyl-2-phenyloxazol (290 mg) and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl [1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]ethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (260 mg, yield: 46%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7.0 Hz), 2.43(3H, s), 3.15(2H, t, J=7.4 Hz), 3.57(2H, s), 4.13(2H, q, J=7.0 Hz), 4.31(2H, t, J=7.4 Hz), 4.97(2H, s), 6.91-6.96(2H, m), 7.03-7.08(2H, m), 7.26-7.45(7H, m), 7.58-7.63(2H, m), 7.99-8.04(2H, m).

Example 137.

A mixture of ethyl [1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)-phenyl]ethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (260 mg), 1 N. aqueous sodium hydroxide solution (1 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for one hour. Then the reaction mixture was added 1 N. hydrochloric acid (1 ml), the reaction mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) concentrically. The obtained crystals were collected by filtration and obtained 1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]-ethyl-3-phenyl-1H-pyrazole-4-luksusowe acid (170 mg, yield: 68%). Their recrystallized from ethyl acetate-hexane. Melting point: 104-105°C.

Example 138.

A mixture of 4-(4-chloromethylene)methyl-5-methyl-2-phenyloxazole (3.55 g), ethyl 1H-pyrazole-4-carboxylate (1.50 g), potassium carbonate (2.76 g) and N,N-dimethylformamide (25 ml) was stirred at room temperature for 24 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained crystals were collected by filtration and obtained ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carboxylate (3,79 g, yield: 91%). Their recrystallized from ethyl acetate-hexane. Melting point: 108-109°C.

Example 139.

Sodium hydride (60%in oil, 336 mg) was added at 0°C solution of ethyl diethylphosphonoacetate (1,67 ml) in tetrahydrofuran (20 ml) and stirred at 0°C for 30 minutes. To this solution was added dropwise a solution of 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-carbaldehyde (2,61 g) in tetrahydrofuran (20 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was poured in at the y and was extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propenoate (2,78 g, yield: 90%). Their recrystallized from ethyl acetate-hexane. Melting point: 112-113°C.

Example 140.

A mixture of ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propenoate (887 mg), 1 N. aqueous sodium hydroxide solution (4 ml), ethanol (8 ml) and tetrahydrofuran (8 ml) was stirred at 40°C for 3 hours. Then the reaction mixture was acidified using 1 N. hydrochloric acid, the resulting crystals were collected by filtration and was obtained (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propanolol acid (672 mg, yield: 81%). Their recrystallized from ethanol. Melting point: 186-187°C.

Example 141.

A mixture of ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propenoate (1.78 g), 5% palladium on coal (2.0 g), ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred at room temperature for one hour in hydrogen atmosphere. After removal of catalyst by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), is Uchali ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (1,57 g, yield: 88%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 2.42(3H, s), 2.52(2H, t, J=7.2 Hz), 2.77(2H, t, J=7.2 Hz), 4.10(2H, q, J=7.0 Hz), 4.97(2H, s), 5.17(2H, s), 6.98(2H. D. J=8.6 Hz), 7.15(1H, s), 7.18(2H, d, J=8.6 Hz), 7.36(1H, s), 7.39-7.46 (3H, m), 7.97-8.03(2H, m).

Example 142.

A mixture of ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-1H-pyrazole-4-yl]propionate (1,34 g), 1 N. aqueous sodium hydroxide solution (6 ml), ethanol (12 ml) and tetrahydrofuran (12 ml) was stirred at room temperature for two hours. Then the reaction mixture was added 1 N. hydrochloric acid (6 ml), the reaction mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration, was obtained 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (1,21 g, yield: 97%). Their recrystallized from ethanol-hexane. Melting point: 124-125°C.

Example 143

To a solution of 3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-carbaldehyde (900 mg) and ethyl diethylphosphonoacetate (1.10 g) in N,N-dimethylformamide (20 ml), was added sodium hydride (60%in oil, 200 mg) at 0°and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer is amywali water, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration and obtained ethyl (E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propenoate (740 mg). Then, the original solution was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio), additionally received 150 mg of crystals. Just received 890 mg (yield: 87%). Their recrystallized from ethyl acetate-isopropyl ether. Melting point: 98-99°C.

Example 144.

A mixture of ethyl (E)-3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propenoate (800 mg), 5% palladium on coal (400 mg), ethanol (30 ml) and tetrahydrofuran (10 ml) was stirred at room temperature for one hour in hydrogen atmosphere. Then the catalyst was removed by filtration and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3,5-dimethyl-1- [4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (770 mg, yield: 96%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7 Hz), 2.09(3H, s), 2.22(3H, s), 2.35-2.5(5H, m), 2.6-2.75(2H, m), 4.09(2H, q, J=7 Hz), 4.96(2H, s), 5.14(2H, s), 6.94(2H, d, J=9 Hz), 7.02(2H, d, J=9 Hz), 7.4-7.5(3H, m), 7.95-8.1(2H, m)

Example 145.

A mixture of ethyl 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (760 mg), 1 N. aqueous sodium hydroxide solution (5 ml), ethanol (5 ml) and tetrahydrofuran (5 ml) was stirred at room temperature for two hours. The reaction mixture was poured into water and acidified 1 N. hydrochloric acid, and the precipitated crystals were collected by filtration. Their recrystallized from methanol-ethyl acetate and obtained 3-[3,5-dimethyl-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (550 mg, yield: 77%). Melting point: 170-171°C.

Example 146.

A mixture of ethyl [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (440 mg), 1 N. aqueous sodium hydroxide solution (2 ml), ethanol (2 ml) and tetrahydrofuran (2 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified using 1 N. hydrochloric acid. The obtained crystals were collected by filtration and was received [1-[2-(4-benzyloxyphenyl)ethyl]-3-phenyl-1H-pyrazole-4-yl]acetic acid (350 mg, yield: 85%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 199-200°C.

Example 147.

A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (12,18 g), 4-(4-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazole (55,11 g), potassium carbonate (25,52 g) and N,N-dimethylformamide (300 ml) was stirred at 90°C for 8 hours. The reaction to shift the ü poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-carboxylate (48,16 g, yield: 87%) as colorless crystals. Their recrystallized from acetone-hexane. Melting point: 118-119°C.

Example 148.

In a mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-carbaldehyde (25,20 g), ethyl diethylphosphonoacetate (9,50 g) and N,N-dimethylformamide (200 ml) was added sodium hydride (60%in oil, 1.68 g) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water, the resulting crystals were collected by filtration and obtained ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyloxy]-1H-pyrazole-4-yl]propenoate (25,58 g, yield: 92%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 148-149°C.

Example 149.

A mixture of ethyl (E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)-Ben is yloxy]-1H-pyrazole-4-yl]propenoate (24,15 g), 5% palladium on coal (34,22 g) and tetrahydrofuran (400 ml) was stirred at room temperature in hydrogen atmosphere overnight. Then the catalyst was removed by filtration and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (2:1, volume ratio)was obtained ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate as colorless crystals (13,93 g, yield: 92%). Their recrystallized from tetrahydrofuran-hexane.

Melting point: 137-138°C.

Example 150.

After a mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (650 mg), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature for three hours, the mixture was added 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (560 mg, yield: 91%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 197-198°C.

Example 151.

In rest the p ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (1,00 g) in tetrahydrofuran (80 ml) was added sodium hydride (60%, in oil, 100 mg) at 0°and the solution was stirred for 30 minutes. In the reaction mixture were added N-phenyltrichlorosilane (930 mg) and stirred at room temperature for two hours. The reaction mixture was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then with saturated sodium chloride solution, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (1.31 g, yield: 100%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.0 Hz), 2.43 (3H, s), 2.48-2.56 (2H, m), 2.69-2.76 (2H, m), 4.09 (2H, q, J=7.0 Hz), 4.99 (2H, s), 5.10 (2H, s), 6.98-7.02 (2H, m), 7.11-7.20 (3H, m), 7.42-7.46 (3H, m), 7.99-8.04 (2H, m).

Example 152.

To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 40,0 mg) at 0°and the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added logmean (0,187 ml) and stirred at room temperature for one hour. The reaction mixture was poured in in the control and were extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (382 mg, yield: 80%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.2 Hz), 2.43 (3H, s), 2.46-2.54 (2H, m), 2.60-2.68 (2H, m), 3.90 (3H, s), 4.09 (2H, q, J=7.2 Hz), 4.98 (2H, s), 5.01 (2H, s), 6.93 (1H, s), 6.98 (2H, d, J=8.8 Hz), 7.15 (2H, d, J=8.8 Hz), 7.40-7.47 (3H, m), 7.99-8.04 (2H, m).

Example 153.

A mixture of ethyl 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (380 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, diluted with 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-methoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (319 mg, yield: 89%). Their recrystallized from ethanol-hexane. Melting point: 127-128°C.

Example 154.

To a solution of ethyl 3-[3-is hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (462 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%, in oil, 40,0 mg) at 0°and the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added Iodate (0,240 ml) and stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (452 mg, yield: 92%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.2 Hz), 1.36 (3H, t, J=7.0 Hz), 2.43 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J=7.2 Hz), 4.23 (2H, q, J=7.0 Hz), 4.98 (2H, s), 5.00 (2H, s), 6.93 (1H, s), 6.97 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.40-7.47 (3H, m), 7.97-8.06 (2H, m).

Example 155.

A mixture of ethyl 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (441 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4and the end of what was tarawali. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H - pyrazole-4-yl]propionic acid (328 mg, yield: 79%). Their recrystallized from ethanol-hexane. Melting point: 96-97°C.

Example 156.

To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (710 mg) in N,N-dimethylformamide (10 ml), was added sodium hydride (60%in oil, 72,0 mg) at 0°and the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added jumprope (0.33 g) and stirred at room temperature for two hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated aqueous solution of CHL is reed sodium, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-propyloxy-1H-pyrazole-4-yl]propionic acid (0,59 g, yield: 81%). Their recrystallized from acetone-hexane. Melting point: 108-109°C.

Example 157.

A mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (700 mg), potassium carbonate (250 mg), jeditorpane (1,03 g) and N,N-dimethylformamide (15 ml) was stirred at 80-90°C for four hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate as a colorless oily substance (460 mg, yield: 60%).

NMR (Dl3)δ: 1.21 (3H, t, J=7 Hz), 1.32 (6N, d, J=6 Hz), 2.43 (3H, s), 2.45-2.7 (4H, m), 4.09 (2H, q, J=7 Hz), 4.75-4.95 (1H, m), 4.98 (2H, s), 5.00 (2H, s), 6.92 (1H, s), 6.97 (2H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz), 7.4-7.5 (3H, m), 7.95-8.1 (2H, m).

Example 158

A mixture of ethyl 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (440 mg), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydro the uranium (5 ml) and ethanol (5 ml) was stirred at room temperature for one hour, diluted 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-isopropoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (380 mg, yield: 91%). Their recrystallized from acetone-isopropyl ether. Melting point: 106-107°C.

Example 159.

A mixture of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (165 mg), benzylbromide (205 mg) and N.N-dimethylformamide (10 ml) was stirred at 80°C for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (385 mg, yield: 64%) as a colorless oily substance.

NMR (Dl3)δ: 1.19 (3H, t, J=7 Hz), 2.44 (3H, s), 2.45-2.7 (4H, m), 4.07 (2H, q, J=7 Hz), 4.99 (2H, s), 5.03 (2H, s), 5.24 (2H, s), 6.96 (1H, s), 6.98 (2H, d, J=9 Hz), 7.14 (2H, d, J=9 Hz), 7.3-7.5 (8H, m), 7.95-8.1 (2H, m).

Example 160.

A mixture of ethyl 3-[3-gasoline is hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (380 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for one hour and then diluted with 1 N. hydrochloric acid (5 ml) to give colorless crystals, which were collected by filtration. Their recrystallized from ethyl acetate-hexane, to yield 3-[3-benzyloxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (300 mg, yield: 83%). Melting point: 108-109°C.

Example 161.

To a solution of ethyl 3-[3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (1,00 g) in N,N-dimethylformamide (80 ml) was added sodium hydride (60%in oil, 100 mg) at 0°and the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added 2-chloro-5-triptorelin (0.45 g) and stirred at 90°C for two hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (10 ml) was stirred at room temperature overnight, diluted 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(5-trifluoromethyl-2-pyridyloxy)-1H-pyrazole-4-yl]propionic acid (960 mg, yield: 76%). Their recrystallized from ethyl acetate-hexane. Melting point: 107-108°C.

Example 162.

A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (5.50 g), 4-(4-chloromethylphenoxyacetic)-2-(2-furyl)-5-methoxazole (22,85 g), potassium carbonate (15,11 g) and N,N-dimethylformamide (200 ml) was stirred at 90°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 1-[4-[2-(2-furyl)- 5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyloxy]-1H-pyrazole-4-carboxylate (19,96 g, yield: 82%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 133-134°C.

Example 163.

In the mixture is 1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyloxy]-1H-pyrazole-4-carbaldehyde (14,09 g), the ethyl diethylphosphonoacetate (5,88 g) and N,N-dimethylformamide (100 ml) was added sodium hydride (60%in oil, 1.01 g) at 0°and the mixture was stirred at room temperature for two hours. The reaction mixture was poured into ice water and the resulting crystals were collected by filtration and obtained ethyl (E)-3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyloxy]-1H-pyrazole-4-yl]-propanoate (13,91 g, yield: 89%). Their recrystallized from ethyl acetate-hexane. Melting point: 138-139°C.

Example 164.

A mixture of ethyl (E)-3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyloxy]-1H-pyrazole-4-yl]propenoate (12.5 g), 5% palladium on coal (20,0 g), ethanol (200 ml) and tetrahydrofuran (200 ml) was stirred in hydrogen atmosphere at room temperature for 7 hours. Then the catalyst was removed by filtration, the filtrate was concentrated. The obtained crystals were collected by filtration and obtained ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-hydroxy-1H-pyrazole-4-yl]propionate (4,40 g, yield: 56%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 145-146°C.

Example 165.

To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-hydroxy-1H-pyrazole-4-yl]propionate (4,29 g) in tetrahydrofuran (100 ml), sodium hydride (60%in oil, 420 mg) EXT is ulali at 0° And the solution was stirred for 10 minutes. In the reaction mixture were added N-phenyltrichlorosilane (3.75 g) and stirred at 0°C for 20 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated aqueous sodium bicarbonate solution, 1 N. hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-tripterocalyx-1H-pyrazole-4-yl]propionate (5,02 g, yield: 91%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.2 Hz), 2.42 (3H, s), 2.53 (2H, t, J=7.0 Hz), 2.73 (2H, t, J=7.0 Hz), 4.09 (2H, q, J=7.2 Hz), 4.98 (2H, s), 5.10 (2H, s), 6.52 (1H, DD, J=3.6. 1.8 Hz), 6.96-7.01 (3H, m), 7.12 (1H, s), 7.17 (2H, d, J=8.8 Hz), 7.53 (1H, DD, J=1.8, 0.8 Hz).

Example 166.

To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-hydroxy-1H-pyrazole-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 40,0 mg) at 0°and the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added Iodate (0,240 ml) and stirred at room temperature for one hour. The reaction mixture was you who ivali in the water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionate (348 mg, yield: 73%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.0 Hz), 1.36 (3H; so J=7.0 Hz), 2.47 (3H, s), 2.48-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J=7.0 Hz), 4.22 (2H. kV, J=7.0 Hz), 4.97 (2H, s), 5.00 (2H, s), 6.52 (1H, DD, J=3.6, 2.0 Hz), 6.92-6.99 (4H, m), 7.13 (2H, d, J=8.8 Hz), 7.54 (1H, DD, J=2.0, 0.6 Hz).

Example 167.

A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionate (381 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for four hours, diluted with 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionic acid (327 mg, yield: 91%). Their recrystallized from ethanol-hexane. Melting point: 129-130°S./p>

Example 168.

To a solution of ethyl 3-[1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-hydroxy-1H-pyrazole-4-yl]propionate (452 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 40,0 mg) at 0°and the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added benzylbromide (0,178 ml) and stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionate (383 mg, yield: 71%) as a colorless oily substance.

NMR (Dl3)δ: 1.19 (3H, t, J=7.2 Hz), 2.42 (3H, s), 2.47-2.55 (2H, m), 2.63-2.71 (2H, m), 4.07 (2H, q, J=7.2 Hz), 4.97 (2H, s), 5.02 (2H, s), 5.23 (2H, s), 6.52 (1H, DD, J=3.6, 1.8 Hz), 6.90-6.99 (4H, m), 7.13 (2H, d, J=8.4 Hz), 7.27-7.47 (5H, m), 7.54 (1H, DD, J=1.8, 1.0 Hz).

