New catechin derivative, pharmaceutical composition containing catechin derivative, using catechin derivative and using pharmaceutical composition

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention offers compounds presented by general formula (I): or their pharmaceutically acceptable salts wherein R1, R2, R3 and R4 are presented in the description and exhibit substantial COMT inhobotory activity. Besides, the present invention described pharmaceutical compositions inhibiting catechol-O-transferase activity which contain the compound or its pharmaceutically acceptable salt as an active ingredient, and a pharmaceutically acceptable carrier.

EFFECT: there are declared pharmaceutical combinations for treatment or prevention of Parkinson's disease which contain (1) the pharmaceutical composition containing the compound under any cl 1-8 or its pharmaceutically acceptable salt and the pharmaceutically acceptable carrier, and (2) at least one compound specified in L-dope or carbidole.

10 cl, 9 ex, 17 tbl

 

The technical field

The present invention relates to new derivatives of catechin, which exhibit inhibitory catechol-O-methyltransferase activity, containing their pharmaceutical compositions and to their use.

The level of technology

Parkinson's disease is a progressive neurodegenerative disease that usually affects elderly patients. The number of patients with Parkinson's disease a progressive growing aging society. Parkinson's disease is characterized by lesions in coordinated motor functions, such as tremor at rest, rigidity, akinesis, postural instability, etc. Believe that Parkinson's disease is the result of a deficiency of dopamine in the striatum, which causes the degeneration of dopamine neurons in the black substance. For these reasons, L-DOPA or stimulants of dopamine receptor is used to treat Parkinson's disease.

L-DOPA is a precursor of dopamine and is metabolized to dopamine, which shows its effectiveness in the brain. Since L-DOPA has a very short half-life in serum, L-DOPA is usually administered in combination with an inhibitor of peripheral decarboxylase of aromatic L-amino acids and/or inhibitor of catechol-O-methyltransferase, which inhibits the metabolism of L-DOPA in the body. Catego is-O-methyltransferase (hereinafter referred to as "AMT") is an enzyme which catalyzes the transfer of a methyl group of S-adenosyl-L-methionine to catechin substrate. Enzyme inhibition of COMT slows down the metabolism of L-DOPA to 3-O-methyl-L-DOPA, which leads to a significant increase in the half-life of L-DOPA in the serum and the number of L-DOPA, passing through the barrier the blood-(the brain). In this case, the inhibitor of COMT when introduced in combination with L-DOPA increases the bioavailability of L-DOPA and extends its activity (see non-patent literature reference 1).

Also inhibitors of COMT are expected to be useful in the treatment or prevention of hypertension, as inhibitors of COMT shown to stimulate secretion of urinary sodium activity (see non-patent literature reference 2). Inhibitors of COMT, as expected, should also be useful in the treatment or prevention of depression (see non-patent literature reference 3).

Recently introduced a number of inhibitors of COMT. Among them tolkapon (3,4-dihydroxy-4'-methyl-5-nitrobenzophenone, patent literature 1) and entacapone ((E)-2-cyano-N,N-diethyl-3-(3,4-dihydroxy-5-nitrophenyl)acrylamide, patent literature reference 2) are the most effective inhibitors of COMT known today. Tolkapon or entacapone clinically administered to patients for the treatment of Parkinson's disease. However, it was reported that tolkapon calls the t strong affection of the liver and can be used for patients with Parkinson's disease only when regular checks of liver function (see, non-patent literature reference 4). On the other hand, entacapone less effective than tolkapon, and has the problem of very limited duration of action (see, non-patent literature reference 5). Thus, there is still a need for new inhibitors of COMT with strong inhibitory of COMT activity and the desired security profile.

In patent literature 1 is disclosed 5-(3-methyl-1,2,4-oxadiazol-5-yl)-3-nitropyrimidin as derived [1,2,4]oxadiazole with inhibitory of COMT activity (see, example 75 in the patent reference 1). However, the position of the binding 1,2,4-oxadiazole rings nitrocatechol residue in the compounds of the patent reference 1 is different from the position of the bonding in the compounds of the present invention.

The list citation

Patent literature

1. Publication descriptions of pending applications at the European patent No. 237929.

2. Publication description pending application for British patent No. 2200109.

Non-patent literature

1. J.G. Nutt et al., "Lancet, 1998, vol.351, No.9111, p.1221-1222.

2. Eklof A.C. et al., "Kidney Int., 1997, vol.52, No.3, p.742-747.

3. Moreau J.L. et al., "Behav. Pharmacol.", 1994, vol.5, No.3, p.344-350.

4. Benabou R. et al., "Expert Opin. Drug Saf.", 2003, vol.2, No.3, p.263-267.

5. Forsberg M. et al., "J. Pharmacol. Exp. Ther.", 2003, vol.304, No.2, p.498-506.

6. Koga K. et al., "Eur. J. Pharmacol.", 2000, vol.408, p.249-255.

Description of the invention

The purpose of the present invention to provide new compounds with strong inhibitory of COMT activity and more preferably with the desired security profile.

Conducted thorough research to achieve the aforementioned purpose, and found that derivatives of catechin represented by the General formula (I)exhibit excellent inhibitory of COMT activity and have a high safety. Based on these discoveries made the present invention.

Thus, the present invention provides a compound represented by the General formula (I):

or its pharmaceutically acceptable salt,

where

R1and R2each independently from each other represent a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group, aralkylamines group or-C(O)NR11R12or R1and R2together with the formation of-C(O)- or lower alkalinous group;

R3represents:

a) halogen(lower)alkyl group;

b) a lower acyl group;

(C) halogen(lower)alkylcarboxylic group;

d) cycloalkylcarbonyl group;

e) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group, who with a halogen atom, lower alkyl group, halo(lower)alkyl group, a lower alkoxy group, cycloalkyl-(lower)alkoxy group, hydroxy group, lower alkoxycarbonyl group, -C(O)NR11R12and cyano group,

f) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halo(lower)alkyl group and a lower alkoxy group,

g) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halo(lower)alkyl group and a lower alkoxy group,

h) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halo(lower)alkyl group and a lower alkoxy group,

i) lower alkoxycarbonyl group,

j) cycloalkylcarbonyl group,

k) a lower alkoxy-(lower)alkoxycarbonyl group,

l) carboxy group,

m) cyano group,

n) -C(O)NR11R12,

o) -C(O)C(O)NR11R12,

R) lower alkylsulfonyl group,

) -SO 2NR11R12or

r) heteroaryl group, where the ring heteroaryl group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halo(lower)alkyl group and a lower alkoxy group;

R4represents:

a) a lower alkyl group,

b) halogen(lower)alkyl group,

C) cycloalkyl group,

d) geterotsyklicescoe group,

e) a lower alkoxy-(lower)alkyl group,

f) aryloxy-(lower)alkyl group,

g) lower alkoxycarbonyl-(lower)alkyl group, or

h) hydroxy(lower)alkyl group; and

R11and R12each independently from each other represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a bridged cyclic hydrocarbon group, phenyl group or aracelio group, or R11and R12together with the nitrogen atom to which they are attached, form a cyclic amino group.

In another aspect the present invention provides a pharmaceutical composition which contains as active ingredient a compound of General formula (I) or its pharmaceutically acceptable salt.

In another aspect the present invention provides an inhibitor of catechol-O-methyltransferase, which contains as active and is gradient, the compound of General formula (I) or its pharmaceutically acceptable salt.

In another aspect the present invention provides a pharmaceutical combination which contains a compound of General formula (I) or its pharmaceutically acceptable salt and at least a compound selected from L-DOPA or decarboxylase inhibitor of aromatic L-amino acids.

In another aspect the present invention provides therapeutic or prophylactic agent for Parkinson's disease, depression, or hypertension, which contains as active ingredient a compound of General formula (I) or its pharmaceutically acceptable salt.

In another aspect the present invention provides the use of compounds represented by the General formula (I)or its pharmaceutically acceptable salt for the manufacture of a medicinal product for the treatment or prevention of Parkinson's disease, depression or hypertension.

In another aspect the present invention provides a method of treatment or prophylaxis of Parkinson's disease, depression, or hypertension, which comprises introducing an effective amount of the compound represented by the General formula (I)or its pharmaceutically acceptable salt.

The present invention is described using the terms defined below, unless otherwise stated.

Defined the e "lower" in this case means remains with 1-6 carbon atoms, unless otherwise requested.

The term "halogen atom" refers to fluorine atom, chlorine, bromine or iodine.

The definition of "lower alkyl group" refers to linear or branched C1-6is an alkyl group such as methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina, tert-bucilina, pentilla, isopentyl, neopentyl, tert-pencilina, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropylene, hexeline, isohexyl group, etc. are Preferred lower alkyl groups for the substituents R4, R11and R12are1-4is an alkyl group and more preferably a methyl group.

The definition of "halo(lower)alkyl group" is a C1-6is an alkyl group substituted by the same or different 1 to 3 halogen atoms, such as permetrina, deformational, triptoreline, 2,2,2-triptorelin group and other, preferably deformational or triptorelin group.

The definition of "hydroxy(lower)alkyl group" refers to hydroxy-C1-6is an alkyl group, such as hydroxymethylene, 1-hydroxyethylene, 1-hydroxy-1,1-dimethylethylene, 2-hydroxyethylene, 2-hydroxy-2-methylpropyl, 3-hydroxiproline group and others

The definition of "lower alkoxy group" refers to linear or razvetvlenno is th 1-6-alkoxy group such as methoxy, ethoxy-, propoxy-, isopropoxy, butoxy, isobutoxy-, second -, butoxy-, tert-butoxy-, pentyloxy, hexyloxy group and others

The definition of "cycloalkyl group" refers to a 3-7-membered saturated cyclic hydrocarbon, such as cyclopropyl, cyclobutyl, cyclopentamine, tsiklogeksilnogo and cycloheptyl group.

The definition of "heterocytolysine group" refers to a 4-7-membered saturated heterocyclic group, which contains an-NH-, -O - or-S - as part of a ring and is linked via a carbon atom. Examples geterotsiklicheskikh groups are tetrahydropyridine, tetrahydrothiophene, tetrahydropyranyl, pyrrolidin-2-ilen, pyrrolidin-3-ilen, piperidine-2-ilen, piperidine-3-ilen, piperidine-4-ilen group and others

The definition of "bridged cyclic hydrocarbon group" refers to a 5-7-membered bridged saturated cyclic hydrocarbon containing 7-10 carbon atoms, such as bicyclo[2.2.1]heptane-2-ilen and adamantane-1-ilen group and others

The definition of "aryl group" refers to C6-10aromatic hydrocarbon group, such as phenyl, 1-naftalina and 2-naftalina group, preferably phenyl group.

The definition of "kalkilya group" refers to aryl-C1-6is an alkyl group, that is Oh how benzyl, penicilina, 1-phenylethylene, 3-phenylpropionate, 4-phenylbutyrate, naphthylmethyl group and others

The definition of "cycloalkyl-(lower)alkoxy group" refers to cycloalkyl-C1-6-alkoxy group, such as cyclopropylmethoxy, cyclopentyloxy, cyclohexyloxy group and others

The definition of "heteroaryl group" refers to 5 - or 6-membered monocyclic aromatic heterocycle containing 1-5 carbon atoms and 1-4 heteroatoms selected independently from the group comprising an oxygen atom, nitrogen and sulfur; or an 8-10-membered bicyclic aromatic heterocycle containing 1-9 carbon atoms and 1-4 heteroatoms selected independently from the group comprising an oxygen atom, nitrogen and sulphur, provided that the above heterocycles are not adjacent atoms of oxygen and/or sulfur. Examples of monocyclic heteroaryl groups are pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, tetrazolyl, thiazolyl, isothiazole, 1,2,3-thiadiazolyl, triazolyl, pyridyl, pyrazinyl, pyrimidyl and pyridazinyl, preferably pyridyl, triazolyl or 1,2,4-oxadiazolyl. Examples of bicyclic heteroaryl groups are indolyl, indazoles, benzofuranyl, benzothiazol, benzothiazolyl, hinely, ethanolic, phthalazine, benzimidazolyl, benzoxazolyl and other Heterocycles include seismometry provisions such as 2-pyridyl, 3-pyridyl or 4-pyridyl.

The definition of "(lower)alkoxy(lower)alkyl group" is a C1-6-alkoxy-C1-6is an alkyl group, such as methoxymethyl, 2-methoxyaniline, ethoxymethylene, 2-ethoxyethylene group and other, preferably methoxymethyl or 2-ethoxyethylene group.

The definition of "aryloxy-(lower)alkyl group" refers to aryloxy-C1-6is an alkyl group, such as proximately, 1-paroxetina, 2-paroxetina, 1-methyl-1-paroxetina, 3-phenoxypropionyl, naphthalocyanine group and others

The definition of "lower acyl group" refers to a (C1-6-alkyl)-CO-group, such as acetyl, propylaniline, Butyrina, isobutylene, bialoleka, valerina, isovaleryl group and others

The definition of "halogen(lower)alkylcarboxylic group" refers to (halogen-C1-6-alkyl)-C(O)-group, such as trifluoracetyl, trichloroethylene group and others

The definition of "cycloalkylcarbonyl group" refers to (cycloalkyl)-C(O)-group, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl group and others

The definition of "arylcarbamoyl group" refers to (aryl)-C(O)-group, such as benzoline group and others

Examples of "arylcarboxylic groups", where Ko is eco arylcarboxylic group is unsubstituted or substituted by 1-5 substituents, selected from the group comprising halogen atom, a lower alkyl group, halo(lower)alkyl group, a lower alkoxy group, cycloalkyl-(lower)alkoxy group, hydroxy group, lower alkoxycarbonyl group, -C(O)NR11R12and cyano group", in the case of R3are benzoline, 2-tormentilla, 3-tormentilla, 4-tormentilla, 2,4-diferentila, 4-chlorbenzoyl, 2-methylbenzoyl, 3-methylbenzoyl, 4-methylbenzoyl, 2-methoxybenzoyl, 3-methoxybenzoyl, 4-methoxybenzoyl, 4-hydroxybenzoyl, 4-cyanobenzoyl, 4-methoxycarbonylbenzyl, 4-ethoxycarbonylbutyl, 4-cyclopropylmethanol group and other, preferably benzoline, 2-tormentilla or 4-hydroxybenzoyl group, and more preferably benzoline group.

The definition of "heteroarylboronic group" refers to (heteroaryl)-(CO)-group, such as 2-shrinkability, 2-taylorsville, 2-oxazolidinyl, 2-thiazolyl-carbonyl, 5-isoxazolecarboxylic, 2-pyridylcarbonyl, 3-pyridylcarbonyl, 4-pyridylcarbonyl group and others

The definition of "analceleberty group" refers to (aralkyl)-C(O)-group, such as benzylcarbamoyl, 2-phenylethylenediamine group and others

The definition of "aryloxy-(lower)alkylcarboxylic group" refers to (ar is lexi-C 1-6-alkyl)-C(O)-group, such as phenoxymethylpenicillin group and others

The definition of "lower alkoxycarbonyl group" refers to a (C1-6-alkoxy)-C(O)-group, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, solutionline, second-butoxycarbonyl, tert-butoxycarbonyl, ventilatsiooniga, hexyloxyphenyl group and others

The definition of "cycloalkylcarbonyl group" refers to (cycloalkyl)-O-C(O)-group, such as cyclopentanecarbonyl, cyclohexyloxycarbonyl group and others

The definition of "(lower)alkoxy(lower)alkoxycarbonyl group" refers to a (C1-6-alkoxy-C1-6-alkoxy)-C(O)-group, such as 2-methoxyethoxymethyl, 2-ethoxyacetylene, 3-methoxypropionitrile group and others

The definition of "(lowest)alkoxycarbonyl-(lower)alkyl group" refers to a (C1-6-alkoxy)-C(O)-C1-6is an alkyl group, such as methoxycarbonylmethylene, ethoxycarbonylmethyl, 2-(etoxycarbonyl)ethyl group, etc.

The definition of "lower alkylsulfonyl group" refers to a (C1-6-alkyl)-SO2group, such as methanesulfonyl, acanaloniidae, propanesulfonyl, butanesulfonyl, pentanesulfonate, hexanes lifornia group and others, preferably methanesulfonyl group.

The definition of "cyclic amino group" refers to a 5-7 membered saturated cyclic amine which may contain-NH-, -O - or-S - in as element of the ring. Examples of cyclic amino groups are 1-pyrrolidine, piperidine, piperazine derivatives, morpholino - thiomorpholine group. Cyclic amino group optionally may be substituted by one or two alkyl groups.

The definition of "lower Allenova group" refers to divalent saturated With1-6is a hydrocarbon chain that may be linear or branched. Examples of the lower alkilinity groups are-CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)CH2-, -CH2CH(CH3)-, -C(CH3)2and other, preferably CH(CH3)- or-C(CH3)2-.

In the case where the compound represented by the General formula (I)contains one or more asymmetric carbon atoms, then all stereoisomers in the R - or S-configuration at each asymmetric carbon atom, and mixtures thereof refers within the scope of the present invention. In such cases, racemic compounds, racemic mixtures, individual enantiomers and mixtures of diastereomers also implied within the scope of the present invention.

In the case where a connection pre is submitted to the General formula (I), exists in the form of one or more geometric isomers, all geometric isomers also implied within the scope of the present invention.

In the case where the compound represented by the General formula (I), exists in the form of one or more atropisomers, all atropisomers also considered within the scope of the present invention.

The connection represented by the General formula (I)may form a MES with a pharmaceutically acceptable solvent, such as water, ethanol, etc.

Compounds represented by the General formula (I)can exist in the form of salts. Examples of such salts are acid additive salts formed with mineral acids such as hydrochloric acid, Hydrobromic acid, uudistoodetena acid, sulfuric acid, nitric acid, phosphoric acid, etc.; acid additive salts formed with organic acids such as formic acid, acetic acid, triperoxonane acid, methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid is one and so on; basic salts formed with inorganic bases, such as lithium, sodium, potassium, calcium, magnesium, etc.; basic salts formed with organic bases such as triethylamine, piperidine, morpholine, lysine, etc.

In one of the embodiments of the compounds represented by the General formula (I)of the present invention

preferably R1and R2each independently from each other represent a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group or C(O)NR11R12or R1and R2together with the formation of-C(O) -, and more preferably R1and R2represent a hydrogen atom;

R3preferably represents:

a) halogen(lower)alkyl group;

b) a lower acyl group;

(C) halogen(lower)alkylcarboxylic group;

d) cycloalkylcarbonyl group;

e) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

f) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted or substituted by 1-3 substituents selected from the group comprising an atom of GoLoG is on, lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

g) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

h) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

i) lower alkoxycarbonyl group,

j) cycloalkylcarbonyl group,

k) a lower alkoxy-(lower)alkoxycarbonyl group,

l) carboxy group,

m) cyano group,

n) -C(O)NR11R12,

o) -C(O)C(O)NR11R12,

R) lower alkylsulfonyl group,

q) -SO2NR11R12or

r) heteroaryl group, where the ring heteroaryl group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group;

more preferably R3represents:

a) a lower acyl group;

b) halogen(NISS the Yu)alkylcarboxylic group;

c) cycloalkylcarbonyl group;

d) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

e) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

f) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

g) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

h) lower alkoxycarbonyl group,

i) cycloalkylcarbonyl group,

(j) a lower alkoxy-(lower)alkoxycarbonyl group,

k) -C(O)C(O)NR11R12or

l) lower alkylsulfonyl the ing group,

even more preferably R3represents:

a) a lower acyl group;

b) cycloalkylcarbonyl group;

C) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

d) lower alkoxycarbonyl group,

e) cycloalkylcarbonyl group,

f) a lower alkoxy-(lower)alkoxycarbonyl group or

g) -C(O)C(O)NR11R12and

particularly preferably, R3represents:

a) a lower acyl group;

b) cycloalkylcarbonyl group;

C) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

d) lower alkoxycarbonyl group or

e) -C(O)C(O)NR11R12;

R4preferably represents:

a) a lower alkyl group,

b) halogen(lower)alkyl group,

C) cycloalkyl group,

d) geterotsyklicescoe group,

e) a lower alkoxy-(lower)alkyl group,

f) aryloxy-(lower)alkyl group, or

g) Nissho alkoxycarbonyl-(lower)alkyl group, and

more preferably R4represents:

a) a lower alkyl group,

b) cycloalkyl group,

c) a lower alkoxy-(lower)alkyl group, or

d) lower alkoxycarbonyl-(lower)alkyl group, or

preferably R11and R12each independently from each other represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a bridged cyclic hydrocarbon group, or phenyl group.

In a preferred embodiment of the present invention

R1and R2each independently from each other represents a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group or-C(O)NR11R12or R1and R2together with the formation of-C(O)-;

R3represents:

a) halogen(lower)alkyl group;

b) a lower acyl group;

(C) halogen(lower)alkylcarboxylic group;

d) cycloalkylcarbonyl group;

e) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

f) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted Elizabeta 1-3 substituents, selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

g) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

h) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

i) lower alkoxycarbonyl group,

j) cycloalkylcarbonyl group,

k) a lower alkoxy-(lower)alkoxycarbonyl group,

l) carboxy group,

m) cyano group,

n) -C(O)NR11R12,

o) -C(O)C(O)NR11R12,

R) lower alkylsulfonyl group,

q) -SO2NR11R12or

r) heteroaryl group, where the ring heteroaryl group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group;

R4represents:

a) lower alkyl, y is the UPP,

b) halogen(lower)alkyl group,

C) cycloalkyl group,

d) geterotsyklicescoe group,

e) a lower alkoxy-(lower)alkyl group,

f) aryloxy-(lower)alkyl group, or

g) lower alkoxycarbonyl-(lower)alkyl group, and

R11and R12each independently from each other represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a bridged cyclic hydrocarbon group, phenyl group or aracelio group, or R11and R12together with the nitrogen atom to which they are attached, form a cyclic amino group.

