Heterocyclic compounds having 11β-hydroxysteroid dehydrogenase type 1 inhibiting activity

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

and pharmaceutically acceptable salts and solvates thereof, in which R1 is an optionally substituted alkyl or similar, R2 is a group of formula: -Y-R5, where Y is -O- or S; R5 is a substituted alkyl (the substitute is an optionally substituted cycloalkyl or similar), a branched alkyl or similar; R4 is hydrogen or C1-10 alkyl; R3 is a group of formula: -C(=O)-Z-R6, where Z is -NR7- or -NR7-W-; R6 is an optionally substituted cycloalkyl or similar; R7 is hydrogen or C1-10 alkyl, W is C1-10 alkylene; X is =N- provided that a compound in which R2 is 2-(4-morpholino)ethoxy, 2-, 3- or 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy or 4-substituted benzyloxy is excluded; and R3 is N-(1-adamantyl)carbamoyl, N-(2-adamantyl)carbamoyl and N-(3-noradamantyl)carbamoyl. Said compound is an 11β-hydroxysteroid dehydrogenase type 1 inhibitor. The invention also relates to a pharmaceutical composition containing said compound as an active ingredient.

EFFECT: improved properties of the compound.

23 cl, 72 ex

 

The scope to which the invention relates

This invention relates to pharmaceutically useful compound with inhibitory activity against 11β-hydroxysteroiddehydrogenase type 1, hereinafter called the 11β-HSD-1.

The level of technology

11β-HSD-1 is an enzyme that converts inactive steroid 11β-dihydroxystearic, active steroids and it is believed to be important in the primary metabolism in vivo (non-patent document 1). Moreover, 11β-HSD-1 knockout mice are resistant to hyperglycemia caused by obesity or stress (non-patent document 2). In addition, a similar phenomenon was observed in people with the introduction of an inhibitor of 11β-HSD-1, carbenoxolone (non-patent document 3). These facts suggest that inhibitors of 11β-HSD-1 could be useful as medicines for the treatment of non-insulin-dependent diabetes or obesity (non-patent document 4).

In patent document 1 describes that the derivatives of pyrazole applicable as a herbicide. In patent document 2 describes that the derivatives of pyrazole applicable as a pesticide. In patent document 3 describes that the derivatives of pyrazole applicable as a herbicide. In patent document 4 describes that the derivatives of pyrazole applicable as in the of acticide. In patent document 5 describes that the derivatives of pyrazole used as insecticide. In patent document 6 describes that the derivatives of pyrazole applicable as a pesticide. In patent document 7 describes that the derivatives of pyrazole applicable as a herbicide. The compounds described in these patents contain karbamoilnuyu group, which is substituted by the Deputy selected from the group consisting of substituted aryl, substituted arylalkyl, substituted heteroaryl and alkyl, in position 4 pyrazol ring, and they differ from the compounds of the present invention.

In addition, in patent document 8 describes compounds having the unbranched alkoxygroup in position 5 of the pyrazole nucleus rings applicable for the treatment of schizophrenia, and they differ from the compounds of the present invention.

Moreover, in patent document 9 describes that the derivatives of pyrazole, shown below, is applicable as a cannabinoid receptor, but not documented inhibitory activity against 11β-HSD-1.

[Formula 1]

[Non-patent document 1] Clin. Endocrinol, 1996, 44, 493.

[Non-patent document 2] Proc. Nat. Acad. Sci. USA, 1997, 94, 14924.

[Non-patent document 3] J. Clin. Endocrinol. Metab. 1995, 80, 3155.

[Non-patent document 4] Lancet, 1997, 349, 1210.

[Patent document 1] WO05/070889.

[PA entry document 2] WO02/096882.

[Patent document 3] WO93/25535.

[Patent document 4] JP06-025199.

[Patent document 5] JP03-223256.

[Patent document 6] JP01-207289.

[Patent document 7] JP60-214785.

[Patent document 8] US4226877.

[Patent document 9] WO98/41519.

Description of the invention

Tasks are addressed invention

The present invention provides a useful compounds with inhibitory activity against 11β-hydroxysteroiddehydrogenase 1 type.

Means for solving the task

The present invention provides:

(1) the compound represented by formula (I)

[Formula 2]

its pharmaceutically acceptable salt or MES,

where

R1represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

one of R2and R4represents a group of the formula: -Y-R5,

where Y represents-O - or-S-, and

R5represents a substituted unbranched alkyl, in which the Deputy indicated unbranched alkyl represents neo is Astelin substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

optionally substituted branched alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

the other of R2and R4represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

R3represents a group of formula: -C(=O)-Z-R6,

where Z represents a-NR7- or-NR7-W-, and

R6represents an optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle,

R7represents hydrogen or optionally substituted alkyl, or R6and R7taken together can form an optionally substituted ring,

W is an optional semestrielle,

X represents =N - or =CR8-and

R8represents hydrogen or optionally substituted alkyl,

provided that excluded the compounds in which R2represents a 2-(morpholino)ethoxy, R3represents N-(1-substituted)carbarnoyl and R1represents benzyl,

(2) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R1represents a substituted alkyl where the Deputy specified substituted alkyl is an optionally substituted an amino group or optionally substituted heterocycle,

(3) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R1represents a substituted ethyl, where the Deputy indicated substituted ethyl represents optionally substituted by an amino group or optionally substituted heterocycle,

(4) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R1represents unsubstituted alkyl,

(5) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R2represents a group of the formula: -Y-R5,

where Y and R5have the same meanings as defined in the above (1),

(6) with the unity according to the above (5), its pharmaceutically acceptable salt or MES, in which Y represents-O-,

(7) the compound according to the above (5) or (6), its pharmaceutically acceptable salt or MES, in which R5represents a substituted unbranched alkyl, where the Deputy indicated substituted unbranched alkyl is an optionally substituted cycloalkyl,

(8) the compound according to the above (7), its pharmaceutically acceptable salt or MES, in which R5represents a substituted methylene where the Deputy indicated substituted methyl is an optionally substituted cycloalkyl,

(9) the compound according to the above (7) or (8), its pharmaceutically acceptable salt or MES, wherein said optionally substituted cycloalkyl is an optionally substituted cyclohexyl,

(10) the compound according to the above (5) or (6), its pharmaceutically acceptable salt or MES, in which R5represents a branched alkyl,

(11) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which Z represents-NR7-, and R7has the same meaning as defined in the above (1),

(12) the compound according to the above (11), its pharmaceutically acceptable salt and is and MES, in which R7represents hydrogen,

(13) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R6represents an optionally substituted cycloalkyl,

(14) the compound according to the above (13), its pharmaceutically acceptable salt or MES, in which R6represents substituted,

(15) the compound according to the above (13), its pharmaceutically acceptable salt or MES,

in which R3represents a group of formula (II):

[Formula 3]

(16) the compound according to any of the above (1)to(15), its pharmaceutically acceptable salt or MES, in which X represents =N-,

(17) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R1represents a group of formula: -CH=CH-C(R9R10)-R11-R12,

where R9and R10each independently represents hydrogen, optionally substituted alkyl or halogen, or R9and R10taken together with the carbon atom to which they are attached, can form an optionally substituted ring,

R11represents -(CH2)n-, where n is an integer from 0 to 3, and

R12represents hydrogen, hydroxy, carboxy, is iano, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted allyloxycarbonyl, optionally substituted arylalkylamines, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted sulfamoyl, optionally substituted by an amino group, optionally substituted by carbamoyloximes, optionally substituted by alkoxygroup or optional substituted alkylthiols,

a group of the formula: -C(=O)-NR13R14,

where R13and R14each independently represents hydrogen, optionally substituted by an amino group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optional samisen the th heteroarylboronic or optionally substituted heterozygosity, or R13and R14taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring, or

a group of the formula: -NR15R16,

where R15and R16each independently represents hydrogen, carboxy, hydroxy, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted allyloxycarbonyl or optionally substituted sulfamoyl, or R15and R16taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring,

(18) the compound according to the above (1), its pharmaceutically acceptable salt or MES, in which R1represents a group of formula: -CH2-CH2-C(R9R10)-R11-R12,

where R9, R10, R11and R12have the same meanings as defined in the above (17),

(19) connect the tion according to the above (17) or (18), its pharmaceutically acceptable salt or MES, in which each of R9and R10independently represents an optionally substituted alkyl, or R9and R10taken together with the carbon atom to which they are attached, can form an optionally substituted ring,

(20) the compound according to any of the above (17)-(19), its pharmaceutically acceptable salt or MES, in which R11represents -(CH2)n-, where n is an integer from 0 to 1,

(21) the compound according to any of the above (17)to(20), its pharmaceutically acceptable salt or MES, in which R12represents carboxy, cyano or a heterocycle,

(22) the compound according to any of the above (17)to(20), its pharmaceutically acceptable salt or MES, in which R12represents a group of formula: -C(=O)-NR13R14,

where R13and R14each independently represents hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity or optionally substituted heterocycle, or R13and R14taken together with the nitrogen atom, to which they are attached, can form an optionally substituted ring,

(23) the compound according to any of the above (17)to(20), its pharmaceutically acceptable salt or MES, in which R12represents a group of formula: -NR15R16,

where R15and R16have the same meanings as defined in the above (17),

(24) the compound according to the above (23), its pharmaceutically acceptable salt or MES, in which R15represents a group of formula: -C(=O)R',

where R' represents an optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted by an amino group or optionally substituted alkyloxy,

(25) a pharmaceutical composition which contains a compound according to any of the above (1)to(24), its pharmaceutically acceptable salt or MES as the active ingredient,

(26) the pharmaceutical composition according to the above (25) for the treatment and/or prevention of diabetes.

The present invention is characterized as follows.

1) Contains a 5-membered N-containing heterocycle.

2) Contains a Deputy of the formula: -Y-R5in the above-mentioned 5-membered heterocycle.

3) R5represents a substituted unbranched alkyl, where the Deputy decree the frame of the substituted alkyl is a substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

optionally substituted branched alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle.

4) Contains a Deputy of the formula: -C(=O)-Z-R6in the above-mentioned 5-membered heterocycle,

5) R6represents an optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle, or R6and R7taken together can form an optionally substituted ring.

6) Contains optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle with the nitrogen atom of the above 5-membered heterocycle.

The implementation of the invention

Compounds of the present invention have inhibitory activity against 11β-hydroxysteroid is the dehydrogenase type 1 1, and enclosing the pharmaceutical composition is very useful as medicines, especially as medicines for the treatment and/or prevention of hyperlipidemia, diabetes, obesity, arteriosclerosis, atherosclerosis, hyperglycemia and/or syndrome X. moreover, the compounds of the present invention selectively inhibit 11β-hydroxysteroiddehydrogenase 1 type. Preferred compounds of the present invention have a high metabolic stability, a weak induction of the enzyme metabolizing drugs, weak inhibition of the enzyme metabolizing drugs, or high oral absorption, and they are especially applicable in the quality of medicines. In addition, the present invention includes compounds having low ground clearance and prolonged half-life in order to demonstrate the activity of the drug.

The preferred embodiment of the invention

Below explains the terms used in the present description. Each term has the following values individually or together with other terms.

"Alkyl" means1-C10unbranched or branched alkyl group, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,n-hexyl, isohexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like. It is preferable1-C6alkyl or C1-C4alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl.

"Unbranched alkyl" means1-C10unbranched alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl or the like. It is preferable1-C6or1-C4unbranched alkyl.

"Branched alkyl" means3-C10branched alkyl group such as isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, tert-pentyl, isohexyl or the like. It is preferable3-C6branched alkyl.

"Alkylene" means a divalent group derived from the above "alkyl", which includes1-C10unbranched or branched alkylen. Preferred is methylene, ethylene, propylene, trimethylene, tetramethylene, ethylethylene, pentamethylene, hexamethylene or the like.

"Alkenyl" means C2-C8unbranched or branched alkenylphenol group that includes a group having one or more of Voynich links, for example 1-3 double bonds in the above "alkyl". An example is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butadienyl, 3-methyl-2-butenyl or the like.

"Quinil" means2-C8unbranched or branched alkylamino group that includes a group having one or more triple relations, for example 1-3 triple bond in the above "alkyl". An example is ethinyl or the like. In addition, "quinil" may contain 1-3 double bonds.

"Cycloalkyl" means3-C15the saturated cyclic hydrocarbon group. Also included bridged cyclic hydrocarbon group. An example is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or bridged cyclic hydrocarbon, is shown below.

[Formula 4]

"Cycloalkenyl" means3-C7unsaturated aliphatic hydrocarbon group, including bridged cyclic hydrocarbon group. An example is cyclopropyl, cyclobutyl, cyclopentenyl, cyclohexenyl or cycloheptenyl. It is preferable cyclopropyl, cyclobutyl, cyclopentenyl or cyclohexenyl. In addition, cycloalkenyl means a group that contains an unsaturated bond in the above as the application is and bridged cyclic hydrocarbon group.

"Aryl" means a monocyclic aromatic hydrocarbon group (e.g. phenyl) or condensed aromatic hydrocarbon group (for example, 1-naphthyl, 2-naphthyl, 1-antrel, 2-antrel, 9-antrel, 1-phenanthrol, 2-phenanthrol, 3-phenanthrol, 4-phenanthrol, 9-phenanthrol etc). Preferred is phenyl or naphthyl (1-naphthyl, 2-naphthyl or the like.

"Heteroaryl" means a monocyclic aromatic heterocyclic group or condensed aromatic heterocyclic group.

Monocyclic aromatic heterocyclic group means a group derived from (5-8)-membered aromatic heterocycle, which may contain from 1 to 4 atoms of oxygen, sulfur and/or nitrogen in the ring. Connecting link can be at any substitutable position.