Example 169.

A mixture of ethyl 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionate (379 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature in those who tell 5 hours, diluted 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-benzyloxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-benzyl]-1H-pyrazole-4-yl]propionic acid (299 mg, yield: 83%). Their recrystallized from ethanol-hexane. Melting point: 104-105°C.

Example 170.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (1,59 g), 4-benzyloxy-3-methoxybenzylamine (1.97 g) and N,N-dimethylformamide (30 ml) was added sodium hydride (60%, in oil, of 0.30 g) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and fractions, buervenich with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[1-(4-benzyloxy-3-methoxybenzyl)-3-ethoxy-1H-pyrazole-4-yl]propionate (2,93 g, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.2 Hz), 1.36 (3H, t, J=7.0 Hz), 2.46-2.54 (2H, m), 2.60-2.68 (2H, t), 3.84 (3H, s), 4.08(2H, q, J=7.2 Hz), 4.22 (2H, q, J=7.0 Hz), 4.97 (2H, s), 5.14 (2H, s), 6.66 (1H, DD, J=84, 2.0 Hz), 6.76 (1H, d, J=2.0 Hz), 6.81 (1H, d, J=8.4 Hz), 6.93 (1H, s), 7.28-7.44 (5H, m).

Example 171.

To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazole-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 58,0 mg) at 0°and then the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added 4-chloromethyl-5-methyl-2-phenyloxazol (301 mg) and stirred at 60°C for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane

(1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (661 mg, yield: 88%) as a colorless oily substance.

NMR (Dl3)δ: 1.22 (3H, t, J=7.2 Hz), 1.37 (3H. t, J=7.2 Hz), 2.41 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.82 (3H, s), 4.09 (2H, q, J=7.2 Hz), 4.23 (2H, q, J=7.2 Hz), 5.00 (2H, s), 5.04 (2H, s), 6.72 (1H, DD, J=8.2, 2.2 Hz), 6.76 (1H, d, J=2.2 Hz), 6.95 (1H, s), 7.00 (1H, d, J=8.2 Hz), 7.40-7.46 (3H, m), 7.98-8.03 (2H, m).

Example 172.

A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (660 mg), 1 N. aqueous hydroxide solution is of the atrium (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate.

An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-1H-pyrazole-4-yl]propionic acid (510 mg, yield: 82%). Their recrystallized from ethanol-hexane. Melting point: 122-123°C.

Example 173.

To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazole-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 58,0 mg) at 0°and then the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added 4-chloromethyl-2-(2-furyl)-5-methoxazole (573 mg) and stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazole is methoxy]-3-methoxybenzyl]-1H-pyrazole-4-yl]-propionate (564 mg, yield: 76%) as a yellow oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.2 Hz), 1.37 (3H, t, J=7.2 Hz), 2.40 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.82 (3H, s), 4.09 (2H, q, J=7.2 Hz), 4.23 (2H, q, J=7.2 Hz), 4.99 (2H, s), 5.03 (2H, s), 6.52 (1H, DD, J=3.6, 1.8 Hz), 6.71 (1H, DD, J=8.2, 2.0 Hz), 6.75 (1H, d, J=2.0 Hz), 6.94 (1H, s), 6.96 (1H, d, J=8.2 Hz), 6.96 (1H, DD, J=3.6, 0.8 Hz), 7.53 (1H, DD, J=1.8, 0.8 Hz).

Example 174.

A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxybenzyl]-1H-pyrazole-4-yl]propionate (561 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxybenzyl]-1H-pyrazole-4-yl]propionic acid (506 mg, yield: 96%). Their recrystallized from ethanol-hexane. Melting point: 133-134°C.

Example 175.

To a solution of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl]-1H-pyrazole-4-yl]propionate (505 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 58,0 mg) at 0°and then the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added 4-Limeil-5-methyl-2-(2-thienyl)oxazole (310 mg) and stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[3-methoxy-4-[5-methyl-2-(2-thienyl)-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionate (500 mg, yield: 66%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.2 Hz), 1.37 (3H, t, J=7.2 Hz), 2.39 (3H, s), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.82(3H, s), 4.09 (2H, q, J=7.2 Hz), 4.23 (2H, q, J=7.2 Hz), 4.99 (2H, s), 5.01 (2H, s), 6.71 (1H, DD, J=8.0, 2.2 Hz), 6.75 (1H, d, J=2.2 Hz), 6.94 (1H, s), 6.96 (1H, d, J=8.0 Hz), 7.09 (1H, DD, J=4.8, 3.6 Hz), 7.39 (1H, DD, J=4.8, 1.2 Hz), 7.62 (1H, DD, J=3.6, 1.2 Hz).

Example 176.

A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-[5-methyl-2-(2-thienyl)-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionate (499 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[3-methoxy-4-[5-methyl-2-(2-thienyl)-4-OK is azolylmethyl]benzyl]-1H-pyrazole-4-yl]propionic acid (392 mg, yield: 83%). Their recrystallized from ethanol-hexane. Melting point: 123-124°C.

Example 177.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazole-4-yl]propionate (505 mg), hydrochloride 3-picolylamine (476 mg), potassium carbonate (601 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate, was obtained ethyl 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (531 mg, yield: 83%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz), 2.47-2.55 (2H, m), 2.61-2.69 (2H, t), 3.84 (3H, s), 4.09 (2H, q, J=7.0 Hz), 4.22 (2H. kV, J=7.0 Hz), 4.99 (2H, s), 5.13 (2H, s), 6.68 (1H, DD, J=8.0, 2.2 Hz), 6.77 (1H, d, J=2.2 Hz), 6.84 (1H, d, J=8.0 Hz), 6.95 (1H, s), 7.31 (1H, DD, J=8.0, 4.8 Hz), 7.79 (1H, dt, J=8.0, Hz), 8.57 (1H, d, J=4.8 Hz), 8.67 (1H, s).

Example 178.

A mixture of ethyl 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridyloxy)-benzyl]-1H-pyrazole-4-yl]propionate (527 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (2.5 ml)and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[3-methoxy-4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (381 mg, yield: 77%). Their recrystallized from ethanol-hexane. Melting point: 124-125°C.

Example 179.

In a mixture of ethyl 3-[3-ethoxy-1H-pyrazole-4-yl]propionate (1.50 g), 4-benzyloxybenzaldehyde (1,81 g) and N,N-dimethylformamide (30 ml), was added sodium hydride (60%in oil, 0.35 g) at 0°and then the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazole-4-yl]propionate (2.76 g, yield: 96%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz), 2.44-2.70 (4H, m), 4.09 (2H, q, J=7.0 Hz), 4.25 (2H, q, J=7.0 Hz), 5.03 (2H, s), 5.05 (2H, s), 6.88-6.98 (3H, m), 7.09-7.19 (2H, m), 7.30-7.48 (5H, m).

Example 180.

A mixture of ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazole-4-yl]propionate (490 mg), N. an aqueous solution of sodium hydroxide (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (3 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazole-4-yl]propionic acid (430 mg, yield: 94%). Their recrystallized from acetone-hexane. Melting point: 115-116°C.

Example 181.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (1.50 g), 4-chloromethyl-2-phenylthiazole (1,05 g), potassium carbonate (1.30 grams) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature T. the value of two hours, diluted 1 N. hydrochloric acid (10 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-1H-pyrazole-4-yl]propionic acid (1.60 g, yield: 73%). Their recrystallized from acetone-hexane. Melting point: 114-115°C.

Example 182.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (1.20 g), 4-chloromethyl-5-methyl-2-phenylthiazole (0.95 g), potassium carbonate (1.06 g) and N,N-dimethylformamide (20 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained colorless oily substance. A mixture of the obtained oily substance, 1 N. aqueous sodium hydroxide solution (10 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (10 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed n is sasenum aqueous solution of sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-(5-methyl-2-phenyl-4-thiazoleacetate)benzyl]-1H-pyrazole-4-yl]propionic acid (1,46 g, yield: 81%). Their recrystallized from ethyl acetate-hexane. Melting point: 73-74°C.

Example 183.

In a mixture of ethyl 3-[3-ethoxy-1H-pyrazole-4-yl]propionate (318 mg), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)-pyridine (472 mg) and N,N-dimethylformamide (10 ml), was added sodium hydride (60%in oil, 60,0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridylmethyl]-1H-pyrazole-4-yl]propionate (651 mg, yield: 88%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.2 Hz), 1.36 (3H, t, J=7.0 Hz), 2.47-2.55 (5H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J=7.2 Hz), 4.21 (2H, q, J=7.0 Hz), 4.98 (2H. s), 5.28 (2H, s), 6.77 (1H, d, J=8.4 Hz), 6.97 (1H, s), 7.39-7.46 (4H, m), 7.98-8.04 (3H, m).

Example 184.

A mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone-5-pyridylmethyl]-1H-pyrazole-4-yl]propionate (638 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (495 mg, yield: 82%). Their recrystallized from ethanol-hexane. Melting point: 143-144°C.

Example 185.

In a mixture of ethyl 3-[3-ethoxy-1H-pyrazole-4-yl]propionate (318 mg), 4-(4-chloromethylphenoxyacetic)-2-phenyloxazole (450 mg) and N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 60,0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained ethyl 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (616 mg, yield: 86%). Their recrystallized from ethyl acetate-hexane. Melting point: 80-81°C.

Example 186.

A mixture of ethyl 3-[3-this is the XI-1-[4-(2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (523 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (456 mg, yield: 93%). Their recrystallized from ethanol-hexane. Melting point: 135-136°C.

Example 187.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (415 mg), 3-(4-chloromethylphenoxyacetic)pyridine (554 mg) and N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 80.0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (340 mg, yield: 55%) as a colorless oily substance.

NMR (Dl3)B4; : 1.21 (3H, t, J=7.2 Hz), 1.36 (3H, t, J=7.0 Hz), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09 (2H, q, J=7.2 Hz), 4.22 (2H, q, J=7.0 Hz), 5.00 (2H, s), 5.07 (2H, S), 6.92 (2H. D. J=8.8 Hz), 6.93 (1H, s), 7.14 (2H, d, J=8.8 Hz), 7.32 (1H, DD, J=7.4, 4.8 Hz), 7.77 (1H, dt, J=7.4, 2.0 Hz), 8.59 (1H, DD, J=4.8, 2.0 Hz), 8.68 (1H, d, J=2.0 Hz).

Example 188.

A mixture of ethyl 3-[3-ethoxy-1-[4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (340 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (2 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-(3-pyridyloxy) benzyl] -1H-pyrazole-4-yl] propionic acid (260 mg, yield: 82%). Their recrystallized from ethanol-hexane. Melting point: 120-121°C.

Example 189.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (300 mg), 4-(4-chloromethylphenoxyacetic)-5-methyl-2-(2-thienyl)oxazole (450 mg) and N,N-dimethylformamide (5 ml), was added sodium hydride (60%in oil, 70.0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dry the Lee (gSO 4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), obtained colorless oily substance. A mixture of the obtained colorless oily product, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature overnight, diluted with 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-[5-methyl-2-(2-thienyl)-4-oxazolidinone]benzyl]-1H-pyrazole-4-yl]propionic acid (460 mg, yield: 70%). Their recrystallized from acetone - hexane. Melting point: 156-157°C.

Example 190.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (415 mg), 2-[N-[2-(4-chloromethylene)ethyl]-N-methylamino]pyridine (554 mg) and N,N-dimethylformamide (10 ml), was added sodium hydride (60%in oil, 80.0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes.

The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The rest who have adversely chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzyl]-1H-pyrazole-4-yl]propionate (771 mg, yield: 85%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.2 Hz), 1.36 (3H, t, J=7.2 Hz), 2.47-2.54 (2H, m), 2.59-2.67 (2H, m), 3.14 (3H, s), 3.97 (2H, t, J=5.6 Hz), 4.08 (2H, q, J=7.2 Hz), 4.17 (2H, t, J=5.6 Hz), 4.21 (2H, q, J=7.2 Hz), 4.97 (2H, s), 6.49-6.58 (2H, m), 6.84 (2H, d, J=8.6 Hz), 6.89 (1H, s), 7.10 (2H, d, J=8.6 Hz), 7.45 (1H, DDD, J=8.6, 7.2, 1.8 Hz), 8.15 (1H, DDD. J=5.0, 1.8, 1.0 Hz).

Example 191.

A mixture of ethyl 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]benzyl]-1H-pyrazole-4-yl]propionate (769 mg), 1 N. aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (4 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate, was obtained 3-[3-ethoxy-1-[4-[2-[N-methyl-N-(2-pyridyl) amino]ethoxy]-benzyl]-1H-pyrazole-4-yl]propionic acid (402 mg, yield: 56%) as a colorless oily substance.

NMR (Dl3)δ: 1.34 (3H, t, J=7.0 Hz), 2.50-2.68 (4H, m), 3.12 (3H, s), 3.94 (2H, t, J=5.4 Hz), 4.15 (2H, t, J=5.4 Hz), 4.21 (2H, q, J=7.0 Hz), 4.97 (2H, s), 6.50-6.58 (2H, m), 6.82 (2H, d, J=8.8 Hz), 6.0 (1H, s), 7.08 (2H, d, J=8.8 Hz), 7.45 (1H, DDD, J=8.6, 7.2, 2.0 Hz), 8.15 (1H, DDD, J=7.2, 2.0, 1.0 Hz).

Example 192.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (318 mg), 2-[4-(4-chloromethylene)piperidine-1-yl]pyridine (404 mg) and N,N-dimethylformamide (10 ml), was added sodium hydride (60%in oil, 60,0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazole-4-yl]propionate (609 mg, yield: 85%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz), 1.76-1.93 (2H, m), 1.98-2.12 (2H, t), 2.48-2.55 (2H, t), 2.61-2.69 (2H, t), 3.39-3.49 (2H, t), 3.85-3.97 (2H, t), 4.09 (2H, q, J=7.0 Hz), 4.23 (2H, kV, J=7.0 Hz), 4.46-4.57 (1H, m), 4.99 (2H, s), 6.60 (1H, DDD, J=7.0, 5.0. 0.8 Hz), 6.69 (1H, dt, J=8.8, 0.8 Hz), 6.88 (2H, d, J=8.8 Hz), 6.93 (1H, s), 7.12 (2H, d, J=8.8 Hz), 7.47 (1H, DDD, J=8.8, 7.0, 1.8 Hz), 8.19 (1H, DDD, J=5.0, 1.8, 0.8 Hz).

Example 193

A mixture of ethyl 3-[3-ethoxy-1-[4-[1-(2-pyridyl)piperidine-4-yloxy]benzyl]-1H-pyrazole-4-yl]propionate (598 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-[1-(2-pyridyl) piperidine-4-yloxy]-benzyl]-1H-pyrazole-4-yl]propionic acid (408 mg, yield: 72%). Their recrystallized from ethanol-hexane. Melting point: 142-143°C.

Example 194.

In a mixture of ethyl 3- (3-ethoxy-1H-pyrazole-4-yl]propionate (318 mg), 2-[2-(4-chloromethylene)ethyl]-5-ethylpyridine (414 mg) and N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 60,0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]-1H-pyrazole-4-yl]propionate (520 mg, yield: 77%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.0 Hz), 1.24 (3H, t, J=7.6 Hz), 1.36 (3H, t, J=7.0 Hz), 2.46-2.54 (2H, m), 2.57-2.68 (4H, m), 3.22 (2H, t, J=6.6 Hz), 4.08 (2H, q, J=7.0 Hz), 4.12 (2H, q, J=7.0 Hz), 4.33 (2H, t, J=Hz), 4.97 (2H, s), 6.85 (2H, d, J=8.6 Hz), 6.90 (1H, s), 7.11 (2H, d, J=8.6 Hz), 7.18 (1H, d, J=7.8 Hz), 7.45 (1H, DD, J=7.8, 2.0 Hz), 8.39 (1H, d, J=2.0 Hz).

Example 195.

A mixture of ethyl 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl) ethoxy]benzyl]-1H-pyrazole-4-yl]propionate (519 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (2.5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid (228 mg, yield: 47%). Their recrystallized from ethanol-hexane. Melting point: 89-90°C.

Example 196.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (690 mg), 4-[2-(4-chloromethylene)ethyl)]-5-methyl-2-phenyloxazole (1,05 g) and N,N-dimethylformamide (20 ml), was added sodium hydride (60%in oil, 130 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and of the fraction, e is new with ethyl acetate-hexane (1:2, the volumetric ratio), obtained colorless oily substance. A mixture of the obtained colorless oily substance 1 h, aqueous sodium hydroxide solution (6 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (6 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated solution of sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid (1,09 g, yield: 72%). Their recrystallized from acetone-hexane. Melting point: 142-143°C.