In a more preferred embodiment of the present invention

R1and R2represent a hydrogen atom,

R3represents:

a) halogen(lower)alkyl group;

b) a lower acyl group;

(C) halogen(lower)alkylcarboxylic group;

d) cycloalkylcarbonyl group;

e) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

f) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted or substituted by 1-3 substituents, vibrancies group, includes halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

g) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

h) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

i) lower alkoxycarbonyl group,

j) cycloalkylcarbonyl group,

k) a lower alkoxy-(lower)alkoxycarbonyl group,

l) carboxy group,

m) cyano group,

n) -C(O)NR11R12,

o) -C(O)C(O)NR11R12,

R) lower alkylsulfonyl group,

q) -SO2NR11R12or

r) heteroaryl group, where the ring heteroaryl group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group;

R4represents:

a) a lower alkyl group,

b) halogen(issuu)alkyl group,

C) cycloalkyl group,

d) geterotsyklicescoe group,

e) a lower alkoxy-(lower)alkyl group,

f) aryloxy-(lower)alkyl group, or

g) lower alkoxycarbonyl-(lower)alkyl group, and

R11and R12each independently from each other represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a bridged cyclic hydrocarbon group, phenyl group or aracelio group, or R11and R12together with the nitrogen atom to which they are attached, form a cyclic amino group.

In an even more preferred embodiment of the present invention

R1and R2represent a hydrogen atom,

R3represents:

a) a lower acyl group;

b) halogen(lower)alkylcarboxylic group;

c) cycloalkylcarbonyl group;

d) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

e) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(nissu is)alkyl group and a lower alkoxy group,

f) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

g) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

h) lower alkoxycarbonyl group,

i) cycloalkylcarbonyl group,

(j) a lower alkoxy-(lower)alkoxycarbonyl group,

k) -C(O)C(O)NR11R12or

l) a heteroaryl group, where the ring heteroaryl group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group;

R4represents:

a) a lower alkyl group,

b) halogen(lower)alkyl group,

C) cycloalkyl group,

d) geterotsyklicescoe group,

e) a lower alkoxy-(lower)alkyl group,

f) aryloxy-(lower)alkyl group, or

g) lower alkoxycarbonyl-(lower)alkyl group, and

R11and R1 each independently from each other represents a hydrogen atom, a lower alkyl group, cycloalkyl group, a bridged cyclic hydrocarbon group, phenyl group or aracelio group, or R11and R12together with the nitrogen atom to which they are attached, form a cyclic amino group.

In another even more preferred embodiment of the present invention

R1and R2represent a hydrogen atom,

R3represents:

a) a lower acyl group;

b) halogen(lower)alkylcarboxylic group;

c) cycloalkylcarbonyl group;

d) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

e) heteroarylboronic group, where the ring heteroarylboronic group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

f) aralkylamines group, where the ring aralkylamines group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower al the ilen group, halogen(lower)alkyl group and a lower alkoxy group,

g) aryloxy-(lower)alkylcarboxylic group, where the ring of aryloxy-(lower)alkylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

h) lower alkoxycarbonyl group,

i) cycloalkylcarbonyl group,

(j) a lower alkoxy-(lower)alkoxycarbonyl group,

k) -C(O)C(O)NR11R12or

l) a heteroaryl group, where the ring heteroaryl group is unsubstituted or substituted by 1-3 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group and

R4represents:

a) a lower alkyl group,

b) cycloalkyl group,

C) a lower alkoxy-(lower)alkyl group, or

d) lower alkoxycarbonyl-(lower)alkyl group.

In another even more preferred embodiment of the present invention

R1and R2represent a hydrogen atom,

R3represents:

a) a lower acyl group;

b) cycloalkylcarbonyl group;

C) arylcarbamoyl group, where the ring arylcarboxylic group is asamese the major or substituted by 1-5 substituents, selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

d) lower alkoxycarbonyl group,

e) cycloalkylcarbonyl group,

f) a lower alkoxy-(lower)alkoxycarbonyl group or

g) -C(O)C(O)NR11R12and

R4represents:

a) a lower alkyl group,

b) cycloalkyl group,

C) a lower alkoxy-(lower)alkyl group, or

d) lower alkoxycarbonyl-(lower)alkyl group.

In a particularly preferred embodiment of the present invention

R1and R2represent a hydrogen atom,

R3represents:

a) a lower acyl group;

b) cycloalkylcarbonyl group;

C) arylcarbamoyl group, where the ring arylcarboxylic group is unsubstituted or substituted by 1-5 substituents selected from the group comprising halogen atom, a lower alkyl group, halogen-(lower)alkyl group and a lower alkoxy group,

d) lower alkoxycarbonyl group or

e) -C(O)C(O)NR11R12and

R4represents:

a) a lower alkyl group,

b) cycloalkyl group,

C) a lower alkoxy-(lower)alkyl group, or

d) lower alkoxycarbonyl-(lower)alkyl group.

Specific examples of the preferred embodiments of the present invention are compounds selected from the group including:

[3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone;

1-[3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]Etalon;

methyl-3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrobenzoate;

N-cyclohexyl-2-[3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]-2-oxoacetate;

N-cyclohexyl-2-[3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]-N-methyl-2-oxoacetate;

1-{6-[5-(2-ethoxyethyl)-[1,2,4]oxadiazol-3-yl]-3,4-dihydroxy-2-nitrophenyl}Etalon; and

cyclohexyl-[3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]metano.

Compounds represented by the General formula (I)can be obtained by methods illustrated in schemes 1-5.

where R3and R4have the above specified values, R10represents a lower acyl, or lower alkoxy-carbonyl group or-CONR11R12and Bn represents a benzyl group.

Stage 1-1

The acylation amidoxime (X) allermuir reagent in the presence of a base in an inert solvent or in solvent-based network arylamidine derivative (XI). Allerease reagents used in the reaction of acylation are allalone, acid anhydride, mixed acid anhydride, benzotriazol-1 silt ether, 4-frienly ether, 2,5-dioxopyrimidine ether or other Bases include triethylamine, pyridine, N,N-diisopropylethylamine or other Inert solvents are tetrahydrofuran, methylene chloride or other acylation Reaction is conducted usually at a temperature from -20°C to the boiling temperature under reflux. The reaction time varies depending on the starting material, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 24 hours.

On the other hand, arylamidine derivative (XI) can be obtained by condensation amidoxime (X) with a carboxylic acid in the presence of a condensing reagent such as dicyclohexylcarbodiimide, the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, achilleifolia, diphenylphosphoryl or other condensation Reaction is usually carried out at temperatures from -20°C to the boiling temperature under reflux. The reaction time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 24 hours.

Stage 1-2

Cyclization allmedexchange derivative (XI) in the presence of a base, such as pyridine, tetrabutylammonium-fluoride or other inert solvent such as tetrahydrofuran or other, gives the derivative of oxadiazole (XII). The reaction is usually carried out at temperature the round from 0 to 120°C. The reaction time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 12 hours.

On the other hand, the derived oxadiazole (XII) can be obtained by cyclization of allmedexchange derivative (XI) in the base, such as pyridine or other Cyclization is usually carried out at temperatures from 20°C to the boiling temperature under reflux. The reaction time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 24 hours.

Stage 1-3

Benzyl group derived oxadiazole (XII) is removed in the presence of a metal catalyst such as palladium on charcoal, palladium oxide or other, in an atmosphere of hydrogen in an inert solvent, such as ethanol, N,N-dimethylformamide, tetrahydrofuran or other, to obtain the derivative of phenol (XIII). The reaction is usually carried out at a temperature from room temperature to 80°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 30 minutes to 12 hours.

On the other hand, the reaction of dibenzylamine may be performed by processing the derived oxadiazole (XII) with an acid or a Lewis acid such as hydrogen bromide, chlorine is the ID of aluminum, the titanium tetrachloride or other, in an inert solvent such as methylene chloride, toluene or other Reaction is usually carried out at temperatures from 0 to 80°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 24 hours.

Stage 1-4

Nitration derived phenol (XIII) nitrous reagent in an inert solvent gives NITROPHENOL derivative (XIV). Used in a reaction inert solvents are methylene chloride, 1,2-dichloroethane, ethyl acetate, acetic acid, tetrahydrofuran, acetic anhydride or other Mitrowski agents are nitric acid, fuming nitric acid, detroitmetroairport or other Reaction is usually carried out at temperatures from -40 to 80°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 5 minutes to 12 hours. The nitration reaction can also be carried out, if desired, by introducing additives, such sulfuric acid or other

Stage 1-5

Demethylation nitrophenols derivative (XIV) using demetrious reagent in an inert solvent gives compound (Ia). Inert solvents used in the reaction include ethyl acetate, pyridine, 1,4-dioxane or other Demetrious eagency include system (chloride alumni)-pyridine, tribromide boron or other Reaction is usually carried out at temperatures from -20 to 120°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but is usually from 1 to 24 hours.

On the other hand, demethylation can be carried out by processing the derived NITROPHENOL (XIV) Hydrobromic acid or itestosterone acid in acetic acid as solvent. The reaction is usually carried out at temperatures from 20°C to the boiling temperature under reflux. The reaction time varies depending on starting materials, the reaction temperature or other, but is usually from 1 to 24 hours.

Stage 1-6

The acylation of the compound (Ia) allermuir reagent gives compound (Ib). Such acylation reaction is well known to the ordinary person skilled in the art and can be carried out in accordance with the techniques described in the publication by T.W. Green, P.G.H. Wuts, "Protective Groups in Organic Synthesis", 4-th edition.

where R4and Bn take the above specified values, R20represents aryl, lower alkyl, halogen-(lower)alkyl, cycloalkyl, heteroaryl or aralkyl and X represents a chlorine, bromine or-N(CH3)OCH3.

Stage 2-1

Iodination derived aldehyde (XV) with the help of Jodi the respective reagent, such as iodine, N-jodatime or monochloride iodine in an inert solvent such as methylene chloride, methanol, acetic acid or other, gives identilied (XVI). The reaction is usually carried out at temperatures from 20°C to the boiling temperature under reflux. The reaction time varies depending on starting materials, the reaction temperature or the other, but usually ranges from 15 minutes to 24 hours.

Iodination can be carried out, if desired, by introducing additives, such as triperoxonane acid, triptorelin silver or other

Stage 2-2

Oxymorphine of identilied (XVI) with hydroxylamine in an inert solvent, such as ethanol, N,N-dimethylformamide, tetrahydrofuran or other, gives oxime derivative (XVII). The reaction is usually carried out at temperatures from 20°C to the boiling temperature under reflux. The reaction time varies depending on starting materials, the reaction temperature or the other, but usually ranges from 15 minutes to 24 hours. The reaction can also be carried out, if desired, by introducing additives, such as sodium acetate, sodium hydroxide or other

Stage 2-3

Chlorination Aksenovo derivative (XVII) using glorieuses reagent, such as N-chlorosuccinimide, in an inert solvent, such as N,N-Dimethylol the amide, tetrahydrofuran or other, gives N-hydroxybenzonitrile. The reaction is usually carried out at temperatures from 0 to 80°C. the reaction Time varies depending on starting materials, the reaction temperature or other, but is usually from 5 minutes to 24 hours.

The derived N-hydroxybenzomorpholine process aminimum reagent, such as aqueous ammonia or other, in an inert solvent, such as N,N-dimethylformamide, tetrahydrofuran or other, get amidoxime derivative (XVIII). The reaction is usually carried out at a temperature of from 0 to 30°C. the reaction Time varies depending on starting materials, the reaction temperature or the other, but usually ranges from 15 minutes to 24 hours.

Stage 2-4

The acylation amidoxime derivative (XVIII) in accordance with the techniques described in stage 1-1, gives arylamidine derivative (XIX).

Stage 2-5

Cyclization allmedexchange derivative (XIX) in accordance with the techniques described in stage 1-2, gives the derivative of oxadiazole (XX).

Stage 2-6

Derived oxadiazole (XX) is treated with an organic magnesium reagent in an inert solvent, followed by reaction with aldehyde (XXI) with a derivative of benzyl alcohol (XXII). Inert solvents used in the reaction are tetrahydrofuran or the R. Organic magnesium reagents are isopropylaniline or other Reaction is usually carried out at temperatures from -78 to 10°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 2 hours.

Stage 2-7

Derived oxadiazole (XX) is treated with an organic magnesium reagent in an inert solvent, followed by reaction with N,N-dimethylformamide (DMF), get the derived aldehyde (XXIII). Inert solvents used in the reaction are tetrahydrofuran or other Organic magnesium reagents are isopropylaniline or other Reaction is usually carried out at temperatures from -78 to 10°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 2 hours.

Stage 2-8

The derived aldehyde (XXIII) is treated with an organic magnesium reagent (XXIV) or an organic lithium reagent (XXV) in an inert solvent, such as tetrahydrofuran or other, get a derivative of benzyl alcohol (XXII). The reaction is usually carried out at temperatures from -78 to 10°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually the leaves from 15 minutes to 2 hours.

Stage 2-9

Derived oxadiazole (XX) is treated with an organic magnesium reagent in an inert solvent, followed by reaction with the anhydride of the acid (XXVI), galogenangidridy acid or N-methoxy-N-methylamide (XXVII)are derived ketone (XXVIII). Inert solvents used in the reaction are tetrahydrofuran or other Organic magnesium reagents are isopropylaniline or other Reaction is usually carried out at temperatures from -78 to 50°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 2 hours.

Stage 2-10

Oxidation derivative of benzyl alcohol (XXII) with an oxidizing agent in a suitable solvent gives the derivative of the ketone (XXVIII). Solvents used in the reaction are methylene chloride, acetonitrile or other Oxidizing agents are dioxide, magnesium system (sulfur trioxide)-(pyridine complex)-sulfoxide, 4-methylmorpholin-N-oxide or other Reaction is usually carried out at a temperature of from 0 to 30°C. the reaction Time varies depending on starting materials, solvent, oxidizing agent, the reaction temperature or the other, but usually ranges from 15 minutes to 3 days.

Then the compound (Ic) can be obtained from the manufacturer is one of the ketone (XXVIII) in accordance with the methods described in stages from 1-3 to 1-5.

where R4, R11, R12and Bn take the above specified values, R30represents lower alkyl, cycloalkyl or (lower)alkoxy(lower)alkyl.

Stage 3-1

Condensation of compound (XX) with alcohol (XXIX) in the atmosphere of carbon monoxide in the presence of a base, a palladium catalyst and a phosphine ligand in an inert solvent gives the ester derivative (XXX). Inert solvents used in the reaction are N,N-dimethylformamide, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, toluene or other Bases are triethylamine, N,N-diisopropylethylamine or other Palladievye catalysts are Tris(dibenzylideneacetone)dipalladium(0), palladium acetate or other Phosphine ligands are 1,1'-bis(diphenylphosphino)ferrocene, triphenylphosphine or other Reaction is usually carried out at a temperature of from 80 to 110°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but usually from 1 to 24 hours.

Stage 3-2

Oxidation of the derived aldehyde (XXIII) with an oxidizing agent in an inert solvent gives the carboxylic acid derivative (XXXII). Solvents used in the reaction are methylene chloride, azet the nitrile, water, methanol or other oxidizing agents are potassium permanganate, manganese dioxide, the system (sodium chlorite)-(hydroperoxide), system (sodium chlorite)-sulfoxide or other Reaction is usually carried out at temperatures from 0 to 80°C. the reaction Time varies depending on starting materials, solvent, oxidizing agent, the reaction temperature or the other, but usually ranges from 15 minutes to 3 days. The reaction, if desired, can be carried out with the introduction of additives, such as sodium phosphate, sulfuric acid or other

Stage 3-3

Carboxylic acid derivative (XXXII) is treated with alkylhalogenide (XXXI) in the presence of a base in an inert solvent, receive ester derivative (XXX). Inert solvents used in the reaction, are 1,4-dioxane, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran or other Grounds are tert-piperonyl sodium tert-piperonyl potassium, potassium carbonate or other Reaction is usually carried out at temperatures from 0 to 100°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but is usually from 5 minutes to 24 hours.

Ester derivative (XXX) can be obtained by condensation of the carboxylic acid derivative (XXXII) with alcohol (XXIX) in the presence of condensing the th agent, such as dicyclohexylcarbodiimide, the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diethylthiophosphate, diphenylphosphinite or other, in an inert solvent such as methylene chloride, N,N-dimethylformamide or other Reaction can be carried out, if desired, by introducing a base, such as triethylamine or other

Stage 3-4

Carboxylic acid derivative (XXXII) is treated with amine (XXXIII) in the presence of a condensing agent, such as dicyclohexylcarbodiimide, the hydrochloride of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, diethylthiophosphate, diphenylphosphinite or other, in an inert solvent such as methylene chloride, N,N-dimethylformamide, tetrahydrofuran or other, get amide derivative (XXXIV). The reaction is carried out usually at a temperature from -20°C to the boiling temperature under reflux. The reaction time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 15 minutes to 24 hours. The reaction can be carried out, if desired, by introducing additives such as triethylamine or other

Then the compound (Id) can be obtained from compound (XXX) in accordance with the techniques described in the stages from 1-3 to 1-5. The compound (Ie) can be obtained from compound (XXXIV) in accordance with the techniques described nastavak from 1-3 to 1-5.

where R4, R11, R12, R30and Bn take the above specified values.

Stage 4-1

Condensation of compound (XX) with triisopropylsilane (XXXV) in the presence of a base, a palladium catalyst and a phosphine ligand in an inert solvent gives triisopropyl-soilfertility (XXXVI). Inert solvents used in the reaction are toluene, N,N-dimethylformamide, 1,4-dioxane, 1,2-dimethoxyethane or other Grounds are hexamethyldisilazide sodium, hexamethyldisilazide lithium, tert-piperonyl potassium or other Palladium catalysts are Tris(dibenzylideneacetone)dipalladium(0), tetrakis(triphenylphosphine)palladium(0), palladium acetate or other Phosphine ligands are (hydroxy-di-2,1-phenylene)bis(diphenylphosphine) or other Reaction is usually carried out at a temperature of from 60 to 110°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but is usually from 1 to 24 hours.

Stage 4-2

Triisopropylsilyl group derived triisopropylsilyl of tiefer (XXXVI) is transformed into the corresponding alkyl group (R30) treatment alkylhalogenide (XXXI) in the presence of a base such as cesium fluoride, tetrabutylammonium or other, in inert the second solvent, such as 1,4-dioxane, N,N-dimethylformamide, 1,2-dimethoxyethane, tetrahydrofuran or other, get derived alkylenediamine. The reaction is usually carried out at temperatures from 0 to 100°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but is usually from 5 minutes to 24 hours.

Oxidation derived alkylenediamine using an oxidizing agent in a suitable solvent gives a sulfonic derivative (XXXVII). The solvents used in the reaction include methylene chloride, acetone, acetic acid, water or other Oxidizing agents are m-chlorbenzene acid, Oxon (oxone, registered trademark), a solution of the hydroperoxide, perborate sodium or other Reaction is usually carried out at temperatures from 0 to 80°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but is usually from 5 minutes to 24 hours.

Stage 4-3

Triisopropylchlorosilane derivative (XXXVI) is treated with sulfurylchloride in the presence of nitrate, such as potassium nitrate, sodium nitrate, silver nitrate or other, in an inert solvent, such as acetonitrile, N,N-dimethylformamide or other, get sulphonylchloride derived. The reaction is usually carried out at temperatures from 0 to 40°C. the reaction Time m is applied depending on the starting materials, solvent, reaction temperature or the other, but usually ranges from 5 minutes to 5 hours.

Condensation sulphonylchloride derivative with the amine (XXXIII) in the presence of a base, such as triethylamine, N,N-diisopropylethylamine or other, in an inert solvent, such as tetrahydrofuran, N,N-dimethylformamide, ethyl acetate, methylene chloride or other, gives sulfonamidnuyu derivative (XXXVIII). The reaction is usually carried out at temperatures from 0 to 40°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or the other, but usually ranges from 5 minutes to 5 hours.

Then the compound (If) can be obtained from compound (XXXVII) in accordance with the techniques described in the stages from 1-3 to 1-5. The compound (Ig) can be obtained from compound (XXXVIII) in accordance with the techniques described in the stages from 1-3 to 1-5.

where R4, R11, R12and Bn take the above specified values, and R31represents a lower alkyl or cycloalkyl.

Stage 5-1

The condensation of the aldehyde derivative (XXIII) with isocyanides (XXXIX) in the presence of acetic acid in an inert solvent, such as acetonitrile, methylene chloride, diethyl ether or other, gives ester derivative (XL). The reaction is usually carried out at a temperature of from 20 to 100°C. the reaction Time of a man who is depending on raw materials, solvent, reaction temperature or other, but is usually from 5 minutes to 24 hours. The reaction can also be carried out with the introduction of additives, such as titanium tetrachloride or other

Stage 5-2

Hydrolysis of the ester derivative (XL) in the presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide or other, in an inert solvent, such as tetrahydrofuran, methanol, ethanol, water or other, gives the derivative of the alcohol (XLI). The reaction is usually carried out at a temperature of from 20 to 100°C. the reaction Time varies depending on starting materials, solvent, reaction temperature or other, but is usually from 5 minutes to 24 hours.

Stage 5-3

Oxidation of the alcohol derivative (XLI) in accordance with the techniques described in stage 2-10, gives the derivative of the ketone (XLII).

Then the compound (Ih) can be obtained from compound (XLII) in accordance with the techniques described in the stages from 1-3 to 1-5.

The above diagrams give examples of preparing compounds represented by the General formula (I)of the present invention and intermediates for their synthesis. Specialists in the art will understand that various changes or modifications of the above schemes can be made without deviation from the scope of the present invention.