Condensed aromatic heterocyclic group means a group derived from (5-8)-membered aromatic heterocycle, which may contain from 1 to 4 atoms of oxygen, sulfur and/or nitrogen in the ring, condensed with one to four (5-8)-membered aromatic carbocycle(s) or other (5-8)-membered aromatic heterocycle(s). Connecting link can be at any substitutable position.

Examples include furyl (e.g., furan-2-yl or furan-3-yl), thienyl (for example, thiophene-2-yl or thiophene-3-yl), pyrrolyl (in the example, pyrrol-1-yl, pyrrol-2-yl or pyrrol-3-yl), imidazolyl (for example, imidazol-1-yl, imidazol-2-yl or imidazol-4-yl), pyrazolyl (for example, pyrazole-1-yl, pyrazole-3-yl or pyrazole-4-yl), triazolyl (for example, 1,2,4-triazole-1-yl, 1,2,4-triazole-3-yl or 1,2,4-triazole-4-yl), tetrazolyl (for example, tetrazol-1-yl, tetrazol-2-yl or tetrazol-5-yl), oxazolyl (for example, oxazol-2-yl, oxazol-4-yl or oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl or isoxazol-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl or thiazol-5-yl), thiadiazolyl, isothiazolin (for example, isothiazol-3-yl, isothiazol-4-yl or isothiazol-5-yl), pyridyl (for example, pyridine-2-yl, pyridin-3-yl or pyridin-4-yl), pyridazinyl (for example, pyridazin-3-yl or pyridazin-4-yl), pyrimidinyl (for example, the pyrimidine-2-yl, pyrimidine-4-yl or pyrimidine-5-yl), pyrazinyl (for example, furazan-3-yl), pyrazinyl (for example, pyrazin-2-yl), oxadiazolyl (for example, 1,3,4-oxadiazol-2-yl), benzofuran (for example, benzo[b]furan-2-yl, benzo[b]furan-3-yl, benzo[b]furan-4-yl, benzo[b]furan-5-yl, benzo[b]furan-6-yl or benzo[b]furan-7-yl), sensational (for example, benzo[b]thiophene-2-yl, benzo[b]thiophene-3-yl, benzo[b]thiophene-4-yl, benzo[b]thiophene-5-yl, benzo[b]thiophene-6-yl or benzo[b]thiophene-7-yl), benzimidazolyl (for example, the benzimidazole-1-yl, benzimidazole-2-yl, benzimidazole-4-yl or benzimidazole-5-yl), dibenzofuran, benzoxazolyl, Minoxidil (for example, chinoxl the h-2-yl, cinoxacin-5-yl or cinoxacin-6-yl), cannoli (for example, cinnolin-3-yl, cinnolin-4-yl, cinnolin-5-yl, cinnolin-6-yl, cinnolin-7-yl or cinnolin-8-yl), chinadoll (for example, hinzelin-2-yl, hinzelin-4-yl, hinzelin-5-yl, hinzelin-6-yl, hinzelin-7-yl or hinzelin-8-yl), chinolin (for example, quinoline-2-yl, quinoline-3-yl, quinoline-4-yl, quinoline-5-yl, quinoline-6-yl, quinoline-7-yl or quinoline-8-yl), phthalazine (for example, phthalazine-1-yl, phthalazine-5-yl or phthalazine-6-yl), ethanolic (for example, isoquinoline-1-yl, isoquinoline-3-yl, isoquinoline-4-yl, isoquinoline-5-yl, isoquinoline-6-yl, isoquinoline-7-yl or isoquinoline-8-yl), peril, pteridinyl (for example, pteridine-2-yl, peridin-4-yl, pteridine-6-yl or pteridine-7-yl), carbazolyl, phenanthridines, acridines (for example, acridine-1-yl, acridine-2-yl, acridine-3-yl, acridine-4-yl or acridine-9-yl), indolyl (e.g., indol-1-yl, indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl or indol-7-yl), isoindolyl, phenazines (for example, fenesin-1-yl or fenesin-2-yl), phenothiazines (e.g., phenothiazines-1-yl, phenothiazines-2-yl, phenothiazines-3-yl or phenothiazines-4-yl), or the like.

"Heterocycle" means (5-8)-membered non-aromatic heterocyclic group which may contain from 1 to 4 atoms of oxygen, sulfur and/or nitrogen in the ring. The connecting link may be at any substitutable position. Moreover, non-aromatic heterocyclic group can be the t can be replaced With 1-C5alkalinous chain or With2-C5alkenylamine chain with the formation of condensed rings (including bicyclic ring) or spirocyclic or may be condensed with cycloalkanes (preferred is 5 to 6-membered ring or benzene ring. The heterocycle may be saturated or unsaturated, provided that it is non-aromatic. Preferred is (5-8)-membered cycle. An example is 1-pyrrolidyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1-pyrazolidone, 3-pyrazolidone, 4-pyrazolidine, piperidine, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 1-piperazinil, 2-piperazinil, 2-morpholinyl, 3-morpholinyl, morpholino, tetrahydropyranyl or the following group. Each ring may be optionally substituted at any substitutable position.

[Formula 5]

The ring formed together R6and R7"means (5-8)-membered ring including the nitrogen atom attached to R7in the ring. The above ring is attached to the carbon atom of the carbonyl group via a connecting link from the nitrogen atom attached to R7. Ring SOS is OIT of carbon atoms, oxygen, sulfur or the like, in addition to the above nitrogen atom. The ring can contain 1 to 4 oxygen atoms, sulfur and/or nitrogen in the ring. Moreover, the ring may be substituted With1-C5alkalinous chain or With2-C5alkenylamine chain with the formation of condensed rings (including bicyclic ring), spirocyclic, or may be condensed with cycloalkanes (preferred is 5 to 6-membered ring or benzene ring. The ring may be saturated or unsaturated. Preferred is (5-8)-membered ring, such as 1-pyrrolyl, 1-pyrrolidinyl, 1-imidazolyl, 1-imidazolidinyl, 1-pyrazolyl, 1-pyrazolidine, piperidine, 1-piperidinyl, morpholino or the following group. Each ring may be optionally substituted.

[Formula 6]

"The ring formed by R9and R10taken together with the carbon atom to which they are attached, means (3-15)-membered saturated or unsaturated hydrocarbon ring or (3-15)-membered saturated or unsaturated heterokonta containing from 1 to 4 atoms of oxygen, sulfur and/or nitrogen in the specified hydrocarbon ring. Preferred is a non-aromatic ring such as cyclopropane, CYCLOBUTANE, cyclopentane, cyclohexane, Cycloheptane, cyclooctane, cyclopropene, cyclo what uten, cyclopenten, cyclohexen, cyclohepten or the like. An example is a saturated or unsaturated heterokonta containing from 1 to 4 atoms of oxygen, sulfur and/or nitrogen in the hydrocarbon ring.

For example, a group of the formula-C(R9R10)-, where R9and R10taken together with the carbon atom to which they are attached, can form an optionally substituted ring, is illustrated as follows. Each ring may be optionally substituted.

[Formula 7]

"The ring formed by R13and R14taken together with the nitrogen atom to which they are attached, and the ring formed by R15and R16taken together with the nitrogen atom to which they are attached, means (3-15)-membered non-aromatic heterokonta, which may contain from 1 to 4 atoms of oxygen, sulfur and/or nitrogen, in addition to the nitrogen atom in the ring. Nah heterokonta may be connected by bridge with1-C4alkyl chain condensed with cycloalkanes (preferred is 5 to 6-membered ring or benzene ring. The ring may be saturated or unsaturated, provided that it is non-aromatic. Preferred is (5-8)-membered ring. For example, a group of the formula: -NR13R14where R13and R14taken together with the atoms is ω nitrogen, to which they are attached, can form an optionally substituted ring, and a group of the formula: -NR15R16where R15and R16taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring, is illustrated as follows. Examples are 1-pyrrolidyl, 1-pyrrolidinyl, 1-imidazolyl, 1-imidazolidinyl, 1-pyrazolyl, 1-pyrazolidine, piperidine, morpholine and the following group. Each ring may be optionally substituted.

[Formula 8]

"Optionally substituted cycloalkyl", "optionally substituted cycloalkenyl", "optionally substituted aryl", "optionally substituted heteroaryl", "optionally substituted heterocycle", "optionally substituted alkyl", "optionally substituted alkylene", "optionally substituted of alkenyl", "optionally substituted quinil", "substituted unbranched alkyl", "optionally substituted branched alkyl", "a ring formed together R6and R7", "optionally substituted aminogroup", "a ring formed by R9and R10taken together with the carbon atom to which they are attached", "a ring formed by R13and R14taken together with the nitrogen atom to which they are attached, ring formation is consistent R 15and R016taken together with the nitrogen atom to which they are attached", and "optionally substituted methylene may be substituted by 1-4 substituents selected from the group consisting of, for example, from

hydroxy, carboxy, halogen (such as F, Cl, Br, I),

optionally substituted alkyl (e.g. methyl, ethyl, isopropyl, tert-butyl, halogenated alkyl (e.g.,- CF3, -CH2CF3, -CH2CCl3),

optionally substituted, alkylthio (for example, methylthio),

optionally substituted alkylsulfonyl (for example, methanesulfonyl, acanalonia),

optionally substituted of carbamoyl (for example, optionally substituted of allylcarbamate (for example, methylcarbamoyl of ethylcarbitol, dimethylcarbamoyl), optionally substituted of alkylsulphonyl),

optionally substituted alkenyl (e.g., vinyl),

optionally substituted, alkenylacyl (for example, vinyloxy, allyloxy),

the quinil (for example, ethinyl),

optionally substituted cycloalkyl (for example, cyclopropyl),

optionally substituted cycloalkenyl (for example, cyclopropyl),

optionally substituted, acyloxy (for example, methoxy, ethoxy, propoxy, butoxy, carboxymethoxy),

optionally substituted allyloxycarbonyl (for example, methoxycarbonyl, taxicab the sludge, tert-butoxycarbonyl), nitro, nitroso,

optionally substituted amino (for example, alkylamino (for example, methylamino, ethylamino, diethylamino), acylamino (for example, optionally substituted, alkylcarboxylic, optionally substituted, arylcarboxamide, optionally substituted, heteroarylboronic, optionally substituted, getrollbackonly), optionally substituted, arylalkylamine (for example, benzylamino, trailmen), hydroxyamino, optionally substituted, allyloxycarbonyl, optionally substituted, alkylsulfonyl, optionally substituted, carbamoylating, optionally substituted, arylsulfonyl, optionally substituted, arylamino),

optionally substituted aryl (e.g. phenyl),

optionally substituted arylalkyl (e.g., benzyl),

optionally substituted heteroaryl,

optionally substituted heterocycle,

cyano, isocyano, isocyanate, thiocyanate, isothiocyanate, mercapto,

optionally substituted sulfamoyl,

acyl (e.g. formyl, optionally substituted alkylsulphonyl, optionally substituted alkenylboronic, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic, optionally substituted geterotsiklicheskikh),

formyloxy, garagentor the sludge, oxalo, tjformal, dicarboxy, dithiocarbonic, optionally substituted of thiocarbamoyl,

sulfine, sulfo, sulfamido, hydrazine, azide, ureido, amidino,

guanidino, phthalimide, oxo, alkylene,

alkylenedioxy (-O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O - or the like),

optionally substituted geterotsiklicheskikh, complex pastefire (for example, -P(=O)(OEt)2),

optionally substituted, cycloalkyl, optionally substituted, aaltio, optionally substituted, heteroaromatic,

optionally substituted, heteroaromatic, optionally substituted, aryloxy, optionally substituted, heterocyclic, optionally substituted imino,

optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted, alkylcarboxylic, optionally substituted, arylcarboxylic, optionally substituted, heteroarylboronic, optionally substituted, geterotsiklicheskikh,

optionally substituted alkylsulphonyl,

optionally substituted arylcarbamoyl,

optionally substituted heteroarylboronic,

optionally substituted aryloxyalkyl,

optionally substituted het is of reallocatable,

optionally substituted geterotsiklicheskikh,

optionally substituted methylene.

Alkyl part is optionally substituted alkylsulfonyl", "optionally substituted alkylsulfonyl", "optionally substituted, alkyloxy", "optionally substituted, alkylsulfonyl", "optionally substituted, alkylcarboxylic", "optionally substituted alkylcarboxylic", "optionally substituted allyloxycarbonyl", "optionally substituted, allyloxycarbonyl", "optionally substituted, alkylthio", "optionally substituted of allylcarbamate" and "optionally substituted of alkylsulfonyl" is the same as in the case of the above "alkyl". The alkyl portion may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted alkyl".

Alchemilla part of the "optionally substituted alkenylboronic", "optionally substituted, alkenylacyl" is the same as in the case above "alkenyl". Alchemilla part can be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted alkenyl".

Cycloalkyl part of the "optionally substituted, cycloalkyl" is the same as in the case above "cycloalkyl". Cycloalkene the art may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted cycloalkyl".

Aryl part is optionally substituted arylsulfonyl", "optionally substituted arylsulfonyl", "optionally substituted, arylsulfonyl", "optionally substituted, arylcarboxylic", "optionally substituted aryloxyalkyl", "optionally substituted arylcarbamoyl", "optionally substituted, arylamino", "optionally substituted, aristeo", "optionally substituted, aryloxy" is the same as in the case of the above-mentioned "aryl". Aryl part may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted aryl".

Heteroaryl part is optionally substituted, heteroarylboronic", "optionally substituted heteroarylboronic", "optionally substituted heteroarylboronic", "optionally substituted, heteroaromatic" and "optionally substituted, heteroaromatic" is the same as in the case above "heteroaryl". Heteroaryl portion may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted heteroaryl".

Heterocyclic part of the "optionally substituted, geterotsiklicheskikh", "optionally substituted heterocyclization the onila", "optionally substituted geterotsiklicheskikh" and "optionally substituted, heterocyclic" is the same as in the case of the above "heterocycle". Heterocyclic portion may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted heterocycle".