Example 197.

To a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (780 mg) in N,N-dimethylformamide (50 ml) was added sodium hydride (60%in oil, 180 mg) at 0°and then the solution was stirred at room temperature for 30 minutes. In the reaction mixture at 0°With added 2-[4-(5-methyl-2-phenyl-4-oxazolyl)methoxy]phenyl]ethylmethanesulfonate (2.17 g) and the mixture is then stirred at 90°C for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography is and a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]ethyl]-1H-pyrazole-4-yl]propionate (1.08 g, yield: 58%) as a colorless oily substance.

NMR (Dl3)δ: 1.23 (3H, t, J=7.0 Hz), 1.38 (3H, t, J=7.0 Hz), 2.43 (3H, s), 2.49-2.65 (4H, m), 3.00 (2H, t, J=7.0 Hz), 4.04 (2H, t, J=7.0 Hz), 4.11 (2H, q, J=7.0 Hz), 4.24 (2H, q, J=7.0 Hz), 4.97 (2H, s), 6.78 (1H, s), 6.89-7.01 (4H, m), 7.42-7.46 (3H, m), 7.99-8.04 (2H, m).

Example 198

A mixture of ethyl 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]ethyl]-1H-pyrazole-4-yl]propionate (1.08 g), 1 N. aqueous sodium hydroxide solution (4,2 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained crystals were collected by filtration and obtained 3-[3-ethoxy-1-[2-[4-(5-methyl-2-phenyl-4-oxazolidinone)phenyl]ethyl]-1H-pyrazole-4-yl]propionic acid (880 mg, yield: 88%). Their recrystallized from ethyl acetate-hexane. Melting point: 110-111°C.

Example 199.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (509 mg), 4-(2-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazole (753 mg) and N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 96.0 mg) at 0°When then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (1,09 g, yield: 93%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.2 Hz), 1.34 (3H, t, J=7.2 Hz), 2.39 (3H, s), 2.46-2.54 (2H, m), 2.60-2.68 (2H, m), 4.08 (2H, q, J=7.2 Hz), 4.20 (2H, q, J=7.2 Hz), 5.03 (2H, s), 5.11 (2H, s), 6.91-6.93 (2H, m,), 7.01-7.06 (2H, m), 7.22-7.31 (1H, m), 7.41-7.48 (3H, m), 7.98-8.05 (2H, m).

Example 200.

A mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (1,09 g), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for two hours, diluted with 1 N. hydrochloric acid (5 ml) and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (834 mg, yield: 82%). Their precrystallization is from ethanol-hexane. Melting point: 127-128°C.

Example 201.

In a mixture of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl]propionate (509 mg), 4-(3-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazole (753 mg) and N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 96.0 mg) at 0°and then the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio)was obtained ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (809 mg, yield: 69%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.2 Hz), 1.36 (3H, t, J=7.2 Hz), 2.42 (3H, s), 2.48-2.55 (2H, m), 2.61-2.69 (2H, m), 4.09(2H, q, J=7.2 Hz), 4.22 (2H, q, J=7.2 Hz), 4.95 (2H, s), 5.04(2H, s), 6.74-6.83 (2H, m,), 6.91-6.97 (2H, m), 7.25 (1H, t, J=7.8 Hz), 7.42-7.45 (3H, m), 7.99-8.04 (2H, m).

Example 202.

A mixture of ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (808 mg), 1 N. aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours, diluted with 1 N. hydrochloric acid (4 ml) and was extracted with ethyl acetate. telecity layer was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-methanol (5:1, volume ratio)was obtained 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (709 mg, yield: 93%) as a colorless oily substance.

NMR (Dl3)δ: 1.35 (3H, t, J=7.0 Hz), 2.48 (3H, s), 2.67 (4H, s), 4.21 (2H, q, J=7.0 Hz), 4.96 (2H, s), 5.11 (2H, s), 6.42 (1H, s), 6.84-6.91 (2H. m), 7.19 (1H, s), 7.26 (1H, d, J=8.0 Hz), 7.43-7.47 (3H, m), 7.94-7.99 (2H. m).

Example 203.

A mixture of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1H-pyrazole-4-carboxylate (2,84 g), 5% palladium on coal (5,00 g), ethanol (25 ml) and tetrahydrofuran (25 ml) was stirred in hydrogen atmosphere at room temperature for 4 hours. Then the filter was removed, the catalyst, the filtrate was concentrated. The obtained crystals were collected by filtration and obtained ethyl 3-hydroxy-1-[4-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-1H-pyrazole-4-carboxylate (968 mg, yield: 56%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 152-153°C.

Example 204.

A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (10.30 g), chloride 4-benzyloxybenzyl (18,60 g), potassium carbonate (16,60 g) and N,N-dimethylformamide (200 ml) was stirred at 100°With during the night. The reaction mixture howled the Wali in the water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate, was obtained ethyl 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-carboxylate (11,90 g, yield: 54%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 124-125°C.

Example 205.

In the solution ethyldiethanolamine (2,74 ml) in tetrahydrofuran (50 ml) was added sodium hydride (60%in oil, 552 mg) at 0°and then the solution was stirred at room temperature for 30 minutes. In the reaction mixture was slowly added a solution of 1-(4-benzyloxybenzyl)-3-(4-benzyloxybenzyl)-1H-pyrazole-4-carbaldehyde (of 6.31 g) in tetrahydrofuran (100 ml) and the solution was stirred at room temperature for 15 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid, then saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained crystals were collected by filtration and obtained ethyl 3-[1-(4-benzyloxybenzyl)-3-(4-benzyloxy-benzyloxy)-1H-pyrazole-4-yl]propionate (6,79 g, yield: 95%). Their recrystallized from ethyl acetate-hexane. T is CCA melting point: 98-99° C.

Example 206.

To a solution of ethyl 3-[3-hydroxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (435 mg) in N,N-dimethylformamide (10 ml) was added sodium hydride (60%in oil, 120 mg) at 0°and then the solution was stirred at room temperature for 30 minutes. In the reaction mixture was added 3-picolylamine (574 mg) and stirred at room temperature for one hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with diluted hydrochloric acid, then saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate, was obtained ethyl 3-[3-(3-pyridyloxy)-1-[4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (533 mg, yield: 75%) as a colorless oily substance.

NMR (Dl3)δ: 1.19 (3H, t, 3=1.2 Hz), 2.46-2.54 (2H, m), 2.62-2.70 (2H, m), 4.07 (2H, q, J=7.2 Hz), 5.01 (2H, s). 5.07 (2H, s), 5.25 (2H, s), 6.93 (2H, d, J=8.8 Hz), 7.14 (2H, d, J=8.8 Hz), 7.26-7.36 (2H, t), 7.74-7.80 (2H, t), 8.55-8.60 (2H, t), 8.69 (2H, s).

Example 207.

A mixture of ethyl 3-[3-(3-pyridyloxy)-1-[4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (529 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for one hour, diluted with 1 N. hydrochloric acid (3 ml) and EXT who was agarawala with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration and obtained 3-[3-(3-pyridyloxy)-1-[4-(3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (427 mg, yield: 86%). Their recrystallized from ethanol-hexane. Melting point: 116-117°C.

Example 208.

A mixture of ethyl 3-[1-(4-benzyloxy-3-methoxybenzyl)-3-ethoxy-1H-pyrazole-4-yl]propionate (2,92 g), 5% palladium on coal (6,00 g), ethanol (20 ml) and tetrahydrofuran (20 ml) was stirred at room temperature for one hour in hydrogen atmosphere. Then the filter was removed, the catalyst, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel and the fractions elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio)was obtained ethyl 3-[3-ethoxy-1-(4-hydroxy-3-methoxybenzyl)-1H-pyrazole-4-yl]propionate (2,04 g, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.21 (3H, t, J=7.0 Hz), 1.37 (3H, t, J=7.0 Hz), 2.47-2.55 (2H, m), 2.61-2.69 (2H, m), 3.85 (3H, s), 4.08 (2H, q, J=7.0 Hz), 4.23 (2H, q, J=7.0 Hz), 4.97 (2H. s), 5.65 (1H, users). 6.71 (1H, d, J=8.0 kV), 6.73 (1H, s), 6.86 (1H, d, J=8.0 Hz), 6.93 (1H, s).

Example 209.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (360 mg), hydrochloride 2-chloromethylpyridine (270 mg), potassium carbonate (300 mg) and N,N-dimethylformamide (10 ml) PE is amasyali at 80° C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain a colorless oily substance from the fraction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio). Then the mixture obtained oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(2-chinaillon)benzyl]-1H-pyrazole-4-yl]propionic acid (420 mg, yield: 86%). Their recrystallized from acetone-hexane. Melting point: 140-141°C.

Example 210.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) and 4-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in in the control and were extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone)-4-pyridylmethyl]-1H-pyrazole-4-yl]propionate (640 mg, yield: 87%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 1.35(3H, t, J=7.0 Hz), 2.46(3H, s), 2.49-2.57(2H, m), 2.62-2.70(2H, m), 4.10(2H, q, J=7.0 Hz), 4.19(2H, q, J=7.0 Hz), 5.01(2H, s), 5.27(2H, s), 6.46(1H, s), 6.63(1H, d, J=5.2 Hz), 7.03(1H, s), 7.39-7.46(3H, m), 7.97-8.04(2H, m), 8.09(1H, d, J=5.2 Hz).

Example 211.

After a mixture of ethyl 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolidinone)-4-pyridylmethyl]-1H-pyrazole-4-yl]-propionate (638 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-4-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (495 mg, yield: 82%). Their recrystallized from ethanol-Exane. Melting point: 114-115°C.

Example 212.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) and 3-chloromethyl-5-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (472 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate, the ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (616 mg, yield: 84%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.43(3H, s), 2.47-2.55(2H, m), 2.61-2.69(2H, m), 4.10(2H, q, J=7.0 Hz), 4.21(2H, q, J=7.0 Hz), 5.00(2H, s), 5.07(2H, s), 7.02(1H, s), 7.14(1H. DD, J=1.4, 3.0 Hz), 7.41-7.47(3H, m), 7.97-8.03(2H, m), 8.10(1H. d, J=1.4 Hz), 8.34(1H, d, J=3.0 Hz).

Example 213.

After a mixture of ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (613 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture is then extragere the Ali ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (532 mg, yield: 92%). Their recrystallized from ethanol-hexane. Melting point: 133-134°C.

Example 214.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) and 4-(5-chloromethyl-2-methoxyphenoxy)-5-methyl-2-phenyloxazole (516 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (647 mg, yield: 83%) as colorless crystals from the fraction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio). Their recrystallized from ethyl acetate-hexane. Melting point: 109-110°C.

Example 215.

After a mixture of ethyl 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-feast of the ol-4-yl]propionate (572 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-methoxy-3-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (498 mg, yield: 92%). Their recrystallized from ethanol-hexane. Melting point: 136-137°C.

Example 216.

Sodium hydride (60%in oil, 50.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (265 mg) and 4-(4-chloromethyl-2-ethoxyphenoxy)-5-methyl-2-phenyloxazole (447 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (548 mg, yield:82%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 1.37(3H, t, J=7.0 Hz). 1.42(3H, t, J=7.0 Hz), 2.43(3H, s), 2.47-2.55(2H, m), 2.61-2.69(2H, m), 4.05(2H, q, J=7.0 Hz), 4.09(2H, q, J=7.0 Hz), 4.23(2H, q, J=7.0 Hz), 4.98(2H, s), 5.06(2H, s), 6.70(1H, DD, J=1.8, 8.0 Hz), 6.75(1H, d, J=1.8 Hz), 6.94(1H, s), 6.98(1H, d, J=8.0 Hz), 7.40-7.49(3H, m), 7.96-8.03(2H, m).

Example 217.

After a mixture of ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionate (544 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid (466 mg, yield: 90%) was recrystallized from ethanol-hexane. Melting point: 105-106°C.

Example 218.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) and 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolidinone)isoxazol (457 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with et is lacerata. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated.

The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolidinone)-5-isoxazolyl]-1H-pyrazole-4-yl]propionate (653 mg, yield: 91%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 82-83°C.

Example 219.

After a mixture of ethyl 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolidinone)-5-isoxazolyl]-1H-pyrazole-4-yl]propionate (519 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-5-isoxazolyl]-1H-pyrazole-4-yl]propionic acid (459 mg, yield: 94%). Their recrystallized from ethanol-hexane. Melting point: 142-143°C.

Example 220.

Sodium hydride (60%in oil, to 90.3 mg) was added to a solution of ethyl 3-(3-ethoxy-H-pyrazole-4-yl)propionate (400 mg) and 2-[2-(4-chloromethylene)ethyl)-1(2H)-phthalazinone (650 mg) in N,N-dimethylformamide (10 ml) at 0° C and the mixture was stirred at room temperature overnight. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with water and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), a colorless oily substance. After the mixture colorless oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-[2-[1-acceptilation-2(1H)-yl]-ethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid (730 mg, yield: 84%). Their recrystallized from acetone-hexane. Melting point: 152-153°C.

Example 221.

Sodium hydride (60%in oil, to 90.3 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (400 mg) and 2-[2-(3-chloromethylene)ethyl]-1-(2H)-phthalazinone (650 mg) in N,N-dimethylformamide (10 m is) at 0° C and the mixture was stirred at room temperature overnight. The reaction mixture was poured into diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with water and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), a colorless oily substance. After the mixture of the obtained colorless oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-[2-[1-acceptilation-2(1H)-yl]ethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid (690 mg, yield: 79%). Their recrystallized from acetone-hexane. Melting point: 146-147°C.

Example 222.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) and 2-chloromethyl-6-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (472 mg) in NN-dimethylformamide (10 ml) at 0° C and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]-1H-pyrazole-4-yl]propionate (656 mg, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=Hz), 1.37(3H, t, J=7.0 Hz), 2.47(3H, s), 2.51-2.59(2H, m), 2.66-2.74 (2H, m), 4.11(2H, q, J=7.0 Hz), 4.23(2H, q, J=7.0 Hz), 5.11(2H, s), 5.28(2H, s), 6.46(1H, d, J=7.2 Hz), 6.70(1H, d, J=8.0 Hz), 7.13(1H, s). 7.41-7.46(3H, m), 7.48(1H, DD, J=7.2, 8.0 Hz), 7.99-8.05(2H, m).

Example 223.

After a mixture of ethyl 3-[3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]-1H-pyrazole-4-yl]propionate (652 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6(5-methyl-2-phenyl-4-oxazolyl-methoxy)-2-pyridylmethyl] -1H-pyrazole-4-yl] propionic acid (522 mg, yield: 85%). Their recrystallized from ethanol-hexane. Melting point: 144-145°C.

Example 224.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (302 mg) and 5-chloro-2-chloromethylketone[1,2-a]pyridine (302 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate, the ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (625 mg, yield: 86%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 69-70°C.

Example 225.

After a mixture of ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)benzyl]-3-ethoxy-1H-pyrazole-4-yl]-propionate (507 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried the (MgSO 4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionic acid (448 mg, yield: 94%). Their recrystallized from ethanol. Melting point: 153-154°C.

Example 226.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (478 mg) and 2-chloromethyl-5-toxemias[1,2-a]pyridine (316 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 3-[3-ethoxy-1-[4-(5-toxemias[1,2-a]-pyridine-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (442 mg, yield: 60%) as a colorless oily substance from the fraction, elyuirovaniya with ethyl acetate.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 1.55(3H, t, J=7.0 Hz), 2.47-2.54(2H, m), 2.61-2.68(2H, m), 4.08(2H, q, J=7.0 Hz), 4.22(2H, q, J=7.0 Hz), 4.29(2H, q, J=7.0 Hz), 4.99(2H, s), 5.25(2H, s), 6.02(1H, DD, J=2.0, 6.2 Hz), 6,92(1H, s), 7.00(2H, d, J=8.8 Hz), 7.13(2H, d, J=8.8 Hz), 7.18-7.25(2H, t), 7.71(1H, s).

Example 227.

After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-toxemias[1,2-a]pyridine-2-is metoxi)benzyl]-1H-pyrazole-4-yl]propionate (441 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-toxemias-[1,2-a]pyridine-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (335 mg, yield: 81%). Their recrystallized from ethanol-hexane. Melting point: 197-198°C.

Example 228.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (478 mg) and 1-chloromethyl-1H-benzotriazole (251 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[1-[4-(1H-benzotriazol-1 ylethoxy)-benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (652 mg, yield: 97%) as a colourless oil is NISTO substances.