Connection, before the purposes of the General formula (I), the present invention and intermediate compounds for preparing compounds of the present invention can be isolated or purified, if required, in accordance with conventional methods for the extraction or purification, which are well known to specialists in this field, such as by solvent extraction, crystallization, recrystallization, chromatography, preparative high performance liquid chromatography or other

Compounds of General formula (I) exhibit excellent inhibitory of COMT activity and can be used as a therapeutic or prophylactic agent for Parkinson's disease. Compounds of General formula (I) preferably used in combination with L-DOPA. Compounds of General formula (I) can be used with L-DOPA and a decarboxylase inhibitor of aromatic L-amino acids. Examples of inhibitors decarboxylase of aromatic L-amino acid, which can be used in combination with inhibitors of COMT of the present invention are carbidopa, benserazida or other

Inhibitors of COMT of the present invention can be used, if required, in combination with protivookisliteljami drugs other than L-DOPA. Such ANTIPARKINSONISM drugs are droxidopa, melliodora, treetops (threodops); agonists of the receptor dopamine D2that is their as cabergoline, bromocriptine, terguride, talibancontrolled, ropinirolee, Pergolesi, pramipexole, rotigotine and others; anticholinergics such as propanamine, trihexyphenidyl.html, mysticalgroove, biperiden, miragedigital.net, meixensberger and others; receptor antagonists of the adenosine A2Asuch as istradefylline and others; NMDA antagonists, such as BODIPY and others; monoamine oxidase inhibitors, such as selegilinecitalopram, rasagiline, safinamide and others; zonisamide; mantadigital and other

Compounds of the present invention can be used as a therapeutic or prophylactic agent for depression. Compounds of the present invention can be used as a therapeutic agent for hypertension, because the compounds of the present invention are active, stimulating secretion of urinary sodium.

Pharmaceutical compositions containing a compound of General formula (I) or its pharmaceutically acceptable salt, can be introduced in various dosage forms depending on their purpose. Examples of dosage forms include powders, granules, fine granules, dry syrups, tablets, capsules, injections, liquids, ointments, candles, lotions, etc. that BB is out of oral or parenteral.

The pharmaceutical compositions can be obtained by mixing, diluting or dissolving with appropriate pharmaceutical carriers, such as fillers, dispersing agents, binders, lubricants, diluents, buffers, isotonic agents, preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents, solubilizing agents and others, in accordance with usual practice, preparation, depending on their dosage forms.

The dosage of the compounds represented by the General formula (I)or its pharmaceutically acceptable salt appropriately determined depending on age, gender or body mass of the individual patient, the severity of the disease, condition that is being treated, etc. Typical dosage for oral administration is in the range from about 10 to 3000 mg per day for an adult. Typical dosage for parenteral administration is in the range from about 5 mg to 1000 mg per day for an adult. The dosage can be entered in a single dose or divided doses, for example, from one to seven times a day.

The pharmaceutical composition containing the compound represented by the General formula (I)or the pharmaceutically priemlemaya, and at least one compound selected from L-DOPA and decarboxylase inhibitor of aromatic L-amino acid can be introduced in a single pharmaceutical composition containing all of the active ingredients, or in the form of a separately prepared in pharmaceutical compositions, each of which contains one active ingredient. When using a separately prepared pharmaceutical compositions compositions can be introduced separately, simultaneously or at different intervals. On the other hand, when using a separately prepared pharmaceutical compositions compositions can be mixed together with the appropriate diluent and entered at the same time.

In the pharmaceutical composition containing the compound represented by the General formula (I)or its pharmaceutically acceptable salt, and at least one compound selected from L-DOPA and decarboxylase inhibitor of aromatic L-amino acid, the dosage of each active ingredient may be appropriately determined depending on age, gender or body mass of an individual patient, the severity of the disease, time of administration, dosage form, route of administration, combination of active ingredients, etc.

The positive effects of the present invention

Compounds of this image is plants exhibit high inhibitory of COMT activity. Moreover, the compounds of the present invention possess the desired security profile, as the compounds of the present invention have exceptionally weak hepatotoxicity. On the other hand, the compounds of the present invention can be used as a therapeutic or prophylactic agent for Parkinson's disease, depression or hypertension. Especially compounds of the present invention can be used as a therapeutic or preventive agent for Parkinson's disease, since the use of the compounds of the present invention in combination with L-DOPA significantly increases the bioavailability of L-DOPA.

The best way of carrying out the invention

Following reference examples, examples and sample tests illustrate the invention in more detail. It should be understood that these examples in no way should be considered as examples, the bounding volume of the present invention.

Reference example 1-1

4-Benzyloxy-2-iodine-5-methoxybenzaldehyde

To a mixture of 4-benzyloxy-3-methoxybenzaldehyde (10 g), triptoreline silver (11.4 g) and methylene chloride (105 ml) at room temperature add iodine (13.1 g). After stirring 2 hours, the mixture is passed through a layer of Celite (registered trademark). The filtrate is successively industry is up hydrogen sulfite solution of sodium and salt solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a mixture of methanol:water (4:1)get a named connection (13,2 g).

1H-NMR (CDCl3) δ ppm: 3,91 (3H, s), 5,19 (2H, s), 7,30 is 7.50 (7H, m), 9,86 (1H, s)

Reference example 1-2

5-Benzyloxy-2-iodine-4-methoxybenzaldehyde

The named compound is obtained by the method similar to the method described in reference example 1-1, using 3-benzyloxy-4-methoxybenzaldehyde instead of 4-benzyloxy-3-methoxybenzaldehyde.

1H-NMR (CDCl3) δ ppm: 3,95 (3H, s), 5,16 (2H, s), 7,29-7,47 (6N, m)of 7.48 (1H, s), 9,84 (1H, s)

Reference example 2-1

The oxime of 4-benzyloxy-2-iodine-5-methoxybenzaldehyde

A mixture of 4-benzyloxy-2-iodine-5-methoxybenzaldehyde (reference example 1-1( (12.2 g), hydroxylamine hydrochloride (2,54 g), sodium acetate (6 g) and ethanol (170 ml) was stirred at 70°C for 1.5 hours. The mixture is concentrated under reduced pressure. To the residue water is added and the mixture is stirred at room temperature for 30 minutes. The solid is filtered off, get the named compound (12.8 g).

1H-NMR (CDCl3) δ ppm: 3,88 (3H, s)to 5.13 (2H, s), 7,19 (1H, s), 7,29 (1H, s), 7,30-7,50 (6N, m), 8,30 (1H, s)

Reference examples 2-2 and 2-3 receive in a manner analogous to the method described in reference example 2-1 using the corresponding aldehydes instead of 4-Ben is yloxy-2-iodine-5-methoxybenzaldehyde. The results are presented in table 1.

Table 1
Reference exampleStructureReference exampleStructure
2-12-3
2-2

Physical properties of reference example 2-3 is shown below.

Reference example 2-3

1H-NMR (CDCl3) δ ppm: 3,88 (3H, s)to 5.13 (2H, s), 7,25 (1H, s), 7.29 trend was 7.45 (6N, m), of 8.28 (1H, s)

Reference example 3-1

4-Benzyloxy-N-hydroxy-2-iodine-5-methoxybenzamide

To a mixture of the oxime of 4-benzyloxy-2-iodine-5-methoxybenzaldehyde (reference example 2-1) (12.8 g) and N,N-dimethylformamide (110 ml) at room temperature add N-chlorosuccinimide (4.9 g). After stirring at room temperature for 20 minutes to the mixture while cooling in an ice bath, add water and ethyl acetate. The separated organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4-benzo is lexi-N-hydroxy-2-iodine-5-methoxybenzeneboronic.

To a mixture of 4-benzyloxy-N-hydroxy-2-iodine-5-methoxybenzimidazole and N,N-dimethylformamide (110 ml) was added 28% ammonia solution in water (12 ml) under cooling in an ice bath. After stirring for 3 hours while cooling in an ice bath, to the mixture are added water and ethyl acetate. The separated organic layer is washed successively with water and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a mixture of hexane:(diethyl ether) (1:4)get the named compound (9.3 g).

1H-NMR (DMSO-d6) δ ppm: of 3.77 (3H, s), 5,12 (2H, s), the 5.65 (2H, USS), 6,91 (1H, s), 7,30-7,50 (6N, m), a 9.35 (1H, s)

Reference examples 3-2 and 3-3 receive in a manner analogous to the method described in reference example 3-1, using appropriate Asimov instead of the oxime of 4-benzyloxy-2-iodine-5-methoxybenzaldehyde. The results are presented in table 2.

Table 2
Reference exampleStructureReference exampleStructure
3-13-3
3-2

Physical properties of reference example 3-3 is shown below.

Reference example 3-3

1H-NMR (CDCl3) δ ppm: a 3.87 (3H, s), 5,09 (2H, s), 7,00 (1H, s), 7,27-to 7.50 (5H, m)

Reference example 4-1

3-(4-Benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]-oxadiazol

To a mixture of 4-benzyloxy-N-hydroxy-2-iodine-5-methoxybenzamide (reference example 3-1) (35 g), triethylamine (31 ml) and tetrahydrofuran (31 ml) add acetylchloride (8.2 ml) under cooling in an ice bath. The mixture is stirred at the same temperature for 1 hour. Insoluble materials are filtered off. To the filtrate add tetrabutylammonium (1 mol/l solution in tetrahydrofuran, 89 ml). After stirring at the same temperature for 2 hours to the mixture are added water and ethyl acetate. The separated organic layer is washed successively with hydrochloric acid (1 mol/l)aqueous solution of sodium hydroxide (1 mol/l)aqueous solution of sodium bicarbonate and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is triturated with methanol, get a named connection (31,5 g).

1H-NMR (CDCl3) δ ppm: to 2.67 (3H, s), 3,90 (3H, s), 5,16 (2H, s), 7,28 (1H, s), 7,30-7,50 (6N, m)

Reference example 4-2

3-(5-B is siloxy-2-iodine-4-methoxyphenyl)-5-methyl-[1,2,4]-oxadiazol

To a mixture of 5-benzyloxy-N-hydroxy-2-iodine-4-methoxybenzamide (reference example 3-3, 20 g) and pyridine (115 ml) add acetylchloride (3.8 ml) under cooling in an ice bath. After stirring at the same temperature for 3 hours, the mixture is stirred and heated at 120°C for 3 hours. After cooling to room temperature the mixture is concentrated under reduced pressure. To the residue is added ethyl acetate and hydrochloric acid (2 mol/l). The separated organic layer is washed successively with hydrochloric acid (2 mol/l) and saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: elution with a gradient of 15-50% mixture of ethyl acetate/hexane)get the named compound (17.0 g).

1H-NMR (CDCl3) δ ppm: 2,66 (3H, s), 3,91 (3H, s), 5,14 (2H, s), 7,25 is 7.50 (7H, m)

Reference examples from 4-3 to 4-13 receive in a manner analogous to the method described in reference example 4-1 using appropriate amidines and acid chlorides or anhydrides, acid instead of 4-benzyloxy-N-hydroxy-2-iodine-5-methoxybenzamide and acetylchloride. The results are presented in table 3.

Table 3
Reference example StructureReference exampleStructure
4-14-8
4-24-9
4-34-10
4-44-11
4-54-12
4-64-13
4-7

Physical its the CTV reference samples from 4-3 to 4-13 shown below.

Reference example 4-3

1H-NMR (CDCl3) δ ppm: 2,59 (3H, s), 2,60 (3H, s), of 3.97 (3H, s), with 5.22 (2H, s), 7,25 is 7.50 (7H, m)

Reference example 4-4

1H-NMR (CDCl3) δ ppm: 1,23 of 1.28 (2H, m), of 1.30 to 1.34 (2H, m), 2,24-of 2.30 (1H, m)to 3.89 (3H, s), of 5.15 (2H, s), 7,25 (1H, s), 7,31-7,45 (6N, m)

Reference example 4-5

1H-NMR (CDCl3) δ ppm: 3,57 (3H, s), 3,90 (3H, s), of 4.77 (2H, s)to 5.17 (2H, s), 7,32 (1H, s), 7,33-7,46 (5H, m), 7,47 (1H, s)

Reference example 4-6

1H-NMR (CDCl3) δ ppm: 1,51 (N, C), 3,91 (3H, s), 5,16 (2H, s), 7,29 (1H, s), 7,31-7,45 (6N, m)

Reference example 4-7

1H-NMR (CDCl3) δ ppm: 3,90 (3H, s)to 5.17 (2H, s), lower than the 5.37 (2H, s), 7,00-7,10 (3H, m), 7,25-7,50 (N, m)

Reference example 4-8

1H-NMR (CDCl3) δ ppm: 1,40-1,50 (6N, m), 3,20-3,40 (1H, m), 3,90 (3H, s), 5,16 (2H, s), 7,29 (1H, s), 7,30-7,50 (6N, m)

Reference example 4-9

1H-NMR (CDCl3) δ ppm: 1,00-1,10 (3H, m), 1,80-2,00 (2H, m), 2,90-of 3.00 (2H, m), 3,90 (3H, s), 5,16 (2H, s), 7,28 (1H, s), 7,30-7,50 (6N, m)

Reference example 4-10

1H-NMR (CDCl3) δ ppm: of 1.27 (3H, t, J=7.2 Hz), to 2.94 (2H, t, J=7.4 Hz), or 3.28 (2H, t, J=7.4 Hz), 3,90 (3H, s), 4,19 (2H, q, J=7.2 Hz), 5,16 (2H, s), 7,20 is 7.50 (7H, m)

Reference example 4-11

1H-NMR (CDCl3) δ ppm: to 3.92 (3H, s), is 5.18 (2H, s), 7,33-7,46 (6N, m)to 7.50 (1H, s)

Reference example 4-12

1H-NMR (CDCl3) δ ppm: 2,05-of 2.15 (4H, m), 3,24-to 3.34 (1H, m), 3,54-of 3.64 (2H, m), 3,90 (3H, s), a 4.03-4,10 (2H, m), 5,16 (2H, s), 7,30 (1H, s), 7,31-of 7.48 (6N, m)

Reference example 4-13

1The NMR (CDCl 3) δ ppm: of 1.20 (3H, t, J=6.8 Hz), 3,24 (2H, t, J=6,7 Hz), of 3.56 (2H, q, J=6.8 Hz), 3,85-4,00 (5H, m), 5,16 (2H, s), 7,30 (1H, s), 7,30-7,50 (6N, m)

Reference example 5-1

5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzoic acid

To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzaldehyde (reference example 15-1) (5,38 g), dimethyl sulfoxide (of 5.89 ml), concentrated sulfuric acid (0,506 ml), water (8 ml) and acetonitrile (41 ml) is added a mixture of sodium chlorite (2.25 g) and water (10 ml). After stirring at room temperature for 30 minutes, add water to the mixture. The solid is filtered off, get the named compound (3.58 g).

1H-NMR (CDCl3) δ ppm: to 2.67 (3H, s), of 3.95 (3H, s), 5,23 (2H, s), 7,19 (1H, s), 7,30 is 7.50 (5H, m), 7,68 (1H, s)

Reference example 6-1

[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanol

To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzaldehyde (reference example 15-1) (450 mg) and tetrahydrofuran (5.6 ml) is added dropwise phenylmagnesium (1,08 mol/l solution in tetrahydrofuran, 1.4 ml) under cooling bath of ice and salt. After stirring at the same temperature for 30 minutes to the mixture an aqueous solution of ammonium chloride, hydrochloric acid (2 mol/l) and ethyl acetate. The separated organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure is, get the named compound (564 mg).

1H-NMR (CDCl3) δ ppm: of 2.64 (3H, s), of 3.94 (3H, s), 4,60-4,70 (1H, m), 4,90-5,10 (2H, m), 6,10-of 6.20 (1H, m), 6,72 (1H, s), 7,20-7,40 (10H, m), 7,49 (1H, s)

Reference examples 6-2 to 6-7 receive in a manner analogous to the method described in reference example 6-1 using the corresponding aldehydes and magnesium-organic compounds, instead of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde and phenylmagnesium. The results are presented in table 4

Table 4
Reference exampleStructureReference exampleStructure
6-16-5
6-26-6
6-36-7
6-4

Physical properties of reference examples 6-2 to 6-4 and 6-6 and 6-7 are shown below.

Reference example 6-2

1H-NMR (CDCl3) δ ppm: of 1.40-1.50 (3H, m)to 2.67 (3H, s), 3,76 (1H, USS), of 3.94 (3H, s), 5,20-and 5.30 (3H, m), 7,20 (1H, s), 7,30-7,50 (6N, m)

Reference example 6-3

1H-NMR (CDCl3) δ ppm: 2,35 (3H, s), 2.63 in (3H, s), of 3.94 (3H, s), 4,50-4,60 (1H, m), 4,90-5,10 (2H, m), 6,10-of 6.20 (1H, m), 6,76 (1H, s), 7,00-7,30 (N, m)of 7.48 (1H, USS)

Reference example 6-4

1H-NMR (CDCl3) δ ppm: 0.76 to 1.18 to (7H, m)and 1.51-1,72 (3H, m), 1,95 of 1.99 (1H, m), 2,65 (3H, s), 3,20 (1H, d, J=5.5 Hz), of 3.94 (3H, s), 4,76-of 5.81 (1H, m), 5,20-and 5.30 (2H, m), 7,07 (1H, s), 7,27-7,45 (6N, m)

Reference example 6-6

1H-NMR (CDCl3) δ ppm: 1,40-1,50 (N, m), 3,20-3,40 (1H, m), of 3.94 (3H, s), 3.95 to-4,10 (1H, m), 5,00-5,20 (1H, m), 5,20-and 5.30 (2H, m), 7,19 (1H, s), 7,30-7,50 (6N, m)

Reference example 6-7

1H-NMR (CDCl3) δ ppm: 1,00-1,10 (3H, m), of 1.40-1.50 (3H, m), 1,80-2,00 (2H, m), 2,90-of 3.00 (2H, m), 3,90-4,00 (4H, m), 5,10-and 5.30 (3H, m), 7,19 (1H, s), 7,20-7,50 (6N, m)

Reference example 7-1

1-[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-2-methylpropan-1-ol

A mixture of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (844 mg) and tetrahydrofuran (6 ml) cooled in an ice bath salt in an argon atmosphere. Add isopropylaniline (2.0 mol/l solution in tetrahydrofuran, 1.2 ml) and the mixture premesis the Ute in an ice bath with salt for 10 minutes. After adding Isobutyraldehyde (0,55 ml) the mixture is stirred in an ice bath with salt for 10 minutes and at room temperature for 30 minutes. To the mixture add water and hydrochloric acid (2 mol/l), and the mixture is extracted with ethyl acetate. The separated organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 15-35% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (533 mg).

1H-NMR (CDCl3) δ ppm: 0,63 (3H, d, J=6,7 Hz), and 0.98 (3H, d, J=6,7 Hz), 1,87 is 1.96 (1H, m)to 2.66 (3H, s)to 3.36 (1H, d, J=5.5 Hz), of 3.94 (3H, s), 4,69-4,72 (1H, m), a total of 5.21 (1H, d, J=12.3 Hz), 5,27 (1H, d, J=12.3 Hz), 7,10 (1H, C), 7,28-7,39 (3H, m), 7,44-7,46 (3H, m)

Reference examples 7-2 to 7-8 receive in a manner analogous to the method described in reference example 7-1, using appropriate jodbasedow and aldehydes or N,N-dimethylformamide instead of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole and Isobutyraldehyde. The results are presented in table 5.

Table 5
Reference exampleStructureReference exampleStructure
7-17-5
7-27-6
7-37-7
7-47-8

Physical properties of reference examples 7-2 and 7-3 and 7-5 to 7-8 below.

Reference example 7-2

1H-NMR (CDCl3) δ ppm: 2,66 (3H, s), 3,93 (3H, s), 4.95 points-of 5.15 (2H, m), the ceiling of 5.60 (1H, d, J=4.4 Hz), 6,50-6,60 (1H, m), 6,79 (1H, s), 7,10-7,40 (7H, m), 7,47 (1H, s), 7,50-the 7.65 (1H, m), 8,45-8,55 (1H, m)

Reference example 7-3

MS (ESI, m/z): 391 (M+Na)+.

Reference example 7-5

1H-NMR (CDCl3) δ ppm: 1,92 is 2.01 (1H, m), 2,07-2,17 (1H, m), 2.57 m)-2,66 (4H, m), 2,73-of 2.81 (1H, m), 3,68 (1H, d, J=5.0 Hz), of 3.94 (3H, s), 5,01-of 5.06 (1H, m), 5,17-of 5.26 (2H, m), 7,12-7,46 (N, m)

Reference example 7-6

1H-NMR (CDCl3) δ ppm: 0,73 (N, in), 2.25 (1H, USS), of 2.64 (3H, s), of 3.94 (3H, s), a total of 5.21 (1H, d, J=12,6 Hz), from 5.29 (1H, d, J=12,6 Hz), the 5.45 (1H, USS), 7,21 (1H, s),7,28-7,31 (1H, m), 7,33-7,38 (3H, m), 7,44-7,46 (2H, m)

Reference example 7-7

1H-NMR (CDCl3) δ ppm: 2,61 (3H, s), 3,93 (3H, s), of 4.57 (1H, d, J=5,2 Hz), 4,99-5,10 (4H, m), 6,13 (1H, d, J=5,2 Hz), 6,77 (1H, s), to 6.88 (2H, d, J=8.7 Hz), 7,18 (2H, d, J=8.7 Hz), 7.23 percent-7,47 (10H, m), of 7.48 (1H, s)

Reference example 7-8

1H-NMR (CDCl3) δ ppm: of 0.33 to 0.39 (2H, m), and 0.62 to 0.69 (2H, m), 1,22-of 1.35 (1H, m)of 2.64 (3H, s), 3,80 (2H, d, J=7,0 Hz), of 3.94 (3H, s), 4,56 (1H, d, J=5.5 Hz), 4,99-5,11 (2H, m), 6,11 (1H, d, J=5.5 Hz), 6,77 (1H, s), for 6.81 (2H, d, J=8.6 Hz), 7,16 (2H, d, J=8.6 Hz), 7,25-7,34 (5H, m), of 7.48 (1H, s)

Reference example 8-1

5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzonitrile

A mixture of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (500 mg), copper cyanide(I) (424 mg), Tris(dibenzylideneacetone)diplegia(0) (271 mg), tetraethylammonium (222 mg), 1,1'-bis(diphenylphosphino)ferrocene (525 mg) and 1,4-dioxane (12 ml) was stirred at 105°C in argon atmosphere for 2.5 hours. After cooling to room temperature, the mixture is passed through a layer of Celite (registered trademark). The filtrate is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 25-50% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (231 mg).