Aryl part is optionally substituted, arylalkylamine" is the same as in the case of the above-mentioned "aryl", and the alkyl part is the same as in the case of the above "alkyl". Aryl part may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted aryl", and the alkyl portion may be optionally substituted by the same Deputy, as in the case of the above-mentioned "optionally substituted alkyl".

Deputy "optionally substituted amino", "optionally substituted, carbamoylating", "optionally substituted of carbamoyl", "optionally substituted of thiocarbamoyl", "optionally substituted sulfamoyl", "optionally substituted imino" includes optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted aryl, optionally substituted heteroaryl, acyl, hydroxy, optionally substituted alkylsulfonyl, optionally substituted alkylsulfonyl, long is correctly substituted arylsulfonyl, optionally substituted arylsulfonyl, optionally substituted amino, or the like.

Deputy "optionally substituted alkylsulfonyl", "optionally substituted alkylsulfonyl", "optionally substituted arylsulfonyl", "optionally substituted arylsulfonyl" include the same substituents as in the case of optionally substituted alkyl or optionally substituted aryl.

"Acyl" means a formyl, optionally substituted alkylaryl, optionally substituted alkenylboronic, optionally substituted arylcarbamoyl, optionally substituted heteroarylboronic or optionally substituted heterocyclicamines.

Deputy "optionally substituted alkylcarboxylic", "optionally substituted alkenylboronic", "optionally substituted arylcarbamoyl", "optionally substituted heteroarylboronic", "optionally substituted geterotsiklicheskikh" include the same substituents as in the case of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle.

"Arylalkyl" means the above-mentioned alkyl, which is substituted by 1-3 above Allami.

R1represents an optionally substituted alkyl, not battelino replaced alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle. Preferably R1represents a substituted alkyl where the Deputy specified substituted alkyl is an optionally substituted an amino group or optionally substituted heterocycle, unsubstituted alkyl, a group of the formula: -CH=CH-C(R9R10)-R11-R12or a group of the formula: -CH2-CH2-C(R9R10)-R11-R12where R9and R10each independently represents hydrogen, optionally substituted alkyl or halogen, or R9and R10taken together with the carbon atom to which they are attached, can form an optionally substituted ring.

R11represents -(CH2)n-, where n is an integer from 0 to 3,

R12represents hydrogen, hydroxy, carboxy, cyano, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted the initial allyloxycarbonyl, optionally substituted arylalkylamines, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted sulfamoyl, optionally substituted by an amino group, optionally substituted by carbamoyloximes, optionally substituted by alkyloxy or optional substituted alkylthiols,

a group of the formula: -C(=O)-NR13R14,

where R13and R14each independently represents hydrogen, optionally substituted by an amino group, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted heteroarylboronic, optionally substituted heterozygosity, or R13and R14taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring, or

a group of the formula: -NR15R16,

where R15and R16each independently represents hydrogen, carb is XI, hydroxy, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycle, optionally substituted acyl, optionally substituted carbarnoyl, optionally substituted thiocarbamoyl, optionally substituted alkylsulfonyl, optionally substituted arylsulfonyl, optionally substituted allyloxycarbonyl, optionally substituted sulfamoyl, or R15and R16taken together with the nitrogen atom to which they are attached, can form an optionally substituted ring.

One of R2and R4represents a group of the formula: -Y-R5,

where Y represents-O - or-S-, and

R5represents a substituted unbranched alkyl, where the Deputy substituted unbranched alkyl is an optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

optionally substituted branched alkyl, optionally substituted of alkenyl or optionally substituted quinil, optional samisen the th cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle,

the other of R2and R4represents hydrogen, optionally substituted alkyl, optionally substituted of alkenyl, optionally substituted quinil, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heterocycle.

Preferably R2represents a group of formula Y-R5where R5has the same meaning as in the above (1). Preferred as R2is a group of the formula: -Y-R5where Y represents-O-, and R5represents a substituted unbranched alkyl, where the Deputy indicated substituted unbranched alkyl is optionally substituted by cycloalkyl. With regard to the specified alkyl, preferred are methyl, ethyl, propyl (especially methyl). With regard to the specified cycloalkyl, are preferred cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl (especially cyclohexyl).

R3represents a group of formula: -C(=O)-Z-R6,

where Z represents a-NR7- or-NR7-W-, and

R6represents the t an optionally substituted cycloalkyl, optionally substituted cycloalkenyl or optionally substituted heterocycle,

R7represents hydrogen or optionally substituted alkyl, or R6and R7taken together can form an optionally substituted ring,

W represents an optionally substituted alkylene.

Preferred as Z is-NR7-where R7has the same meaning as defined in the above (1). More preferred as Z is-NH-.

In addition, with regard to R6preferred is optionally substituted cycloalkyl. Preferred as R6is substituted (2-substituted).

X represents =N - or =CR8-where R8represents hydrogen or optionally substituted alkyl. Preferred is =N-.

As for R1preferred are, for example, the following group.

[Formula 9]

where each R independently represents an optionally substituted alkyl, and “Tet” means tetrazolyl.

[Formula 10]

where n is an integer from 1 to 3.

[Formula 11]

where R represents optionally substituted alkyl or optionally substituted aryl.

As the W group of formula: -V-R 5for example, preferred are the following groups.

[Formula 12]

As for the substituent of the substituted alkyl of R5preferred are the following substituents:

A) optionally substituted cycloalkyl (for example, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl),

B) optionally substituted cycloalkenyl (for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctyl),

C) optionally substituted aryl (phenyl, naphthyl),

D) heteroaryl (for example, pyridyl, imidazolyl),

E) optionally substituted heterocycle (for example, 4-piperidinyl, 2-pyrrolidinyl, morpholino, 2-morpholinyl, piperidino, 3,5-dimethylmorpholine, piperazinil, N-tert-butoxycarbonyl-3-piperidinyl, 1-pyrrolidinyl, tetrahydropyranyl).

As for optionally substituted cycloalkyl of R6preferred are the following groups.

[Formula 13]

[Formula 14]

Pharmaceutically acceptable salts of the compounds of the present invention are illustrated in the following. Basic salts, for example, are salts of alkaline metal such as sodium, potassium or the like; salts of alkaline earth metal such as calcium, magnesium or the like; ammonium salts; Sol is aliphatic amines, such as trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, procaine, meglumin, diethanolamine, Ethylenediamine or the like; salts arylalkylamines, such as N,N-dibenziletilendiaminom, Benyamin or the like; salts of heteroaromatic amines such as pyridine, picoline, quinoline, isoquinoline or the like; Quaternary ammonium salt such as Tetramethylammonium, tetraethylammonium, designed, benzyltriethylammonium, benzyltrimethylammonium, methyltrioctylammonium, tetrabutylammonium, or the like; salts of basic amino acids such as arginine, lysine or the like.

Acid salt, for example, are salts of inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, carbonic acid, gidrocarbonata acid, Perlina acid or the like; salts of organic acids such as acetic acid, propionic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, malic acid, citric acid or ascorbic acid; salts of sulfonic acid, such as methanesulfonate acid, setinova (2-hydroxyethanesulfonic) acid, benzolsulfonat acid, p-toluensulfonate acid or the like; acid salt amino acids, the aka as aspartic acid, glutamic acid or the like.

MES means MES compounds of the present invention or its pharmaceutically acceptable salt, for example an alcohol MES (e.g., ethanol), hydrate or the like. With regard to hydrate, illustrative examples are monohydrate, dihydrate or the like.

General method for obtaining compounds of the present invention is explained below. Each symbol is the same as in the above (1). In addition, for the synthesis of compounds of the present invention can be used treatment of traditional organic synthesis, such as extraction, purification and the like.

[Formula 15]

where R1, R5and R6are the same as above, R10represents a protective group (for example, alkyl or the like), R11represents a protective group (for example, benzyl or the like), and X represents a leaving group (e.g. halogen or the like).

1st stage

Stage 1 represents a method for obtaining compounds of formula (II-2), which includes the interaction of the compounds of formula (II-1) with R1NH2NH2.

R10OH you can use as a reaction solvent. This reaction can be performed at room temperature is e or at the temperature of reflux.

Stage 2

Stage 2 represents a method for obtaining compounds of formula (II-3), which includes the interaction of the compounds of formula (II-2) with R11X.

As R11X you can use benzylchloride.

This reaction is preferably carried out in the presence of a base, and it can be done at room temperature or at the temperature of reflux. As the reaction solvent can be used acetone, dimethylformamide or the like.

3rd stage

3rd stage is a method of obtaining the compounds of formula (II-4), which includes the hydrolysis of compounds of formula (II-3).

This reaction can be performed in aqueous solvent and in the presence of a base. The aqueous solvent comprises aqueous alcohol, aqueous tetrahydrofuran or the like. You can use a mixed solvent of the above. As a basis you can use sodium hydroxide, lithium hydroxide or the like. This reaction can be performed at room temperature or at the temperature of reflux. The preferred reaction temperature is room temperature.

4th phase

4th stage is a method of obtaining the compounds of formula (II-5), which includes the interaction of the compounds of formula (II-4) with R6Other7.

This reaction monosemantic under reaction conditions, known as the conditions used for the condensation reaction of carboxylic acid and amine. For example, you can use a condensing agent such as 1,3-dicyclohexylcarbodiimide (into), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (WSCI) or the like. As a Supplement you can use 1-hydroxybenzotriazole (HOBt), 3,4-dihydroperoxy-4-oxo-1,2,3-benzotriazine (HOOBt), or the like.

The solvent can be used dimethylformamide. This reaction can be performed at room temperature.

In addition, after the amidation reaction using R6NH2the group R7can be introduced by reacting the compounds with R7X in the presence of a base. Moreover, instead of R6Other7you can use R6WNHR7.

5-stage I

5th stage is a method of obtaining the compounds of formula (II-6), which involves removal of the protective group from compounds of formula (II-5).

If R11represents a benzyl group, the reaction of removing the protection can be accomplished by catalytic regeneration.

As a solvent, you can use alcohol. This reaction can be carried out using palladium on coal (5-10%) as catalyst in hydrogen atmosphere.

6th stage

The 6th stage is a way recip is of the compounds of formula (I-1), which includes the interaction of the compounds of formula (II-6) with R5X.

This reaction can be performed in the presence of a base. As a basis you can use potassium carbonate, sodium carbonate, sodium hydroxide, lithium hydroxide or the like.

This reaction can be performed at room temperature or at the temperature of reflux. The solvent can be used dimethylformamide.

The compound of the present invention, in which X represents =CR8-can be synthesized by using a compound having a pyrrole ring instead of the pyrazol ring described in the above formula (II-2) in accordance with the above scheme.

Various substituents of the compounds of the present invention can be input using references (1) Alan R. Katriszly et al., Comprehensive Heterocyclic Chemistry, (2) Alan R. Katriszly et al., Comprehensive Heterocyclic Chemistry II, (3) RODD''S CHEMISTRY OF CARBON COMPOUNDS VOLUME IV HETEROCYCLIC COMPOUNDS, or the like.

The compound of the present invention has a high inhibitory activity against 11β-hydroxysteroiddehydrogenase 1 type. In this regard, the connection of the present invention can be used for the treatment and/or prevention of diseases related to 11β-hydroxysteroiddehydrogenase type 1, especially hyperlipidemia, diabetes, obesity, arteriosclerosis, atheroscle the oz, hyperglycemia and/or syndrome X. In particular, the connection according to the present invention is applicable to treatment and/or prevention of diabetes.

The compound of the present invention can be administered orally or parenterally. When the present compound is administered orally, the compound can be any form of conventional pharmaceutical preparations, for example, solid preparations such as tablets, powders, granules, capsules or the like; drugs are water-based; oil suspensions; or drugs in the form of a solution, such as syrup or elixir. If this compound is administered parenterally, then this connection can be used as injection water or oil suspensions, or nose drops. As part of these preparations, if necessary, you can use conventional pharmaceutical excipients, binders, lubricants, aqueous solvents, oily solvents, emulsifying agents, suspendresume agents, preservatives, stabilizers and the like. In particular, the compound of the present invention is preferably used in the form of oral means.

The drug of the present invention can be manufactured by combining (e.g., mixing) a therapeutically effective amount of the compounds of the present invention with pharmaceutically pickup is acceptable carrier or diluent. The drug can be manufactured using well known and readily available ingredients in accordance with the known method.

The dosage of the compounds of the present invention depends on the method of administration, age, weight, condition of the patient and the disease, but in the case of oral administration the daily dose for an adult may be about 0.05 to 3000 mg, preferably approximately 0.1-1000 mg Daily dose can be administered parts. If the connection of the present invention is administered parenterally, the daily dose for an adult may be about 0.01 to 1000 mg, preferably about 0.05 to 500 mg. in Addition, the compound of the present invention can be entered with other medicines.

The following are examples to further illustrate the present invention but they should not be construed as limiting scope of the present invention.

Example 1

[Formula 16]

To a solution of compound1(50.0 g) in ethanol was added dropwise methylhydrazine (13.5 ml) under cooling in an ice bath, then the reaction solution was stirred at room temperature for one hour and boiled under reflux for 4 hours. Under reduced pressure, the solvent was removed, obtaining a solid substance. The solid is washed hexa is om, receiving the connection2(34,2 g).

To a solution of compound2(20,0 g) in dimethylformamide (200 ml) was added potassium carbonate (48,7 g) and benzylbromide (15,4 ml), then the resulting mixture was stirred at room temperature for 4 hours. The insoluble substance was removed by filtration and the filtrate was poured into a solution of ethyl acetate and 0.1 G. of an aqueous solution of HCl and was extracted with ethyl acetate. The extract is successively washed with 0.1 N. aqueous solution of HCl, H2O and saturated salt solution, then dried over sodium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, receiving the connection3(24,0 g).