NMR (Dl3)δ: 1.19(3H, t, J=7.2 Hz), 1.35(3H, t, J=7.0 Hz), 2.45-2.53(2H, m), 2.59-2.67(2H, m), 4.08(2H, q, J=7.2 Hz), 4.20(2H, q, J=7.0 Hz), 4.96(2H, s), 6.53(2H, s), 6.90(1H, s), 7.01-7.11(4H, m), 7.40(1H, DDD, J=1.2, 7.0, 8.4 Hz), 7.53(1H, DDD, J=1.2, 7.0, and 8.4 Hz), 7.69(1H, DD, J=1.2, and 8.4 Hz), 8.07(1H, DD, J=1.2, 8.4 Hz).

Example 229.

After a mixture of ethyl 3-[1-[4-(1H-benzotriazol-1 ylethoxy) benzyl] -3-ethoxy-1H-pyrazole-4-yl] propionate (652 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(1H-benzotriazol-1 ylethoxy)benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionic acid (576 mg, yield: 94%). Their recrystallized from ethanol-hexane. Melting point: 136-137°C.

Example 230.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (690 mg), 5-chloromethyl-2-phenylpyridine (470 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4and Kon who was entrirely. The residue was subjected to chromatography on silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), a colorless oily substance. Then a mixture of the obtained colorless oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (900 mg, yield: 91%). Their recrystallized from acetone-hexane. Melting point: 140-141°C.

Example 231.

A mixture of ethyl 3-[1-[4-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (676 mg), phenylboronic acid (195 mg), tetrakis(triphenylphosphine)-palladium (40,4 mg), sodium carbonate (339 mg), ethanol (3 ml), water (3 ml) and toluene (15 ml) was boiled under reflux overnight in an argon atmosphere. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The mod is subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate, the ethyl 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridine-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (707 mg, yield: 96%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 104-105°C.

Example 232.

After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridine-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (551 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenylimidazo[1,2-a]pyridine-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (469 mg, yield: 90%). Their recrystallized from ethanol-hexane. Melting point: 160-161°C.

Example 233.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) and 4-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolidinone]pyridine (457 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with atilas what tatom. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolidinone]-4-pyridylmethyl]-1H-pyrazole-4-yl]propionate (643 mg, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7.2 Hz), 1.36(3H, t, J=7.0 Hz), 2.46(3H, s), 2.49-2.57(2H, m), 2.63-2.71(2H, m), 4.10(2H, q, J=7.2 Hz), 4.20(2H, q, J=7.0 Hz), 5.01(2H, s), 5.25(2H, s), 6.44(1H, DD, J=0.8, 1.8 Hz), 6.51(1H, DD, J=1.8, 3.4 Hz), 6.63(1H, DD, J=1.8, 5.4 Hz), 6.97(1H, DD, J=0.8, 3.4 Hz), 7.03(1H, s), 7.52(1H, DD, J=0.6, 1.8 Hz), 8.08(1H, DD, J=0.6, 5.4 Hz).

Example 234.

After a mixture of ethyl 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolidinone]-pyridylmethyl]-1H-pyrazole-4-yl]propionate (639 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]-4-pyridylmethyl]-1H-pyrazole-4-yl]propionic sour is s (569 mg, yield: 94%). Their recrystallized from ethanol-hexane. Melting point: 138-139°C.

Example 235.

Sodium hydride (60%in oil, 160 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (849 mg) and 5-chloro-2-(4-chloromethyl-2-pyridyloxy)imidazo[1,2-a]pyridine (1230 mg) in N,N-dimethylformamide (20 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate, the ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (1570 mg, yield: 81%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7.2 Hz), 1.36(3H, t, J=7.2 Hz), 2.50-2.58(2H, m), 2.63-2.71(2H, m), 4.11(2H, q, J=7.2 Hz), 4.20(2H, q, J=7.2 Hz), 5.04(2H, s), 5.56(2H, d, J=0.8 Hz), 6.50(1H, d, J=0.6 Hz), 6.65(1H, DD, J=1.4, 5.2 Hz), 6.89(1H, DD, J=0.8, 7.2 Hz), 7.05(1H, s), 7.18(1H, DD, J=7.2, 9.2 Hz), 7.55-7.60(1H, m), 7.84(1H, d, J=0.8 Hz), 8.12(1H, DD, J=0.6, 5.2 Hz).

Example 236.

After a mixture of ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (605 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at anatoy temperature for 3 hours, to the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[2-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazole-4-yl]propionic acid (534 mg, yield: 94%). Their recrystallized from ethanol-hexane. Melting point: 160-161°C.

Example 237.

A mixture of ethyl 3-[1-[2-(5-chloroimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (968 mg), phenylboronic acid (280 mg), tetrakis (triphenylphosphine)palladium (of 57.8 mg), sodium carbonate (488 mg), ethanol (3 ml), water (3 ml) and toluene (15 ml) was boiled under reflux overnight in an argon atmosphere. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate, the ethyl 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-1H-pyrazole-4-yl]propionate (1040 mg, yield: 99%) as a colorless oily substance.

NMR (l3) δ: 1.21(3H, t, J=7.0 Hz), 1.35(3H, t, J=7.0 Hz), 2.49-2.56(2H, m), 2.62-2.70(2 is, m), 4.10(2H, q, J=7.0 Hz), 4.19(2H, q, J=7.0 Hz), 5.01(2H, s), 5.49(2H, s), 6.47(1H, s), 6.61(1H, d, J=5.2 Hz), 6.74(1H, d, J=7.0 Hz), 7.02(1H, s), 7.27(1H, DD, J=7.0, 9.2 Hz), 7.42-7.72(7H, m), 8.08(1H, d, J=5.2 Hz).

Example 238.

After a mixture of ethyl 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-1H-pyrazole-4-yl]propionate (1030 mg), 1 N. aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (8 ml) and ethanol (8 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (4 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[2-(5-phenylimidazo[1,2-a]pyridine-2-ylethoxy)-4-pyridylmethyl]-1H-pyrazole-4-yl]-propionic acid (922 mg, yield: 95%). Their recrystallized from ethanol-hexane. Melting point: 177-178°C.

Example 239.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (700 mg), 3-chloromethyl-5-phenylpyridine (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to a chromatograph is on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (720 mg, yield: 67%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.45-2.70(4H, m), 4.09(2H, q, J=7.0 Hz), 4.22(2H, q, J=7.0 Hz), 5.01(2H, s), 5.13(2H, s), 6.88-7.02(2H. m), 7.10-7.22(2H, m), 7.40-7.64(5H. m), 7.96(1H, t, J=2.2 Hz), 8.65(1H, d, J=2.2 Hz), 8.82(1H, d, J=2.2 Hz).

Example 240.

After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (700 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenyl-3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (560 mg, yield: 85%). Their recrystallized from acetone-hexane. Melting point: 92-93°C.

Example 241.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (371 mg) and 2-(5-chloromethyl-3-isoxazolyl)quinoline (481 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred PR the room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[3-(2-chinaillon)-5-isoxazolyl]-1H-pyrazole-4-yl]propionate (722 mg, yield: 92%) as a colorless oily substance.

NMR (Dl3)δ: 1.23(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.49-2.57(2H, m), 2.62-2.70(2H, m), 4.11(2H, q, J=7.0 Hz), 4.20(2H, q, J=7.0 Hz), 5.06(2H, s), 5.54(2H. s), 5.86(1H, s), 7.09(1H), 7.51-7.60(2H, m), 7.73(1H, DDD, J=1.6, 7.0, 8.6 Hz), 7.83(1H, DD, J=1.6, 8.0 Hz), 8.06-8.12(1H, m), 8.20(1H, d, J=8.6 Hz).

Example 242.

After a mixture of ethyl 3-[3-ethoxy-1-[3-(2-chinaillon)-5-isoxazolyl]-1H-pyrazole-4-yl]propionate (721 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-(2-chinaillon)-5-isoxazolyl-methyl]-1H-pyrazole-4-yl]propionic acid (608 mg, you who od: 90%). Their recrystallized from ethanol-hexane. Melting point: 123-124°C.

Example 243.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]-propionate (478 mg) and 3-chloro-2-chloromethyl-6-phenylpyridine (357 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridyl-methoxy) benzyl] -3-ethoxy-1H-pyrazole-4-yl] propionate (740 mg yield: 95%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 1.36(3H, t, J=7.2 Hz), 2.46-2.54(2H, m), 2.60-2.68(2H, m), 4.09(2H, q, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz), 5.00(2H, s), 5.34(2H, s), 6.92(1H, s), 7.03(2H, d, J=8.8 Hz), 7.15(2H, d, J=8.8 Hz), 7.37-7.51(3H, m), 7.67(1H, d, J=8.4 Hz), 7.78(1H, d, J=8.4 Hz), 7.91-7.98(2H, m).

Example 244.

After a mixture of ethyl 3-[1-[4-(3-chloro-6-phenyl-2-pyridyloxy)benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionate (738 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture shall obavljale 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(3-chloro-6-phenyl-2-pyridyloxy)benzyl]-3-ethoxy-1H-pyrazole-4-yl]propionic acid (669 mg, yield: 96%). Their recrystallized from ethyl acetate-hexane. Melting point: 120-121°C.

Example 245.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of ethyl 3- [3-ethoxy-1- (4-hydroxybenzyl) 1H-pyrazole-4-yl] -propionate (478 mg) and 2-chloromethyl-6-phenylpyridine (306 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (689 mg, yield: 95%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.2 Hz), 1.36(3H, t, J=7.2 Hz), 2.46-2.55(2H, m), 2.60-2.68(2H, m), 4.12(2H, d, J=7.2 Hz), 4.22(2H, q, J=7.2 Hz), 5.00(2H, s), 5.28(2H, s), 6.93(1H, s), 6.97(2H, d, J=8.8 Hz), 7.13(2H, d, J=8.8 Hz), 7.38-7.53(4H, m), 7.64(1H, DD, J=0.8, 7.6 Hz), 7.71(1H, t, J=7.6 Hz), 7.97-8.03(2H, m).

Example 246.

After a mixture of ethyl 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (685 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(6-phenyl-2-pyridyloxy) benzyl] -1H-pyrazole-4-yl] propionic acid (482 mg, yield: 75%). Their recrystallized from ethanol-hexane. Melting point: 95-96°C.

Example 247.

A mixture of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (600 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (360 mg), potassium carbonate (550 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio),ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (730 mg, yield: 84%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 1.35(3H, t, J=7.0 Hz), 2.44-2.68(4H, m), 3.88(3H, s), 4.08(2H, q, J=7.0 Hz), 4.21(2H, q, J=7.0 Hz), 4.98(2H, s), 5.38(2H, s), 6.91(1H, s), 6.98-7.17(4H, m), 7.23-7.41(3H, m), 7.72-7.82(1H, m).

Example 248.

After a mixture of ethyl 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]-1H-pyrazole-4-yl]propionate (700 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(1-methyl-1H-benzimidazole-2-yl-methoxy)benzyl]-1H-pyrazole-4-yl]propionic acid (520 mg, yield: 79%). Their recrystallized from ethanol-water. Melting point: 177-178°C.

Example 249.

A mixture of 5-phenyl-2-pyridinemethanol (300 mg), thionyl chloride (0.25 ml) and toluene (10 ml) was stirred at 80°C for 1hour. Then the reaction mixture was concentrated under reduced pressure, the obtained crystals were filtered and washed with hexane. A mixture of the obtained crystals of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (420 mg) and N,N-dimetilformamida (10 ml) was stirred at 70° With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (730 mg, yield: 96%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.44-2.70(4H, m), 4.09(2H, q, J=7.0 Hz), 4.22(2H, q, J=7.0 Hz), 5.00(2H, s), 5.24(2H, s), 6.90-7.02(3H, m), 7.07-7.19(2H, m), 7.34-7.68{6N, m), 7.91(1H, DD, J=2.2, 8.0 Hz), 8.82(1H, d, J=2.2 Hz).

Example 250.

After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (700 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (620 mg, yield: 94%). Their recrystallized from Cetona-hexane. Melting point: 127-128°C.

Example 251.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 2-(5-chloromethyl-2-pyridyloxy)quinoline (498 mg), ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (371 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-ethoxy-1-[6-(2-chinaillon)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (733 mg, yield: 91%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.47-2.55(2H, m), 2.60-2.68(2H, m), 4.09(2H, q, J=7.0 Hz), 4.21(2H, q, J=7.0 Hz), 4.98(2H, s), 5.67(2H, s), 6.87(1H, DD, J=0.8, 8.4 Hz), 6.97(1H, s), 7.48(1H, DD, J=2.6, 8.4 Hz), 7.53(1H, DDD, J=1.4, 7.0, 8.4 Hz), 7.57(1H, d, J=8.6 Hz), 7.72(1H, DDD, J=1.4, 7.0, 8.4 Hz), 7.81(1H, DD, J=1.4, 8.4 Hz), 8.00(1H, DD, J=0.8, 2.6 Hz), 8.07-8.13(1H, m,), 8.15(1H, d, J=8.6 Hz).

Example 252.

After a mixture of ethyl 3-[3-ethoxy-1-[6-(2-chinaillon)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (732 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, SMEs was added to 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(2-chinaillon)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (629 mg, yield: 91%). Their recrystallized from ethanol-hexane. Melting point: 133-134°C.

Example 253.

Sodium hydride (60%in oil, 60,0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazoleacetate)pyridine (475 mg), ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (318 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio), ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (657 mg, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.47-2.56(2H, m), 2.61-2.69(2H, m), 4.10(2H, q, J=7.0 Hz), 4.22(2H, q, J=7.0 Hz), 5.00(2H, s), 5.54(2H, d, J=0.8 Hz), 6.81(1H, d, J=8.4 Hz), 7.31(1H, is, J=0.8 Hz), 7.40-7.49 (4H, m), 7.92-8.01(2H, m), 8.04(1H, d, J=2.6 Hz).

Example 254.

After a mixture of ethyl 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazoleacetate) -3-pyridylmethyl] -1H-pyrazole-4-yl] propionate (655 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[6-(2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (569 mg, yield: 92%). Their recrystallized from ethanol-hexane. Melting point: 121-122°C.

Example 255.

A mixture of 2-(4-chloromethyl-3-methyl-1H-pyrazole-1-yl)pyridine (350 mg), ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (500 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, surround with the compared), ethyl 3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-1H-pyrazole-4-yl]propionate (700 mg, yield: 91%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 1.36(3H, t, J=7.0 Hz), 2.38(3H, s), 2.44-2.71(4H, m), 4.09(2H, q, J=7.0 Hz), 4.22(2H, q, J=7.0 Hz), 4.96(2H, s), 5.00(2H, s), 6.88-6.98(3H, m), 7.08-7.20(3H, m), 7.72-7.82(1H, m), 7.86-7.94(1H, m), 8.35-8.40(1H, m), 8.53(1H, s).

Example 256.

After a mixture of ethyl 3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-1H-pyrazole-4-yl]-propionate (680 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid (620 mg, yield: 97%). Their recrystallized from acetone-hexane. Melting point: 126-127°C.

Example 257.

A mixture of 5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridyl-methanol (550 mg) and thionyl chloride (10 ml) was stirred at 0°C for 2 hours and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, n is consequently washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (gSO4) and concentrated. A mixture of the obtained residue, ethyl 3-(3-ethoxy-1H-pyrazole-4-yl)propionate (400 mg), potassium carbonate (510 mg) and N,N-dimethylformamide (15 ml) was stirred at 80°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:1, volume ratio), ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]-1H-pyrazole-4-yl]propionate (730 mg, yield: 80%) as a colorless oily substance.

NMR (Dl3)δ: 1.22(3H, t, J=7.2 Hz), 1.36(3H, t, J=7.0 Hz), 2.44(3H, s), 2.47-2.75(4H, m), 4.03-4.28(4H, m), 5.02(2H, s), 5.15(2H, s), 6.93(1H, d, J=8.8 Hz), 7.09(1H, s), 7.28(1H, DD, J=3.0, 8.8 Hz), 7.38-7.50(3H, t), 7.94-8.06(2H, t), 8.35(1H, d, J=3.0 Hz).

Example 258.

After a mixture of ethyl 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]-1H-pyrazole-4-yl]propionate (730 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO ) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[5-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-2-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (650 mg, yield: 95%). Their recrystallized from acetone-hexane. Melting point: 133-134°C.

Example 259.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 4-(4-chloromethylphenoxyacetic)-5-methyl-2-phenyloxazole (549 mg), ethyl 3-ethoxy-1H-pyrazole-4-ilaclama (347 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-ilaclama (618 mg, yield: 74%) as a colorless oily substance.