1H-NMR (CDCl3) δ ppm:2,69 (3H, s)to 4.01 (3H, s), a total of 5.21 (2H, s), 7,24 (1H, s), 7,30 is 7.50 (5H, m), EUR 7.57 (1H, s)

Reference example 9-1

1-[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,]oxadiazol-3-yl)phenyl]-2-phenylethanone

A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (817 mg), thionyl chloride (0,53 ml), N,N-dimethylformamide (1 drop) and toluene (10 ml) was stirred at 80°C for 30 minutes. The mixture is concentrated under reduced pressure. To the residue is added toluene and the mixture is concentrated under reduced pressure to obtain 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride.

A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoyl chloride, bromide Benzedrine (0.5 mol/l solution in tetrahydrofuran, 4,4 ml), dichlorobis(triphenylphosphine)palladium (II) (153 mg) and toluene (6 ml) was stirred at room temperature in an argon atmosphere for 5 hours. To the mixture are added ethyl acetate and hydrochloric acid (2 mol/l). The separated organic layer is washed successively with water, aqueous sodium bicarbonate solution and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 5-20% of a mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (307 mg).

1H-NMR (CDCl3) δ ppm: of 1.84 (3H, s), 3,29 (1H, d, J=14,2 Hz), 3,42 (1H, d, J=14,2 Hz), 3,91 (3H, s), 5,19-a 5.25 (2H, m), 7,11 (1H, s), 7,15-7,20 (3H, m), 7,26-7,28 (2H, m), 7,30 (1H, s), 7,32 was 7.45 (5H, m)

Reference example 10-1

5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl-N-phenylbenzene

To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzoic acid (reference example 5-1) (500 mg), hexaflurophosphate benzotriazol-1-electroparadise (1,15 g), 1-hydroxybenzotriazole (20 mg), methylene chloride (3 ml) and N,N-dimethylformamide (3 ml) was added aniline (0.2 ml) and triethylamine (of 0.62 ml). After stirring at room temperature for 4 hours to the mixture are added ethyl acetate and hydrochloric acid (2 mol/l). The separated organic layer is successively washed with an aqueous solution of sodium hydroxide (2 mol/l)aqueous solution of sodium bicarbonate and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is triturated with methanol, get the named compound (449 mg).

1H-NMR (CDCl3) δ ppm: 2,58 (3H, s), of 3.96 (3H, s), with 5.22 (2H, s), 7,11-7,14 (1H, m), 7,31-7,56 (11N, m), 8,03 (1H, ush)

Reference examples from 10-2 to 10-4 receive in a manner analogous to the method described in reference example 10-1, using the appropriate amines or alcohols instead of aniline. The results are presented in table 6.

Table 6
Reference exampleStructureReference exampleStructure
10-110-3
10-210-4

Physical properties of reference examples 10-2 and 10-4 are shown below.

Reference example 10-2

1H-NMR (CDCl3) δ ppm: 1.70 to (6N, USS), 2,00-2,20 (N, m), 2.63 in (3H, s), 3,93 (3H, s), 5,20 (2H, s), of 5.53 (1H, USS), 7,14 (1H, USS), 7,28 (1H, USS), 7,30 is 7.50 (5H, m)

Reference example 10-4

1H-NMR (CDCl3) δ ppm: 2,63 (3H, s), of 3.32 (3H, s), 3,50-3,60 (2H, m), of 3.94 (3H, s), 4,20-and 4.40 (2H, m), with 5.22 (2H, s), 7,14 (1H, s), 7,30-7,50 (6N, m)

Reference example 11-1

Isopropyl-5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzoate

A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoic acid (reference example 5-1) (308 mg), 2-jumprope (0,225 ml), potassium carbonate (312 mg) and N,N-dimethylformamide (2.6 ml) was stirred at 60°C for 2.5 hours. After cooling to room temperature, to the mixture are added water and ethyl acetate. The separated organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, get the named compound (342 mg).

1H-NMR(CDCl 3) δ ppm: 1,10-1,25 (6N, m)of 2.64 (3H, s), 3,93 (3H, s), 5,00-5,20 (1H, m), 5,23 (2H, s), 7,10 (1H, s), 7,33-7,50 (6N, m)

Reference example 11-2

Ethyl-5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzoate

The named compound is obtained by the method similar to the method described in reference example 11-1 using iodata instead of 2-jumprope.

1H-NMR (CDCl3) δ ppm: 1,10-1,30 (3H, m)of 2.64 (3H, s), of 3.94 (3H, s), 4,20-4,30 (2H, m), with 5.22 (2H, s), 7,13 (1H, s), 7,30-7,50 (6N, m)

Reference example 12-1

[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-tert-butylcarbamoyl ether acetic acid

A mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzaldehyde (reference example 15-1, 453 mg), tert-utilizationa (465 mg), acetic acid (0,32 ml) and acetonitrile (8 ml) was stirred at 70°C for 13 hours. After cooling to room temperature, to the mixture are added ethyl acetate and water. The separated organic layer is washed successively with water, aqueous sodium bicarbonate solution and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 15-50% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (604 mg).

1H-NMR (CDCl3) δ ppm:1.26 in (N,C)to 2.06 (3H,s), 2,69 (3H,s), of 3.95 (3H, s), to 5.21-and 5.30 (2H, m),6,38 (1H, C), 7,27-to 7.50 (8H, m)

Reference example 12-2

[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]cyclohexylcarbamate ether acetic acid

The named compound is obtained by the method similar to the method described in reference example 12-1, using cyclohexyldiamine instead of tert-utilizationa.

1H-NMR (CDCl3) δ ppm: 0,95-1,43 (5H, m), 1,48-1,71 (4H, m), 1.93 and of 1.99 (1H, m)2,07 (3H, s), 2,70 (3H, s), 3,67 is 3.76 (1H, m), of 3.94 (3H, s), 5,20-and 5.30 (2H, m), 6.48 in (1H, s), 7,28-to 7.50 (8H, m)

Reference example 13-1

2-[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-N-tert-butyl-2-hydroxyacetamido

A mixture of [5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]-tert-butylcarbamoyl ether acetic acid (reference example 12-1) (604 mg), aqueous solution of hydroxy sodium (5 mol/l, 1 ml) and methanol (8 ml) was stirred at room temperature for 1.5 hours. To the mixture are added ethyl acetate and water. The separated organic layer is washed successively with water, aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure, get the named compound (552 mg).

MS (ESI, m/z): 426 (M+1).

Reference example 13-2

2-[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-N-cyclohexyl-2-hydroxyacetamido

The named compound is obtained by method, similar to cnym method, described in reference example 13-1, using [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]cyclohexylcarbamate ether acetic acid (reference example 12-2) instead of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-tert-butylcarbamoyl ester of acetic acid.

1H-NMR (CDCl3) δ ppm: 0,97 is 1.48 (5H, m), 1,54-of 1.95 (5H, m), 2,69 (3H, s), 3,71-of 3.80 (1H, m), 3,93 (3H, s), 4,84 (1H, d, J=5.5 Hz), is 5.18 (2H, s), the 5.51 (1H, d, J=5.5 Hz), 7,16 (1H, s), 7,29-7,47 (6N, m), to 7.67 (1H, d, J=a 7.6 Hz)

Reference example 14-1

[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanone

A mixture of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]phenylmethanol (reference example 6-1) (526 mg), manganese dioxide (1.18 g) and methylene chloride (6.8 ml) was stirred at room temperature overnight. After adding manganese dioxide (1.18 g) and the mixture is stirred for 7.5 hours and add manganese dioxide (0,59 g), the mixture is stirred over night. The mixture is passed through a layer of Celite (registered trademark). The filtrate is concentrated under reduced pressure, get the named compound (526 mg).

1H-NMR (CDCl3) δ ppm: to 2.42 (3H, s)to 4.01 (3H, s), is 5.18 (2H, s), 7,06 (1H, s), 7,30-7,50 (N, m), 7,60-of 7.70 (2H, m)

Reference example 14-2

1-[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]alanon

To a mixture of 1-[5-benzyloxy-4-methoxy-2-(5-methyl-[,2,4]-oxadiazol-3-yl)phenyl]ethanol (reference example 6-2) (467 mg), triethylamine (0,956 ml) and dimethyl sulfoxide (6 ml) is added a mixture of the pyridine complex of sulfur trioxide (655 mg) and dimethyl sulfoxide (2 ml). After stirring at room temperature for 2 hours to the mixture are added water and ethyl acetate. The separated organic layer is washed successively with hydrochloric acid (2 mol/l) and saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 25-34% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (365 mg).

1H-NMR (CDCl3) δ ppm: of 2.38 (3H, s)of 2.64 (3H, s), of 3.96 (3H, s), with 5.22 (2H, s), 7,13 (1H, s), 7,28 (1H, s), 7,30 is 7.50 (5H, m)

Reference examples to 14-3 14-7 receive in a manner analogous to the method described in reference example 14-1 or reference example 14-2, using the appropriate alcohol in place of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]phenylmethanol or 1-[5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]ethanol. The results are presented in table 7.

14-1514-17
14-16

The physical properties of the reference samples from 14-3 to 14-17 shown below.

Reference example 14-3

1H-NMR (CDCl3) δ ppm: 1.06 a (6N, d, J=6.8 Hz), 2,62 (3H, s), 2,79-of 2.86 (1H, m), of 3.97 (3H, s), with 5.22 (2H, s), 6,92 (1H, s), 7,29-7,44 (6N, m)

Reference example 14-4

1H-NMR (CDCl3) δ ppm: 1.32 to (N, C)2,60 (3H, s)to 3.99 (3H, s), 5,19 (2H, s)6,94 (1H, ush.), to 7.18 (1H, s), 7,31-7,47 (6N, m)

Reference example 14-5

1H-NMR (CDCl3) δ ppm: is 2.37 (3H, s), is 2.44 (3H, s)to 4.01 (3H, s), and 5.30 (2H, s), 7,03 (1H, s), 7,10-of 7.70 (10H, m)

Reference example 14-6

1H-NMR (CDCl3) δ ppm: of 2.38 (3H, s)to 4.01 (3H, s), a total of 5.21 (2H, s), 7,20-of 7.55 (8H, m), 7,75-a 7.85 (1H, m), 8,05-to 8.20 (1H, m), 8,35-and 8.50 (1H, m)

Reference example 14-7

MS (ESI, m/z): 407 (M+1).

Reference example 14-8

1H-NMR (CDCl3) δ ppm: 0,89-0,93 (2H, m), 1.18 to 1.22 respectively (2H, m), 2.00 in to 2.06 (1H, m), 2.63 in (3H, s), of 3.96 (3H, s), with 5.22 (2H, s), 7,19 (1H, s), 7,29 (1H, s), 7,30-7,47 (5H, m)

Reference example 14-9

1H-NMR (CDCl3) δ ppm: of 2.45 (3H, s)to 3.99 (3H, s), is 5.18 (2H, s), of 6.96-7,01 (1H, m), 7,08 for 7.12 (1H, m), 7,14 (1H, s), 7,31 was 7.45 (7H, m), 7,52-EUR 7.57 (1H, m)

Reference example 14-10

1H-NMR (CDCl3) δ ppm: of 2.45 (3H, s)to 4.01 (3H, s), with 5.22 (2H, s), 7,25-7,50 (6N, m), 7,51 (1H, s), 7,55-the 7.65 (1H, m), 7,75-a 7.85 (1H, m)

Reference example 14-11

1H-NMR (CDCl3) δ ppm: 2,62 (3H, s), 2,93-to 3.02 (4H, m), of 3.95 (3H, s), 5,14 (2H,s), 6,92 (1H, s), 7,13-7,44 (11N, m)

Reference example 14-12

1H-NMR (CDCl3) δ ppm: 1,11 (N, C)at 2.59 (3H, s), 3,98 (3H, s), with 5.22 (2H, s), 7,28-the 7.43 (5H, m), 7,54 (1H, s)

Reference example 14-13

1H-NMR (CDCl3) δ ppm: 1,40-1,50 (6N, m), a 2.36 (3H, s), 3,20-3,40 (1H, m), of 3.97 (3H, s), with 5.22 (2H, s), 7,13 (1H, s), 7,29 (1H, s), 7,30 is 7.50 (5H, m)

Reference example 14-14

1H-NMR (CDCl3) δ ppm: 1,00-1,10 (3H, m), 1,80-2,00 (2H, m), a 2.36 (3H, s), 2,80-3,00 (2H, m), of 3.96 (3H, s), with 5.22 (2H, s), 7,13 (1H, s), 7,29 (1H, s), 7,30 is 7.50 (5H, m)

Reference example 14-15

1H-NMR (CDCl3) δ ppm: 1,15-of 1.41 (5H, m), 1.60-to a 1.88 (5H, m)2,60 (3H, s), to 3.58-to 3.67 (1H, m)4,00 (3H, s), 5,19 (2H, s), to 6.95 (1H, d, J=8.6 Hz), 7,21 (1H, s), 7,30-of 7.48 (6N, m)

Reference example 14-16

1H-NMR (CDCl3) δ ppm: 2,44 (3H, s), of 4.00 (3H, s), 5,10 (2H, s)to 5.17 (2H, s), 6.89 in (2H, d, J=9.0 Hz), 7,01 (1H, s), 7,27-7,44 (10H, m), of 7.48 (1H, s), 7,66 (2H, d, J=9.0 Hz)

Reference example 14-17

1H-NMR (CDCl3) δ ppm: of 0.33 to 0.39 (2H, m), and 0.62 to 0.70 (2H, m), 1,22-of 1.33 (1H, m), the 2.46 (3H, s), 3,83 (2H, d, J=6,9 Hz)to 4.01 (3H, s)to 5.17 (2H, s), for 6.81 (2H, d, J=9.0 Hz), 7,02 (1H, s), 7,28-7,44 (5H, m), 7,49 (1H, s), 7,66 (2H, d, J=9.0 Hz)

Reference example 15-1

5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)-benzaldehyde

A mixture of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (3,52 g) and tetrahydrofuran (35 ml) cooled in an ice bath salt in an argon atmosphere. Add isopropylaniline (2.0 mol/l solution in tetrahydrofuran, 5 ml). P is after stirring under cooling in an ice bath for 1 hour to the mixture is added N,N-dimethylformamide (1,28 ml). After stirring at room temperature overnight successively added to the mixture of water, hydrochloric acid (2 mol/l) and ethyl acetate. The separated organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 25-34% mixture of ethyl acetate/hexane, elution with a gradient), get a named connection (1,83 g).

1H-NMR (CDCl3) δ ppm: 2,69 (3H, s), was 4.02 (3H, in), 5.25 (2H, s), 7,30-7,50 (6N, m), to 7.67 (1H, s), of 10.58 (1H, s)

Reference examples from 15-2 to 15-14 receive in a manner analogous to the method described in reference example 15-1, using appropriate halogenation and N,N-dimethylformamide, acid anhydrides, acid chlorides of the acids or N-methoxy-N-methylamide instead of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxazole and N,N-dimethylformamide. The results are presented in table 8.

The physical properties of the reference samples from 15-2 to 15-14 shown below.

Reference example 15-2

1H-NMR (CDCl3) δ ppm: 2,68 (3H, s)to 3.99 (3H, s), and 2.27 (2H, s), 7,30 is 7.50 (5H, m), 7,56 (1H, s), a 7.62 (1H, s), 10,61 (1H, s)

Reference example 15-3

1H-NMR (CDCl3) δ ppm: 2,50 (3H, s), a 4.03 (3H, s), 5,23 (2H, s), to 6.67 (1H, d, J=1.7 Hz), 7,21 (1H, s), 7,30 is 7.50 (5H, m), 7,51 (1H, s)8,23 (1H, d, J=1.7 Hz)

Reference example 15-4

1H-NMR (CDC 3) δ ppm: 2,63 (3H, s), of 4.00 (3H, s), a total of 5.21 (2H, s), 7,12 (1H, s), 7,25-7,55 (6N, m)

Reference example 15-5

MS (ESI, m/z): 431 (M+1).

Reference example 15-6

1H-NMR (CDCl3) δ ppm: 2,35 (3H, s), of 3.96 (3H, s), 5,23 (2H, s), of 5.34 (2H, s), 6,95-7,10 (3H, m), 7,14 (1H, s), 7,20-of 7.60 (8H, m)

Reference example 15-7

1H-NMR (CDCl3) δ ppm: 1,40-1,50 (6N, m), 3,20-3,40 (1H, m), was 4.02 (3H, in), 5.25 (2H, s), 7,30-7,50 (6N, m), to 7.67 (1H, s), 10,59 (1H, s)

Reference example 15-8

1H-NMR (CDCl3) δ ppm: 1,00-1,10 (3H, m), 1,90-2,00 (2H, m), 2,90-of 3.00 (2H, m), was 4.02 (3H, in), 5.25 (2H, s), 7,30-7,50 (6N, m), to 7.67 (1H, s), 10,59 (1H, s)

Reference example 15-9 Appendix

1H-NMR (CDCl3) δ ppm: of 1.27 (3H, t, J=7,1 Hz)to 2.35 (3H, s), 2,90 (2H, t, J=7.2 Hz), 3,24 (2H, t, J=7.2 Hz), of 3.96 (3H, s), 4,18 (2H, q, J=7,1 Hz), to 5.21 (2H, s), 7,11 (1H, s), 7,29 (1H, s), 7,25 is 7.50 (5H, m)

Reference example 15-10

1H-NMR (CDCl3) δ ppm: 2,44 (3H, s), 3,98 (3H, in), 5.25 (2H, s), 7,21 (1H, s), 7,25 (1H, s), 7,30 is 7.50 (5H, m)

Reference example 15-11

1H-NMR (CDCl3) δ ppm: 1,95-2,15 (4H, m), is 2.37 (3H, s), 3,19-3,30 (1H, m), 3,52-3,62 (2H, m), of 3.97 (3H, s), 4,00-4,08 (2H, m), with 5.22 (2H, s), 7,13 (1H, s), 7,29 (1H, s), 7,30 is 7.50 (5H, m)

Reference example 15-12

1H-NMR (CDCl3) δ ppm: 1,19 (3H, d, J=7,0 Hz), a 2.36 (3H, s), 3,21 (2H, t, J=6.6 Hz), of 3.54 (2H, q, J=7.0 Hz), with 3.89 (2H, t, J=6.6 Hz), of 3.96 (3H, s), with 5.22 (2H, s), 7,13 (1H, s), 7,29 (1H, s), 7,30 is 7.50 (5H, m)

Reference example 15-13

1H-NMR (CDCl3) δ ppm: to 2.42 (3H, s), 3,93 (3H, s), was 4.02 (3H, s), 5,19 (2H, s), 7,06 (1H, s), 7,30-7,44 (5H, m), 7,49 (1H, s), 7,71 (2H, d J=8.6 Hz), 7,98 (2H, d, J=8.6 Hz)

Reference example 15-14

1H-NMR (CDCl3) δ ppm: 2,44 (3H, s), was 4.02 (3H, s), 5,20 (2H, s),? 7.04 baby mortality (1H, s), 7,30-7,46 (5H, m)to 7.50 (1H, s), to 7.61 (2H, d, J=8,8 Hz), 7,73 (2H, d, J=8,8 Hz)

Reference example 16-1

Methyl-5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzoate

A mixture of Tris(dibenzylideneacetone)diplegia(0) (163 mg), 1,1'-bis(diphenylphosphino)ferrocene (394 mg) and N,N-dimethylformamide (10 ml) is stirred in an argon atmosphere for 10 minutes. To the mixture is added 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazol (reference example 4-1) (1.5 g), methanol (15 ml) and triethylamine (1.5 ml). After replacing the atmosphere of carbon monoxide, the mixture was stirred at 90°C for 16 hours. After cooling to room temperature, to the mixture are added ethyl acetate and hydrochloric acid (2 mol/l). The separated organic layer is washed successively with water, aqueous sodium hydroxide solution (2 mol/l)aqueous solution of sodium bicarbonate and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 15-30% ethyl acetate/hexane, elution with a gradient), get the named compound (1.1 g).

1H-NMR (CDCl3) δ ppm: to 2.65 (3H, s), of 3.77 (3H, s), of 3.94 (3H, s), a total of 5.21 (2H, s), 7,16 (1H, s), 7,31-7,47 (6N, m)

Reference examples 16-2 to 16-4 receive in a manner analogous to the manual, described in reference example 16-1, using appropriate jodbasedow instead of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole. The results are presented in table 9.

Table 9
Reference exampleStructureReference exampleStructure
16-116-3
16-216-4

Physical properties of reference examples 16-2 to 16-4 shown below.

Reference example 16-2

1H-NMR (CDCl3) δ ppm: 1,22-of 1.30 (4H, m), 2.21 are of 2.27 (1H, m), 3,76 (3H, s), of 3.94 (3H, s), a total of 5.21 (2H, s), to 7.15 (1H, s), 7,31-7,46 (6N, m)

Reference example 16-3

1H-NMR (CDCl3) δ ppm: of 3.56 (3H, s), of 3.77 (3H, s), of 3.95 (3H, s), was 4.76 (2H, s), with 5.22 (2H, s), 7,17 (1H, s), 7,32-7,47 (5H, m), 7,49 (1H, s)

Reference example 16-4

1H-NMR (CDCl3) δ ppm: 1,49 (N, C)of 3.73 (3H, s), of 3.95 (3H, s), a total of 5.21 (2H, s), 7,18 (1H, s), 7,30-7,46 (6N, m)

Reference example 17-1

3-(4-Benzyloxy-5-methoxy-2-triptoreline)-5-methyl-[1,2,4]oxadiazol

A mixture of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1), methylbenzenesulfonamide (0,59 ml), copper iodide(I) (88 mg) and N,N-dimethylformamide (8 ml) was stirred at 90°C for 3.5 hours. After cooling to room temperature, to the mixture is added ethyl acetate. The mixture is passed through a layer of Celite (registered trademark). The filtrate is washed successively with an aqueous solution of sodium hydroxide, an aqueous solution of sodium bicarbonate and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 10-40% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (522 mg).