To a solution of compound3(24,0 g) in methanol (150 ml)-tetrahydrofuran (30 ml)-H2O (130 ml) was added 4 N. aqueous solution of lithium hydroxide (100 ml) under cooling in an ice bath. The resulting solution was stirred at room temperature for 30 min and at 60°C for 3 hours. The solution was neutralized 2 N. aqueous solution of HCl under cooling in an ice bath and extracted with ethyl acetate. The extract was washed H2O, saturated salt solution, dried over magnesium sulfate and concentrated in vacuum, obtaining the connection4(18,9 g) as a crystalline substance.

[Formula 17]

To a solution of compound4(2,32 g), hydrochloride 2-aminoethane the Tana (2.25 g) and 1-hydroxybenzotriazole (405 mg) in dimethylformamide (25 ml) was sequentially added triethylamine (3,35 ml) and the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2.30 g), then the resulting mixture was stirred at room temperature overnight. The reaction mixture was poured into a solution of 0.1 G. of an aqueous solution of HCl and ethyl acetate and was extracted with ethyl acetate. The extract was washed H2O, saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, receiving the connectionA-4(3.12 g).

Example 2

[Formula 18]

To a solution of compoundA-4(1.0 g) in ethanol (10 ml) was added 5% Pd-C (174 mg), and then the resulting mixture was stirred in an atmosphere of H2(1 ATM) for four hours. The insoluble substance was removed by filtration using celite, then the filtrate was concentrated in vacuum, obtaining the connection5(711 mg) as a solid.

To a solution of compound5(110 mg) in dimethylformamide (1.5 ml) was added potassium carbonate (165 mg) and bromocyclohexane (59 μl), then the resulting solution was stirred at 150°C for 1.5 hours using microwave radiation. The reaction solution was poured into a solution of 0.1 G. of an aqueous solution of HCl and ethyl acetate and was extracted with ethyl acetate. The extract was washed H2O, saturated salt solution, dried over magnesium sulfate and concentrated in vacuum. The residue was purified column chromatography on silica gel, receiving the connectionA- (16 mg).

Example 3

[Formula 19]

Interaction connection2with phosphorus oxychloride gave the connection6. Interaction connection6with thiophenols in the presence of cesium carbonate gave the connectionA-2.

Example 4

[Formula 20]

ConnectionA-3received through interaction with phenol instead of thiophenol described in example 3.

Example 5

[Formula 21]

Connection3and regioisomer3'synthesized in the same manner as described in example 1.

[Formula 22]

ConnectionA-5synthesized using the connection3'.

Example 6

[Formula 23]

The catalytic reduction reaction of the compoundA-4given the connection5. The compound obtained was subjected to interaction with cyclohexylamine in the presence of potassium carbonate, receiving the connectionA-6.

Example 7

[Formula 24]

Connection5,obtained in example 6 were subjected to interaction with phenetermine, receiving the connectionA-7. In addition, the compound of the present invention can be obtained by using various halides and halides shown in the use of the Ah 6 and 7. ConnectionC-36~38, 41synthesized according to the method shown in the above examples.

Example 8

[Formula 25]

Connection8and8' synthesized using the connection1as the initial substance and HOCH2CH2NHNH2instead MeNHNH2in example 1. The compounds obtained8were subjected to interaction with 2-adamantanamine, receiving the connectionA-8.

Example 9

[Formula 26]

Under this scheme received the connectionA-33. In addition, the synthesized compoundC-70using hydroxyadamantane instead adamantanamina.

Example 10

[Formula 27]

The compound obtainedA-33were subjected to interaction with methylchloride in the presence of triethylamine, receiving the connectionB-1.ConnectionB-1were subjected to interaction with various amines, receiving connectionA-40, A-41, A-42, A-44, A-45 and A-46. In addition, from the connectionA-33synthesized compoundsC-1, 2, 12-28, 51-53, 84, 101, 102, 108-110.In addition, from the connectionA-44synthesized compoundsC-3-6, 11.

Example 11

[Formula 28]

Connection6were subjected to interaction with various benzyl alcohols, receiving connectionA-21, A-22, A-23andA-2 through reaction Mitsunobu.

Example 12

[Formula 29]

Connection6were subjected to interaction with various benzylbromide in the presence of cesium carbonate, receiving connectionA-26, A-27andA-28.

Example 13

[Formula 30]

ConnectionA-26hydrolyzed in alkali, receiving the connectionA-29.

Example 14

[Formula 31]

Connection4were subjected to interaction with 1-aminopiperidine, receiving the connectionA-25. According to the above example was synthesized compoundsA-13, A-14, A-19, A-20, A-29, A-34andA-35.

Example 15

[Formula 32]

ConnectionA-7, A-13, A-14, A-19, A-20, A-22, A-23, A-24, A-26, A-27, A-28, A-29, A-34, A-35, A-51, A-52andA-59-65synthesized from compound6through reaction Mitsunobu or alkylation reaction.

Example 16

[Formula 33]

Connection11were subjected to interaction with sodium hydroxide, receiving the connection12.

[Formula 34]

Connection12were subjected to interaction with various amines in the presence of HOBt and WSC, receiving the connectionA-36. ConnectionA-37, A-38, A-47-50, A-53, A-55, A-57, A-58, A-66, A-67, C-7-10, 45and54-58synthesized as in Visayas nnom example.

Example 17

[Formula 35]

ConnectionA-50were subjected to interaction with methyliodide and sodium iodide, receiving connectionA-54andA-55. According to the above method synthesized compoundsA-47-49, 57, 58, 66and67.

Example 18

[Formula 36]

ConnectionA-8were subjected to interaction with methylchloride in the presence of triethylamine, receiving the connectionB-2. ConnectionB-2were subjected to interaction with phthalimide potassium, receiving the connectionB-9.

Example 19

[Formula 37]

ConnectionB-2were subjected to interaction with sodium azide, receiving the connection14. Connection14were subjected to interaction with cyclohexylethylamine, receiving the connectionB-3and the connection15.

Example 20

[Formula 38]

Catalytic reduction ofB-3followed by treatment with hydrochloric acid, gave the connectionA-30(HCl salt). The amidation reaction of the resulting product gave the connectionC-61and62.

Example 21

[Formula 39]

Example 22

[Formula 40]

According to the above scheme of the connectionA-33synthesized is soedineniya B-6andB-7.

Example 23

[Formula 41]

According to the above scheme was synthesized compoundsC-39, 40, 42,72, 73, 74,75and76.ConnectionC-79, 81, 151-153synthesized as in the above example.

Example 24

[Formula 42]

According to the above scheme was synthesized compoundsC-46, 47, 59and60.

Example 25

[Formula 43]

According to the above scheme was synthesized compoundC-30.

Example 26

[Formula 44]

According to the above scheme was synthesized compoundsC-48, 49and50.ConnectionC-126-128synthesized as in the above example.

Example 27

[Formula 45]

According to the above scheme was synthesized compoundsC-43,66,77, 78and133.

Example 28

[Formula 46]

According to the above scheme was synthesized compoundsC-67,68, 69, 92, 93, 94, 95, 96, 97, 98, 99, 100, 132andE-33.

Example 29

[Formula 47]

To a solution of compound17(5.7 g) in ethyl acetate (160 ml) was added IBX (7.5 g), then the resulting mixture was boiled under reflux for 6 hours. PEFC the completion of the reaction, the insoluble substance was removed by filtration and the filtrate was concentrated, receiving the connection18(5.6 g). The obtained product was used for next reaction without further purification.

To a solution of compound18in tetrahydrofuran (40 ml) was added phosphonium salt (13.5 g). The solution for 20 min dropwise added triethylamine (3.4 g), then the whole mixture was stirred at room temperature for 3 hours. After completion of the reaction, to the mixture was added H2O (40 ml), then was extracted with AcOEt. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection19(5,2 g).

The solution Diisopropylamine (1.3 ml) in tetrahydrofuran (60 ml) was cooled to -78°C, then to the solution was added dropwise n-utility (of 3.25 ml, 2,8 M in hexane). After stirring at -78°C for 30 min to the solution was added compound19(2.8 g) in tetrahydrofuran (40 ml) and the whole mixture was stirred for 30 minutes To the mixture was added logmean (1,4 ml), then the whole mixture was made to gradually warm to 0°C. After 3 hours the mixture was diluted with saturated aqueous ammonium chloride and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection20(2,42 g).

To a solution of compound20(173 mg) in a mixture of tetrahydrofuran (4 ml)-methanol (2 ml) was added 4 N. aqueous solution of lithium hydroxide (0.9 ml), then the resulting solution was stirred at room temperature for 24 hours. After completion of the reaction the solution was acidified using 2 N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated, obtaining the connection21(181 mg). The obtained product was used for next reaction without further purification.

To a solution of compound21(181 mg) in dimethylformamide was added hydroxyadamantane (94 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (118 mg), 1-hydroxybenzotriazole (21 mg) and triethylamine (121 μl), then the resulting solution was stirred at room temperature for 24 hours. After the reaction solution was diluted 2 N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution and dried over magnesium sulfate. The residue was purified column chromatography on silica gel, receiving the connection22(176 mg). To a solution of compound22(176 mg) in methylene chloride (3 ml) was added to a mixture of 4 N. HCl/dioxane (2 ml), then the resulting solution was stirred at room the Oh temperature for 26 hours. After completion of the reaction the solution was diluted with diisopropyl ether, obtaining crystalline substance. The resulting crystalline substance was collected by filtration and washed with diisopropyl ether, and then dried, obtaining the connectionC-182(120 mg).

To a solution of compoundC-182(55 mg) in dimethylformamide (1 ml) was added 1,1'-carbonyldiimidazole (30 mg), then the resulting solution was stirred at room temperature for 45 minutes To the solution was added 28% aqueous ammonia (0.2 ml) and the whole solution was stirred for 1.5 hours. After the reaction solution was diluted with water and extracted with ethyl acetate. The organic layer is successively washed with 0.1 G. of aqueous HCl solution and a saturated salt solution, dried over magnesium sulfate and concentrated. The resulting crystalline substance washed with diisopropyl ether, receiving the connectionC-144(35 mg).

To a solution of compoundC-144(118 mg) in a mixture of tetrahydrofuran (4.4 ml)-methanol (0.4 ml) was added 10% Pd-C (40 mg), and then the resulting mixture was stirred for 3.5 hours in an atmosphere of H2. After completion of the reaction Pd-C was removed by filtration and the solvent was removed, receiving the connectionC-181(117 mg).

ConnectionC-147,160,163, 187and195synthesized as in the above example.

Example 30

[Formula 48]

To a solution of compound23in methylene chloride (100 ml) was added triperoxonane acid (50 ml), the resulting solution was stirred at room temperature for 3 hours. After completion of the reaction the solvent was removed, the residue was diluted with H2O (100 ml) and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated, obtaining the connection24(16.6 g).

To a solution of compound24(16.6 g) in toluene (70 ml) was added triethylamine (5,67 g), diphenylphosphoryl (14,7 g), then the resulting solution was stirred at 100°C for 3 hours. After the reaction solution was diluted with toluene (70 ml) and the organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution, dried over magnesium sulfate and concentrated. The obtained product was used for next reaction without further purification.

In accordance with the above method of the compound obtained25was dissolved in toluene (30 ml) and to the solution was added 4-methoxybenzyloxy alcohol (10.6 g). The solution was stirred at 50°C for 24 hours. After completion of the reaction the solvent was removed and the residue was purified column chromatography on silica gel, receiving the connection26(19.2 g).

To a solution of compound26in methylene chloride (100 m is) was added anisole (13,6 g) and triperoxonane acid (20 ml), then the resulting solution was stirred at room temperature for 2 hours. After completion of the reaction the solvent was removed and the residue was diluted 1 N. aqueous solution of HCl (50 ml) and H2O (60 ml). The aqueous layer was washed with hexane and podslushivaet 2 N. aqueous solution of NaOH (30 ml). The solution was extracted with ethyl acetate, the organic layer was washed with saturated salt solution, dried over magnesium sulfate and concentrated, obtaining the connection27(9.6 g).

To a solution of compound27(9.6 g) in methylene chloride (50 ml) was added pyridine (3.9 g) and acetic anhydride (4.0 g), then the resulting solution was stirred at room temperature for 2 hours. After the reaction solution was diluted with chloroform and the organic layer was sequentially washed 2 N. aqueous solution of HCl, a saturated solution of sodium bicarbonate and a saturated solution of salt. The organic layer was dried with magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection28(7,1 g).

To a solution of compound28(7,1 g) in a mixture of tetrahydrofuran (20 ml) and methanol (20 ml) was added 2 N. aqueous LiOH solution (21 ml), then the resulting solution was stirred at room temperature for 16 hours. After completion of the reaction the solution was acidified using 2 N. aqueous solution of HCl and was extracted with ethyl acetate. Organic the ski layer was washed with saturated salt solution, was dried with magnesium sulfate and concentrated, obtaining the connection29(6.3 g).

To a solution of compound29(102 mg) in methylene chloride (2 ml) was added hydroxyadamantane (81 mg, the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (82 mg), 1-hydroxybenzotriazole (14 mg) and triethylamine (115 μl), then the resulting solution was stirred at room temperature for 13 hours. After completion of the reaction the solution was acidified using 2 N. aqueous solution of HCl and was extracted with methylene chloride. The organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution and dried with sodium sulfate. The residue was purified column chromatography on silica gel, receiving the connectionC-202(123 mg).

ConnectionC-194and204synthesized as in the above example.