NMR (Dl3)δ: 1.25(3H, t, J=7.0 Hz), 1.34(3H, t, J=7.0 Hz), 2.43(3H, s), 3.36(2H, s), 4.14(2H, q, J=7.0 Hz), 4.23(2H, q, J=7.0 Hz), 4.98(2H, s), 5.04(2H, s), 6.98(1H, d, J=8.8 Hz), 7.13(1H, s), 7.17(1H, d, J=8.8 Hz), 7.40-7.50 (3H, m, 7.97-8.04(2H, m).

Example 260.

After a mixture of ethyl 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-ilaclama (618 m is), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-ethoxy-1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl-acetic acid (502 mg, yield: 86%). Their recrystallized from ethanol-hexane. Melting point: 125-126°C.

Example 261.

Sodium hydride (60%in oil, 70.0 mg) was added into the solution

5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (551 mg), ethyl 3-ethoxy-1H-pyrazole-4-ilaclama (347 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridylmethyl]-1H-pyrazole-4-ilaclama (608 mg, yield: 73%) as a colourless is Akanistha substances.

NMR (Dl3)δ: 1.25(3H, t, J=7.2 Hz), 1.35(3H, t, J=7.0 Hz), 2.47(3H, s), 3.36(2H, s), 4.15(2H, q, J=7.2 Hz), 4.22(2H, q, J=7.0 Hz), 5.02(2H, s), 5.29(2H, s), 6.78(1H, d, J=8.4 Hz), 7.19(1H, s), 7.39-7.49(4H, m), 7.98-8.07(3H, m).

Example 262.

After a mixture of ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-1H-pyrazole-4-ilaclama (605 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-1H-pyrazole-4-luxusni acid (518 mg, yield: 91%). Their recrystallized from ethanol-hexane. Melting point: 126-127°C.

Example 263.

Sodium hydride (60%in oil, to 39.4 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]pyridine (300 mg), ethyl 3-ethoxy-1H-pyrazole-4-ilaclama (195 mg) in N.N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried the (MgSO 4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-pyridylmethyl]-1H-pyrazole-4-ilaclama (364 mg, yield: 79%) as a colorless oily substance.

NMR (Dl3)δ: 1.25(3H, t, J=7.2 Hz), 1.35(3H, t, J=7.0 Hz), 2.46(3H, s), 3.66(2H, s), 4.14(2H, q, J=7.2 Hz), 4.22(2H, q, J=7.0 Hz), 5.02(2H, s), 5.26(2H, s), 6.52(1H, DD, J=1.8, Hz), 6.76(1H, d, J=8.6 Hz), 6.98(1H, DD, J=0.8, Hz), 7.19(1H, s), 7.46(1H, DD, J=2.4. 8.6 Hz), 7.52(1H, DD, J=0.8, 1.8 Hz), 8.05(1H, d, J=2.4 Hz).

Example 264.

After a mixture of ethyl 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-pyridylmethyl]-1H-pyrazole-4-ilaclama (364 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-ethoxy-1-[6-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]-3-pyridylmethyl]-1H-pyrazole-4-luxusni acid (308 mg, yield: 90%). Their recrystallized from ethanol-hexane. Melting point: 155-156°C.

Example 265.

Sodium hydride (60%in oil, to 0.30 g) was added to a solution of ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (1,83 g) in N,N-dimethylformamide (20 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-phenylthiazole (1,05 g) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (513 mg, yield: 14%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.2 Hz), 2.52(2H, t, J=7.8 Hz), 2.95(2H, t, J=7.8 Hz), 4.08(2H, q, J=7.2 Hz), 4.95(2H, s), 5.21(4H, s), 6.47(2H, d, J=2.2 Hz), 6.52(1H, d, J=2.4 Hz), 6.66(1H, t, J=2.2 Hz), 6.72(1H, d, J=2.4 Hz), 7.16-7.46(13H, m), 7.90-7.97(4H, m).

Example 266.

After a mixture of ethyl 3-[1-[3,5-bis(2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (498 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and then the mixture was extracted with ethyl acetate. The ethyl acetate is the first layer was washed with a saturated aqueous solution of sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[3,5-bis(2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (378 mg, yield: 79%). Their recrystallized from ethyl acetate-hexane. Melting point: 78-79°C.

Example 267.

Sodium hydride (60%in oil, 190 mg) was added to a solution of 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-errorcorrected (1,05 g) and ethyl-diethylphosphonoacetate (1,05 g) in N,N-dimethylformamide (50 ml) at 0°and the mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into water and the precipitated crystals were collected by filtration to obtain ethyl (E)-3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]-propanoate. The crystals were dissolved in ethanol (80 ml) and was first made on 5% palladium on coal (800 mg) at room temperature under normal pressure. The catalyst was filtered and the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3 [1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (of 1.05 g, yield: 86%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7 Hz), 2.48(3H, s), 2.4-2.55(2H, m), 2.9-3.0(2H, m), 4.08(2H, q, J=7 Hz), 4.94(2H, s), N, s), 6.51(1H, d, J=2.5 Hz), 6.70(1H, d, J=2 Hz), 6.80(1H, d, J=8.5 Hz), 7.15-7.5(M, m), 7.95-8.1(3H, m).

Example 268.

A mixture of ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionate (1,03 g), 1 N. aqueous sodium hydroxide solution (8 ml), ethanol (10 ml) and tetrahydrofuran (10 ml) was stirred at room temperature. The reaction mixture was poured into water, neutralized 1 N. hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya acetone-hexane (1:1, volume ratio), crystals of 3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-3-pyrrolyl]propionic acid. Their recrystallized from ethyl acetate-hexane to obtain colorless prismatic crystals (740 mg, yield: 74%). Melting point: 123-124°C.

Example 269.

Sodium hydride (60%in oil, 0.56 g) was added to a solution of ethyl 3-[1-(3,5-dihydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (5,12 g) in N,N-dimethylformamide (50 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added ethyliodide (1,12 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer premillenarianism aqueous solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[1-(3,5-diethoxybenzoic)-4-FINEP-3-pyrrolyl]propionate (1040 mg, yield: 24%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 1.38(6H, t, J=7.0 Hz), 2.48-2.56(2H, m), 2.91-2.99(2H, m), 3.97(2H, q, J=7.0 Hz), 4.08(4H, q, J=7.0 Hz), 4.91(2H, s), 6.29(2H, d, J=2.2 Hz), 6.36(1H, t, J=2.2 Hz), 6.51(1H, d, J=2.4 Hz), 6.72(1H, d, J=2.4 Hz), 7.15-7.25(1H, m), 7.29-7.42(4H, m).

Example 270.

Chromatography on a column of silica gel as described in example 269, gave from the faction, elyuirovaniya after the connection described in example 269, ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (2040 mg, yield: 37%) as a colorless oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.0 Hz), 1.37(3H, t, J=7.0 Hz), 2.47-2.55(2H, m), 2.92-3.00(2H, m), 3.96(2H, q, J=7.0 Hz), 4.09(2H, q, J=7.0 Hz), 4.89(2H, s), 5.67(1H, s), 6.06(1H, s), 6.29-6.32(2H, m,), 6.50(1H, d, J=2.4 Hz), 6.71(1H, d, J=2.4 Hz), 7.15-7.41(5H, m).

Example 271.

Sodium hydride (60%in oil, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-5-methyl-2-phenyloxazol (260 mg) and the mixture was stirred at room temperature for the of 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]propionate (622 mg, yield: 88%) as a colorless oily substance from the fraction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio).

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 1.38(3H, t, J=7.0 Hz), 2.41(3H, s), 2.47-2.55(2H, m), 2.91-2.99(2H, m), 3.98(2H, q, J=7.0 Hz), 4.08(2H, q, J=7.0 Hz), 4.93(4H, s), 6.34(1H, s), 6.43(1H, s), 6.51(1H, s), 6.52(1H, d, J=2.4 Hz), 6.72(1H, d, J=2.4 Hz), 7.16-7.45(8H, m), 7.98-8.03(2H, m).

Example 272.

After a mixture of ethyl 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-4-phenyl-3-pyrrolyl]propionate (621 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2.5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-(5-methyl-2-phenyl-4-oxazolyl-methoxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (mg, yield: 74%). Their recrystallized from ethanol-hexane. Melting point: 126-127°C.

Example 273.

Sodium hydride (60%in oil, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-phenylthiazole (262 mg) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (601 mg, yield: 85%) as a colorless oily substance.

NMR (Dl3)δ: 1.20 (3H, t, J=7.0 Hz), 1.38(3H, t, J=7.0 Hz), 2.48-2.56(2H, m), 2.91-2.99(2H, m), 3.97(2H, q, J=7.0 Hz), 4.08(2H, q, J=7.0 Hz), 4.93(2H, s), 5.20(2H, s), 6.34(1H, s), 6.42(1H, s), 6.50(1H, d, J=2.4 Hz), 6.52(1H, s), 6.72(1H, d, J=2.4 Hz), 7.15-7.46(M, m), 7.92-7.96(2H, m).

Example 274.

After a mixture of ethyl 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (595 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol is (5 ml) was stirred at room temperature for 2 hours, to the mixture was added 1 N. hydrochloric acid (2.5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-(2-phenyl-4-thiazoleacetate)-benzyl]-4-phenyl-3-pyrrolyl]propionic acid (538 mg, yield: 95%). Their recrystallized from ethanol-hexane. Melting point: 109-110°C.

Example 275.

Sodium hydride (60%in oil, 50.0 mg) was added to a solution of ethyl 3-[1-(3-ethoxy-5-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (492 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 15 minutes. To the mixture was added 4-chloromethyl-2-(2-thienyl)thiazole (270 mg) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:3, volume ratio), ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (657 mg, yield: 92%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz, 1.38(3H, t, J=7.0 Hz), 2.48-2.56(2H, m), 2.91-2.99(2H, m), 3.97(2H, q, J=7.0 Hz), 4.08(2H, q, J=7.0 Hz), 4.92(2H, s), 5.16(2H, s), 6.33(1H, s), 6.41(1H, s), 6.48(1H, t, J=2.2 Hz), 6.51(1H, d, J=2.4 Hz), 6.72(1H, d, J=2.4 Hz), 7.06(1H, DD, J=3.6, 5.2 Hz), 7.19-7.25(2H,m), 7.29-7.40(5H, m), 7.50(1H, DD, J=1.2, 3.6 Hz).

Example 276.

After a mixture of ethyl 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazoleacetate)benzyl]-4-phenyl-3-pyrrolyl]propionate (653 mg), 1 N. aqueous sodium hydroxide solution (2.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2.5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[3-ethoxy-5-[2-(2-thienyl)-4-thiazoleacetate)-benzyl]-4-phenyl-3-pyrrolyl]propionic acid (545 mg, yield: 88%). Their recrystallized from ethanol-hexane. Melting point: 104-105°C.

Example 277.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]-propionate (600 mg), 5-chloromethyl-2-phenylpyridine (370 mg), potassium carbonate (450 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. About what's headed the remainder was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), a colorless oily substance. Then a mixture of the obtained colorless oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[4-phenyl-1-[4-(6-phenyl-3-pyridyloxy)benzyl]-3-pyrrolyl]propionic acid (820 mg, yield: 98%). Their recrystallized from acetone-hexane. Melting point: 185-186°C.

Example 278

A mixture of 5-phenyl-2-pyridinemethanol (390 mg), thionyl chloride (0.3 ml) and toluene (10 ml) was stirred at 80°C for 1 hour. Then the reaction mixture was concentrated under reduced pressure, the obtained crystals were filtered and washed with hexane. A mixture of the obtained crystals of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrole]propionate (790 mg), potassium carbonate (700 mg) and N,N-dimethylformamide (15 ml) was stirred at 70°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was digging nasystem aqueous solution of sodium chloride, with the sewed (MgSO 4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[1-[4-(5-phenyl-2-pyridyloxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (1050 mg, yield: 96%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 2.46-2.58(2H, m), 2.88-3.00(2H, m), 4.08(2H, q, J=7.0 Hz), 4.95(2H, s), 5.25(2H, s), 6.51(1H, d, J=2.6 Hz), 6.71(1H, d, J=2.6 Hz), 6.94-7.04(2H, m), 7.08-7.64(13H, m), 7.91(1H, DD, J=2.2, 8.0 Hz), 8.82(1H, d, J=2.2 Hz).

Example 279.

After a mixture of ethyl 3-[1-[4-(5-phenyl-2-pyridyloxy)benzyl]-4-phenyl-3-pyrrolyl]propionate (mg), 1 N. aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (4 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(5-phenyl-2-pyridyloxy)benzyl]-4-phenyl-3-pyrrolyl]propionic acid (930 mg, yield: 97%). Their recrystallized from acetone-hexane. Melting point: 169-170°C.

Example 280.

A mixture of 4-benzyloxybenzaldehyde (11,60 g), ethyl 3-(4-forfinal)-1H-pyrazole-4-carboxylate (11,70 g), potassium carbonate (13,80 g) and N,N-dimethy is of formamide (150 ml) was stirred at room temperature for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain ethyl 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-carboxylate (16,90 g, yield: 79%). Their recrystallized from ethyl acetate-hexane. Melting point: 103-104°C.

Example 281.

Sodium hydride (60%in oil, 1.10 g) was added to a solution of 1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-carbaldehyde (9,66 g) and ethyl diethylphosphonoacetate (5,46 ml) in N,N-dimethylformamide (150 ml) at 0°and the mixture was stirred at room temperature for 2 hours. In the reaction mixture is poured into ice water and the resulting crystals were collected by filtration. Then dried, recrystallized from ethyl acetate-hexane to obtain ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl]propenoate (or 10.60 g, yield: 93%). Melting point: 113-114°C.

Example 282.

Sodium hydride (60%in oil, 140 mg) was added to a solution of 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carbaldehyde (1.20 g) and ethyl diethylphosphonoacetate (780 mg) in N,N-dimethylformamide (30 ml) at 0°and the mixture was stirred at 0°C for 2 hours. The reaction mixture was poured into water and the precipitated crystals were collected fil is a walkie-talkie to obtain ethyl (E)-3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate. The crystals were dissolved in ethanol (100 ml) and was first made on 5% palladium on coal (1.0 g) at room temperature under normal pressure. The catalyst was removed by filtration and the resulting filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 3-[1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (1.20 g, yield: 86%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7 Hz), 2.47(3H, s), 2.52(2H, t, J=7.5 Hz), 2.94(2H, t, J=7.5 Hz), 4.08(2H, q, J=7 Hz), 5.23(2H, s), 5.29(2H, s), 6.80(1H, d, J=8.5 Hz), 7.2-7.65 (10H, m), 7.95-8.15(3H, m).

Example 283.

A mixture of ethyl 3-[1-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (1.20 g), 1 N. aqueous sodium hydroxide solution (10 ml) and ethanol (20 ml) was stirred at room temperature for 2 hours. Then the reaction mixture was poured into water and neutralized 1 N. hydrochloric acid, the precipitated crystals of 3-[1-[2-(5-methyl-2-phenyl-4-oxazolidinone)-5-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid was collected by filtration. Their recrystallized from ethyl acetate to obtain colorless prismatic crystals (810 mg, yield: 71%). Melting point: 172-173°C.

Example 284.

A mixture of 1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-ylmethanol (26,39 g), activated manganese dioxide (70,26 g) and tetrahydrofuran (30 ml) was stirred at room temperature overnight. Then the manganese dioxide was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), a colorless oily substance. Sodium hydride (60%in oil, 3,20 g) was added to a solution of the obtained colorless oily substance and ethyl diethylphosphonoacetate (18,19 g) in N,N-dimethylformamide (100 ml) at 0°and the mixture was stirred at room temperature for 2 hours. In the reaction mixture is poured into ice water and the resulting crystals were collected by filtration. Then dried, recrystallized from ethyl acetate-hexane to obtain ethyl (E)-3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propenoate (26,71 g, yield: 86%). Melting point: 94-95°C.

Example 285.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (600 mg), hydrochloride 2-chloromethylpyridine (380 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), b is izvetnogo oily substance. Then a mixture of the obtained colorless oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-chinaillon)benzyl]-1H-pyrazole-4-yl]-propionic acid (660 mg, yield: 83%). Their recrystallized from acetone-hexane. Melting point: 147-148°C.

Example 286.