1H-NMR (CDCl3) δ ppm: to 2.67 (3H, s), of 3.95 (3H, s), with 5.22 (2H, s), 7,25 (1H, s), 7,31 (1H, s), 7,32-7,47 (5H, m)

Reference example 18-1

2-[5-Benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]-N-cyclohexyl-N-methyl-2-oxoacetate

To a mixture of 2-[5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]-N-cyclohexyl-2-oxoacetate (reference example 14-15) (860 mg) and N,N-dimethylformamide (6 ml) is added sodium hydride (60%, 92 mg). After stirring at room temperature for 20 minutes to the mixture add logmean (0,48 ml). After stirring at to matnog temperature for 8 hours the mixture is then poured into a mixture of hydrochloric acid (2 mol/l) and ice-water. To the mixture is added ethyl acetate. The separated organic layer is washed sequentially with water, aqueous sodium bicarbonate solution and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 0-50% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (605 mg).

MS (ESI, m/z): 464 (M+1).

Reference example 19-1

5-Methanesulfonyl-2-methoxy-4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenol

A mixture of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (0.7 g), triisopropylsilane (0,391 ml), Tris(dibenzylideneacetone)-diplodia(0) (152 mg), (oxydi-1,2-phenylene)bis-(diphenylphosphine) (90 mg), bis(trimethylsilyl)amide, sodium (1.0 mol/l solution in tetrahydrofuran, to 0.39 ml) and toluene (20 ml) was stirred at 80°C in argon atmosphere for 2 hours. After cooling to room temperature, to the mixture Florisil (registered mark) (1 g). After stirring for 10 minutes, the mixture is passed through a layer of Celite (registered trademark). The filtrate is concentrated under reduced pressure to obtain 3-(4-benzyloxy-5-methoxy-2-triisopropylphenylsulfonyl)-5-methyl-[1,2,4]oxadiazol.

A mixture of 3-(4-benzyloxy-5-methoxy-2-triisopropylphenylsulfonyl)-5-methyl-[1,2,4]oxadiazole, iodine is ETANA (0,155 ml), fluoride, cesium (756 mg) and N,N-dimethylformamide (20 ml) was stirred at room temperature for 30 minutes. To the mixture are added water and ethyl acetate. The separated organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3-(4-benzyloxy-5-methoxy-2-methylsulfinylphenyl)-5-methyl-[1,2,4]-oxadiazol.

A mixture of 3-(4-benzyloxy-5-methoxy-2-methylsulfinylphenyl)-5-methyl-[1,2,4]oxadiazole, m-chlorbenzoyl acid (60%, 1,43 g) and methylene chloride (30 ml) is stirred over night. To the mixture add water Hydrosulphite solution of sodium and methylene chloride. The separated organic layer is successively washed with an aqueous solution (2 mol/l) of sodium hydroxide and saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3-(4-benzyloxy-2-methanesulfonyl-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazol.

To a mixture of 3-(4-benzyloxy-2-methanesulfonyl-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole and methylene chloride (20 ml) is added chloride titanium(IV) (0,472 g). After stirring at room temperature for 15 minutes to the mixture is added hydrochloric acid (2 mol/l) and methylene chloride. The separated organic layer is concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 10-100% of a mixture of ethyl acetate/hexane, elution with a gradient), poluchautsya compound (112 mg).

1H-NMR (CDCl3) δ ppm: to 2.67 (3H, s), 3,42 (3H, s)to 3.99 (3H, s), 7,18 (1H, s), 7,76 (1H, s)

Reference example 20-1

5-Hydroxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzosulfimide

A mixture of 3-(4-benzyloxy-2-iodine-5-methoxyphenyl)-5-methyl-[1,2,4]oxadiazole (reference example 4-1) (0.7 g), triisopropylsilane (0,391 ml), Tris(dibenzylideneacetone)-diplodia(0) (152 mg), (oxydi-1,2-phenylene)bis(diphenyl-phosphine) (90 mg), bis(trimethylsilyl)amide, sodium (1.0 mol/l solution in tetrahydrofuran, to 0.39 ml) and toluene (20 ml) is stirred at 80°C in argon atmosphere for 2 hours. After cooling to room temperature, to the mixture Florisil (registered mark) (1 g). After stirring for 10 minutes, the mixture is passed through a layer of Celite (registered trademark). The filtrate is concentrated under reduced pressure to obtain 3-(4-benzyloxy-5-methoxy-2-triisopropylphenylsulfonyl)-5-methyl-[1,2,4]oxadiazol.

To a mixture of 3-(4-benzyloxy-5-methoxy-2-triisopropylphenylsulfonyl)-5-methyl-[1,2,4]oxadiazole, sodium nitrate (352 mg) and acetonitrile (16 ml) add sulfurylchloride (0,336 ml) under cooling in an ice bath. After stirring at room temperature for 1 hour the mixture was poured into water with ice. To the mixture is added ethyl acetate. The separated organic layer is dried over anhydrous magnesium sulfate, and concentrate the ri reduced pressure, get a 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzosulphochloride.

To a mixture of 5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)benzosulfimide, dimethylamine hydrochloride (203 mg) and tetrahydrofuran (20 ml), add triethylamine (0,693 ml) under cooling in an ice bath. After stirring at room temperature over night to the mixture is added hydrochloric acid (2 mol/l). The separated organic layer is washed successively with hydrochloric acid (2 mol/l) and saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 5-benzyloxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzosulfimide.

To a mixture of 5-benzyloxy-4-methoxy-N,N-dimethyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)benzosulfimide and methylene chloride (20 ml) is added chloride titanium(IV) (0,472 g) under cooling in an ice bath. After stirring at room temperature over night to the mixture is added hydrochloric acid (2 mol/l) and methylene chloride. The separated organic layer is successively washed with hydrochloric acid (2 mol/l) and with brine and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 10-100% of a mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (121 mg).

1H-NMR (CDCl3) δ ppm:2,66 (3H, C), 2,78 (6N, (C), of 3.95 (3H, s), to 6.95 (1H, s)to 7.50 (1H, s)

Reference example 21-1

[5-Hydroxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]phenylmethanone

To a mixture of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]phenylmethanone (reference example 14-1) (526 mg) and methylene chloride (22 ml) is added chloride titanium(IV) (in 0.288 ml) at room temperature. After stirring 30 minutes to the mixture at room temperature, add hydrochloric acid (2 mol/l) and ethyl acetate. The separated organic layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 50-67% of a mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (383 mg).

1H-NMR (CDCl3) δ ppm: 2,44 (3H, s), Android 4.04 (3H, s), to 5.93 (1H, s), 7,07 (1H, s), 7,30-7,80 (6N, m)

Reference examples from 21-2 21-45 to receive in a manner analogous to the method described in reference example 21-1, using appropriate simple benzyl ester instead of [5-benzyloxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanone. The results are presented in table 10.

The physical properties of the reference samples from 21-2 to 21-35 and from 21-37 up 21-45 shown below.

1H-NMR (CDCl3) δ ppm: 2,48 (3H, s), 2.63 in (3H, s), 3,98 (3H, s), 5,90 (1H, s), 7,17 (1H, s)

Reference example 21-3

1H-NMR (CDCl3) δ ppm: 1,16 (6N, d, J=7,0 Hz), 2,62 (3H, s), 2,90-of 3.00 (1H, m)to 3.99 (3H, s), 5,91 (1H, s), 7,01 (1H, s), 7,38 (1H, s)

Reference example 21-4

1H-NMR (CDCl3) δ ppm: to 2.67 (3H, s), 3,98 (3H, s), 5,90 (1H, s), 7,24 (1H, s), of 7.36 (1H, s)

Reference example 21-5

1H-NMR (CDCl3) δ ppm: of 2.64 (3H, s), of 3.80 (3H, s), of 3.97 (3H, s), to 5.85 (1H, s), 7,17 (1H, s), 7,44 (1H, s)

Reference example 21-6

1H-NMR (CDCl3) δ ppm: 2,59 (3H, s), 2,60 (3H, s), of 4.00 (3H, s), 5,88 (1H, s), 7,34 (1H, s), 7,39 (1H, s)

Reference example 21-7

1H-NMR (CDCl3) δ ppm: 1,21-of 1.29 (4H, m), 2.21 are of 2.27 (1H, m), of 3.78 (3H, s), of 3.96 (3H, s), of 5.83 (1H, s), 7,16 (1H, s), 7,42 (1H, s)

Reference example 21-8

1H-NMR (CDCl3) δ ppm: 2,69 (3H, s), Android 4.04 (3H, s), 5,96 (1H, s), 7,33 (1H, s), EUR 7.57 (1H, s)

Reference example 21-9

1H-NMR (CDCl3) δ ppm: 3,55 (3H, s), with 3.79 (3H, s), of 3.97 (3H, s), 4,74 (2H, s), by 5.87 (1H, s), 7,18 (1H, s), 7,46 (1H, s)

Reference example 21-10

1H-NMR (CDCl3) δ ppm: 1,49 (N, C)3,76 (3H, s), 3,98 (3H, s), of 5.84 (1H, s), 7,19 (1H, s), 7,42 (1H, s)

Reference example 21-11

1H-NMR (CDCl3) δ ppm: 1,20-1,26 (6N, m)of 2.64 (3H, s), of 3.96 (3H, s), 5,00-5,20 (1H, m), 5,86 (1H, s), 7,11 (1H, s), 7,46 (1H, s)

Reference example 21-12

1H-NMR (CDCl3) δ ppm: 1.30 and 1,90 (10H, m), 2.63 in (3H, s), of 3.96 (3H, s), 4.80 to 5,00 (1H, m), of 5.83 (1H, s), 7,10 (1H, s)of 7.48 (1H, s)

Reference example 21-13

1H-NMR (CDCl3) δ ppm: 2,63 (3H, s)to 3.35 (3H, s), 3,50-3,60 (2H, m), of 3.96 (3H, s), 4,30-and 4.40 (2H, m), of 5.89 (1H, s), 7,14 (1H, s)of 7.48 (1H, s)

Reference example 21-14

1H-NMR (CDCl3) δ ppm: 1,20-1,30 (3H, m)of 2.64 (3H, s), of 3.96 (3H, s), 4,20-4,30 (2H, m), of 5.84 (1H, s), 7,14 (1H, s), 7,47 (1H, s)

Reference example 21-15

1H-NMR (CDCl3) δ ppm: 1,21 (N, C)2,60 (3H, s), 3,90 (3H, s),? 7.04 baby mortality (1H, s), 7,30 (1H, s), 7,98 (1H, ush), 10,10 (1H, s)

Reference example 21-16

MS (ESI, m/z): 249 (M-1).

Reference example 21-17

1H-NMR (CDCl3) δ ppm: 2,39 (3H, s), 2,47 (3H, s)4,08 (3H, s), 7,10-7,30 (2H, m), 7,60-of 7.70 (2H, m), 7,79 (1H, s), 10,70 (1H, USS)

Reference example 21-18

1H-NMR (CDCl3) δ ppm: to 2.57 (3H, s), a 3.87 (3H, s), 7,02 (1H, s),? 7.04 baby mortality-7,07 (1H, m), 7,28-to 7.32 (2H, m), 7,35 (1H, s), to 7.61-7,63 (2H, m), of 10.01 (1H, s), 10,23 (1H, ush)

Reference example 21-19

1H-NMR (CDCl3) δ ppm: 2,39 (3H, s), a 4.03 (3H, s)5,94 (1H, USS), 7,12 (1H, s), 7,25-7,40 (1H, m), 7,49 (1H, s), 7,75-of 7.90 (1H, m), 8,10-to 8.20 (1H, m), 8,40-8,55 (1H, m)

Reference example 21-20

1H-NMR (CDCl3) δ ppm: 1,16-1,24 (3H, m), of 1.40 to 1.48 (2H, m), 1,63-of 1.93 (5H, m), 2,61 (3H, s), 2.63 in-a 2.71 (1H, m), 3,98 (3H, s), 5,88 (1H, s), 7,00 (1H, s), 7,38 (1H, s)

Reference example 21-21

1H-NMR (CDCl3) δ ppm: 1,11-to 1.14 (2H, m), 1,43 of 1.46 (2H, m), 2,09-to 2.15 (1H, m)of 2.64 (3H, s), Android 4.04 (3H, s), to 7.64 (1H, s), 10,26 (1H, s)

Reference example 21-22

1H-NMR (CDCl3) δ ppm: 2,47 (3H, s), was 4.02 (3H, s), 5,90 (1H, s), 7,00-7,05 (1H, m), 7,12 (1H, s), 7,12-7,17 (1H, m), 7,39(1H, C), 7,42-of 7.48 (1H, m), 7,63-to 7.67 (1H, m)

Reference example 21-23

1H-NMR (CDCl3) δ ppm: of 2.45 (3H, s), a 4.03 (3H, s)5,94 (1H, s), 7,31 (1H, s), 7,51 (1H, s), a 7.62 (1H, d, J=3.0 Hz), to 7.84 (1H, d, J=3.0 Hz)

Reference example 21-24

1H-NMR (CDCl3) δ ppm: 2,50 (3H, s), of 4.05 (3H, s), of 5.99 (1H, OSS), to 6.80 (1H, d, J=2.0 Hz), 7,22 (1H, s), 7,52 (1H, s), compared to 8.26 (1H, d, J=2.0 Hz)

Reference example 21-25

1H-NMR (CDCl3) δ ppm: 1,85 (3H, s), or 3.28 (1H, d, J=14,2 Hz), 3,43 (1H, d, J=14,2 Hz), of 3.95 (3H, s), 6,07 (1H, s), 7,10 (1H, s), 7,13-7,21 (3H, m), 7,26-7,29 (2H, m), 7,32 (1H, s)

Reference example 21-26

1H-NMR (CDCl3) δ ppm: 2,61 (3H, s), 3,02-is 3.08 (4H, m), 3,98 (3H, s), 5,88 (1H, s), 7,03 (1H, s), 7,16-7,20 (3H, m), 7,25-7,29 (2H, m), 7,33 (1H, s)

Reference example 21-27

1H-NMR (CDCl3) δ ppm: 1,25 (N, C)2,60 (3H, s), 3,98 (3H, s), to 5.93 (1H, s), PC 6.82 (1H, s), 7,53 (1H, s)

Reference example 21-28

1H-NMR (CDCl3) δ ppm: 2,62 (3H, s), a 4.03 (3H, s), of 5.99 (1H, s), 7,15-7,20 (1H, m), 7,47 (1H, s)

Reference example 21-29

1H-NMR (CDCl3) δ ppm: 1.70 to (6N, USS), 2,08 (N, Ochs), 2,62 (3H, s), of 3.95 (3H, s), of 5.53 (1H, USS), 7,10 (1H, USS), 7,29 (1H, USS)

Reference example 21-30

1H-NMR (CDCl3) δ ppm: 2,50 (3H, s), of 4.00 (3H, s), 4,96 (2H, s), of 5.92 (1H, s), 6,83-of 6.96 (3H, m), 7,12 (1H, s), 7,21-7,26 (2H, m), 7,41 (1H, s)

Reference example 21-31

1H-NMR (CDCl3) δ ppm: 2,46 (3H, s), 3,98 (3H, s)5,33 (2H, s), 5,91 (1H, s), 6,95-7,10 (3H, m), 7,19 (1H, s), 7,25-7,40 (2H, m)

Reference example 21-32

1H-NMR (CDCl 3) δ ppm: 1,40-1,50 (6N, m)to 2.46 (3H, s), 3,20-3,40 (1H, m), 3,98 (3H, s), to 5.93 (1H, s), to 7.15 (1H, s), 7,28 (1H, s)

Reference example 21-33

1H-NMR (CDCl3) δ ppm: 1,00-1,10 (3H, m), 1,80-2,00 (2H, m), the 2.46 (3H, s), 2,80-3,00 (2H, m), 3,98 (3H, s), of 5.92 (1H, s), 7,16 (1H, s), 7,27 (1H, s)

Reference example 21-34

1H-NMR (CDCl3) δ ppm: of 1.27 (3H, t, J=7.2 Hz), a 2.45 (3H, s), 2,90 (2H, t, J=7.4 Hz), 3,24 (3H, t, J=7.4 Hz), 3,98 (3H, s), 4,18 (2H, q, J=7.2 Hz), of 5.89 (1H, s), 7,14 (1H, s), 7,27 (1H, s)

Reference example 21-35

1H-NMR (CDCl3) δ ppm: to 2.54 (3H, s), of 4.00 (3H, s), 5,97 (1H, s), 7.23 percent (1H, s), 7,29 (1H, s)

Reference example 21-37

1H-NMR (CDCl3) δ ppm: 1,19 (3H, t, J=7.0 Hz), a 2.45 (3H, s), 3,20 (2H, t, J=6,7 Hz), of 3.54 (2H, q, J=7.0 Hz), with 3.89 (2H, t, J=6,7 Hz), 3,98 (3H, s), 5,91 (1H, s), 7,16 (1H, s), 7,28 (1H, s)

Reference example 21-38

1H-NMR (CDCl3) δ ppm: 2,66 (3H, s), 2,78 (6N, (C), of 3.95 (3H, s), to 6.95 (1H, s)to 7.50 (1H, s)

Reference example 21-39

1H-NMR (CDCl3) δ ppm: to 2.67 (3H, s), 3,42 (3H, s)to 3.99 (3H, s), 7,18 (1H, s), 7,76 (1H, s)

Reference example 21-40

1H-NMR (CDCl3) δ ppm: 1,17-of 1.41 (5H, m), 1,59 is 1.91 (5H, m), 2,59 (3H, s), 3,59-3,68 (1H, m), was 4.02 (3H, s)5,94 (1H, ush), 6,97 (1H, d, J=8,3 Hz), 7,16 (1H, s)of 7.48 (1H, s)

Reference example 21-41

MS (ESI, m/z): 372 (M-1).

Reference example 21-42

1H-NMR (CDCl3) δ ppm: of 2.45 (3H, s)to 4.01 (3H, s), 5,09 (2H, s), 6,13 (1H, s), 6,92 (2H, d, J=8,9 Hz), 7,02 (1H, s), 7,30-the 7.43 (5H, m), 7,47 (1H, s), 7,74 (2H, d, J=8,9 Hz)

Reference example 21-43

1Mr. YAM is (CDCl 3) δ ppm: at 0.31 to 0.39 (2H, m), and 0.61 to 0.69 (2H, m), to 1.21 to 1.31 (1H, m), the 2.46 (3H, s), 3,83 (2H, d, J=6,9 Hz)to 4.01 (3H, s), 6,11 (1H, s), at 6.84 (2H, d, J=8,8 Hz), 7,02 (1H, s)of 7.48 (1H, s), 7,73 (2H, d, J=8,9 Hz)

Reference example 21-44

1H-NMR (CDCl3) δ ppm: to 2.42 (3H, s), 3,93 (3H, s), Android 4.04 (3H, s), 7,07 (1H, s), 7,49 (1H, s), 7,80 (2H, d, J=8.5 Hz), 8,02 (2H, d, J=8,5 Hz)

Reference example 21-45

1H-NMR (CDCl3) δ ppm: of 2.45 (3H, s), 3,93 (3H, s), to 6.95 (1H, s), 7,45 (1H, s), 7,73 (2H, d, J=8,4 Hz), to $ 7.91 (2H, d, J=8,4 Hz)

Reference example 22-1

[3-Hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone

To a mixture of [5-hydroxy-4-methoxy-2-(5-methyl-[1,2,4]-oxadiazol-3-yl)phenyl]phenylmethanone (reference example 21-1, 383 mg) and methylene chloride (10 ml) is added at room temperature fuming nitric acid (68 ml) and the mixture is stirred for 20 minutes. The separated organic layer is washed with water, saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The residue is triturated with a mixture of hexane:methylene chloride (4:1)get the named compound (377 mg).

1H-NMR (CDCl3) δ ppm: 2,46 (3H, s), 4.09 to (3H, s), 7,30-of 7.90 (6N, m), of 10.72 (1H, s)

Reference examples from 22-2 to 22-45 receive in a manner analogous to the method described in reference example 22-1, using the appropriate phenol in place of [5-hydroxy-4-methoxy-2-(5-methyl-[1,2,4]oxadiazol-3-yl)phenyl]phenylmethanone. The results are presented in table 11.

The physical properties of the reference samples from 22-2 to 22-20, 22-22 before 22-32, 22-34, 22-35 and from 22-37 to 22-45 shown below.

Reference example 22-2

1H-NMR (CDCl3) δ ppm: of 2.64 (3H, s), 2,68 (3H, s), Android 4.04 (3H, s), of 7.75 (1H, s)

Reference example 22-3

1H-NMR (DMSO-d6) δ ppm: 1,01 (6N, d, J=6.8 Hz), 2.57 m-of 2.64 (1H, m)to 2.67 (3H, s), of 4.00 (3H, s), 7,54 (1H, s), 11,47 (1H, USS)

Reference example 22-4

1H-NMR (DMSO-d6) δ ppm: 2,70 (3H, s)to 3.99 (3H, s), the 7.43 (1H, s), 11,82 (1H, ush)

Reference example 22-5

MS (ESI, m/z): 308 (M-1).

Reference example 22-6

1H-NMR (DMSO-d6) δ ppm: 2,59 (3H, s), 2,62 (3H, s), a 4.03 (3H, s), a 7.62 (1H, s)

Reference example 22-7

1H-NMR (CDCl3) δ ppm: 1,12-of 1.15 (2H, m), 1,28-1,32 (2H, m), 2,38 is 2.43 (1H, m), 3,68 (3H, s)to 3.99 (3H, s)to 7.50 (1H, s), 11,54 (1H, ush)

Reference example 22-8

1H-NMR (CDCl3) δ ppm: 2,72 (3H, s), 4,10 (3H, s), to 7.67 (1H, s), 9,99 (1H, USS)

Reference example 22-9

1H-NMR (DMSO-d6) δ ppm: 3,42 (3H, s), of 3.69 (3H, s)to 4.01 (3H, s), a 4.83 (2H, s), 7,55 (1H, s), 11,66 (1H, ush.)