Example 31

[Formula 49]

To a solution of compound30(400 mg) in toluene (8 ml) was added triethylamine (180 μl) and diphenylphosphoryl (279 μl), then the resulting solution was stirred at 100°C for 2 hours. After cooling to 0°C. to the solution was added 28% aqueous ammonia (2 ml) and the whole solution was stirred at room temperature for 80 minutes After completion of the reaction the solution was added H2O and was extracted with ethyl acetate. The organic layer was washed saturated with the second solution of sodium bicarbonate, saturated salt solution, dried with sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection31(303 mg).

To a solution of compound31(303 mg) in a mixture of tetrahydrofuran (3 ml)-methanol (1.5 ml) was added 2 N. aqueous LiOH solution (0.68 ml), then the resulting solution was stirred at room temperature for 19 hours. After completion of the reaction the solution was diluted with H2O and the organic layer washed with diethyl ether. The mixture was acidified using 2 N. aqueous solution of HCl and was extracted with a mixture of ethyl acetate-tetrahydrofuran. The organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated. The obtained crystalline material was washed with a mixture of ethyl acetate-hexane, receiving the connection32(193 mg).

To a solution of compound32(193 mg) in dimethylformamide (4 ml) was added hydroxyadamantane (152 mg), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (155 mg), 1-hydroxybenzotriazole (26 mg) and triethylamine (217 μl), then the resulting solution was stirred at room temperature for 18 hours. After completion of the reaction the solution was acidified using 2 N. aqueous solution of HCl and was extracted with methylene chloride. The organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution and dried sulfate is m sodium. The residue was purified column chromatography on silica gel, receiving the connectionC-186(36 mg).

To a solution of compoundC-186(25 mg) in a mixture of tetrahydrofuran (1 ml)-methanol (0.1 ml) was added 10% Pd-C (12 mg), and then the resulting mixture was stirred for 24 hours in an atmosphere of H2. After completion of the reaction Pd-C was removed by filtration and the solvent was removed, receiving the connectionC-184(25 mg).

ConnectionC-183, 185, 198and199synthesized as in the above example.

Example 32

[Formula 50]

According to example 29 compound33synthesized from compound24. To a solution of compound33(149 mg) in methylene chloride (3 ml) was added pyridine (74 μl) and anhydrous triperoxonane acid (98 μl), then the resulting solution was stirred at room temperature for 45 minutes After completion of the reaction the solution was added an aqueous solution of HCl. The mixture was extracted with ethyl acetate and the organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution, dried with sodium sulfate and concentrated, obtaining the connection34(141 mg).

According to the above method synthesized compoundC-192.

Example 33

[Formula 51]

To a solution of compound35in methylene chloride (4 ml) is obavljale 1,1'-carbonyldiimidazole (200 mg), then the resulting solution was stirred at room temperature for 2 hours and was cooled to 0°C. To the solution was added acetohydrazide (69 mg) and methylene chloride (2 ml) and the whole mixture was stirred at room temperature for 2 hours. After completion of the reaction, to the mixture was added an aqueous solution of HCl. Was carried out by extraction with ethyl acetate and the organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution and dried with sodium sulfate. Solvent was removed, getting a crystalline substance. The obtained crystalline material was washed with hexane, receiving connection36(190 mg).

To a solution of compound36(140 mg) in tetrahydrofuran (2.8 ml) was added Burgess reagent (259 mg), then the resulting solution was stirred at 120°C for 15 minutes using microwave radiation. After completion of reaction solvent was removed and the residue was purified column chromatography on silica gel, receiving the connection37(126 mg).

In accordance with the above methodology synthesized compoundsC-190and191.

Example 34

[Formula 52]

To a solution of compound38in toluene (2 ml) was added 2-chloroethanol (103 μl), triethylamine (2 drops), then the resulting solution was stirred at room temperature for 24 hours. PEFC is the completion of reaction solvent was removed and the residue was purified column chromatography on silica gel, receiving the connection39(215 mg).

To a solution of compound39(211 mg) in a mixture of tetrahydrofuran (4 ml)-dimethylformamide (4 ml) was added sodium hydride (32 mg, 60% suspension in oil), then the resulting solution was stirred at room temperature for 140 minutes After completion of the reaction the solution was added an aqueous solution of HCl. Was carried out by extraction with ethyl acetate and the organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection40(191 mg).

In accordance with the above methodology synthesized compoundsC-201and203.

Example 35

[Formula 53]

To a solution of compound41(237 mg) in tetrahydrofuran (3 ml) was added triethylamine (152 μl) and ethylchloride (84 μl) at 0°C, then the resulting solution was stirred at room temperature for 1 hour. To the solution at 0°C was added sodium borohydride (69 mg) and H2O (1 ml) and the whole mixture was stirred for 20 minutes After completion of the reaction, to the mixture was added an aqueous solution of HCl. Was carried out by extraction with ethyl acetate and the organic layer was washed with saturated salt solution, dried over sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection<> 42(185 mg).

To a solution of compound42(185 mg) in methylene chloride (5 ml) was added DAST (102 μl) at -78°C, then the resulting solution was stirred at the same temperature for 30 minutes After completion of the reaction the solution was added a saturated solution of ammonium chloride. Was carried out by extraction with ethyl acetate, the organic layer was dried with sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection43(62 mg).

In accordance with the above methodology synthesized compoundC-179.

[Formula 54]

In accordance with the above method, the recovery of carboxylic acids, the connectionC-182given the connectionC-193.

ConnectionC-162synthesized as in the above example. According to example 29 from the connectionC-162synthesized compoundC-164.

Example37

[Formula 55]

In accordance with the above scheme was synthesized compoundC-159.

Example38

[Formula 56]

In accordance with the above scheme was synthesized compoundC-196.

Example39

[Formula 57]

In accordance with the above scheme was synthesized compoundC-197.

auctionee conditions, such as a reagent, reaction temperature, reaction time, solvent, can be applied to the normal condition.

Example40

[Formula 58]

In accordance with the above scheme was synthesized compoundC-205. The reaction conditions such as reagent, reaction temperature, reaction time, solvent, can be applied to the normal condition.

Example41

[Formula 59]

According to the above scheme was synthesized compoundC-207. The reaction conditions such as reagent, reaction temperature, reaction time, solvent, can be applied to the normal condition.

Example42

[Formula 60]

According to the above scheme of the connectionC-208synthesized compoundC-209. The reaction conditions such as reagent, reaction temperature, reaction time, solvent, can be applied to the normal condition.

Example43

[Formula 61]

According to the above scheme was synthesized compoundsC-130, 131, 200and206. The reaction conditions such as reagent, reaction temperature, reaction time, solvent, can be applied to the normal condition.

Example44

[Formula 62]

To a solution of dityatkin is telemagenta (21,6 g) in ethanol (80 ml) was added dropwise Gidrodinamika (8 g) in ethanol (20 ml) for 30 min at -4°C. The resulting solution was stirred at 40°C for 1 hour and the solvent was removed. The residue was dissolved in chloroform and the organic layer was washed with a saturated solution of sodium bicarbonate, dried with magnesium sulfate and concentrated. The residue was dissolved in ethanol (80 ml) and the solution boiled under reflux for 18 hours. After completion of the reaction the solvent was removed, receiving the connection45(18.5 g).

To a solution of compound45(6.3 g) in dimethylformamide (30 ml) was added cesium carbonate (15,4 g) and isobutyramide (5.6 g), then the resulting mixture was stirred at 70°C for 3 hours. After completion of the reaction, to the mixture was added H2O (60 ml). Was carried out by extraction with ethyl acetate and the organic layer was washed with saturated salt solution, dried by magnesium sulfate and concentrated, obtaining the connection46(5.7 g).

To a solution of compound46(8.0 g) in methanol(70 ml) was added 2 N. aqueous solution of NaOH (60 ml), then the resulting solution was stirred at room temperature for 24 hours. After completion of the reaction the solution was acidified using 2 N. aqueous solution of HCl (65 ml) and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried by magnesium sulfate and concentrated. The resulting crystalline substance washed with diisopropyl ether, receiving the connection47(6.0 g).

K R is the target connection 47(5.0 g) in dimethylformamide (50 ml) were added hydrochloride 2-adamantanamina (5.35 g), the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (5,04 g), 1-hydroxybenzotriazole (3.55 g) and triethylamine (7,6 ml), then the resulting solution was stirred at room temperature for 24 hours. After the reaction solution was diluted 2 N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium bicarbonate and a saturated salt solution, dried by magnesium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection48(4.0 g).

To a solution of compound48(4.0 g) in ethyl acetate (80 ml) was added IBX (6.2 g), then the resulting mixture was boiled under reflux for 6 hours. After completion of the reaction, the insoluble substance was removed by filtration and the solvent was concentrated, receiving the connection49(4.0 g). The obtained product was used in next reaction without further purification.

To a solution of compound49(4.0 g) in tetrahydrofuran (50 ml) was added (carletonville)triphenylphosphorane (5,27 g), then the resulting solution was stirred at room temperature for 4 hours. After completion of the reaction the solution was diluted with H2O and was extracted with ethyl acetate. The organic layer was washed with saturated RA is tworoom salt, was dried with sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection50(3,9 g)

To a solution of Diisopropylamine (2,72 ml) in tetrahydrofuran (40 ml) was added dropwise n-BuLi (12,2 ml, 1,59 M in hexane) at -78°C. After stirring at the same temperature for 45 minutes to the solution was added compound50(of 3.9 g) in tetrahydrofuran (40 ml) and the whole solution was stirred for 1 hour. To the solution was added logmean (0.6 ml), then the solution was stirred for 1.5 hours. After the reaction solution was diluted 2 N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated. The residue was purified column chromatography on silica gel, receiving the connection51(2.4 g).

To a solution of compound51(280 mg) in a mixture of tetrahydrofuran (2.5 ml)-methanol (2.5 ml) was added 2 N. aqueous solution of NaOH (2.5 ml), then the resulting solution was stirred at room temperature for 1 hour. After completion of the reaction the solution was acidified using 2 N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried with sodium sulfate. Solvent was removed, receiving the connectionC-137(259 mg).

To a solution of compoundC-137(141 mg) in dimethylformamide (3 ml) doba is Lyali tert-butyl-2-aminoethylamino (68 mg), hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (76 mg) and 1-hydroxybenzotriazole (53 mg), and then the resulting solution was stirred at room temperature for 24 hours. After the reaction solution was diluted 2 N. aqueous solution of HCl and was extracted with ethyl acetate. The organic layer was sequentially washed with a saturated solution of sodium bicarbonate and a saturated salt solution and dried with sodium sulfate. Solvent was removed and the residue was purified column chromatography on silica gel, receiving the connection52(146 mg).

To a solution of compound52(146 mg) in dioxane (1.5 ml) was added 4 N. HCl/dioxane (1.5 ml), then the resulting solution was stirred at room temperature for 3 hours. After completion of the reaction the solution was diluted with diisopropyl ether, obtaining crystalline substance. The crystalline substance was collected by filtration, washed with diisopropyl ether and dried, obtaining the connectionC-134(94 mg).

In the same way synthesized compoundsC-129, D-13-35.

Example45

[Formula 63]

To a solution of compoundC-137(118 mg) in ethanol (3 ml) was added 10% Pd-C (12 mg), and then the resulting mixture was stirred in an atmosphere of H2within 5 hours. After completion of the reaction Pd-C was removed by filtration. The filtrate was concentrated, receiving from the unity C-138(116 mg). In accordance with the usual technique of synthesized compoundC-135.

In addition, as in the above example, the synthesized compoundsC-139, D1-12.

Example46

[Formula 64]

According to the method of synthesis of the synthesized compoundsC-137andC-142.ConnectionC-142converted into compoundsC-149, 150, 154-156and175the usual procedure.

Example47

[Formula 65]

According to the method of synthesis of the synthesized compoundsC-137andC-143.ConnectionC-143converted into compoundsC-147, 148and157the usual procedure.

Example48

[Formula 66]

According to the method of synthesis of compoundsC-184(example 31) was synthesized above connection from the connectionC-137.

Example49

[Formula 67]

According to the above scheme was synthesized compoundsC-177and178.

Example50

[Formula 68]

According to the method of synthesis of compoundsC-193(example 36) connectionC-168synthesized from compoundC-137.In addition, in the above method the connectionC-168transformed to a compoundC-172.

Example51

[Formula 69]

According to the method of synthesis of compoundsC-191(example 33) connectionC-180synthesized from compoundC-137.

Example52

[Formula 70]

Hydrolysis connectionC-119given the connectionC-88, followed by catalytic reduction of compoundC-88in connectionC-89.

Example53

[Formula 71]

According to the above scheme of the connectionC-88synthesized compoundC-91.

[Formula 72]

According to the above methodology was synthesized following the connection.

Example54

[Formula 73]

According to the above scheme was synthesized compounds53and54. ConnectionC-120synthesized from compound53.

Example55

[Formula 74]

The above starting material was subjected to hydrolysis, receiving connection55and56. Connection55are condensed with an amine, followed by removal of protection by HCl getting connectionC-125.Connection56are condensed with an amine, followed by removal of protection by HCl getting connectionC-124.

Example56

[Formula 75]

With the according to the above scheme has received the connection C-121.

Example57

[Formula 76]

According to the above scheme received connectionC-123and122.

Example58

[Formula 77]

Under this scheme received the connectionC-136.

Example59

[Formula 78]

According to the above scheme received connectionC-210and211.

Example60

[Formula 79]

According to the above scheme received connectionC-29and31.ConnectionC-104synthesized as in the above example.

Example61

[Formula 80]

According to the above scheme was synthesized compoundC-32, followed by reaction with 1,1'-carbonyl diimidazol getting connectionC-33.

Example62

[Formula 81]

ConnectionC-32were subjected to interaction with thionyl chloride in the presence of pyridine, receiving the connectionC-34.

Example63

[Formula 82]

According to the above scheme was synthesized compoundC-35.