A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (1050 mg), 1(2H)-phthalazinone (530 mg), potassium carbonate (1000 mg) and N,N-dimethylformamide (15 ml) was stirred at 90°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), a colorless oily substance. Then a mixture of the obtained colorless oily substance, 1 N. in the underwater of sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 3 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-[2-[1-acceptilation-2(1H)-yl]ethoxy]benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (1460 mg, yield: 90%). Their recrystallized from acetone-hexane. Melting point: 155-156°C.

Example 287.

A mixture of ethyl 3-[1-[4-(2-bromoethoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (883 mg), 2H-1,4-benzothiazin-3(4H)-she (320 mg), potassium carbonate (530 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), a colorless oily substance. Then a mixture of the obtained colorless oily substance, 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) PE is amasyali at room temperature for 3 hours, to the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain 3-[1-[4-[2-(3-oxo-2,3-dihydro-4H-1,4-benzothiazin-4-yl) -ethoxy] bunzip] -3-phenyl-1H-pyrazole-4-yl] propionic acid (680 mg, yield: 69%) as a colorless amorphous substance.

Example 288.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (600 mg), 5-chloromethyl-2-phenylpyridine (350 mg), potassium carbonate (460 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), a colorless oily substance. Then a mixture of the obtained colorless oily substance, 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated aqueous solution of sodium chloride, with the sewed (MgSO 4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(6-phenyl-3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (710 mg, yield: 85%). Their recrystallized from acetone-hexane. Melting point: 155-156°C.

Example 289.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (840 mg), 3-chloromethyl-5-phenylpyridine (550 mg), potassium carbonate (500 mg) and N,N-dimethylformamide (10 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-phenyl-1-[4-(5-phenyl-3-pyridyloxy)-benzyl]-1H-pyrazole-4-yl]propionate (1010 mg, yield: 81%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.0 Hz), 2.46-2.56(2H, m), 2.88-3.00(2H, m), 4.12(2H, q, J=7.0 Hz), 5.15(2H, s), 5.25(2H, s), 6.92-7.04(2H, m), 7.16-7.67(13H, m), 7.94-7.99(1H, m), 8.65(1H, d, J=2. 2 Hz), 8.82(1H, d, J=2.2 Hz).

Example 290.

After a mixture of ethyl 3-[3-phenyl-1-[4-(5-phenyl-3-pyridyloxy) benzyl]-1H-pyrazole-4-yl]propionate (980 mg), 1 N. aqueous sodium hydroxide solution (4 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred the ri room temperature for 2 hours, to the mixture was added 1 N. hydrochloric acid (4 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(5-phenyl-3-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (760 mg, yield: 82%). Their recrystallized from acetone-hexane. Melting point:

161-162°C.

Example 291.

A mixture of ethyl 3-[1-(4-hydroxybenzyl)-3-phenyl-1H-pyrazole-4-yl]propionate (460 mg), 2-chloromethyl-1-methyl-1H-benzimidazole (250 mg), potassium carbonate (360 mg) and N,N-dimethylformamide (15 ml) was stirred at 80°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:1, volume ratio), ethyl 3-[1-[4-(1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (550 mg, yield: 85%) as a colorless oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.0 Hz), 2.45-2.56 (2H, m), 2.86-2.98(2H, m), 3.89(3H, s), 4.06(2H, q, J=7.0 Hz), 5.22(2H, s), 5.39(2H, s), 7.01-7.10(2H, m), 7.16-7.47(M, m), 7.58-7.66(2H, m), 7.73-7.82(1H, m).

Example 292.

After ka is a mixture of ethyl 3-[1-[4-(1-methyl-1H-benzimidazole-2-ylethoxy)benzyl]-3-phenyl-1H-pyrazole-4-yl]propionate (520 mg), 1 N. aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(1-methyl-1H-benzimidazole-2-ylethoxy)-benzyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (420 mg, yield: 86%). Their recrystallized from ethanol-hexane. Melting point: 225-226°C.

Example 293.

A mixture of ethyl 3-[3-(4-forfinal)-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (950 mg), hydrochloride 2-chloromethylpyridine (600 mg), potassium carbonate (700 mg) and N,N-dimethylformamide (15 ml) was stirred at 60°C for 5 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[3-(4-forfinal)-1-[4-(2-chinaillon)benzyl]-1H-pyrazole-4-yl]propionate (1210 mg, yield: 92%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.0 is C), 2.45-2.56(2H, m), 2.83-2.96(2H, m), 4.07(2H, q, J=7.0 Hz), 5.21(2H, s), 5.38(2H, s), 6.94-7.26(7H, m), 7.50-7.88(6N, m), 8.04-8.13(1H, m), 8.16-8.24(1H, m).

Example 294.

After a mixture of ethyl 3-[3-(4-forfinal)-1-[4-(2-chinaillon)benzyl]-1H-pyrazole-4-yl]propionate (1150 mg), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-(4-forfinal)-1-[4-(2-chinaillon)benzyl]-1H-pyrazole-4-yl]propionic acid (1010 mg, yield: 93%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 178-179°C.

Example 295.

A mixture of 5-phenyl-2-pyridinemethanol (330 mg), thionyl chloride (0.3 ml) and toluene (10 ml) was stirred at 80°C for 1 hour. Then the reaction mixture was concentrated under reduced pressure, the obtained crystals were filtered and washed with hexane. A mixture of the obtained crystals of ethyl 3-[3-(4-forfinal)-1-(4-hydroxybenzyl)-1H-pyrazole-4-yl]propionate (650 mg), potassium carbonate (550 mg) and N,N-dimethylformamide (10 ml) was stirred at 70° With during the night. The reaction mixture was poured into water and was extracted with atilas what tatom. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[3-(4-forfinal)-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (850 mg, yield: 90%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.0 Hz), 2.44-2.56 (2H, m), 2.85-2.97(2H, m), 4.07(2H, q, J=7.0 Hz), 5.22(2H, s), 5.25(2H, s), 6.94-7.26(8H, m), 7.34-7.68(7H, m), 7.91(1H, DD, J=2.2, 8.4 Hz), 8.82(1H, d, J=2.2 Hz).

Example 296.

After a mixture of ethyl 3-[3-(4-forfinal)-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (800 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (3 ml) and ethanol (3 ml) was stirred at room temperature for 5 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-(4-forfinal)-1-[4-(5-phenyl-2-pyridyloxy)-benzyl]-1H-pyrazole-4-yl]propionic acid (700 mg, yield: 93%). Their recrystallized from ethanol-water. Melting point: 162-163°C.

Example 297.

Sodium hydride (60%in oil, 70.0 mg) doba is ranged in a solution of 2-(5-chloromethyl-2-pyridyloxy)quinoline (498 mg), ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (428 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-phenyl-1-[6-(2-chinaillon)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (651 mg, yield: 76%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.2 Hz), 2.48-2.56(2H, m), 2.90-2.98(2H,m), 4.07(2H, q, J=7.2 Hz), 5.22(2H, s), 5.68(2H, s), 6.89(1H, d, J=8.8 Hz), 7.23(1H, s), 7.29-7.65(8H, m), 7.53(1H, DDD, J=1.4, 7.0, 8.4 Hz), 7.72(1H, DDD, J=1.8, 6.8, 8.4 Hz), 7.81(1H, DD, J=1.8, 8.2 Hz), 8.08-8.18(3H, m).

Example 298.

After a mixture of ethyl 3-[3-phenyl-1-[6-(2-chinaillon)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (650 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals gathered and filtered to obtain 3-[3-phenyl-1-[6-(2-chinaillon)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (489 mg, yield: 80%). Their recrystallized from acetone-hexane. Melting point: 166-167°C.

Example 299.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazoleacetate)pyridine (554 mg), ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (428 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4)and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio), ethyl 3-[3-phenyl-1-[2-(2-phenyl-4-thiazolyl-methoxy)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionate (678 mg, yield: 74%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 88-89°C.

Example 300.

After a mixture of ethyl 3-[3-phenyl-1-[2-(2-phenyl-4-thiazoleacetate)-5-pyridylmethyl]-1H-pyrazole-4-yl]propionate (603 mg), 1 n sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried the (MgSO 4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[6-(2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-1H-pyrazole-4-yl]propionic acid (500 mg, yield: 88%). Their recrystallized from acetone-hexane. Melting point: 107-108°C.

Example 301.

A mixture of 4- (5-phenyl-2-pyridyloxy)benzyl alcohol (600 mg), thionyl chloride (0.35 ml) and toluene (30 ml) was stirred at 80° C for 2 hours. The reaction mixture was concentrated under reduced pressure and dissolved in ethyl acetate. The solution was sequentially washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride, dried (gSO4) and concentrated. Sodium hydride (60%in oil, 92.0 mg) was added to the solution precipitated oily substance and ethyl 3- (3-phenyl-1H-pyrazole-4-yl) propionate (510 mg) in N,N-dimethylformamide (15 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[3-phenyl-1-[4-(5-phenyl-2-pyridyloxy)-benzyl]-1H-pyrazole-4-yl]p is obinata (970 mg, yield: 91%) as a colorless oily substance.

NMR (Dl3)δ: 1.18(3H, t, J=7.4 Hz), 2.47-2.57 (2H, m), 2.90-3.00(2H, m), 4.07(2H, q, J=7.4 Hz), 5.24(2H, s), 5.26(2H, s), 7.00(2H, d, J=8.8 Hz), 7.19-7.68(14N, m), 7.91(1H, DD, J=2.2, 8.0 Hz), 8.83(1H, d, J=2.2 Hz).

Example 302.

After a mixture of ethyl 3-[3-phenyl-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionate (970 mg), 1 n sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(5-phenyl-2-pyridyloxy)benzyl]-1H-pyrazole-4-yl]propionic acid (820 mg, yield: 90%). Their recrystallized from acetone-hexane. Melting point: 149-150°C.

Example 303.

Sodium hydride (60%in oil, 110 mg) was added to a solution of 4-(4-chloromethylphenoxyacetic)-2-phenylthiazole (760 mg) and ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (580 mg) in N.N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO 4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolyl-methoxy)benzyl]-1H-pyrazole-4-yl]propionate (1110 mg, yield: 89%) as a colorless oily substance.

NMR (Dl3)δ: 1.19(3H, t, J=7.0 Hz), 2.47-2.57(2H, m), 2.89-3.00(2H, m), 4.07(2H, q, J=7.0 Hz), 5.24(2H, s), 5.27(2H, s), 6.96-7.05(2H, m), 7.18-7.49(10H, m), 7.59-7.68(2H, m), 7.90-7.99-(2H, m).

Example 304.

After a mixture of ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-1H-pyrazole-4-yl]propionate (1110 mg), 1 n sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-1H-pyrazole-4-yl]propionic acid (630 mg, yield: 60%). Their recrystallized from acetone-hexane. Melting point: 132-133°C.

Example 305.

A mixture of 5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridine-methanol (630 mg) and thionyl chloride (10 ml) was stirred at 0°C for 2 hours and the reaction mixture is the end of what was tarawali under reduced pressure. The residue was dissolved in ethyl acetate, sequentially washed with saturated aqueous sodium bicarbonate and saturated aqueous sodium chloride, dried (gSO4) and concentrated. A mixture of the obtained crystals of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (520 mg), potassium carbonate (590 mg) and N,N-dimethylformamide (15 ml) was stirred at 80°With during the night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:1, volume ratio), ethyl 3-[1-[5-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-2-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (950 mg, yield: 85%) as a colorless oily substance.

NMR (Dl3)δ: 1.20(3H, t, J=7.0 Hz), 2.44(3H, s), 2.48-2.58(2H, m), 2.92-3.03(2H, m), 4.09(2H, q, J=7.0 Hz), 5.02(2H, s), 5.38(2H, s), 7.08(1H, d, J=8.4 Hz), 7.20-7.54(8H, m), 7.60-7.68(2H, m), 7.95-8.08(2H, m), 8.38(1H, d, J=2.6 Hz).

Example 306.

After a mixture of ethyl 3-[1-[5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionate (930 mg), 1 n sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 m is) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[5-(5-methyl-2-phenyl-4-oxazolidinone)-2-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]propionic acid (830 mg, yield: 94%). Their recrystallized from acetone-hexane. Melting point: 175-176°C.

Example 307.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (551 mg) and ethyl (3-phenyl-1H-pyrazole-4-yl) acetate (403 mg) in N.N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:3, volume ratio), ethyl [1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (513 mg, yield: 58%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 2.48(3H, s), 3.60(2H, s), 4.13(2H, q, J=7.0 Hz), 5.26(2H, s), 5.30(2H, s), 6.81(1H, d, J=8.8 Hz), 7.30-7.47(7H, m), 7.53-7.62(3H, m), 7.98-8.05(2H, m), 8.16(1H, d, J=2.2 Hz).

Example 308.

After a mixture of ethyl 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (509 mg), 1 n sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain [1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetic acid (408 mg, yield: 85%). Their recrystallized from acetone-hexane. Melting point: 144-145°C.

Example 309.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 5-chloromethyl-2-(2-phenyl-4-thiazoleacetate)pyridine (554 mg) and ethyl (3-phenyl-1H-pyrazole-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl [3-phenyl-1-[6-(2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-1H-pyrazole-4-yl]acetate (594 mg, yield: 66%) as colorless crystals. Their paracrystal obyvali from ethyl acetate-hexane. Melting point: 75-76°C.

Example 310.

After a mixture of ethyl [3-phenyl-1-[6-(2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-1H-pyrazole-4-yl]acetate (536 mg), 1 n sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain [3-phenyl-1-[6-(2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-1H-pyrazole-4-yl]acetic acid (459 mg, yield: 91%). Their recrystallized from ethanol-hexane. Melting point: 118-119°C.

Example 311.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-thiazoleacetate)pyridine (579 mg) and ethyl (3-phenyl-1H-pyrazole-4-yl) acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (2:3, volume soo is wearing), ethyl [1-[6-(5-methyl-2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (476 mg, yield: 52%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, 3=1.2 Hz), 2.56(3H, s), 3.60(2H, s), 4.13(2H, q, J=7.2 Hz), 5.26(2H, s), 5.44(2H, s), 6.82(1H, d, J=8.0 Hz), 7.29-7.47(7H, m), 7.53-7.62(3H, m), 7.86-7.92(2H, m), 8.17(1H, d, J=2.2 Hz).

Example 312.

After a mixture of ethyl [1-[6-(5-methyl-2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (475 mg), 1 n sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain [1-[6-(5-methyl-2-phenyl-4-thiazoleacetate)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetic acid (402 mg, yield: 89%). Their recrystallized from ethanol-hexane. Melting point: 140-141°C.

Example 313.

Sodium hydride (60%in oil, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]pyridine (575 mg) and ethyl (3-phenyl-1H-pyrazole-4-yl) acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured in in the control and were extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)-ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (575 mg, yield: 63%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 2.34(3H, s), 2.98(2H, t, J=6.8 Hz), 3.59(2H, s), 4.12(2H, q, J=7.0 Hz), 4.56(2H, t, J=6.8 Hz), 5.24(2H, s), 6.71(1H, d, J=8.4 Hz), 7.29-7.47(7H, m), 7.51-7.61 (3H. m), 7.94-8.01(2H, m), 8.12(1H, d, J=2.6 Hz).

Example 314.

After a mixture of ethyl [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]-acetate (575 mg), 1 n sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain [1-[6-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetic acid (466 mg, yield: 86%). Their recrystallized from ethanol-hexane. Melting point: 148-149°C.

Example 315.

GI is reed sodium (60%, in oil, 70.0 mg) was added to a solution of 5-chloromethyl-2-[2-(2-furyl)-5-methyl-4-oxazolidinone]-pyridine (533 mg) and ethyl (3-phenyl-1H-pyrazole-4-yl)acetate (403 mg) in N,N-dimethylformamide (10 ml) at 0°and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (581 mg, yield: 67%) as a colorless oily substance.

NMR (Dl3)δ: 1.21(3H, t, J=7.0 Hz), 2.46(3H, s), 3.60(2H, s), 4.13(2H, q, J=7.0 Hz), 5.26(2H, s), 5.28(2H, s), 6.51(1H, DD, J=1.8, 3.6 Hz), 6.79(1H, d, J=8.4 Hz), 6.98(1H, DD, J=0.6, 3.6 Hz), 7.30-7.46(4H,m), 7.52-7.61(4H, m), 8.14(1H, d, J=2.2 Hz).

Example 316.

After a mixture of ethyl [1-[6-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetate (578 mg), 1 n sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed with a saturated aqueous solution of chloride on the matter, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain [1-[6-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-yl]acetic acid (467 mg, yield: 86%). Their recrystallized from acetone-hexane. Melting point: 135-136°C.

Example 317.