Reference example 22-10

1H-NMR (DMSO-d6) δ ppm: 1,42 (N, C), 3,68 (3H, s), of 4.00 (3H, s), 7,51 (1H, s), 11,58 (1H, ush)

Reference example 22-11

1H-NMR (CDCl3) δ ppm: 1,30-1,40 (6N, m)of 2.64 (3H, s), Android 4.04 (3H, s), and 5.30-of 5.40 (1H, m), and 7.7 (1H, C)10,54 (1H, s)

Reference example 22-12

1H-NMR (CDCl3) δ ppm: 1,00-2,10 10H, m), 2.63 in (3H, s), a 4.03 (3H, s), 5,10-5,20 (1H, m), 7,71 (1H, s), 10,51 (1H, USS)

Reference example 22-13

1H-NMR (CDCl3) δ ppm: of 2.64 (3H, s)to 3.38 (3H, s), 3,70-of 3.80 (2H, m), Android 4.04 (3H, s), 4,50-4,60 (2H, s), 7,74 (1H, s), 10,65 (1H, USS)

Reference example 22-14

1H-NMR (CDCl3) δ ppm: 1,30-1,40 (3H, m)of 2.64 (3H, s), Android 4.04 (3H, s), 4,40-4,50 (2H, m), 7,73 (1H, s), of 10.58 (1H, s)

Reference example 22-15

1H-NMR (DMSO-d6) δ ppm: 1,25 (N, C), 2,62 (3H, s), was 4.02 (3H, s), to 7.59 (1H, s), 8,00 (1H, ush), 11,53 (1H, ush)

Reference example 22-16

1H-NMR (DMSO-d6) δ ppm: 2,66 (3H, s), of 3.97 (3H, s), the 7.43 (1H, s)

Reference example 22-18

MS (ESI, m/z): 369 (M-1).

Reference example 22-19

1H-NMR (DMSO-d6) δ ppm: of 2.45 (3H, s), a 4.03 (3H, s), 7,50-of 7.70 (2H, m), 7,95-of 8.15 (2H, m), 8,40-and 8.50 (1H, m), 11,00-11,70 (1H, ush)

Reference example 22-20

MS (ESI, m/z): 362 (M+1).

Reference example 22-22

1H-NMR (DMSO-d6) δ ppm: 2,48 (3H, s), a 4.03 (3H, s), 7,20-7,28 (2H, m), 7,60 (1H, s), to 7.61-the 7.65 (2H, m), 11,59 (1H, USS)

Reference example 22-23

1H-NMR (DMSO-d6) δ ppm: 2.49 USD (3H, s), of 4.05 (3H, s), the 7.65 (1H, s), 7,94 (1H, d, J=3.0 Hz), by 8.22 (1H, d, J=3.0 Hz), 11,00-12,00 (1H, ush)

Reference example 22-24

1H-NMR (DMSO-d6) δ ppm: 2,53 (3H, s), of 4.05 (3H, s), 7,16 (1H, d, J=2.2 Hz), 7,68 (1H, s), 8,76 (1H, d, J=2.2 Hz)

Reference example 22-25

1H-NMR (DMSO-d6δ ppm: 1.77 in (3H, C)of 3.97 (3H, s), 7,16-of 7.24 (5H, m), EUR 7.57 (1H, s), 11,67 (1H, ush)

Reference example 22-26

1H-NMR (DMSO-d6) δ ppm: 2,66 (3H, s), 2,88-2,95 (4H, m), of 3.97 (3H, s), 7,15-7,28 (5H, m), to 7.61 (1H, s), to 11.56 (1H, ush)

Reference example 22-27

1H-NMR (DMSO-d6) δ ppm: 1.00 and (N, C)to 2.67 (3H, s)to 3.99 (3H, s), 7,54 (1H, s), 11,49 (1H, USS)

Reference example 22-28

1H-NMR (DMSO-d6) δ ppm: 2,68 (3H, s)4,06 (3H, s), to 7.68 (1H, s)

Reference example 22-29

1H-NMR (CDCl3) δ ppm: 1.70 to (6N, USS), 2,05-2,20 (N, m)to 2.65 (3H, s)to 4.01 (3H, s), of 5.39 (1H, USS), 7,53 (1H, s), 9,86 (1H, USS)

Reference example 22-30

1H-NMR (CDCl3) δ ppm: 2,58 (3H, s)4,06 (3H, s), 5,10 (2H, s), 6,78-for 6.81 (2H, m), 6,93-6,97 (1H, m), 7,21-of 7.25 (2H, m), 7,76 (1H, s), 10,85 (1H, s)

Reference example 22-31

1H-NMR (DMSO-d6) δ ppm: 2,30 (3H, s), of 4.00 (3H, s), ceiling of 5.60 (2H, s), 6,95-to 7.15 (3H, m), 7,25-7,40 (2H, m), 7,60 (1H, s)

Reference example 22-32

1H-NMR (CDCl3) δ ppm: of 1.40-1.50 (6H, m), 2,10 (3H, s), 3,20-3,30 (1H, m), of 4.05 (3H, s), to 7.77 (1H, s), of 10.73 (1H, ush)

Reference example 22-34

1H-NMR (DMSO-d6) δ ppm: of 1.18(3H, t, J=7,1Hz), 2,32(3H, s), is 2.88 (2H, t, J=6,8gts), 3,24 (2H, t, J=6,8gts), to 3.99 (3H, s)4,08 (2H, q, J=7,1Hz), 7,56 (1H, s), 11,00-12,00 (1H, ush)

Reference example 22-35

1H-NMR (DMSO-d6) δ ppm: 2,43 (3H, s)to 4.01(3H, s), a 7.62(1H, s) 11,05-12,50 (1H, ush)

Reference example 22-37

1H-NMR (DMSO-d6) δ ppm with 1.07 (3H, t, J=7,0Hz), was 2.34(3H, s)of 3.25 (2H, t, J=6,1 Hz), of 3.46(2H, q, J=7,0 Hz), 3,80 (2H, t, J=6,1 Hz), 3,99 (3H, s), EUR 7.57 (1H, s), 11,40-11,70 (1H, ush)

Reference example 22-38

1H-NMR (CDCl3) δ ppm: 2,69 (3H, s), 2,81(6N, C)to 3.99 (3H, s), of 6.96 (1H, s)

Reference example 22-39

1H-NMR (CDCl3) δ ppm: 2,69(3H, s), 3,55 (3H, s), Android 4.04 (3H, s), to 7.15 (1H, s)

Reference example 22-40

1H-NMR (DMSO-d6) δ ppm: 1,03-1,73 (10H, m), 2,61 (3H, s), 3,39-3,50 (1H, m), a 4.03 (3H, s), to 7.59 (1H, s), 8,66 (1H, d, J=8,Hz), to 11.56 (1H, ush)

Reference example 22-41

1H-NMR (CDCl3) δ ppm: 1,07-2,01 (10H, m), 2,59-2,60 (3H, m), 2,94-to 3.36 (3H, m), a 4.03-Android 4.04(3H, m), 4,25-4,80 (1H, m), 7,75-7,80 (1H, m), 10,87 (1H, ush)

Reference example 22-42

1H-NMR (CDCl3) δ ppm: 2,48 (3H, s)4,08 (3H, s), 5,09 (2H, s), to 6.95 (2H, d, J=9,0 Hz), 7,31-7,44 (5H, m), 7,63-7,80 (3H, m)

Reference example 22-43

1H-NMR (CDCl3) δ ppm: of 0.32 to 0.39 (2H, m), 0,63-of 0.71 (2H, m), 1,22-1,32 (1H, m), 2,48 (3H, s), a-3.84 (2H, d, J=6,GC), 4,08 (3H, s)6,86 (2H, d, J=9,1 Hz), 7,60-7,79 (3H, m)

Reference example 22-44

1H-NMR (CDCl3) δ ppm: of 2.45 (3H, s) 3,93 (3H, s), 4,10 (3H, s), 7,82-7,88 (3H, m), 8,07 (2H, d, J=8,8gts)

Reference example 22-45

1H-NMR (CDCl3) δ ppm: 2,47 (3H, s), 4.09 to (3H, s), 7,69-of 7.95 (5H, m)

Reference example 23-1

[3-Hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]-(4-hydroxyphenyl)metano

To a mixture of (4-benzyloxyphenyl)-[3-hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]methanone (reference example 22-42, 395 mg) and 25% solution of hydrogen bromide hydrogen is in acetic acid (10 ml) was stirred at 45°C for 2 hours. The mixture is concentrated under reduced pressure, get the named compound (310 mg).

1H-NMR (CDCl3) δ ppm: 2,48 (3H, s)4,06 (3H, s), for 6.81 (2H, d, J=8,8gts), 7,53-to 7.68 (2H, m), 7,71 (1H, s)

Example 1-1

[3,4-Dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone (compound 1-1)

To a mixture of [3-hydroxy-4-methoxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone (reference example 22-1) (377 mg) and ethyl acetate (10,6 ml) is added aluminum chloride (361 mg) and pyridine (0,387 ml). The mixture is refluxed for 2.5 hours. After cooling to room temperature, to the mixture is added hydrochloric acid (1 mol/l). The separated organic layer is washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is triturated with a mixture of hexane:methylene chloride (4:1)get the named compound (317 mg) as an amorphous substance.

1H-NMR (DMSO-d6) δ ppm: 2,43 (3H, s), 7,40-7,70(6N, m), 11,28 (2H, USS)

MS (ESI, m/z): 342 (M+1).

Connection from 1-2 to 1-45 receive in a manner analogous to the method described in example 1-1, using the appropriate 3-nitrobenzene-1-methoxy-2-tins instead of [3-hydroxy-4-methoxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone. The results are presented in table 12.

Physical properties of compounds from 1-2 to 1-45 shown below.

Connection 1-2

1H-NMR (DMSO-d6) δ ppm: of 2.34 (3H, s)to 2.65 (3H, s), 7,52 (1H, s), 11,17 (1H, USS)

Connection 1-3

1H-NMR (DMSO-d6) δ ppm: 1.00 and (6N, d, J=6.8 Hz), 2,56-2,63 (1H, m)of 2.64 (3H, s), 7,46 (1H, s), 11,18 (2H, USS).

Connection 1-4

1H-NMR (DMSO-d6) δ ppm:2,68 (3H, s), 7,21 (1H, s), 11,57 (2H, ush)

Connection 1-5

1H-NMR (DMSO-d6) δ ppm: of 2.64 (3H, s)to 3.67 (3H, s), 7,42 (1H, s), 11,29 (2H, ush)

Connection 1-6

1H-NMR (DMSO-d6) δ ppm: 2,56 (3H, s), 2,61 (3H, s), 7,54 (1H, s), 11,38 (2H, ush. C)

Connection 1-7

1H-NMR (DMSO-d6) δ ppm: 1.10 is to 1.14 (2H, m), of 1.26 to 1.31 (2H, m), 2,35-to 2.42 (1H, m), 3,66 (3H, s), 7,40 (1H, s), 11,27 (2H, ush)

Connection 1-8

1H-NMR (DMSO-d6) δ ppm: 2,70 (3H, s), to 7.61 (1H, s)

Connection 1-9

1H-NMR (DMSO-d6) δ ppm: to 3.41 (3H, s)to 3.67 (3H, s), to 4.81 (2H, s), 7,44 (1H, s), 11,38 (2H, ush)

Connection 1-10

1H-NMR (DMSO-d6) δ ppm: 1,41 (N, C)to 3.67 (3H, s), 7,45 (1H, s), 11,33 (2H, ush)

Connection 1-11

1H-NMR (DMSO-d6) δ ppm: 1,10-1,20 (6N, m), 2.63 in (3H, s), 4,90-5,00 (1H, m), 7,63 (1H, s), 11,27 (2H, ush. C)

Connection 1-12

1H-NMR (DMSO-d6) δ ppm: 1,20-1,80 (10H, m), 2,62 (3H, s), 4,70-4,80 (1H, m), 7,63 (1H, s)of 11.26 (2H, ush. C)

Connection 1-13

1H-NMR (DMSO-d6) δ ppm: 2,62 (3H, s)3,18 (3H, s), 3,403,50 (2H, m), 4,10-4,20 (2H, m), 7,38 (1H, s), 11,16 (1H, ush. C)

Connection 1-14

1H-NMR (DMSO-d6) δ ppm: 1,00-1,20 (3H, m)of 2.64 (3H, s), 4,10-4,20 (2H, m), 7,38 (1H, s), 11,25 (1H, ush. C)

Connection 1-15

1H-NMR (DMSO-d6) δ ppm: 1,24 (N, C)2,60 (3H, s)to 7.50 (1H, s), of 7.97 (1H, ush), 11,32 (2H, ush)

Connection 1-16

1H-NMR (DMSO-d6) δ ppm:2,63 (3H, s), 7,31 (1H, s)

Connection 1-17

1H-NMR (DMSO-d6) δ ppm: of 2.33 (3H, s), a 2.45 (3H, s), 7,20-7,30 (2H, m), 7,50-of 7.60 (3H, m), 11,22 (1H, ush. C)

Connection 1-18

1H-NMR (DMSO-d6) δ ppm: to 2.55 (3H, s), 7,05-7,10 (1H, m), 7,27-to 7.32 (2H, m), 7,46-7,49 (2H, m), 7,55 (1H, s), 10,41 (1H, s), 10,98 (1H, ush), 11,08 (1H, ush)

Connection 1-19

1H-NMR (DMSO-d6) δ ppm: to 2.42 (3H, s), 7,50-the 7.65 (2H, m), 7,95-of 8.15 (2H, m), 8,40-and 8.50 (1H, m), 10,50-11,50 (2H, m)

Connection 1-20

1H-NMR (DMSO-d6) δ ppm: 1,02-of 1.78 (10H, m), 2,22-of 2.30 (1H, m), 2,65 (3H, s), 7,46 (1H, s)to 11.11 (1H, ush)

Connection 1-21

1H-NMR (DMSO-d6) δ ppm: 0.91-0.99 are equivocal (4H, m), 1.91 a-to 1.98 (1H, m)of 2.64 (3H, s), the 7.43 (1H, s), 11,18 (2H, ush)

Connection 1-22

1H-NMR (DMSO-d6) δ ppm: of 2.45 (3H, s), 7,19-7,27 (2H, m), 7,51 (1H, s), 7,58-to 7.64 (2H, m), 11,27 (1H, ush. C)

Connection 1-23

1H-NMR (DMSO-d6) δ ppm: 2,46 (3H, s), 7,56 (1H, s), to 7.93 (1H, d, J=3,0Hz), to 8.20 (1H, d, J=3,0 Hz), 10,50-12,00 (2H, ush)

Connection 1-24

1H-NMR (DMSO-d6) δ ppm: 7,13 (1H, d, J=2,0Hz), a 7.62 (1H, s), a total of 8.74 (1H, d, J=2,0 Hz)

Connection 1-25

1H-NMR (who MCO-d 6) δ ppm: a 1.75 (3H, s), 3.25 to to 3.33 (2H, m), 7,13 (1H, s), 7,14-of 7.23 (5H, m), to 11.52 (1H, ush)

Connection 1-26

1H-NMR (DMSO-d6) δ ppm: of 2.64 (3H, s), 2,87-of 2.93 (4H, m), 7,14-7,28 (5H, m), 7,55 (1H, s), 11,17 (2H, ush)

Connection 1-27

1H-NMR (DMSO-d6) δ ppm: 1.00 and (N, C)to 2.65 (3H, s), 7,47 (1H, s)to 11.11 (2H, ush. C)

Connection 1-28

1H-NMR (DMSO-d6) δ ppm: 2,66 (3H, s), to 7.59 (1H, s)

Connection 1-29

1H-NMR (DMSO-d6) δ ppm: 1,60 (6N, ush. C)1,89 (6N, ush. C)to 1.99 (3H, ush. C)2,62 (3H, s), 7,40 (1H, s), 7,81 (1H, s), 10, 69 (1H, ush. C)10,81 (1H, ush. C)

Connection 1-30

1H-NMR (DMSO-d6) δ ppm: 2,56 (3H, s), 4,94 (2H, s), 6,84-of 6.96 (3H, m), 7.23 percent-7,27 (2H, m), 7,58 (1H, s), 11,30 (2H, ush)

Connection 1-31

1H-NMR (DMSO-d6) δ ppm: to 2.29 (3H, s)5,59 (2H, s), 6,95-to 7.15 (3H, m), 7,30-7,40 (2H, m), 7,54 (1H, s), 10,00-12,00 (2H, ush)

Connection 1-32

1H-NMR (DMSO-d6) δ ppm: 1,30-1,40 (6N, m)to 2.35 (3H, s), 7,56 (1H, s), 11,17 (2H, ush. C)

Connection 1-33

1H-NMR (DMSO-d6) δ ppm: 0,90-1,00 (3H, m), 1,70-1,90 (2H, m), of 2.34 (3H, s), 2,90-of 3.00 (2H, m), 7,54 (1H, s), 11,18 (2H, ush. C)

Connection 1-34

1H-NMR (DMSO-d6) δ ppm: 1,10-1,25 (3H, m), 2,31 (3H, s), of 2.86 (2H, t, J=6,8gts), 4,00-to 4.15 (2H, m)to 7.50 (1H, s), 10,50-11,50 (2H, ush)

Connection 1-35

1H-NMR (DMSO-d6) δ ppm: to 2.41 (3H, s), EUR 7.57 (1H, s), 10,50-12,00 (2H, ush)

Connection 1-36

MS (ESI, m/z): 348 (M-1).

Connection 1-37

1H-NMR (DMSO-d6) δ ppm with 1.07 (3H, t, J7,0 Hz), of 2.33 (3H, s), 3,23 (2H, t, J=6,2), OF 3.45 (2H, q, J=7,0 Hz), with 3.79 (2H, t, J=6,2 Hz), 7,52 (1H, s), 10,80-11,80 (2H, ush)

Connection 1-38

1H-NMR (DMSO-d6) δ ppm: 2,63 (6N, (C), to 6.95 (1H, s)

Connection 1-39

1H-NMR (DMSO-d6) δ ppm: 2,68 (3H, s), of 3.46 (3H, s), 7,11 (1H, s)

Connection 1-40

1H-NMR (DMSO-d6) δ ppm: 1,02-1,72 (10H, m), 2,59 (3H, s), 3,37-of 3.48 (1H, m), 7,51 (1H, s), 8,61 (1H, d, J=8,5Hz), 11,32 (2H, ush)

Connection 1-41

1H-NMR (DMSO-d6) δ ppm: 1,03-1,89 (10H, m), 2,60-to 2.65 (3H, m), 2,60 was 3.05 (3H, m), 3,83-of 3.94 (1H, m), 7,40 was 7.45 (1H, m), 11,30 (2H, ush)

Connection 1-42

1H-NMR (DMSO-d6) δ ppm: 2,47 (3H, s), 6,74 (2H, d, J=9,1 Hz), of 7.48 (2H, d, J=8,2 Hz), 7,54 (1H, s)

Connection 1-43

1H-NMR (DMSO-d6) δ ppm: of 0.29 to 0.38 (2H, m), of 0.53 to 0.63 (2H, m), 1,19-of 1.29 (1H, m), 2,47 (3H, s), 3,86-to 3.92 (2H, m), 6.90 to-6,97 (3H, m), 7,51 (2H, d, J=8,8gts)

Connection 1-44

1H-NMR (DMSO-d6) δ ppm: 2,43 (3H, s), 3,86 (3H, s), 7,60 (1H, s), 7,76 (2H, d, J=8,Hz), to 7.99 (2H, d, J=8,Hz)

Connection 1-45

1H-NMR (DMSO-d6) δ ppm: 2,44 (3H, s), 7,60 (1H, s), 7,81 (2H, d, J=8,Hz), 7,92 (2H, d, J=8,Hz)

Example 2-1

6-(2,2-Dimethylpropionic)-3-isobutyryl-4-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyloctyl ether of 2,2-dimethylpropionic acid (compound 2-1)

To a mixture of 1-[3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]-2-methylpropan-1-she (compound 1-3) (100 mg) and tetrahydrofuran (2 ml) add trimethylacetylchloride (92 μl) and triethyl is min (100 μl) with stirring and cooling in an ice bath. The mixture is stirred for 30 minutes, warmed to room temperature and stirred over night. The mixture is diluted with ethyl acetate, washed with hydrochloric acid (1 mol/l) and saline solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 0-20% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (174 mg). The structural formula is presented in table 13.

1H-NMR (CDCl3) δ ppm: 1,20 (6N, d, J=6,GC), 1,34 (N, C)1,36 (N, C)to 2.65 (3H, s), 2,82 (1H, septet, J=6,GC), of 8.04 (1H, s)

Example 3-1

Methyl-4-ethoxycarbonyl-3-hydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 3-1)

A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), atilglukuronida (0,02 ml), potassium carbonate (28 mg) and N,N-dimethylformamide (2 ml) was stirred at 50°C for 3 hours. After cooling to room temperature, to the mixture are added water and ethyl acetate. The separated organic layer is washed successively with water and with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 20-100% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (51 mg). The structure of the Naya formula presented in table 13.

1H-NMR (CDCl3) δ ppm: to 1.42 (3H, t, J=7,2 Hz), of 2.64 (3H, s)to 4.01 (3H, s), to 4.38 (2H, q, J=7,2 Hz), 8,23 (1H, s), 10,98 (1H, ush)

Example 4-1

Methyl-4-diethylcarbamoyl-3-hydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrobenzoate (compound 4-1)

A mixture of methyl 3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrobenzoate (compound 1-5) (50 mg), diethylcarbamazine (0,024 ml), 4-dimethylaminopyridine (4 mg) and pyridine (2 ml) was stirred at room temperature for 3 hours. After adding ethyl acetate, the mixture is acidified with hydrochloric acid (2 mol/l). The separated organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified column chromatography on silica gel (eluent: 20-100% mixture of ethyl acetate/hexane, elution with a gradient), get the named compound (31 mg). The structural formula is presented in table 13.