Example64

[Formula 83]

Under this scheme which was intesively connection C-65.

Example65

[Formula 84]

According to the above scheme was synthesized compoundC-105.

Example66

[Formula 85]

According to the above scheme was synthesized compoundC-106.

Example67

[Formula 86]

According to the above scheme was synthesized compoundC-107.

Example68

[Formula 87]

To a solution of compoundC-185(300 mg) in methylene chloride (20 ml) was added DAST (168 μl) at -78°C, then the resulting solution was kept at the same temperature for 1 hour. After the reaction solution was poured into a saturated solution of sodium bicarbonate and was extracted with ethyl acetate. The organic layer was washed with saturated salt solution, dried by magnesium sulfate and concentrated.The residue was purified column chromatography on silica gel, receiving the connectionC-220(270 mg).

ConnectionC-219synthesized from compoundC-144the same procedure.

Example69

[Formula 88]

To a solution of compoundC-185(250 mg) in tetrahydrofuran (2.5 ml) was added chlorosulfonylisocyanate (69 ml) at -45°C, then the resulting solution was stirred at -25°C for 3 hours. the solution was added sodium hydrogen carbonate (221 mg) and H 2O (50 μl) and the whole mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate and the organic layer was washed with saturated salt solution, dried with sodium sulfate and concentrated.The residue was purified column chromatography on silica gel, receiving the connectionC-214(220 mg).

ConnectionC-231synthesized from compoundC-202and the connectionC-236received from the connectionC-216as in the above example.

The following compounds were synthesized in the same way as in the above example. “ClH” has the same meaning as “HCl”. Describes the results of the measurements of NMR, MS and TPL (see tab. 1-64).

Experimental example 1

Evaluation of inhibitors of 11β-HSD1 (sample enzyme activity on 11β-HSD1 person)

Enzyme activity for 11β-HSD1 man was determined in 10 µl final volume of the analyzed mixture containing 50 mm buffer phosphate (pH 7,6), 1 mg/ml bovine serum albumin, 0,42 mg/ml NADPH, of 1.26 mg/ml glucose-6-phosphate, glucose-6-phosphate dehydrogenase, test the connection, recombinant 11β-HSD1 people and 5 μm cortisone as a substrate. The reaction started with the addition of cortisone. After incubation for 2 hours at 37°C was added 5 μl of labeled Cryptocom europium antibodies against cortisone and 5 μl of cortisone labeled with XL665. Once more the positive incubation for 2 hours at room temperature was measured signal homogeneous fluorescence with a time resolution (HTRF). The production of cortisone quantitatively estimated from the standard curve obtained with several known concentrations of cortisone in each sample.

The number of producing cortisone without connections served as a control, and the expected percentage of inhibition of the test compound at each concentration. The IC50 value of the compound for 11β-HSD1 was obtained using the curve of the inhibition obtained by the graphical application of the percentage of inhibition depends on the concentration of the tested compounds.

Experimental example 2

Evaluation of inhibitors of 11β-HSD1 (sample enzyme activity on 11β-HSD1 mouse)

Enzyme activity for 11β-HSD1 mice was determined in 10 µl final volume of the analyzed mixture containing 50 mm buffer phosphate (pH 7,6), 1 mg/ml bovine serum albumin, 0,42 mg/ml NADPH, of 1.26 mg/ml glucose-6-phosphate, glucose-6-phosphate dehydrogenase, test the connection, recombinant 11β-HSD1 mice and 2 μm 11-dehydrocorticosterone as substrate. The reaction was started by adding 11-dehydrocorticosterone. After incubation for 2 hours at 37°C was added 5 μl of labeled Cryptocom europium antibodies against cortisone and 5 μl of cortisone labeled with XL665. After additional incubation for 2 hours at room temperature was measured signal HTRF. The production of corticosterone quantities of the NGOs was estimated from the standard curve, obtained with several known concentrations of corticosterone in each sample.

Quantity production of corticosterone without connections served as a control, and the expected percentage of inhibition of compound at each concentration. The IC50 value of the compound for 11β-HSD1 was obtained using the curve of the inhibition obtained by the graphical application of the percentage of inhibition depends on the concentration of the tested compounds.

The results of experimental example 1 and 2 are shown in the following table.

Table 65
No.IC50 person (µm)IC50 mouse (µm)
A-10,195,9
A-20,2711
A-30,324,1
A-40,0371,6
A-50,71>30
A-60,00830,94
A-70,0180,71

Experimental example 3

Materials and methods in oral absorption inhibitor of 11β-HSD1.

(1)Animals

Male mice C57BL/6J Jcl at the age of 6 weeks were purchased from CLEA Japan. After 1 week pre-breeding mice used for this study at the age of 7 weeks.

(2)Growing conditions

Mice were placed in the room for the animals, which was established room temperature 23±2°C and humidity 55±10%, and the light cycle was 12 hours [light (8:00-20:00)/dark (20:00-8:00)]. Mice were given free access to solid laboratory food (CE-2, CLEA Japan) and sterile tap water throughout the period prior cultivation and experimental period.

(3)Identification of animals and cells

Mice were identified by labeling tailings oil marker. Labels identifying the research leader, date of purchase, line, sex and provider were placed on each cage. Mice were kept in 20 mice/cage in the period prior cultivation and 3 mice/cage in the experimental period.

(4)The group

Oral introduction: 20 mg/kg (n=3)

Intravenous: 5 mg/kg (n=3)

(5)Preparation of dosage forms

Dosage suspension for oral administration was prepared using 0.5% aqueous solution of methylcellulose (1500 CPS). Metered-dose intravenous solution was prepared using N-dimethylacetamide/polyethylene glycol 400 (1/2).

(6)Method of dosing

As for oral administration, dosage suspension with 10 ml/kg was administered into the stomach using a feeding tube. As for intravenous dosing solution at 2.5 ml/kg was injected into the caudal vein using a glass syringe.

(7)The point estimates

Blood samples were collected from the heart in every moment of sampling. The concentration of drug in plasma was measured using HPLC or LC/MS/MS.

(8)Statistical analysis

The area under the curve of plasma concentration-time (AUC) was calculated using WinNonline®, and the bioavailability was calculated as the AUC values after oral and intravenous administration.

The following examples of formulations 1-8 are presented to further illustrate the present invention and there is no intention to limit the scope of the present invention. The term "active ingredient" means a compound of the present invention, its pharmaceutically acceptable salt or hydrate.

(Example formulation 1)

Prepare gelatin capsules containing the following ingredients:

Dose (mg/capsule)
The active ingredient250
Starch (dry)200
Magnesium stearate10
Only460 mg

(Example formulation 2)

To prepare tablets with the following ingredients:

Dose (mg/tablet)
The active ingredient250
Cellulose (microcrystalline)400
Silicon dioxide, fine grinding10
Stearic acid5
Only665 mg

The ingredients are mixed and compressed to obtain tablets, the mass of each of which is 665 mg

(Example formulation 3)

Tablets, each containing 60 mg of active ingredient, are prepared as follows.

The active ingredient60 mg
Starch45 mg
Microcrystalline cellulose35 mg
Polyvinylpyrrolidone (as 10% solution in water)4 mg
Karboksimetilirovaniya starch sodium4.5 mg
Magnesium stearate0.5 mg
Talc1 mg
Only150 mg

The active ingredient, starch and cellulose are passed through sieve No. 45 mesh U.S. and mix thoroughly. With the obtained powder is mixed aqueous solution containing polyvinylpyrrolidone, and then this mixture is passed through a sieve No. 14 mesh U.S. dollars. Thus obtained granules are dried at 50°C and passed through sieve No. 18 mesh U.S. dollars. To the pellet add karboksimetilirovaniya starch sodium, magnesium stearate and talc, previously passed through sieve No. 60 mesh U.S., mixed and then pressed on teletrauma car, getting pills, weight each of which is 150 mg

(Example formulation 4)

Capsules, each containing 80 mg of the active ingredient, prepared as follows:

The active ingredient80 mg
Starch59 mg
Microcrystalline cellulose59 mg
Magnesium stearate2 mg
Only200 mg

The active ingredient, cellulose, starch and magnesium stearate are mixed, passed through sieve No. 45 mesh U.S. and this mixture fill hard gelatin capsules in 200 mg

(An example of the formulation 5)

Suppositories, each containing 225 mg of active ingredient are made as follows:

The active ingredient225 mg
Glycerides of saturated fatty acids2000 mg
Only2225 mg

The active ingredient is passed through sieve No. 60 mesh U.S. and suspended in the glycerides of saturated fatty acids, previously melted using the minimum heat needed. Then see what camping is poured in the form of a suppository with a nominal capacity of 2 g and allow it to cool.

(Example formulation 6)

Suppositories, each containing 50 mg of active ingredient are made as follows:

The active ingredient50 mg
Sodium-karboksimetilcelljuloza50 mg
Syrup1.25 ml
A solution of benzoic acid0.10 ml
Flavorq.v.
Dyeq.v.
Purified water to total amount5 ml

The active ingredient is passed through a sieve No. 45 mesh U.S. and mixed with the sodium carboxymethyl cellulose and syrup, obtaining a homogeneous paste. A solution of benzoic acid and the flavor is diluted with a part of water is added and stirred. Then add enough water, getting the required amount.

(Example formulation 7)

The formulation for intravenous administration can be prepared as follows:

The active ingredient100 mg
Glycerides of saturated fatty acids1000 ml

The solution of the above ingredients is usually administered intravenously to a patient at a rate of 1 ml per minute.

1. The compound represented by formula (I)
[Formula I]

its pharmaceutically acceptable salt or MES,
R1represents an optionally substituted C1-10alkyl or optionally substituted C2-8alkenyl, or phenyl, substituted carboxy (C1-10by alkyl) or (C1-10alkyl) carbamoyl,
where optional substitution in the specified alkyl means 1-2 substituent selected from hydroxy; carboxy; cyano; C1-10alkylsulfonyl; halogen atoms; carbamoyl; C1-10allylcarbamate and di (C1-10alkyl) carbamoyl, are not substituted by carboxy, amino, or amino(C1-10by alkyl), optionally N-substituted With1-10alkyl groups; C1-10alkylsulphonyl; C1-10alkyloxy:1-10allyloxycarbonyl; C1-10alkylamino, in which the alkyl part is optionally substituted by halogen atoms, carboxy, PIP is reinila or phenyl, which may be substituted with halogen;
With1-10alkylcarboxylic, optionally substituted amino;
heteroarylboronic in which heteroaryl means isoxazolyl, substituted carboxy;
5-6-membered, getrollbackonly containing 1-2 nitrogen heteroatom;
heteroarylboronic in which heteroaryl means isoxazolyl, substituted hydroxy-group;
With1-10allyloxycarbonyl;
phenylamino, in which phenyl optionally substituted by carboxy or halogen;
5-membered heteroaryl containing 3-4 heteroatom selected from oxygen, nitrogen and sulfur, optionally substituted C1-10the alkyl or oxo;
5-9-Lenogo monocyclic or bicyclic heterocycle containing 1-2 heteroatoms of nitrogen, optionally substituted Deputy selected from the group consisting of hydroxy, halogen, carboxy, C1-10of alkyl, C1-10alkylsulfonyl, carbamoyl,1-10alkyloxy, amino, C1-10alkylamino, aminomethyl, acylamino, optionally substituted by a hydroxy-group, With1-10allyloxycarbonyl, C1-10alkylsulfonamides, pyrimidinyl, acyl, optionally substituted carboxy, oxo;
5-6-membered geterotsiklicheskikh containing 1-2 heteroatoms of nitrogen, optionally substituted C1-10by alkyl, carboxy, carboxymethyl, oxo, amino and AMI what said;";
sulfanilamide; hydroxyamino; phenyloxy, substituted carboxy; imino, substituted piperidinyloxy;
pyridylamino, optionally substituted carboxy;
amino, optionally substituted by 1-2 substituents selected C1-10alkylsulfonyl, piperidinyl, pyrrolidinyl, C1-10alkoxy, C1-10alkoxyl1-10of alkyl and amino(C1-10alkyl)carbonyl;
With3-6-cyclooctylamino;
oxazolidinyl, substituted oxo;
ureido, optionally substituted by 1-2 C1-10alkyl groups;
optional substitution in the specified alkenyl means 1-2 substituent selected from amino; hydroxy; carboxy; cyano; halogen atoms; C1-10alkyloxy; carbamoyl, optionally substituted amino, piperidinyl or hydroxyadamantane;
With1-10allylcarbamate, which is optionally substituted amino, carboxy, C1-10alkoxy, pyrrolidinyl or aminos1-10the alkyl, optionally N-substituted With1-10alkyl groups;
With1-10allyloxycarbonyl; C1-10alkylcarboxylic;
With1-10alkylsulfonamides; C1-10alkoxycarbonyl;
oxadiazolyl, optionally substituted C1-10by alkyl;
oxazolidinyl, substituted oxo;
5-7-membered geterotsiklicheskikh containing 1-2 heteroatoms of nitrogen, optionally substituted amino;
the carb is molotsi, optionally substituted With 1-21-10alkyl groups;
isopropylidenedioxy;
5-7-membered, geterotsiklicheskikh containing 1-2 heteroatoms of nitrogen, optionally substituted C1-10alkoxycarbonyl; heteroaromatic where heteroaryl chosen from 5-membered heteroaryl containing 2-3 heteroatoms nitrogen, or sulfur;
ureido, optionally substituted With 1-21-10alkyl groups;
R2represents a group of the formula: -Y-R5,
where Y represents-O - or-S-, and
R5represents phenyl, cyclohexyl, branched C3-10alkyl, substituted unbranched1-10alkyl, where the Deputy that substituted unbranched alkyl represents a C3-6cycloalkyl, phenyl, optionally substituted by 1-2 substituents selected from C1-10of alkyl, halogen, C1-10alkoxy, trifloromethyl, triptoreline, nitro, carboxy, cyano, C1-10alkoxycarbonyl, phenyl(C1-2of alkyl, phenyloxy, C1-2alkylenedioxy;
5-6-membered heteroaryl containing 1-2 heteroatom nitrogen or sulfur, or 5-6-membered heterocycle containing a heteroatom of nitrogen, optionally substituted C1-4the alkyl, oxo or1-10allyloxycarbonyl;
R4represents hydrogen or C1-10alkyl;
R3represents a group of formula: -C(=O)-Z-R6, Z represents-NR 7- or-NR7-W-, and
R6represents an optionally substituted C7-C10bicyclic or tricyclic cycloalkyl,
or piperidinyl, optionally substituted C1-4alkyl groups;
where optional substitution in the specified cycloalkyl means 1-4 substituent, selected from the group consisting of: hydroxy, halogen, C1-10the alkyl, optionally substituted hydroxy, carbamoylated or amino, allylcarbamate, alkyloxy, alkylcarboxylic, allyloxycarbonyl, alkylsulfonyl, cyano, amino, carbamoyl, sulfanilamide, carbamoylated, sulfanilate, where the alkyl parts contain 1 to 10 carbon atoms;
R7represents hydrogen or C1-10alkyl, or
R6and R7taken together, may form a 6-7 membered ring, optionally substituted C1-10by alkyl;
W represents C1-10alkylen,
X represents =N-,
provided that excluded the compounds in which R2represents a 2-(4-morpholino)ethoxy, 2-, 3 - or 4-pyridyloxy, 1-methylpiperidine-2-methoxy, benzyloxy or 4-substituted benzyloxy; and R3represents N-(1-substituted)carbarnoyl, N-(2-substituted)carbarnoyl and N-(3-lordamantr)carbarnoyl.

2. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which R 1represents a substituted alkyl where the Deputy specified substituted alkyl is an optionally substituted an amino group or optionally substituted 5-9-membered monocyclic or bicyclic a heterocycle containing 1-2 heteroatoms of nitrogen,
where the substituents selected from the group consisting of hydroxy, carboxy, halogen, alkyl, alkylsulfonyl, carbamoyl, acyloxy, amino, alkylamino, acylamino, allyloxycarbonyl, alkylsulfonyl, pyrimidinyl, acyl, oxo, when R1means alkyl substituted optionally substituted heterocycle, and
where the substituents selected from the group consisting of alkyl, cycloalkyl, piperidinyl, phenyl, pyridyl, pyrrolidinyl, acyl, and alkylsulfonyl, in the case when R1means alkyl, substituted by an optionally substituted amino group, where the alkyl parts contain 1 to 10 carbon atoms.

3. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which R1represents a substituted ethyl, where the Deputy indicated substituted ethyl represents optionally substituted by an amino group or optionally substituted 5-9-membered monocyclic or bicyclic a heterocycle containing 1-2 nitrogen heteroatom, where the substituents for the amino group and heterocyclyl group defined in the .2.

4. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which R1represents unsubstituted With1-10alkyl.

5. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which Y represents-O-.

6. The compound according to claim 5, its pharmaceutically acceptable salt or MES, in which R5represents a substituted unbranched1-10alkyl, where the Deputy indicated substituted unbranched alkyl represents a C3-C6cycloalkyl.

7. The connection according to claim 6, its pharmaceutically acceptable salt or MES, in which R5represents a substituted methylene where the Deputy indicated substituted methyl is a3-C6cycloalkyl.

8. The connection according to claim 6, its pharmaceutically acceptable salt or MES, where3-C6cycloalkyl represents cyclohexyl.

9. The compound according to claim 5, its pharmaceutically acceptable salt or MES, in which R5represents a branched C3-10alkyl.

10. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which Z represents-NR7-, and R7has the same meaning as defined in claim 1.

11. The connection of claim 10, its pharmaceutically acceptable salt or MES, in which R7is the Wallpaper hydrogen.

12. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which R6represents an optionally substituted cycloalkyl, where the term cycloalkyl and alternates for cycloalkyl group defined in claim 1.

13. The connection section 12, its pharmaceutically acceptable salt or MES, in which R6represents substituted.

14. The connection section 12, its pharmaceutically acceptable salt or MES,
in which R3represents a group of formula (II):

15. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which R1represents a group of the formula:
-CH=CH-C(R9-R10)-R11-R12,
where R9and R10each independently represents hydrogen, C1-4alkyl,
R11represents -(CH2)n-, where n is an integer from 0 to 3, and
R12represents hydrogen, hydroxy, halogen atom, carboxy, cyano, optionally substituted With 1-21-4alkyl groups carbamoyloximes,1-4alkoxygroup, piperidinecarboxylate, oxadiazolyl, optionally substituted C1-4by alkyl;
a group of the formula: -C(=O)-NR13R14,
where R13and R14each independently represents hydrogen,
the amino group, optionally substituted C1-4alkyl, g is e Deputy selected from carboxy, With1-4alkoxy, pyrrolidinyl, amino, optionally substituted With 1-21-4alkyl groups, hydroxyadamantane or piperidinyl, or R13and R14taken together with the nitrogen atom to which they are attached, may form diazepinone ring, or
a group of the formula: -NR15R16,
where R15and R16each independently represents hydrogen, acyl, optionally substituted With 1-21-4alkyl groups carbarnoyl, C1-4alkylsulfonyl, C1-4allyloxycarbonyl, or
R15and R16taken together with the nitrogen atom to which they are attached, may form a ring oxazolidinyl, substituted oxo.

16. The compound according to claim 1, its pharmaceutically acceptable salt or MES, in which R1represents a group of the formula:
-CH2-CH2-C(R9-R10)-R11-R12,
where R9and R10each independently represents hydrogen, C1-4alkyl,
R11represents -(CH2)n-, where n is an integer from 0 to 3, and
R12represents hydrogen, hydroxy, carboxy, cyano, piperazinil, oxadiazolyl, optionally substituted C1-4by alkyl;
a group of the formula: -C(=O)-NR13R14,
where R13and R14each independently represents hydrogen, C1-4alkyl, optionally substituted carb is XI, or amino, optionally substituted With 1-21-4alkyl groups, or
a group of the formula: -NR15R16,
where R15and R16each independently represents hydrogen, optionally substituted With 1-21-4alkyl groups carbarnoyl, C1-4allyloxycarbonyl, or R15and R16taken together with the nitrogen atom to which they are attached, may form a ring oxazolidinyl, substituted oxo.

17. The connection of clause 15 or 16, its pharmaceutically acceptable salt or MES, in which each of R9and R10independently represents a C1-4alkyl.

18. The connection of clause 15 or 16, its pharmaceutically acceptable salt or MES, in which R11represents -(CH2)n-, where n is an integer from 0 to 1.

19. The connection of clause 15 or 16, its pharmaceutically acceptable salt or MES, in which R12represents carboxy or cyano.

20. The connection of clause 15 or 16, its pharmaceutically acceptable salt or MES, in which R12represents a group of the formula:
-C(=O)-NR13R14,
where R13and R14each independently has the same values that are defined respectively for each of these groups in PP and 16.

21. The connection of clause 15 or 16, its pharmaceutically acceptable salt or MES, in which R12not only is em a group of the formula: -NR 15R16,
where R15and R16each independently has the same values that are defined respectively for each of these groups in PP and 16.

22. Pharmaceutical composition having inhibitory activity against 11β-HSD-1, which comprises the compound according to any one of claims 1 to 21, its pharmaceutically acceptable salt or MES as an active ingredient.

23. The pharmaceutical composition according to item 22 for the treatment and/or prevention of diabetes.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound of general formula I

,

and a pharmaceutically acceptable salt thereof, where X denotes CH2, CHF or S, Y denotes CN, R1, R2, R3 and R4 denotes hydrogen, n equals 1, m equals 0 or 1, R denotes R11, R12 or R13, where R11 includes at least one group selected from the following b) or c), where optionally substituted heterocyclic and heteroaryl groups are bonded with a noradamantyl part either directly or through a methylene adjacent group or a C-C bond or C-N bond; b) the substituted 5-member heteroaryl group, in which the heteroaryl ring is a monocyclic aromatic ring system, includes two or more heteroatoms selected from nitrogen and oxygen; c) the heterocyclic group is optionally substituted with a C1-C3 alkyl or oxo group, where the heterocyclic ring system is a 5-9-member mono- or bicyclic ring system with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where heteroatoms can also be present as functional groups, where the heterocyclic ring system can contain one or two double bonds, and where the monocyclic heterocyclic ring can be condensed with a phenyl ring, R12 is selected from hydrogen, halogen, hydroxy, amino and C1-C4 alkoxy; R13 is a substituted phenyl, where the substitutes, which can be identical or different, include at least one group selected from a) hydrogen; b) nitro, amino; c) the saturated or unsaturated monocyclic heterocyclic ring system is optionally substituted with one or more groups selected from C1-C3 alkyl and oxo, where the heterocyclic ring system is a 5-member ring with one or more heteroatoms selected from a group consisting of nitrogen and sulphur, where the heteroatoms can also be present as functional groups. The present invention also relates to a pharmaceutical composition having dipeptidyl peptidase IV inhibiting activity, methods of obtaining the novel compound of formula I and use in treating type II diabetes and diabetic complications as well as for treating dyslipidaemia, hypercholesteremia, obesity and hyperglycaemia.

EFFECT: novel dipeptidyl peptidase IV inhibitors.

10 cl, 1 tbl, 43 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the chemistry of N,N-disubstituted nicotinamide-(Z)-O-methyloximes with the general formula I where if X denotes a methylene group, then R denotes phenyl, benzyl or 2-furyl, R' denotes methyl or n-chlorophenyl, if X denotes a carbonyl group, then R denotes styryl, n-chlorostyryl or benzyl, R' denotes methyl that is characterized by the fungicidal activity.

EFFECT: new compounds that can be efficient against maleficent fungi.

1 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to oxadiazolidinone compounds presented by following formula (I), or to their pharmaceutically acceptable salts, (symbols in the presented formula represent the following values, R1: -H, R0: lower alkyl, Rz: the same or different from each other, and each represents -H or lower alkyl, L: *-CH2-O- or *-CH2-NH-, where the symbol * in L represents binding with the ring A and a substitution position in the group L in the ring B represents the 4-position, the ring A: benzole, the ring B: benzole or pyridine, R2; the same or different respectively, and each represents -halogen or -R0, n: 0 or 1, R3: phenyl which can be substituted by a group selected from the group G3, The group G3: halogen, -R0, halogen-lower alkyl, -ORz, -CON(Rz)2, -CON(Rz)-heteroring group, -O-S(O)2-R0, -O-lower alkylene-ORz, -O-lower alkylene-O-COR2, -O-lower alkylene-N(RZ)2, -O-lower alkylene-N(Rz)CO-Rz, -O-lower alkylene-CO2Rz, -O-lower alkylene-CON(Rz)2, -O-lower alkylene-CON(Rz)-(lower alkyl substituted by the group-ORz), -O-lower alkylene-SR0, -O-lower alkylene-cycloalkyl, -O-lower alkylene-CON(Rz)-cycloalkyl, -O-lower alkylene-heteroring group and -O-lower alkylene-CON(Rz)-heteroring group, where lower alkylene in the group G3 can be substituted by halogen or -ORz, and cycloalkyl and the heteroring group in the group G3 can be substituted by the group selected by the group G1, The group G1: halogen, cyano, -R0, -ORz, -N(RZ)2, -S-R0, -SO2-R0, -SO2N(Rz)2, -CO-R2, -CON(Rz)2, -CON(Rz)-lower alkylene-OR2, -N(Rz)CO-Rz, oxo, -(lower alkylene which can be substituted by the group -ORz)-aryl, heteroring group and lower alkylene-heteroring group where aryl and the heteroring group in the group G1 can be substituted by the group selected from the following group G2, the group G2: halogen, cyano where the heteroring group means a group containing a ring selected from i) a monocyclic 5-7-members, saturated or unsaturated heteroring containing 1 to 3 heteroatoms selected from O, S and N, ii) a bicyclic heteroring in which the heterorings selected in i) mentioned above are ring-condensed where the condensed rings can be the same or different, and iii) the bicyclic heteroring in which the heteroring selected in i) mentioned above is condensed with a benzoic ring or 5-7-members cycloalkane, R4: -H. The invention refers to a pharmaceutical composition, to application of the compounds under cl.1, as well as to a method for preventing and/or treating diabetes.

EFFECT: making new biologically active compounds representing GPR40 agonist, an agent stimulating insulin secretion and/or an agent for preventing and/or treating diabetes.

9 cl, 27 ex, 138 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula or pharmaceutically acceptable salt thereof, synthesis methods thereof, pharmaceutical compositions containing said compounds, and use thereof to prepare a medicinal agent having mTOR kinase and/or PI3K kinase inhibiting action.

EFFECT: improved properties of the derivatives.

15 cl, 72 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel derivatives of diazepane of formula , where A, X, R3, R4, R5, R6, R8, R9, R10, R11, R12, R13, n and m have values, given in description and formula of invention, as well as their physiologically acceptable salts. Said compounds are antagonists of chemokine receptors CCR-2, CCR-5 and/or CCR-3 receptor and can be used in medicine as medications.

EFFECT: obtaining novel diazepane derivatives.