A mixture of [1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl]acetonitrile (4,37 g), 4 n sodium hydroxide solution (20 ml), tetrahydrofuran (20 ml) and ethanol (20 ml) was boiled under reflux for 2 days. After cooling, the mixture was neutralized with diluted hydrochloric acid and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated to obtain [1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl]acetic acid (4,37 g, yield: 95%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 194-195°C.

Example 318.

A mixture of [1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl]acetic acid (4,16 g), methyliodide (0.95 ml), potassium carbonate (2.76 g) and N,N-dimethylformamide (50 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated.

About what's headed the remainder was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), methyl [1-(4-benzyloxybenzyl)-3-(4-forfinal)-1H-pyrazole-4-yl]acetate (4,21 g, yield: 98%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 58-59°C.

Example 319.

A mixture of ethyl 3-hydroxy-1H-pyrazole-4-carboxylate (of 8.95 g), 4-phenoxybenzaldehyde (25,35 g), potassium carbonate (31,88 g) and N,N-dimethylformamide (200 ml) was stirred at 90°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and an aqueous solution of sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:4, volume ratio), ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (22,71 g, yield: 76%) as a colorless oily substance.

NMR (Dl3)δ: 1.31(3H, t, J=7.4 Hz), 4.25(2H, q, J=7.4 Hz), 5.09(2H, s), 5.31(2H, s), 6.93-7.50(M, m), 7.67(1H, s).

Example 320.

After a mixture of ethyl 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (500 mg), 1 n sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid is the (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 1-(4-phenoxybenzyl)-3-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (450 mg, yield: 95%). Their recrystallized from acetone-hexane. Melting point: 141-142°C.

Example 321.

A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxy)-2-(2-furyl)-5-methoxazole (3.00 g), potassium carbonate (2,52 g) and N,N-dimethylformamide (30 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and an aqueous solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolyl-methoxy]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5.30 g, yield: 94%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 98-99°C.

Example 322.

After a mixture of ethyl 3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxybenzyloxy]-1-(phenoxybenzyl)-1H-feast of the evil-4-carboxylate (1500 mg), 1 n sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (1330 mg, yield: 93%). Their recrystallized from acetone-hexane. Melting point: 153-154°C.

Example 323.

A mixture of 3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0,80 g), 1H-1,2,3-benzotriazol-1-ol ammonia complex (0,22 g), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimides (0.28 g) and N,N-dimethylformamide (10 ml) was stirred at room temperature over night. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and an aqueous solution of sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), 3-[4-[2-(2-furyl)-5-METI the-4-oxazolidinone]-3-methoxybenzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0.75 g, yield: 94%) as colorless crystals. Their recrystallized from acetone-hexane. Melting point: 105-106°C.

Example 324.

A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (3.00 g), 4-(4-chloromethyl-2-methoxyphenoxy)-5-methyl-2-phenyloxazole (a 3.06 g), potassium carbonate (2.50 g) and N.N-dimethylformamide (30 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and an aqueous solution of sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel to obtain ethyl 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (5,43 g, yield: 95%) as colorless crystals from the fraction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio). Their recrystallized from acetone-hexane. Melting point: 127-128°C.

Example 325.

After a mixture of ethyl 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (750 mg), 1 n sodium hydroxide solution (2 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (2 ml) and the mixture was extracted with ethylacetoacetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolidinone)benzyloxy]-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (680 mg, yield: 95%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 176-177°C.

Example 326.

After a mixture of ethyl 1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyloxy]-1H-pyrazole-4-carboxylate (250 mg), 1 n sodium hydroxide solution (1 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (1 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 1-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone]benzyl]-3-[4-[2-(2-furyl)-5-methyl-4-oxazolidinone] benzyloxy] -1H-pyrazole-4-carboxylic acid (230 mg, yield: 93%). Their recrystallized from acetone-hexane. Melting point: 144-145°C.

Example 327.

Sodium hydride (60%in oil, 310 mg) was added to a mixture of methyl 4-phenyl-3-errorcorrection (1.20 g), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (1.88 g) and N,N-dimethylformamide (50 ml) at room te is the temperature, and the mixture was stirred for 15 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), methyl 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-4-phenyl-1H-pyrrole-3-carboxylate (2,74 g, yield: 96%) as a colorless oily substance.

NMR (Dl3)δ: 2.48(3H, s), 3.72(2H, s), 5.00(2H, s), 5.30(2H, s), 6.66(1H, d, J=1.5 Hz), 6.82(1H, d, J=8.5 Hz), 7.2-7.5(10H, m), 7.95-8.15(3H, m).

Example 328.

Sodium hydride (60%in oil, 270 mg) was added to a mixture of ethyl 3-phenyl-1H-pyrazole-4-carboxylate (1.20 g), 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolidinone)pyridine (1.75 g) and N,N-dimethylformamide (50 ml) at 0°and the mixture was stirred at room temperature for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed with water, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya diethyl ether-hexane (2:3, volume ratio), ethyl 1-[6-(5-methyl-2-phenyl-4-oxazolidinone)-3-pyridylmethyl]-3-phenyl-1H-pyrazole-4-carboxylate (1.56 g, yield: 57%) as a colorless oily substance.

NMR (Dl )δ: 1.14(3H, t, J=7 Hz), 2.45(3H, s), 4.13(2H, q, J=7 Hz), 5.10(2H, s), 5.25(2H, s), 6.72(1H, d, J=Hz), 7.2-7.5(M, m), 7.80(1H, d, J=2 Hz), 7.95-8.05(3H, m).

Example 329.

A mixture of ethyl 3-hydroxy-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylate (4,07 g), 4-chloromethyl-5-methyl-2-phenyloxazole (2.58 g), potassium carbonate (1.73 g) and N,N-dimethylformamide (30 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4 carboxylate (5,86 g, yield: 96%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 96-97°C.

Example 330.

After a mixture of ethyl 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxy-LVL (1600 mg), 1 n sodium hydroxide solution (5 ml), tetrahydrofuran (10 ml) and ethanol (10 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed with saturated concrete water is sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (1470 mg, yield: 97%). Their recrystallized from tetrahydrofuran-hexane. Melting point: 222-223°C.

Example 331.

A mixture of 3-(5-methyl-2-phenyl-4-oxazolidinone)-1- (4-phenoxybenzyl)-1H-pyrazole-4-carboxylic acid (0.75 g), 1H-1,2,3-benzotriazol-1-Aulnay ammonium complex (0.26 g),

1-ethyl-3-(3-dimethylaminopropyl)carbodiimides (0.33 g) and N,N-dimethylformamide (10 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-carbamide (0,70 g, yield: 94%) as colorless crystals.

Their recrystallized from acetone-hexane. Melting point: 158-159°C.

Example 332.

Sodium hydride (60%in oil, 220 mg) was added to a solution of 3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxy)-1H-piraso the-4-carbaldehyde (2.00 g) and ethyldiethanolamine (1.06 g) in N,N-dimethylformamide (25 ml) at 0° C and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)of ethyl (E)-3-[3-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]-propanoate (2,19 g, yield: 95%) as colorless crystals. Their recrystallized from acetone-hexane. Melting point: 93-94°C.

Example 333.

After a mixture of ethyl (E)-3-[3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]propanoate (450 mg), 1 n sodium hydroxide solution (1.5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 50°C for 2 hours, the mixture was added 1 N. hydrochloric acid (1.5 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain (E)-3-[3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]propanolol acid (410 mg, yield: 96%). Their recrystallized from acetone-g is the Xan. Melting point: 210-211°C.

Example 334.

A mixture of ethyl (E)-3-[3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]propenoate (1100 mg), 5% palladium on coal (390 mg) and tetrahydrofuran (30 ml) was stirred at room temperature for 5 hours in an atmosphere of hydrogen. Then palladium on coal was removed by filtration, the filtrate was concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:1, volume ratio), ethyl 3-[3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]propionate (980 mg, yield: 95%) as a colorless oily substance.

NMR (Dl3)δ: 1.17(3H, t, J=7.0 Hz), 2.39(3H, s), 2.45-2.72(4H, m), 4.06(2H, q, J=7.0 Hz), 5.05(2H, s), 5.15(2H, s), 6.90-7.46(13H, m), 7.94-8.06(2H, m).

Example 335.

After a mixture of ethyl 3-[3-(5-methyl-2-phenyl-4-oxazolidinone)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]propionate (800 mg), 1 n sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at room temperature for 2 hours, the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[3-(5-methyl-2-phenyl-4-oxazolyl the si)-1-(4-phenoxybenzyl)-1H-pyrazole-4-yl]propionic acid (740 mg, yield: 97%). Their recrystallized from acetone-hexane. Melting point: 120-121°C.

Example 336.

A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (10,23 g), 4-(4-chloromethylene)methyl-5-methyl-2-phenyloxazole (14,66 g), potassium carbonate (to 13.09 g) and N,N-dimethylformamide (100 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (fall of 19.88 g, yield: 87%). Their recrystallized from ethyl acetate-hexane. Melting point: 113-114°C.

Example 337.

A mixture of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (900 mg), 1 n sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 80°C for 5 hours. After cooling, to the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless Crist is lly was collected by filtration to obtain 1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylic acid (750 mg, yield: 88%). Their recrystallized from acetone-hexane. Melting point: 204-205°C.

Example 338.

A mixture of [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]acetonitrile (1,69 g), 4 n sodium hydroxide solution (10 ml) and ethanol (10 ml) was boiled under reflux overnight. After cooling, to the mixture was added 1 N. hydrochloric acid (40 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain [1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]acetic acid (1.13 g, yield: 64%). Their recrystallized from acetone-hexane. Melting point: 98-99°C.

Example 339.

A mixture of diethyl-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methylmalonate (between 6.08 g), 4 n sodium hydroxide solution (10 ml) and ethanol (10 ml) was boiled under reflux for 1 hour. After cooling, to the mixture was added 1 N. hydrochloric acid (40 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless oily substance was dissolved in pyridine (50 ml) and stirred at 110° C for 2 hours. For the eat pyridine was removed under reduced pressure, to the residue was added ethyl acetate. The resulting solution was successively washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)-benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propionic acid (as 4.02 g, yield: 80%). Their recrystallized from acetone-hexane. Melting point: 172-173°C.

Example 340.

Sodium hydride (60%in oil, 150 mg) was added to a solution of 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carbaldehyde (1.54 g) and ethyldiethanolamine (0,82 g) in N,N-dimethylformamide (15 ml) at 0°and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was sequentially washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio)of ethyl (E)-3-[1-[4-(2-phenyl-4-thiazolyl-methoxy)benzyl] -3- (2-thienyl) -1H-pyrazole-4-yl] -propanoate (1.65 g, yield; 93%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 104-105°is.

Example 341.

After a mixture of ethyl (E)-3-[1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]-propanoate (1,25 d), 1 N. aqueous sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 50°C for 2 hours, the mixture was added 1 N. hydrochloric acid (5 ml) and then the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain (E)-3-[1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propanolol acid (970 mg, yield: 82%). Their recrystallized from ethyl acetate-hexane. Melting point: 137-138°C.

Example 342.

A mixture of diethyl-[1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methylmalonate (4.09 g), 1 N. aqueous sodium hydroxide solution (30 ml), tetrahydrofuran (30 ml) and ethanol (30 ml) was boiled under reflux for 1 hour. After cooling, to the mixture was added 1 N. hydrochloric acid (30 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless oily substance was dissolved in pyridine (50 ml) and the mixture was stirred at 110°C for 2 hours. After removal of pyridine at Pont the leaders introduce pressure, to the precipitate was added ethyl acetate. The resulting solution was successively washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]-propionic acid (3.25 g, yield: 95%). Their recrystallized from ethyl acetate-hexane. Melting point: 133-134°C.

Example 343.

A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (1,43 g), 4-(4-chloromethylene)methyl-2-phenyloxazole (1.88 g), potassium carbonate (1.30 grams) and N,N-dimethylformamide (30 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya with ethyl acetate-hexane (1:2, volume ratio), ethyl 1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (2,81 g, yield: 92%) as colorless crystals. Their recrystallized from ethyl acetate-hexane. Melting point: 114-115°C.

Example 344.

A mixture of diethyl-[1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]methylmalonate (1,75 g), 2 n solution hydrox is Yes sodium (10 ml) and ethanol (10 ml) was boiled under reflux for 2 hours. After cooling, to the mixture was added 1 N. hydrochloric acid (20 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless oily substance was dissolved in pyridine (30 ml) and stirred at 110°C for 2 hours. Then the pyridine was removed under reduced pressure, to the precipitate was added ethyl acetate. The resulting solution was successively washed with diluted hydrochloric acid and saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 3-[1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]-propionic acid (1.24 g, yield: 85%). Their recrystallized from ethyl acetate-hexane. Melting point: 145-146°C.

Example 345.

A mixture of ethyl 3-(2-thienyl)-1H-pyrazole-4-carboxylate (ceiling of 5.60 g), 4-(4-chloromethylene)methyl-2-phenylthiazole (of 7.96 g), potassium carbonate (6,98 g) and N,N-dimethylformamide (75 ml) was stirred at 80°C for 8 hours. The reaction mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (gSO4) and concentrated. The residue was subjected to chromatography on a column of silica gel with obtaining from the faction, elyuirovaniya utilize the atom-hexane (1:2, the volumetric ratio), ethyl 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate as colorless crystals (of 10.93 g, yield: 87%). Their recrystallized from ethyl acetate-hexane. Melting point: 94-95°C.

Example 346.

A mixture of ethyl 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylate (750 mg), 1 N. aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (5 ml) and ethanol (5 ml) was stirred at 80°C for 5 hours. After cooling, to the mixture was added 1 N. hydrochloric acid (3 ml) and the mixture was extracted with ethyl acetate. An ethyl acetate layer was washed saturated aqueous sodium chloride, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to obtain 1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-carboxylic acid (640 mg, yield: 90%). Their recrystallized from acetone-hexane. Melting point: 187~188°C.

Example obtain 1 (receiving capsules)

1) compound of example 4 30 mg

2) powdered cellulose 10 mg

3) lactose 19 mg

4) magnesium stearate 1 mg Total 60 mg

1), 2), 3) and 4) were mixed and filled with a mixture of a gelatin capsule.

Example obtain 2 (taking pills)

1) compound of example 4 30 G.

2) lactose 50 g

3) corn starch 15 g

4) calcium carboxymethylcellulose 44 g

5) stearate mA is of 1 g 1000 tablets 140g

All the number 1), 2) and 3) and 30 g of 4) are mixed together with water and, after vacuum drying, the mixture was granulated. To the granulated mixture was mixed into 14 g of 4) and 1 g of 5) and the resulting mixture alloy preformed using the machine for the production of tablets with getting 1000 tablets each containing 30 mg of compound of example 4.

Industrial application

The compound of the present invention and the pharmaceutical composition of the present invention have low toxicity and can be used as a tool for prevention or treatment of diabetes (such as diabetes mellitus type 1, diabetes mellitus type 2, gestational diabetes); an agent for the prophylaxis or treatment of hyperlipidemia (e.g., hypertriglyceride, hypercholesterolemia, decreased blood high-density lipoprotein, hyperlipemia after eating); as a means to enhance insulin sensitivity; as a means to increase resistance to insulin; as a tool for prevention and treatment reduced glucose tolerance (IGT) and as a means to prevent the development of diabetes with reduced glucose tolerance.

The compound of the present invention and the pharmaceutical composition of the present invention can also be used as a means for prevention or treatment of complications of diabetes (e.g. the, neuropathy, nephropathy, retinopathy, cataract, macroangiopathies, osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g., respiratory infection, urinary tract infections, infections of the gastrointestinal tract, soft tissue infection of the skin, infections of the lower extremities), diabetic gangrene, xerostomia, hearing loss, cerebral-vascular diseases, disorders of peripheral blood circulation, and the like), obesity, osteoporosis, cachexia (e.g., cancerous cachexia, tuberculous cachexia, diabetic cachexia, cachexia in diseases of the blood, endocrinopathic cachexia, infectious cachexia, cachexia due to acquired immunodeficiency syndrome), fatty liver, hypertension, polycystic ovary, renal diseases (e.g., diabetic nephropathy, glomerular nephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, terminal renal disease), muscular dystrophy, myocardial infarction, angina, cerebral-vascular diseases (for example, cerebral infarction, apoplexy of the brain), syndrome of resistance to insulin, syndrome X, hyperinsulinemia, hyperinsulinemia caused by sensory disorders, malignant tumors (e.g., leukemia, the ake breast cancer, prostate cancer, skin cancer), irritable bowel syndrome, acute or chronic diarrhea, inflammatory diseases (e.g., chronic rheumatoid arthritis, spondylitis deformans, osteoarthritis, lumbago, gout, postoperative or traumatic inflammation, tumor remission, neuralgia, pharyngolaryngitis, cystitis, hepatitis (including steatohepatitis, such as non-alcoholic steatohepatitis), pneumonia, pancreatitis, inflammatory colitis, ulcerative colitis, syndrome of visceral obesity and arteriosklerose (e.g., atherosclerosis), and the like.