1H-NMR (CDCl3) δ ppm: 1,14-1.27mm (6N, m), 2,61-to 2.67 (3H, m), 3,32-to 3.36 (4H, m), 3,88-was 4.02 (3H, m), 8,13-8,19 (1H, m)

Table 13
No. of connectionsStructureNo. of connectionsStructure
2-14-1
3-2

Example 5-1

Monogalia salt [3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone (compound 5-1)

To a mixture of [3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone (compound 1-1) (100 mg), water (2.5 ml) and tert-butanol (2.5 ml) is added an aqueous solution of potassium hydroxide (1 mol/l, 0,292 ml). The mixture is concentrated under reduced pressure to obtain compound (103 mg) as an amorphous compound.

1H-NMR (DMSO-d6) δ ppm: of 2.38 (3H, s)6,94 (1H, s), 7,35-7,41 (2H, m), 7,45-7,51 (1H, m), 7,63-to 7.68 (2H, m)

Connections from 5-2 to 5-6 receive in a manner analogous to the method described in example 5-1, using the appropriate 3-nitrobenzene-1,2-diols and sodium hydroxide or potassium hydroxide instead of [3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone and potassium hydroxide.

Connection 5-2

Monosodium salt [3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone

1H-NMR (DMSO-d6) δ ppm: of 2.38 (3H, s), 6,93 (1H, s), 7,34-7,41 (2H, m), 7,44-7,51 (1H, m), 7,62-to 7.68 (2H, m)

Connection 5-3

Monogalia salt methyl-3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)--nitrobenzoate

1H-NMR (DMSO-d6) δ ppm: 2,56 (3H, s), of 3.60 (3H, s), 6,72 (1H, s)

Connection 5-4

Monosodium salt of methyl-3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrobenzoate

1H-NMR (DMSO-d6) δ ppm: 2,56 (3H, s)and 3.59 (3H, s), of 6.68 (1H, s)

Connection 5-5

Monogalia salt of 1-[3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]-2-methylpropan-1-it

1H-NMR (DMSO-d6) δ ppm: 1,04 (6N, d, J=7,0Hz), to 2.55 (3H, s), 2,59-of 2.72 (1H, m), at 6.84 (1H, s)

Connection 5-6

Monosodium salt of 1-[3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]-2-methylpropan-1-it

1H-NMR (DMSO-d6) δ ppm: 1,03 (6N, d, J=6,8gts), to 2.55 (3H, s), 2,59-2,70 (1H, m), for 6.81 (1H, s)

The test example 1

INHIBITING HUMAN COMT ACTIVITY

1. The preparation of recombinant human COMT

(1) preparation of recombinant human catechol-O-methyltransferase

According to the DNA sequence with inventory number NCBI (National Center for Biotechnology Information) (VS) developed two oligonucleotide primers to amplify the target DNA sequence encoding a full-sized human catechol-O-methyltransferase (hereinafter referred to as "AMT"), which is presented in sequence ID NO:1. Sequence 5'-primer and 3'primer specified in sequence ID NO: 3 and 4, respectively. For ease of insertion ratio is estoodeeva of PCR product (PCR) in the target vector such primers include the sites of the restriction enzyme BamH I and EcoR I at the 5'side and 3'side, respectively.

Each of the 5'-primer specified in sequence ID NO: 3, and 3'-primer specified in sequence ID NO: 4, diluted with TE buffer to obtain solutions with a concentration of 15 pmol/ál. Mixture for PCR reactions are obtained from H2(For PCR, to 34.8 μl), 25 mmol/l MgSO4(2,0 ál), 2 mmol/l dNTPs (5,0 ál) and 10-fold concentrated buffer for KOD plus DNA Polymerase (5,0 ál, TOYOBO). After adding each of the pairs of primers (1 μl, 15 pmol) after liver cDNA people (5.0 μl, Clontech) to the above reaction mixture is added to 1.0 μl of KOD plus (TOYOBO). This was followed by a PCR reaction as follows; after the procedure at 94°C for 2 minutes carry out the PCR reactions for 40 cycles, each of which consists of 94°C for 15 seconds, 59°C for 30 seconds, and 68°C for 1 minute and then the complete cycle at 68°C for 5 minutes and at 4°C for 10 minutes.

The PCR product purified using the kit QIAquick PCR Purification Kit (QIAGEN) and the target insert DNA elute using EB buffer (30 μl)included in the corresponding set.

(2) Double burning insert DNA recombinant human COMT and pGEX-2T vector

The resulting insert DNA recombinant human COMT (1,5 μl) is mixed with 10-fold concentrated EcoR I buffer (3,0 μl, New England Biolab), N2On (11,1 mm), BamH I (1,5 µl, 15 IU, 10 IU/ml) and EcoR I (1,0 μl, 15 IU, 10 IU/ml) and then incubated who at 37°C for 1.5 hours. Then to this mixture 10-fold concentrated of the boot buffer. After purification by electrophoresis of the region of the gel containing target burned fragment, delete and clear with a set MinElute Gel Extraction Kit (QIAGEN). Dual combustion and purification of DNA pGEX-2T vector (1,5 μl, Amersham) also carried out in a manner analogous to the above-described method.

(3) Ligation and transformation of E. coli JM109.

Twice burned DNA pGEX-2T vector (2,0 ál, 50 ng) and insert DNA (1,24 µl of 33.4 ng) is added to 2-fold concentrated digirolamo buffer (3,24 μl, Promega) and mix. The mixture was incubated at 25°C for 1 hour, then add T4 ligase (1,0 μl, 3 u/ál, Promega). This solution is treated with ligase mixture (5 μl) is transferred to E. coli JM109 (100 µl) was thawed at 0°C and gently mixed and incubated at 0°C for 30 minutes. The mixture is heated by a heat shock at 42°C for 40 seconds without excessive shaking, and then cooled at 0°C for 10 minutes. After stage heating heat shock type environment SOC (450 μl) and the mixture is shaken at 37°C for 1 hour. Each aliquot (50 µl and 200 µl) of the mixture sequentially plated on LB plates (diameter 9 cm, ampicillin 100 μg/ml) and cultured statically at 37°C for 16 hours. The tablets also noted the presence of colonies.

(4) Selecting colonies JM109 transformed with GST-Liane plasmids recombinant human COMT

From the above-mentioned statically cultured tablets pick several colonies and each colony inoculant in 2 ml of liquid LB-ampicillin (100 µl/ml) using sterile fine-tipped tweezers. After shaking culture at 37°C for 16 hours aliquots (200 µl) of each culture move in microtubes 1.5 ml and plasmid extracted with phenol extraction. The resulting plasmid re solubilizer in TE buffer and separated by electrophoresis. The initially positive colonies identified in accordance with the electrophoretic mobility of their extracted plasmids, similar to the mobility pGEX-2T vector without insert DNA, and re-confirm the double combustion with the use of restriction enzymes as follows.

Solutions of DNA (7 μl), obtained from the initially positive colonies established above, is mixed with 10-fold concentrated EcoR I buffer (0,9 μl, New England Biolab), then added to the mixture BamH I (0,5 µl 10 u/µl) and EcoR I (0,5 ál, 15 u/ál). The solution is analyzed by electrophoresis after heating (37°C, 1 hour). A second positive colonies identified as colonies with a bandwidth of approximately 670 bp.

(5) Extraction and purification of GST-fusion plasmids recombinant human COMT from E.coli JM109.

An aliquot (100 μl) of the culture of E. coli JM109 transformed is by using GST-fusion plasmids recombinant human COMT, which is defined as a second positive colony in paragraph (4), stored in the form of glycerin initial solution, while the remainder centrifuged at 12000 rpm for 10 minutes to obtain a pellet of E. coli. Plasmid DNA secrete from pellets of E. coli using the kit QIAGEN Plasmid mini kit (QIAGEN), and its concentration determined by OD (OD, optical density) at 260 nm (247 ng/ál). Analysis of the DNA sequence in accordance with a customary method confirms that the DNA sequence specified in sequence ID NO:2, properly inserted at the desired site.

(6) the Transformation of competent E.Coli BL21 (DE3) CODON PLUS RP using GST-fusion plasmid DNA recombinant human COMT

For transformation and the culture of the tablet the same way as in paragraph (3), 1 μl of GST-fusion plasmid DNA recombinant human COMT (1 ng/µl) with a reliable sequence specified in (5)add 50 µl of cell suspension competent E.Coli BL21 (DE3) CODON PLUS RP, thawed at 0°C.

(7) the Expression of GST-fusion recombinant human COMT

Out of the tablet with the transformed E. coli BL21 (DE3) CODON PLUS RP selected colony and cultured with shaking at 37°C for 15 hours in 5 ml liquid LB-ampicillin (100 μg/ml). An aliquot of culture medium (50 μl) and stored at -80°C in glycerol source solution. Part glycerin source is astora used for insulinopenia in 150 ml of medium LB-ampicillin (100 μg/ml) and cultured with shaking at 37°C for 16 hours. The diluted culture 7 culture flasks medium (500 ml each) LB-ampicillin (100 μg/ml), and then each culture grown with shaking at 20°C for 4.5 hours until the density of cells OD 600 nm = 0,44, and at this point to each culture add 50 ál of isopropyl-β-D-thiogalactopyranoside (1 mol/l). After that, every culture incubated under the same conditions for another 18 hours. The E. coli pellet collected by centrifugation for 20 minutes at 9000 rpm, divide into four equal portions (4 g) and stored until use at -80°C.

(8) Treatment with thrombin GST-fusion recombinant human COMT

The E. coli pellet obtained in step (7), suspended in reagent BugBuster Reagent (Novagen, 40 ml)containing Bensonase (Novagen, 30 μl) and rLysozyme (Novagen, 1 μl), and E. coli treated with gentle rotation at room temperature for 15 minutes. The obtained cell lysate was separated by centrifugation at 12000 rpm for 20 minutes at 4°C and allocate the supernatant. Specified the supernatant was kept at 4°C for 1 hour on a rotating platform with 20 ml of 50% suspension of Glutathione Sepharose 4B (resin layer of 10 ml), which was pre-equilibrated with D-PBS (saline phosphate buffer, Dulbea). The resulting resin is separated in the filter from the filtrate and washed five times with 30 ml of D-PBS, followed by three additional stages about Yuki with 30 ml of buffer for processing by thrombin (150 mmol/l NaCl, 50 mmol/l Tris-HCl, pH 8.0, 10% glycerol, 2.5 mmol/l CaCl2and 0.5% n-octyl-β-D-glucopyranoside). After the last washing, the resin is again suspended from the buffer for processing by thrombin in the final volume of 30 ml Thirty units of thrombin protease (Amersham Biosciences) are added to a suspension of resin and allow to flow thrombin processing under mild rotation for 15 hours at 4°C. the Suspension resin was filtered and a solution of recombinant human COMT obtained as filtrate, and stored until analysis at -80°C.

2) Measurement of inhibitory human COMT activity

Measurement of inhibitory human COMT activity is carried out in accordance with the method G.Zürcher et al (J. Neurochem., 1982, vol. 38, p. 191-195) with slight modifications. An aliquot of 0.25 ml) of recombinant human COMT obtained in paragraph (1) (approximately 1 mg/ml) pre-incubated with the test compound for 5 minutes at 37°C in a reaction mixture consisting of 40 μl of potassium phosphate buffer (500 mmol/l, pH 6), 10 μl of magnesium chloride (100 mmol/l), 10 μl of dithiothreitol (62.5 mmol/l) and 0.5 μl adelaideans (2550 units/ml). Control samples are prepared in the same way, but compound replace an equal volume (5 μl) of DMSO. After adding 20 μl of [3H]-S-adenosyl-L-methionine (12.5 mmol/l, 1,2 Curie/mol; Amersham Biosciences) reaction beg is only by adding 25 µl of catechin substrate (7 mmol/l). The reaction mixture, final volume of 0.25 ml and incubated at 37°C for 30 minutes. Then the reaction is stopped by adding 0.25 ml ice hydrochloric acid (1 mol/l)containing 0.1 g/l guaiacol. After adding 2.5 ml of scintillator OPTI-FLUOR (registered trademark, Packard) and the subsequent strong shaking for 1 minute radioactivity present in the organic phase directly read in a liquid scintillation counter (Packard TRICARB 1900CA). Blank samples incubated without catechin substrate (the substrate is added after the reaction). The value of the IC50indicates the molar concentration required to inhibit 50% of enzyme activity. As comparative examples similarly analyze tolkapon, entacapone and 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-3-nitrobenzene-1,2-diol (comparative example 1), which is described in example 75 patent reference 1. The results obtained are presented in table 14.

Table 14
Connection, No.IC50(nmol/l)Connection, No.IC50(nmol/l)
1-19,41-37 the 4.7
1-38,11-408,8
1-59,31-41the 4.7
1-97,7Tolkapon9,0
1-208,7Entakapon11,1
1-228,3Comparative example 113,2
1-247,6

The test example 2

Toxicity to rat hepatocytes

After heating at 37°C. cryopreserved rat hepatocytes in the amount of 3×10-6cells/vial, stored at -150°C, hepatocytes add thawed in a medium with glucose (10 ml) and stirred. The suspension is centrifuged at 1000 rpm for 1 minute. After separation of the supernatant the cell pellet is suspended in environment E Williams (15 ml). Prepare a solution of the drug in dimethyl sulfoxide at a concentration of 45, 15, 4,5, 1,5, 0.45 mmol/l, then each of the races the thieves drugs and dimethylsulfoxide as a control distribute 2.0 ál into tubes for testing. The above cell suspension (300 μl) was dispensed into test tubes and re-suspended. Each 100 μl of each suspension was dispensed into 96-well plate and the plate is incubated for 4 hours at 37°C in CO2thermostats. The activity of ATP measured in accordance with the analysis of the viability of the cells offered by Promega Corporation. Is EU50indicates a concentration that gives 50% of the number of viable cells of control. The results obtained are presented in table 15.

Table 15
Connection, No.EC50(µmol/l)Connection, No.EC50(µmol/l)
1-16831-22523
1-26451-24>1000
1-3698Tolkapon34,3
1-5>1000Entakapon111
1-9 >1000Comparative
example 1
172

The obtained results demonstrate that the compounds of the present invention demonstrate only minor hepatocyte toxicity compared with tolkapon, entacapone and comparative example 1.

The test example 3

Estimation of the concentration of L-DOPA in plasma

(1) Introduction connections and sampling plasma

Male rats Sprague-Dawley 6 weeks of age weighing 170-190 g (Charles River Laboratories Japan Inc.) do not feed during the night. Preparing a suspension of the tested compounds (0.6 mg/ml) and a mixed suspension of L-DOPA (1 mg/ml) and carbidopa (6 mg/ml) using an agate mortar using a 0.5% solution of methylcellulose as the environment. A mixed suspension of L-DOPA (5 mg/kg) and carbidopa (30 mg/kg) administered orally or via 4 or 6 hours after oral administration of the tested compounds (3 mg/kg). Blood samples taken 2 hours after oral administration of the mixed suspension of L-DOPA and carbidopa and transferred into tubes on ice containing heparin, etilenditiodiuksusnoi acid and reduced glutathione. Plasma sample to determine the concentration of L-DOPA is produced by centrifugation.

(2) Measurement of the concentration of L-DOPA

To 0.05 ml of plasma obtained in paragraph (1)above, add 0.01 to the l of an aqueous solution of metforminhydrochloride (100 μg/ml) as internal standard in accordance with the usual way and then spend the deproteinization by adding 0.05 ml of a solution of disodium Ethylenediamine salt-tetraoxane acid (250 mmol/l) in perchloro acid (0.5 mol/l). After centrifugation 0.002 ml of the supernatant liquid injected into the system LC-MS/MS. The concentration of L-DOPA in plasma is measured by the system LC-MS/MS in the conditions below. The concentration of L-DOPA is given in table 16 in the form of a percentage of the concentration of L-DOPA in the control group without the introduction of any of the test compounds.

LC

Instrument: Agilent 1100

Column: Capcellpak C18 MGIII 5 µl of 4.6×50 mm

Mobile phase: 0.5% aqueous solution heptapteridae acid/acetonitrile

The column temperature: 40°C

Flow rate: 0.5 ml/min

MS/MS

Instrument: API-4000

The method of ionization, ionization electroreception (ESI) (Turbo Ion Spray)

Table 16
Connection, No.The concentration of L-DOPA in plasma (%)
4 hours6 hours
1-1182,9±5,0189,2±32,8
Comparative example 1br143.3±13,3106,9±18,2

The results clearly show that increasing the concentration of L-DOPA in plasma podderjivaetsa greater extent when the compound of the present invention are administered together with L-DOPA and carbidopa, in comparison with increasing concentration, when the compound of comparative example 1 is administered together with L-DOPA and carbidopa.

The test example 4

Potentiation of the efficacy of L-DOPA in unilaterally affected 6-hydroxydopamine Hemi-parkinsonism rats

(1) Drugs

Use the following connections:

6-hydroxydiphenylamine (6-OHDA; Sigma); desipramine.premarin (desipramine, Sigma); L-ascorbic acid (Sigma); pentobarbital sodium (Nembutal inj., Dainippon Sumitomo Pharma Co., Ltd); hemihydrate apomorphine-hydrochloride (apomorphine, Sigma); 3,4-dihydroxyphenylalanine (L-DOPA, Sigma); carbidopa monohydrate (carbidopa, Kemprotec Ltd.); of 0.5% methylcellulose (Wako Pure Chemicals).

Dissolve 6-OHDA at a concentration of 2 mg/ml in saline containing 0.2% L-ascorbic acid. The desipramine is dissolved at a concentration of 10 mg/ml in distilled water in a bath with hot water. Apomorphine was dissolved in a concentration of 0.1 mg/ml in saline. L-DOPA/carbidopa suspended in 0.5% solution of methylcellulose. Compound dissolved in the solution containing 0.5% DMSO, 20% polyethylene glycol and 79.5% of an aqueous solution of arginine (0.1 mol/l).

(2) Receiving 6-OHDA-affected model

Receiving 6-OHDA-affected model is carried out in accordance with the ways the Ohm non-patent reference 6 with a slight modification. Male rats Sprague-Dawley (age 6 weeks, Charles River Laboratories Japan Inc.) anaesthetize by intraperitoneal administration of pentobarbital sodium (45 mg/kg) and placed in a stereotaxic frame (Narishige, Tokyo, Japan). In order to prevent induced by 6-OHDA lesion of noradrenergic neurons, conduct intraperitoneal injection of desipramine (25 mg/kg) 30 min before injection of 6-OHDA. After identification of Brahma through the incision in the middle of the vault of the skull the skull base are drilled using a drill at the site of injection of 6-OHDA. The lesion produced by injection of 6-OHDA (8 μg in 4 μl at a speed of 1 mm/minute) unilaterally into the left medial beam forebrain (the coordinates of the lesion; a/R-2.5 mm, L/M is-1.8 mm and V/D -8,0 mm, from the point of bregma and the surface of the base of the skull) using injection cannula (needle 30 size), which is connected with microspace (Hamilton). The cannula gently removed from the animal after retention at the site of the lesion within 5 minutes. The base of the skull fill in the hole by a dental cement, disinfected, and the incision in the scalp is surgically sewn. Animals recovered after anesthesia, contain as usual until the day of the experiment.

(3) Assessment of behavior during the rotation

Three weeks after the defeat of the rats tested on the basis of their contralateral rotation (one rotation is defined as 360°) in response to n is 0.1 mg/kg apomorphine, introduced subcutaneously. For behavioral observations of rats placed in plastic cylinders with a radius of 20 cm, the behavior when rotating recorded on video tape and quantify using the system automatically considers turns rats, R-RACS (Kissei Wellcom Co., Ltd.). Animals that rotate within 100 rotational pulses within 1 hour, approve for further experiments. On the day of the experiment animals do not feed within 10 hours from 9 am, and all compound given orally in doses of 10 mg/kg with concomitant orally administered 5 mg/kg L-DOPA and 30 mg/kg carbidopa. The efficacy of a drug is measured as the number of contralateral rotations, and the duration of response is defined as the period of time up until the animal shows no less than 20 of the rotational pulses for 10 minutes over a 60 minute period. The total number of pulses and duration of response are presented in table 17. The results of the control group, which treated only with L-DOPA and carbidopa, presented in the same table.

Table 17
Connection, No.Duration (minutes)The total number of pulses
Control133,8611,9
1-1293,82060,8
1-2312,52103,0
1-5321,32051,9
1-14275,01678,4

From the above results, when compared with control animals treated only with L-DOPA/carbidopa, there is a significant potentiation of drug effects in animals that were administered the compounds of the present invention in combination with L-DOPA/carbidopa.

Application in industry

Compounds of the present invention exhibit significant inhibitory of COMT activity and therefore are useful for the treatment or prevention of Parkinson's disease, depression or hypertension. In particular, the compounds of the present invention can be used for the treatment or prevention of Parkinson's disease, as the use of compounds of the present invention in combination with L-DOPA significantly increases the bioavailability of L-DOPA.

The list of sequences

[SEQ ID NO:1]

The follower is ity ID NO:1 indicates the sequence of recombinant human catechol-O-methyltransferase.

[SEQ ID NO:2]

Sequence ID NO:2 indicates the DNA sequence, which is designed for the expression of recombinant human catechol-O-methyltransferase, is presented in sequence ID NO:1, amplified by the use of primerno pairs, shown in sequence ID NO:3 and 4.

[SEQ ID NO:3]

Sequence ID NO:3 indicates the sequence 5'-primer used for amplification of the DNA sequence presented in the sequence ID NO:2.

[SEQ ID NO:4]

Sequence ID NO:4 indicates the sequence of the 3'-primer used for amplification of the DNA sequence presented in the sequence ID NO:2.