20 cl, 505 ex, 4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel organic compounds of formula where R1 denotes H; halogen; -C0-C7-alkyl-O-R3; -NR4R5; R2 denotes phenyl, substituted with one or two substitutes selected from a group consisting of C1-7alkyl, halogen-C1-7alkyl, C1-7alkoxy, halogen-C1-7alkoxy, phenoxy, halogen, C1-7alkylpiperazinyl-C1-7alkyl, C3-C8-cyclalkyl, C1-7alkylpiperidinyl-C1-7alkyl and C1-7alkylimidazolyl; R3 denotes H or phenyl-lower alkyl; R4 and R5 are independently selected from a group consisting of H; lower alkyl; lower alkoxy-carbonyl and amino; A, B and X are independently selected from C(R7) or N, provided that not more than one or A, B and X denotes N; R7 denotes H; R8 denotes hydrogen; n equals 0; Y denotes O; Z denotes C; W is absent; K denotes N or C, and either a) if K denotes C, the bond shown by a wavy line () is a double bond, Q is selected from O-N, S-N, O-CH and S-CH, where in each case, the left-hand O or S atom is bonded through a bond shown in formula I to K, the right-hand N or carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by the dotted line, is a double bond with C; and the bond shown by a thick line () is a single bond; or b) if K denotes N, the bond shown by a wavy line () is a single bond; Q denotes N=CH, where the left-hand N atom is bonded through a bond shown in formula I to K, the right-hand carbon (CH) atom is bonded to C through a bond shown by a dotted line () in formula I, provided that said bond, which is shown by a dotted line, is a single bond with C; and the bond shown by thick line () is a double bond; or salt thereof (preferably pharmaceutically acceptable salt). The invention also relates to a pharmaceutical composition, having inhibiting action on protein kinase, containing a compound of formula I or salt thereof in an effective amount and at least one pharmaceutically acceptable carrier material.

EFFECT: heterocyclic carboxamides as kinase inhibitors.

12 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

7FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a combination of a co-drug (an auxiliary) and a compound o formula (IV) in which radicals and symbols have the values defined in cl. 1 of the patent claim, or salts, or tautomers, or N-oxides, or solvates of this compound; where the specified auxiliary is specified from a monoclonal antibody, an alkylating agent, a malignant growth agent, other cycline-dependent kinase (CDK) inhibitor and a hormone, a hormone agonist, a hormone antagonist or a hormone-modulating agent specified in cl. 1 of the patent claim. The offered combination is used for tumour cell growth inhibition.

EFFECT: invention also refers to a pharmaceutical composition based on the offered combination, application of the combination and its separate ingredients and methods of treating, preventing and relieving the cancer symptoms in a patient.

77 cl, 2 dwg, 8 tbl, 257 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I), in which (i) R1 denotes C1-C6-alkyl or hydrogen; and R2 denotes hydrogen or a -R7, -Z-Y-R7, -Z-NR9R10, -Z-CO-NR9R10, -Z-NR9-C(O)O-R7 or -Z-C(O)-R7 group; and R3 denotes an undefined pair or C1-C6-alkyl; or (ii) R1 and R3 together with a nitrogen atom with which they are bonded form a 5-6-member heterocycloalkyl ring; and R2 denotes an undefined pair or a -R7 , -Z-Y-R7 group; or (iii) R1 and R2 together with a nitrogen atom with which they are bonded form a 6-member heterocycloalkyl ring, where said ring is substituted with a -Y-R7 group, and R3 denotes an undefined pair or C1-C6-alkyl; R4 and R5 are independently selected from a group consisting of phenyl, C3-C6-cycloalkyl; R6 denotes -OH, C1-C6-alkyl, C1-C6-alkoxy or a hydrogen atom; A denotes an oxygen or sulphur atom; X denotes a C1-C6-alkylene group; R7 denotes C1-C6-alkyl, phenyl, phenyl(C1-C6-alkyl)-, dihydrobenzofuran or pyridine, where any phenyl in group R7 can be optionally substituted with one or two groups independently selected from halogen, aminoacyl, C1-C6-alkoxycarbonyl, aminosulphonyl, C1-C6-alkyl, C1-C6-alkylamino-C1-C6-alkyl, -COOH; and any pyridine in group R7 can be optionaly substituted with C1-C6-alkyl; R8 denotes C1-C6-alkyl or a hydrogen atom; Z denotes a C1-C10-alkylene or C2-C10-alkenylene group; Y denotes a bond or an oxygen atom; R9 and R10 independently denote a hydrogen atom, C1-C6-alkyl group, isoxazole or 8-hydroxy-1H-quinolin-2-one-(C1-C6-hydroxyalkyl); and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition having activity with respect to M3 muscarinic receptor; use of the compounds of formula (I) to produce a medicinal agent for treating and a method of treating diseases or conditions in which M3 muscarinic receptor activity is involved.

EFFECT: compounds of given formula have activity with respect to M3 muscarinic receptor.

26 cl, 8 dwg, 91 ex

FIELD: chemistry.

SUBSTANCE: invention relates to tetrahydroquinoline derivatives of formula (I), where values of C3-C4, R2, R3, R4, R5, L1, L2, Y and X are given in claim 1, as muscarinic receptor agonists; compositions containing said compounds; methods of inhibiting muscarinic receptor activity using said compounds; methods of treating diseased conditions associated with the muscarinic receptor using said compounds, and methods of identifying a subject suitable for treatment using said compounds.

EFFECT: improved properties of compounds.

22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxadiazole derivatives of general formula , where X denotes CH, CH2, CH=CH, CH2CH2, CH2CH=CH or CH2CH2CH2, R1 denotes an unsubstituted or mono- or disubstituted phenyl or pyrrolyl residue or an unsubstituted or mono- or disubstituted phenyl connected through a C1-C3alkyl or a thienyl or indolyl residue, where the said substitutes are selected from a group comprising F, Cl, Br, OCF3, O-C1-C6alkyl or C1-C6alkyl, R2 denotes an unsubstituted or mono- or disubstituted phenyl or thienyl residue or an unsubstituted or mono- or disubstituted phenyl residue connected through a C1-C3alkyl, where the said substitutes are selected from a group comprising F, Cl, and R3 and R4 denote a saturated straight C1-C6alkyl in form of a racemate, diastereomers, mixture of enantiomers and/or diastereomers, or a specific diastereomer, bases and/or salts with physiologically compatible acids. The invention also relates to a method of producing said compounds and a medicinal agent based on said compounds and having affinity to the µ-opioid receptor.

EFFECT: obtaining novel compounds and a medicinal agent based on said compounds, which can be used in medicine to pain killing and for treating depression, enuresis, diarrhoea, skin itching, alcohol and drug abuse, drug induced addiction, aspontaneity or for anxiolyis.

11 cl, 2 tbl, 331 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted oxazole derivatives of general formula I. The disclosed compounds have affinity to the µ-opioid receptor. In general formula I

, n equals 0, 1 or 2, R1 denotes a phenyl residue bonded through a C1-C3alkyl chain, R2 denotes phenyl or thienyl, each of which is unsubstituted or mono-substituted with F or Cl, R3 and R4 independently denote a saturated, branched or straight C1-C6alkyl, phenyl or a phenyl residue bonded through a C1-C3akyl chain, or R3 and R4 together form an unsubstituted five-, six- or seven-member saturated ring which can optionally contain an extra heteroatom selected from a group comprising O or NR9, where R9 denotes phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which is unsubstituted or mono-substituted with a substitute selected from a group comprising F, Cl, Br, I and O-C1-C6alkyl, where the ring can be optionally condensed with a phenyl ring, R5 and R6 independently denote a saturated, branched or straight C1-C6alkyl, R7 and R8 independently denote a saturated, branched or straight unsubstituted C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, or R7 and R8 together form an unsubstituted or mono- or disubstituted five-, six- or seven-member saturated ring, where the substitutes are selected from a group comprising C1-C6alkyl or a phenyl residue bonded through a C1-C3alkyl chain, where the ring can optionally contain an extra heteroatom selected from a group comprising S, O and NR10, where R10 denotes a phenyl or a phenyl residue bonded through a C1-C3alkyl chain, any of which can be unsubstituted or mono-substituted with O-C1-C6alkyl. The invention also relates to methods of producing the disclosed compounds, a medicinal agent containing at least one substituted oxazole derivative of formula I, use of the compounds to prepare a medicinal agent.

EFFECT: improved properties.

13 cl, 1 tbl, 150 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I) or to their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity, and to a based pharmaceutical composition. (I) where P represents phenyl optionally substituted by 1 or 2 substitutes independently selected from halogen, C1-4alkyl, cyano, trifluoromethyl, C1-4alkoxy and trifluormethylthio, and R2 has the values specified in the patent claim.

EFFECT: preparation of new compounds of general formula (I) or their pharmaceutically acceptable salts exhibiting CCR2B antagonist activity.

16 cl, 340 ex

FIELD: medicine.

SUBSTANCE: there is described application of 1-hetaryl-2-nitro-2-(3-phenyl-1,2,4-oxadiazole-5-yl)ethanes of general formula I a-m 1a, e, and R1=NO2, R2=H; 1b, f, to R1=NO2, R2=Me; 1c, g, l R1=CO2Et, R2=H; 1d, h, m R1 =CO2Et, R2 =Me; 1a-d R2 =piperidino; 1e-h R3 =1-pyrrolidinyl, 1j-m R3=morpholino as psychotropic substances.

EFFECT: substances are low-toxic and have an evident psychotropic effect on rats.

4 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treating neurological conditions, more specifically for treating neurodegenerative conditions, such as Alzheimer's disease. In a compound of formula I R2 represents H or CH2NR1R4 where R1 and R4 are independently selected from H, unsubstituted C1-6alkyl, substituted or unsubstituted C3-6 cycloalkyl, R3 represents H; substituted or unsubstituted C1-4alkyl; substituted or unsubstituted C2-4alkenyl; substituted or unsubstituted 6-members aryl condensed or uncondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl, containing 1-2 nitrogen atoms in a cycle; substituted or unsubstituted saturated or unsaturated 5 or 6-members N-containing heterocycle which can additionally contain nitrogen, oxygen or the sulphur atom condensed or ucondensed with substituted or unsubstituted 6-members aryl or 5-6-members heteroaryl containing nitrogen in a cycle; (CH2)nR6 where n is an integer from 1 to 6, and the values of R6 and the values of other radicals are specified in the patent claim.

EFFECT: increased antiamyloidogenic action.

20 cl, 20 tbl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds which are methyl-3-azabicyclo[3.3.0]octane-7-carboxylate, N-methyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, N-propyl-3-azabicyclo[3.3.1]nonane-7-carboxamide, or pharmaceutically acceptable salts thereof. The invention also relates to compounds selected from a group, a pharmaceutical composition, methods of treating or preventing central nervous system disorders, as well as use of compounds in any of claims 1-4.

EFFECT: obtaining novel biologically active compounds having activity on neural nicotinic acetylcholine receptor.

11 cl, 14 ex, 7 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: present invention refers to the field of organic chemistry, notably to derivatives of dihydroimidazole with the general formula (I) and to its pharmaceutically acceptable salts where X1 and X2 denote halogen; R1 and R2 are chosen from the group including -H, -CH3, -CH2CH3 on the condition that both R1 and R2 do not denote hydrogen; R3 denotes -H or -C(=O)-R7; and if R6 denotes hydrogen, then R4 denotes -OCH3, -OCH2CH3 or -OCH(CH3)2; R5 denotes -H, - halogen, -CF3, -OCH3, -C(CH3)2, - cyclopropyl, - cyano group, -C(CH3)3, -C(CH3)2OR (where R denotes -H), -C(CH3)2CH-OR (where R denotes -CH3), -C(CH3)2CN, -C(CH3)2COR (where R denotes -CH3), -SR (where R denotes -CH2CH3) or -SO2R (where R denotes -CH3, -CH2CH3, 1-pyrrolidine, -NH-tert-butyl); and if R6 does not denote hydrogen, then R4 denotes -OCH2CH3; R5 denotes hydrogen, -Cl, -OCH3, tert butyl; R6 denotes -Cl, cyclopropyl, -SO2R (where R denotes -CH3, 1-pyrrolidine, -NH-tert-butyl or -N(CH3)2); and R7 is chosen from the group including i) -CH3, -CH(CH3)2, -CH2CH(CH3)2, cyclopropyl, cyclobutyl, -CH2CH2Ph, 2-furanyl, phenyl or phenyl substituted with chlorine, -OCH3 or cyano group, ii) 1-piperidinyl, iii) -NRc2 (where Rc denotes -CH2CH2OH, -CH2CH2OCH3 or -CH2CH(OH)CH2OH, iv) substituted piperazidine with the formula where R is chosen from the group including a) hydrogen, c) -CH(CH3)2, k) -CH2CH2Rd (where Rd denotes -OH, -OCH3, -CF3, -SO2CH3, -NH2, -NHCOCH3, -NHSO2CH3, 4-morfolinil, 2-izotiazolidinil-1, 1-dioxide), l) -CH2CH2CH2Re (where Re denotes -OCH3, -SO2CH3, -SO2CH2CH3, -CN), m) -CH2-CO-Rh (where Rh denotes -NH2, 1-pyrrolidinyl, 4-morfolinil), n) -SO2Ri (where Ri denotes -CH3, -CH2CH3), o) -CORj (where Rj denotes -CH3, 2-tetrahydrofuranyl, -NH2, -N(CH3)2), p) 4-tetrahydro-2H-thiopiranyl-1,1-dioxide, q) 4-piperidinyl-1-acetyl, r) 4-piperidinyl-1-dimethylcarboxamide, and s) 3-tetrahydrothiophenyl-1,1-dioxide; v) substituted oxopiperazine with the formula where R denotes -H; and vi) substituted piperidine with the formula where R denotes -CONH2, -OH, -CH2OH, -CH2CH2OH, 1-pyrrolidinyl, 1-piperidinyl, 1-(4-methylpiperazinyl) or 4-morfolinil. Moreover, the invention refers to the pharmaceutical composition based on the compound with the formula (I), to application of the formula (I) compound for production of a drug, to the production process of the formula (I) compound.

EFFECT: new derivatives of dihydroimidazole that may be used as anticancer drugs.

40 cl, 204 ex

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