Also the connection of the present invention and the pharmaceutical composition of the present invention can be used to reduce pain, nausea, vomiting, or dysphoria in the epigastrium that accompanies ulcers of the gastrointestinal tract, acute or chronic gastritis, dyskinesia or cholecystitis.

In addition, the compound of the present invention and the pharmaceutical composition of the present invention can control (increase or decrease) of appetite and food intake and, therefore, can be used as a treatment for low weight and pathological aversion to food (cibophobia) (in subjects suffering from low weight or cibophobia, with the introduction of the tool, the weight increased) or as redtwo for the treatment of obesity.

1. The compound of the formula:

where R1represents a

(1) C1-8alkyl group,

(2) C6-14aryl group, or

(3) a 5-7 membered monocyclic heterocyclic group containing, besides carbon atoms, 1-4 heteroatoms, selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, or a condensed heterocyclic group formed by condensation 5-7-membered monocyclic heterocyclic group with 6-membered ring containing 1 or 2 nitrogen atom from the benzene ring or 5-membered ring containing 1 sulfur atom,

each of the above (1), (2) and (3) may be substituted by 1 to 3 substituents selected from (1) halogen atom, 2) C1-10alkyl group which is unsubstituted or substituted by 1-3 halogen atoms, 3) C6-14aryl group, 4) heterocyclic group containing, besides carbon atoms, 1-4 heteroatoms, selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, 5) C1-10alkoxygroup;

X represents a bond or-NR6-where R6represents a hydrogen atom or a C1-4alkyl group;

m is an integer from 0 to 3;

Y represents an oxygen atom, -SO-, -SO2- or-NCO-;

ring a represents a benzene ring, condensed C9-14aromatic hydrocarbon ring or 5 - or 6-membered aromatic heterocyclic ring containing, besides carbon atoms, 1 to 3 heteroatoms selected from nitrogen atom and oxygen atom

each of which may be substituted by 1-3 substituents selected from C7-10aralkylated, hydroxy-group and C1-4alkoxygroup;

n is an integer from 1 to 8;

ring B is a nitrogen-containing 5-membered heterokonta, which may be substituted C1-4alkyl group;

X1represents a bond, an oxygen atom or-O-SO2-;

R2represents a

(1) a hydrogen atom,

(2) C1-8alkyl group, a C7-13aracelio group or a C6-14aryl group, each of which may be substituted by 1 to 3 substituents selected from (1) halogen atom,2) C1-4alkyl group which may be substituted by 1 to 3 halogen atoms, 3) C1-4alkoxygroup, 4) C7-10aralkylated, 5) C6-14alloctype, 6) 5-7-membered aromatic monocyclic heterocyclic g is uppy, containing, besides carbon atoms, 1 to 4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, or

(3) 5 - or 6-membered heterocyclic group containing, besides carbon atoms, 1 to 3 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, which may be substituted by 1 to 3 substituents selected from (1) halogen atom, 2) C1-4alkyl group which may be substituted by 1-3 halogen atoms, and (3) C1-4alkoxygroup;

W represents a bond or alkylene or albaniles containing from 1 to 20 carbon atoms;

R3represents a group of formula OR8(R8represents a hydrogen atom or a C1-4alkyl group) or-NR9R10(each of R9and R10that can be either equal or different, represents a hydrogen atom or a C1-4alkyl group);

or its salt.

2. The compound according to claim 1, where X1is a bond and ring B is a nitrogen-containing 5-membered heterocyclic ring.

3. The compound according to claim 1, where R1represents (1) C6-14aryl group, or (2) a 5-7 membered monocyclic heterocyclic group containing, besides carbon atoms is kind, 1-4 heteroatoms selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, or a condensed heterocyclic group formed by condensation 5-7-membered monocyclic heterocyclic group with 6-membered ring containing 1 or 2 nitrogen atom from the benzene ring or 5-membered ring containing 1 sulfur atom,

each of the above (1) and (2) may be substituted by 1 to 3 substituents selected from (1) halogen atom, 2) C1-10alkyl group which is unsubstituted or substituted by 1-3 halogen atoms, 3) C6-14aryl group, 4) heterocyclic group containing, besides carbon atoms, 1-4 heteroatoms, selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, 5) C1-6alkoxygroup.

4. The compound according to claim 1, where R1is a 5-7-membered monocyclic heterocyclic group containing, besides carbon atoms, 1-4 heteroatoms, selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, or a condensed heterocyclic group formed by condensation 5-7-membered monocyclic heterocyclic group with 6-membered ring containing 1 or 2 nitrogen atom from the benzene ring or 5-membered ring containing 1 atom of CE is s, which may be substituted by 1 to 3 substituents selected from (1) halogen atom, 2) C1-10alkyl group which is unsubstituted or substituted by 1-3 halogen atoms, 3) C6-14aryl group,4) heterocyclic group containing, besides carbon atoms, 1-4 heteroatoms, selected from oxygen atoms, sulfur atoms and nitrogen atoms as constituents of the ring atoms, 5) C1-6alkoxygroup.

5. The compound according to claim 1, where X represents the connection.

6. The compound according to claim 1, where m is 1 or 2.

7. The compound according to claim 1, where Y represents an oxygen atom.

8. The compound according to claim 1 in which the ring a represents a benzene ring or pyridine ring, each of which may contain from 1 to 3 substituents selected from C7-10aralkylated, hydroxy-group and C1-4alkoxygroup.

9. The compound according to claim 1, where n is an integer from 1 to 3.

10. The compound according to claim 1, where X1represents a bond or an oxygen atom.

11. The compound according to claim 1, where W represents alkylene or albaniles containing from 1 to 8 carbon atoms.

12. The compound according to claim 1, where R3represents a group of formula OR8where R8represents a hydrogen atom or a C1-4alkyl group.

13. The compound according to claim 1, which is a

3-[3-ethoxy-1-[4-(2-phenyl-thiazoleacetate)benzyl]-1H-pyrazole-4-yl]propionic acid,

3-[3-ethoxy-1-[4-(2-phenyl-4-oxazolidinone)benzyl]-1H-pyrazole-4-yl]propionic acid,

3-[3-ethoxy-1-[4-[3-methyl-1-(2-pyridyl)-1H-pyrazole-4-ylethoxy]benzyl]-1H-pyrazole-4-yl]propionic acid,

3-[1-[4-(5-methyl-2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propionic acid,

3-[1-[4-(2-phenyl-4-thiazoleacetate)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propionic acid, or

3-[1-[4-(2-phenyl-4-oxazolidinone)benzyl]-3-(2-thienyl)-1H-pyrazole-4-yl]propionic acid.

14. Pharmaceutical composition having hypoglycemic and hypolipidemic activity containing a compound according to claim 1, and a pharmaceutically acceptable carrier.

15. The composition according to 14, where X1is a bond and ring B is a nitrogen-containing 5-membered heterocyclic ring.

16. Agent for the prevention or treatment of diabetes containing the compound according to claim 1.

17. Agent for the prevention or treatment of hyperlipidemia, containing a compound according to claim 1.

18. Agent for the prevention or treatment reduced glucose tolerance, containing a compound according to claim 1.

19. Means regulating the function of retinoid-related receptor containing the compound according to claim 1.

20. The tool according to claim 19, which is a ligand-activated proliferation peroxisome cocktail recipes. is s.

21. The tool according to claim 19, which is a ligand for the retinoid receptors X.

22. A tool that improves the resistance to insulin, which comprises the compound according to claim 1.

23. A method of preventing or treating diabetes in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of a compound according to claim 1.

24. A method of preventing or treating hyperlipidemia in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of a compound according to claim 1.

25. The method of prevention or treatment reduced glucose tolerance in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of a compound according to claim 1.

26. The way the regulation functions reinaissance receptor in a mammal, in need thereof, which consists in the introduction to the specified mammal an effective amount of a compound according to claim 1.

The priority according to claims 1, 14, 16-19 and 22-26 in relation to the subject invention, where X1is a bond and ring b is a nitrogen-containing 5-membered heterokonta installed from 10.11.1999, and for the object of the invention beyond the scope of these claims is installed on 10.12.1999. The priority according to claim 2-9, 11, 12, 15, 20 and 21 is selected from 1011.1999. Priority of claim 10 in relation to the subject invention, where X1is a relationship set from 10.11.1999, and for the object of the invention where X1represents an oxygen atom, is selected from 10.12.1999. The priority clause 13 in respect of the first and second compounds selected from 10.12.1999, and other connections from 09.11.2000. Posted priorities set according to the correspondence of the applicant dated 29.09.2004.



 

Same patents:

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

10 cl, 2 sch, 4 tbl, 9 ex

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to new N-heterocyclic derivatives of the formula (I):

where: A means-OR1-C(O)N(R1R2or-N(R1R21; each X, Y and Z independently represents N or C(R19); each U represents N or C(R5), provided that U is N only when X represents N, and Z and Y denote CR19; each W represents N or CH; V denotes: (1) N(R4); (2) C(R4)H; or (3) the groupdirectly related to the group -(C(R14R20)n-A,denotes a 5-6-membered N-heterocyclyl, optionally containing 6-membered ring additional heteroatom selected from oxygen, sulfur and NR6where R6denotes hydrogen, optionally substituted phenyl, 6-membered heterocyclyl containing 1-2 nitrogen atom, optionally substituted 5-membered heterocyclyl containing 1-2 nitrogen atom, aminosulfonyl, monoalkylammonium, dialkylaminoalkyl,1-6alkoxycarbonyl, acetyl, etc

The invention relates to organic chemistry, in particular, optionally N-oxidized compounds represented by the formula:

in which R1represents a hydrogen atom, a C1-6alkyl group, phenyl group, optionally substituted by a halogen atom, a C1-6alkylthio or C1-6alkylsulfonyl, or amino group, optionally substituted (i) C1-6alkyl group, or (ii) acyl group(C=O)-R5where R5represents C1-6alkyl group, phenyl or pyridyl; R2is6-14aryl group, optionally substituted by a halogen atom or C1-6alkoxy, or 5 - or 6-membered aromatic heterocyclic group containing one sulfur atom or one nitrogen atom; R3represents a phenyl group, optionally substituted by one or two C1-6alkyl groups or C1-6alkoxy; X represents a sulfur atom; Y represents O, S, SO2or NR4where R4represents a hydrogen atom or a C1-6alkyl group; and Z represents a bond, C1-6alkylenes group, optional zameshannuu oxo or C1-6alkyl group

The invention relates to new nitrogen-containing aromatic 6-membered cyclic compounds of the formula (I) or their pharmaceutically acceptable salts, demonstrating excellent selective PDE V inhibitory activity

The invention relates to the field of chemistry, particularly the proton pump inhibitors

FIELD: organic chemistry, pharmaceutical composition.

SUBSTANCE: new isoindoline-1-on-glucokinase activators of general formula I , as well as pharmaceutically acceptable salts or N-oxide thereof are disclosed. In formula A is phenyl optionally substituted with one or two halogen or one (law alkyl)sulfonyl group, or nitro group; R1 is C3-C9cycloalkyl; R2 is optionally monosubstituted five- or six-membered heterocyclic ring bonded via carbon atom in cycle to amino group, wherein five- or six-membered heteroaromatic ring contains one or two heteroatoms selected form sulfur, oxygen or nitrogen, one of which is nitrogen atom adjacent to carbon atom bonded to said amino group; said cycle is monocyclic or condensed with phenyl via two carbon atoms in cycle; said monosubstituted with halogen or law alkyl heteroaromatic ring has monosubstituted carbon atom in cycle which in not adjacent to carbon atom bonded to amino group; * is asymmetric carbon atom. Claimed compounds have glucokinase inhibitor activity and useful in pharmaceutical composition for treatment of type II diabetes.

EFFECT: new isoindoline-1-on-glucokinase activators useful in treatment of type II diabetes.

23 cl, 3 dwg, 43 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of heteroarylalkylpiperazine of the general formula (I):

wherein m = 1, 2 or 3; q means NH or oxygen atom (O); R1, R2, R3, R4 and R5 are taken independently among the group including hydrogen atom, (C1-C15)-alkyl, OR20 wherein R20 represents hydrogen atom; R6, R7 and R8 represent hydrogen atom; R9, R10, R11, R12, R13, R14, R15 and R16 are taken independently among the group including hydrogen atom, (C1-C4)-alkyl; or R9 and R10 in common with carbon atom to which they are joined form carbonyl group; R17 means heteroaryl that is taken among the group including indolyl, benzoxazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, pyridyl, benzopyrazinyl substituted optionally with 1-2 substitutes taken among the group including hydrogen atom, CF3 group, (C1-C8)-alkyl, phenyl, CON(R20)2. Compounds elicit property as a partial inhibitor of oxidation of fatty acids and can be used in therapy for protection of skeletal muscles against results of muscular or systemic diseases. Also, invention describes a pharmaceutical composition based on the claimed compounds.

EFFECT: valuable medicinal properties of compounds.

39 cl, 3 tbl, 25 ex

The invention relates to organic chemistry and can find application in medicine

The invention relates to new derivatives of nitrogen-containing heterocyclic compounds of the formula

or their pharmaceutically acceptable salts, where R1represents H, COCOR2, COOR3or SO2R3, R2is1-6alkyl, C1-6alkenyl,5-7cycloalkyl, 2-thienyl, 3-thienyl, phenyl or substituted phenyl, R3is phenylalkyl,represents a saturated five-membered nitrogen-containing heterocyclic ring with one nitrogen atom or benzododecinium saturated six-membered nitrogen-containing heterocyclic ring;is oxazol, oxadiazole or thiazole, And is associated with carbon atom of the five-membered heteroaromatic rings and represents COO(CH2)mAr,where R1has the values listed above or is CONR4(CH2)mAr or (CH2)mO(CH2)nAr and R1cannot be COCOR2or SO2R3, R4represents H or<

The invention relates to sulfhemoglobinemia heterocyclic compound represented by formula (I), its pharmaceutically acceptable salts and their hydrates

where the values of A, B, K, T, W, X, Y, U, V, Z, R1specified in paragraph 1 of the claims

The invention relates to new and nitrate salts of compounds of formulas (I) to(VI), which can be used in medicine for the treatment of bone disorders such as abnormalities in bone and joints
The invention relates to a method for producing 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole the hydrochloride by hydrochlorination 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole of concentrated hydrochloric acid in the environment of ethyl alcohol at 20-35With target product is separated from the reaction mixture by dilution with water, heating to 75-80With that clarification of the resulting solution activated carbon, cooling the clarified solution to 0-2With, then the selected product is filtered, washed with alcohol and dried at 70C in vacuum (120 mm RT.CT.) get 5-chloro-4-/(2-imidazolin-2-yl)amino/-2,1,3-benzothiadiazole hydrochloride with a melting point 292-294C (with decomposition) and mass fractions of the main substance of at least 99.8%, the product yield is 80% on the original basis

The invention relates to compounds of formula (I)

in which f represents phenylenebis radical, a represents the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; R11represents a hydrogen atom, an unbranched or branched alkyl radical having from 1 to 6 carbon atoms, or the radical

in which Rl, R2, R3, R4, R5represent independently a hydrogen atom, IT is a group or an unbranched or branched alkyl or alkoxyalkyl having from 1 to 6 carbon atoms; b is a thiophene; W is absent or represents an Association or S; X represents a bond or a radical -(CH2)k-NR16-, -O-, -CO-, -NR16-CO-, and so forth, and k is 0 or 1; Y represents a bond or a radical selected from the radicals -(CH2)m-, -(CH2)m-O-(CH2)n, -(CH-Q-(CH2)n; and Q represents pieperazinove radical, m and n are equal to integers from 0 to 6; R16, R17, R18represent independently a hydrogen atom, or a salt of the compounds

The invention relates to new effectors dipeptidylpeptidase IV - the dipeptide mimetics (I) formed from amino acids and thiazolidinone or pyrrolidino groups, namely: L-ALLO-isoleucyl-thiazolidine, L-ALLO-isoleucyl-pyrrolidino and their salts, salts of L-threo-isoleucyl-thiazolidine and L - threo-isoleucyl-pyrrolidine; a pharmaceutical composition having the ability to lower blood sugar, containing at least one of the above-mentioned compounds (1)

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

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