1. The connection represented by the General formula (I):

or its pharmaceutically acceptable salt,
where R1and R2each independently from each other represents a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group or-C(O)NR11R12;
R3is:
a) halogen(lower)alkyl group;
b) a lower acyl group;
c) halogen(lower)alkylcarboxylic group;
d) 3-7-membered saturated cycloalkylcarbonyl group;
e) phenylcarbonylamino group, where the ring phenylcarbonylamino group is unsubstituted or substituted by Deputy, is selected from the group includes halogen atom, a lower alkyl group, a 3-7-membered saturated cycloalkyl-(lower)alkoxygroup, the hydroxy-group, the lower alkoxycarbonyl group and cyano group,
f) 5 - or 6-membered monocyclic heteroarylboronic group, where heteroaryl contains from 3 to 5 carbon atoms and 1 or 2 heteroatoms, independently selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom,
g) phenyl-(lower)alkylcarboxylic group,
h) phenyloxy-(lower)alkylcarboxylic group,
i) lower alkoxycarbonyl group,
j) 3-7-membered saturated cycloalkylcarbonyl group,
k) a lower alkoxy-(lower)alkoxycarbonyl group,
l) carboxy group,
m) cyano group,
n) -C(O)NR11R12,
o) -C(O)C(O)NR11R12,
R) lower alkylsulfonyl group,
q) -SO2NR11R12or
r) 5 - or 6-membered monocyclic heteroaryl group containing from 3 to 5 carbon atoms and 1 or 2 heteroatoms, independently selected from the group comprising an oxygen atom, nitrogen atom and sulfur atom, where the ring heteroaryl group is unsubstituted or substituted lower alkyl group;
R4is:
a) a lower alkyl group,
b) halogen(lower)alkyl group,
c) 3-7-membered saturated cycloalkyl group,
d) tetrahydropyranyloxy group,
e) ness the Yu alkoxy-(lower)alkyl group,
f) phenyloxy-(lower)alkyl group, or
g) lower alkoxycarbonyl-(lower)alkyl group; and
R11and R12each independently from each other represents a hydrogen atom, a lower alkyl group, 6-membered cycloalkyl group, 7-10-membered bridged cyclic hydrocarbon group, or phenyl group.

2. The compound according to claim 1 or its pharmaceutically acceptable salt, where R1and R2each independently from each other represents a hydrogen atom, a lower acyl group, a lower alkoxycarbonyl group or-C(O)NR11R12;
R3is:
a) halogen(lower)alkyl group;
b) a lower acyl group;
c) halogen(lower)alkylcarboxylic group;
d) 3-7-membered saturated cycloalkylcarbonyl group;
e) phenylcarbonylamino group, where the ring phenylcarbonylamino group is unsubstituted or substituted by a Deputy selected from the group comprising a halogen atom and a lower alkyl group,
f) 5 - or 6-membered monocyclic heteroarylboronic group, where heteroaryl contains from 3 to 5 carbon atoms and 1 or 2 heteroatoms, independently selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom,
g) phenyl-(lower)alkylcarboxylic group,
h) phenyloxy-(lower)alkylcarboxylic group,
i) a lower alkoxycarbonyl the second group,
j) 3-7-membered saturated cycloalkylcarbonyl group,
k) a lower alkoxy-(lower)alkoxycarbonyl group,
l) carboxypropyl,
m) cyano group,
n) -C(O)NR11R12,
o) -C(O)C(O)NR11R12,
p) lower alkylsulfonyl group,
q) -SO2NR11R12or
r) 5 - or 6-membered monocyclic heteroaryl group containing from 3 to 5 carbon atoms and 1 or 2 heteroatoms, independently selected from the group comprising an oxygen atom, nitrogen atom and sulfur atom, where the ring heteroaryl group is unsubstituted or substituted lower alkyl group;
R4is:
a) a lower alkyl group,
b) halogen(lower)alkyl group,
c) 3-7-membered saturated cycloalkyl group,
d) tetrahydropyranyloxy group,
e) a lower alkoxy-(lower)alkyl group,
f) phenyloxy-(lower)alkyl group, or
g) lower alkoxycarbonyl-(lower)alkyl group; and
R11and R12each independently from each other represents a hydrogen atom, a lower alkyl group, 6-membered cycloalkyl group, 7-10-membered bridged cyclic hydrocarbon group, or phenyl group.

3. The compound according to claim 2 or its pharmaceutically acceptable salt, where R1and R2represent a hydrogen atom.

4. The compound according to claim 3 or pharmaceutically when mlama salt, where R3is:
a) a lower acyl group;
b) halogen(lower)alkylcarboxylic group;
c) 3-7-membered saturated cycloalkylcarbonyl group;
d) phenylcarbonylamino group, where the ring phenylcarbonylamino group is unsubstituted or substituted by a Deputy selected from the group comprising a halogen atom and a lower alkyl group,
e) 5 - or 6-membered monocyclic heteroarylboronic group, where heteroaryl contains from 3 to 5 carbon atoms and 1 or 2 heteroatoms, independently selected from the group consisting of oxygen atom, nitrogen atom and sulfur atom,
f) phenyl-(lower)alkylcarboxylic group,
g) phenyloxy-(lower)alkylcarboxylic group,
h) lower alkoxycarbonyl group,
i) 3-7-membered saturated cycloalkylcarbonyl group,
(j) a lower alkoxy-(lower)alkoxycarbonyl group,
k) -C(O)C(O)NR11R12or
1) a 5 - or 6-membered monocyclic heteroaryl group containing from 3 to 5 carbon atoms and 1 or 2 heteroatoms, independently selected from the group comprising an oxygen atom, nitrogen atom and sulfur atom, where the ring heteroaryl group is unsubstituted or substituted lower alkyl group.

5. The compound according to claim 4 or pharmaceutically acceptable salt, where R4is:
a) a lower alkyl group,
b) 3-7-membered of NASA the military cycloalkyl group,
c) a lower alkoxy-(lower)alkyl group, or
d) lower alkoxycarbonyl-(lower)alkyl group.

6. The compound according to claim 5 or its pharmaceutically acceptable salt, where R3is:
a) a lower acyl group;
b) 3-7-membered saturated cycloalkylcarbonyl group;
c) phenylcarbonylamino group, where the ring phenylcarbonylamino group is unsubstituted or substituted by a Deputy selected from the group comprising a halogen atom and a lower alkyl group,
d) lower alkoxycarbonyl group,
e) 3-7-membered saturated cycloalkylcarbonyl group,
f) a lower alkoxy-(lower)alkoxycarbonyl group, or
g) -C(O)C(O)NR11R12.

7. The compound according to claim 5 or its pharmaceutically acceptable salt, where R3is:
a) a lower acyl group;
b) 3-7-membered saturated cycloalkylcarbonyl group;
c) phenylcarbonylamino group, where the ring phenylcarbonylamino group is unsubstituted or substituted by a Deputy selected from the group comprising a halogen atom and a lower alkyl group,
d) lower alkoxycarbonyl group, or
e) -C(O)C(O)NR11R12.

8. The compound or its pharmaceutically acceptable salt selected from the group including:
[3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]phenylmethanone;
1-[3,4-dihydroxy-6-(5-methyl-[,2,4]oxidiazol-3-yl)-2-nitrophenyl]Etalon;
methyl-3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrobenzoate;
N-cyclohexyl-2-[3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]-2-oxoacetate;
N-cyclohexyl-2-[3,4-dihydroxy-6-(5-methyl-[1,2,4]-oxadiazol-3-yl)-2-nitrophenyl]-N-methyl-2-oxoacetate;
1-{6-[5-(2-ethoxyethyl)-[1,2,4]oxadiazol-3-yl]-3,4-dihydroxy-2-nitrophenyl}Etalon; and
cyclohexyl-[3,4-dihydroxy-6-(5-methyl-[1,2,4]oxadiazol-3-yl)-2-nitrophenyl]metano.

9. The pharmaceutical composition inhibiting catechol-O-transfersno activity which contains as an active ingredient the compound according to any one of claims 1 to 8, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

10. Pharmaceutical combination for the treatment or prevention of Parkinson's disease, which comprises (1) a pharmaceutical composition comprising a compound according to any one of claims 1 to 8, or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, and (2) at least one compound selected from L-DOPA or carbidopa.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (VI): or its pharmaceutically acceptable salts; wherein n is equal to 0, 1, 2 or 3; R1 means -OH, H; R2a means OH, -CH3, provided at least one of R1 and R2a means -OH;R3 means Cl, Br, cyclopropyl, branched C3-5alkyl R4a means H; R8 means H; wherein the fragment: may be one of the groups B8, B35, B36, B37, B38, B39, B40, B41, B42, B43, B45, B46, B48, B54, B56, B58, B59, B61, B62, B71, B72, B74, B75, B76, B77, B78, B79, B80, B81, B82, B84, B86, B87, B88, B89, B90, B91, B93, B94, B95, B96, B97, B98, B99, B100 and B101 wherein the values are disclosed in the patent claim 1.

EFFECT: compounds show Hsp90 inhibitory activity that enables using them for treating the diseases caused by abnormal cell growth in mammals.

26 cl, 8 dwg, 2 tbl, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine-3-yl derivatives of formula (I)

wherein A represents *-CONH-CH2-, *-CO-CH=CH-, *-CO-CH2CH2-, or wherein asterisks specify a link which binds with a pyridine group of formula (I); R1 represents hydrogen, C1-4alkyl or chlorine; R2 represents C1-5alkyl or C1-4alkoxy group; R4 represents hydrogen or C1-4alkyl; R4 represents hydrogen, C1-4alkyl; C1-4alkoxy group or halogen; R5 represents -CH2-(CH2)n- CONR51R52, -CO-NHR51, 1-(3-carboxyazetidinyl)-2-acetyl, hydroxy group, hydroxyC2-5alkoxy group, di-(hydroxy C1-4alkyl) C1-4alkoxy group, 2,3-dihydroxypropoxy group, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxy group, -OCH2-CH(OH)-CH2-NR51R52 or -OCH2-CH(OH)-CH2-NHCOR54; R51 represents hydrogen, C1-3alkyl, 2-hydroxyetyl, 2-hydroxy-1-hydroxymethyletyl or 2,3-dihydropropyl; R52 represents hydrogen; R54 represents hydroxymethyl; n represents 0 or 1; and R6 represents hydrogen, C1-4alkyl or halogen; and a salt of said compound. Also the invention describes a pharmaceutical composition for prevention or treatment of diseases or conditions associated with activated immune system, on the basis of the compound of formula I and application of said compounds for preparing said pharmaceutical composition.

EFFECT: there are produced and described new compounds which are especially active as immunomodulatory agents.

18 cl, 92 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I):

, where: R=NO2, or and Het denotes an azolyl radical selected from nitroazolyl and tetrazolyl radicals; except 3- and nitro-4-(4-nitro-1,2,3-triazol-1-yl)furazan. The invention also describes a method of producing a compound of formula I and an energy composition based on said compounds.

EFFECT: compounds have high energy characteristics, low sensitivity and high thermal stability.

11 cl, 7 ex, 3 tbl, 2 dwg

FIELD: chemistry.

SUBSTANCE: invention describes isoxazolines of formula (I), in which A denotes C or N; R denotes C1-4 haloalkyl; X denotes identical or different halogens or C1-4 haloalkyl; l equals 0, 1 or 2; Y denotes halogen or C1-4 alkyl, C1-4alkoxy, C1-4haloalkyl, cyano, nitro, amino, C1-4 alkylcarbonylamino, benzoylamino or C1-4 alkoxycarbonylamino; m equals 1 or 1; and G denotes any group selected from heterocyclic groups given in the description, and a method of producing said compounds and use as insecticides for controlling the population of harmful insects or arthropods.

EFFECT: high efficiency of using said compounds.

11 cl, 28 ex, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound with formula (I): where the values of radicals Q, R1, R2, R3, R4, X and Y are as specified in Clause 1 of the patent claim or to a pharmaceutically acceptable salt of such compound or a compound ether hydrolysed in vivo provided such compound is not: {(3S)-1-[5-(adamantan-1-ylcarbamoyl)pyridine-2-yl] piperidine-3-yl} acetic acid or {(3S)-1-[5-(cyclohexylcarbamoyl)-6-(piperazine-1-yl) pyridine-2-yl] piperidine-3-yl} acetic acid or a pharmaceutically acceptable salt thereof or a compound ether hydrolysed in vivo. Additionally, the invention relates to a pharmaceutical composition containing a compound with formula I for treatment of metabolic syndrome, Type II diabetes, adiposity etc and to application of such compound with formula I for manufacture of a medication to be applied for causing an inhibition effect with regard to 11βHSD1 with a homoiothermal animal.

EFFECT: produced and described is a new compound possessing inhibition activity with regard to Type 1 human 11-β-hydroxisteroiddehydrohenase enzyme (11βHSD1).

15 cl, 187 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted cyclohexylmethyl derivatives, having serotonin, noradrenaline or opioid receptor inhibiting activity, optionally in form of cis- or trans-diastereomers or mixture thereof in form of bases or salts with physiologically compatible acids. In formula (1): R2 denotes H or OH; R1 and R2 together denote or =N-OH, R3 denotes a phenyl residue which is unsubstituted or monosubstituted with a halogen atom or a heteroaryl residue selected from a five-member sulphur-containing heteroaryl such as a thienyl residue or an unsubstituted phenyl residue bonded through a C1-C4alkyl group, R4 and R5 independently denote an unsubstituted C1-C3alkyl or R4 and R5 together denote (CH2)3-6, R8 denotes a linear saturated C1-C4 alkyl group bonded with an aryl, which is unsubstituted or monosubstituted with halogen atoms, R9 denotes a saturated C1-C8alkyl; values of radicals R1, m, n, R6, R7, R10-R13 are given in the claim. The invention also relates to methods of producing compounds of formula (I), a medicinal agent containing said compounds, use of compounds of formula (I) to prepare a medicinal agent for anaesthetic treatment during sharp, neuropathic or chronic pain and for treating depression, urinary incontinence, diarrhoea and alcoholism.

EFFECT: high efficiency of using the compounds.

32 cl, 501 ex, 21 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formulae (I) and (III), as well as isomers or pharmaceutically acceptable salts thereof: where the values of radicals are given in claim 1 and 5. The invention also relates to a pharmaceutical composition based on said compounds, which has vanilloid receptor antagonist activity, use of said compounds to produce a medicinal agent for preventing or treating a condition which is associated with aberrant expression and/or aberrant activation of the vanilloid receptor. Described also is a method of producing a compound of formula III.

EFFECT: novel compounds which can be used as vanilloid receptor antagonists, for preventing or treating diseases are obtained and described.

40 cl, 281 ex, 3 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula

wherein A, R1, R2, R3, R4, R5 and R6 are presented in the description, preparing and using them as pharmaceutically active compounds as immunomodulatory agents.

EFFECT: preparing the pharmaceutical composition showing agonist activity with respect to S1P1/EDG1 receptor and using it for prevention and treatment diseases or disorders associated with activated immune system.

20 cl, 244 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclic compounds of formula ,

wherein X2 represents residue C-Z-R2 or C-R3, wherein Z represents NH or S; R1 is selected from structures , and R2 and R3 have the values specified in cl.1 of the patent claim, or to their pharmaceutically acceptable salts. The invention also refers to a pharmaceutical composition, a series of specific compounds, application of the declared compounds and to an intermediate compound for preparing the compounds of formula (I).

EFFECT: compounds under the invention have affinity to muscarine receptors and can be used in treating, relieving and preventing diseases and conditions mediated by muscarine receptors.

13 cl, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine of formula (I) in which R1 denotes a methyl group, R2 denotes a R21NR22 group, where R21 denotes an ethyl group which is substituted with an ethoxycarbonyl group, and R22 denotes a pyridin-2-yl group, R3 denotes an n-hexyloxycarbonyl group, where at step (a) phenyldiamine of formula (II) where R1 and R2 assume values given for formula (I), which reacts with 2-[4-(1,2,4-oxadiazol-5-on-3-yl)phenylamino]acetic acid, to obtain a product of formula (III) where R1 and R2 assume values given for formula (I), which is hydrogenated at temperature from 30 to 60°C at hydrogen pressure from 1 to 10 bar, over palladium on activated charcoal (Pd/C) in a mixture of tetrahydrofuran and water, and then, without any preliminary extraction of the hydrogenation product, the obtained compound of formula (I), in which R3 denotes hydrogen, in the presence of potassium carbonate reacts with a compound of formula (IV) R3-X (IV), where R3 assumes values given for formula (I), and X denotes a suitable splitting group.

EFFECT: simple method of producing optionally substituted 4-(benzimidazo-2-yl methylamino)benzamidine.

3 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new phenyl derivatives with the formula (I) where # symbol indicates two carbon atoms of the phenyl ring bearing R1, R2 and R3; to each of the latter components the A group can be linked; and where A represents or where asterisks indicate the link through which the formula (I) is linked to the phenyl ring bearing R1, R2 and R3; R1 represents hyndrogen or C1-3-alkyl; R2 represents C2-5-alkyl or C1-4-alkoxy group; R3 represents hydrogen, and in case when the A group is linked in the para-position in relation to the phenyl ring of the formula (I) bearing R1, R2 and R3, R3 can additionally represent the methyl group; R4 represents hydrogen; R5 represents C1-3-alkyl; R6 represents a hydroxy group, di-(hydroxy-C1-4-alkyl)-C1-4-alkoxy group, 2,3-dihydroxypropoxy group, -OCH2-CH(OH)-CH2-NR61R62 or -OCH2-CH(OH)-CH2-NHCOR64; R61 represents hydrogen; R62 represents hydrogen; R64 represents hydroxymethyl; and R7 represents C1-3-alkyl; and to its salt. The invention also refers to the pharmaceutical composition that is agonistic in relation to S1P1/EDG1 receptor on the basis of the mentioned compounds.

EFFECT: new compounds and the pharmaceutical composition based on them that may find their application in medicine as immunomodulating agents.

18 cl, 2 tbl, 28 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: 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: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula (IC-2), to their pharmaceutically acceptable salts, N- oxides or solvates. In formula (IC-2) Z represents carbomoyl group, which can be replaced with C1-4 alkyl or hydroxy; R1 represents C1-8 alkyl or C1-8 alkoxy; R4 and R4-1 each independently represent hydrogen atom or C1-8 alkyl; m represents integer number from 1 to 5, when m equals 2 or larger number, all R1 can have same or different values. Invention also relates to compounds, representing 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-napthlenyl}methyl)-3-azetidinecarbonic acid, 1-({6-[(4-isobutyl-2-methoxybenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalinyl}methyl)-3- azetidinecarbonic acid and other, given in formula of claimed invention.

EFFECT: obtaining pharmaceutical composition, which has agonistic activity with respect to EDG-1, EDG-6 and/or EDG-8, containing as active component invention compound, to method of prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8 invention compounds, to method of prevention and/or treatment of disseminated sclerosis and method of immune reaction suppression and/or induction of lymphopenia, to application of invention compounds for obtaining medication for prevention and/or treatment of disease, conditioned by EDG-1, EDG-6 and/or EDG-8, to application of compounds for obtaining medication for prevention and/or treatment of disseminated sclerosis, to application of compounds for obtaining immunodepresant and/or medication inducing lymphopenia and to crystal forms of some individual compounds.

17 cl, 10 dwg, 5 tbl, 251 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 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: 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, pharmaceutics.

SUBSTANCE: invention refers to sulphonic 2-nitro-2-(3-aryl-1,2,4-oxadiazole-5-yl)ethane derivatives of formula I a-g la R=3-NO2C6H4, R1=NO2, R2=H; b R=3-NO2C6H4, R1=NO2, R2=CH3; c R=4-CH3OC6H4, R1=NO2, R2=H; d R=4-CH3OC6H4, R1=NO2, R2=CH3; e R=4-CH3OC6H4, R1=CO2Et, R2=H; f R=4-CH3OC6H4, R1=CO2Et, R2=CH3; g R=4-CH3C6H4, R1=CO2Et, R2=H.

EFFECT: preparation of the compound exhibiting antileprous and antituberculous activity.

1 cl, 1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to the following compounds: N-(1-{4-[2-(1-acetylamino-ethyl)-1-ethyl-1H-imidazol-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trofluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-methyl-1-hydroxy-ethyl)-1-ethyl-1H-imidazole-4-yl}-benzyl}-3-hydroxy-propyl)-3-chloro-4-(,2,2,2-trifluoro-1-methyl-ethoxy)-benzamide, N-(1-{4-[2-(1-hydroxy-1-methyl-ethyl)-1-methyl-1H-imidazole-4-yl]-benzyl}-3-hydroxy-propyl)-3-chloro-4-(2,2,2,-trifluoro-1-methyl-ethoxy)-benzamide, 3-chloro-N-[2-[(N,N-dimethylglicyl)amino]-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)ethyl]-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-(1-(2-(dimethylamino)acetamido)-3-(4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl)propan-2-yl)-4-isopropoxybenzamide, 3-chloro-N-(2-[(2-methylalanyl)amino]-1-{[4-(8-methylimidazo[1,2-a]pyridin-2-yl)phenyl]methyl}ethyl)-4-[(1-methylethyl)oxy]benzamide, 3-chloro-N-[(3-hydroxy)-1-({4-[8-(1-hydroxyethyl)imidazo[1,2-a]pyridine-2-yl]phenyl}methyl)propyl]-4-[(1-methylethyl)oxy]benzamide, as well as to their pharmaceutically acceptable salts.

EFFECT: obtained compounds and salts can be used for treatment cell proliferative diseases and disorders by modulating activity of mitotic kinesin CENP-E.

26 cl, 102 ex, 7 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide, and/or their mixture, as well as to applying it in a pharmaceutical composition, a method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease. Also, the invention refers to methods for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)-piperidin-4-ylidene)methyl)benzamide and its intermediate compounds. .

EFFECT: developing the method of treating to be applied for treating pain, anxiety, depression, worried depression or Parkinson's disease.

12 cl, 1 ex

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