Derivatives of aryl- and heteroarylpiperidinecarboxylates, their production and their use as inhibitors of faah ferment

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of aryl and heteroarylpiperidinecarboxylates, of formula (I): , where: type means integer numbers from 1 to 3, such that m+n is integer number from 2 to 5; p means integer number from 1 to 7; A means simple connection or is selected from one or several groups X, Y; X means -CH2-; Y means C2-alkynilene group; R1 means group R5, substituted with one or several groups R6 and/or R7; R2 means H, F, OH; R3 means H; R4 means H, C1-6-alkyl; R5 means group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinolynyl, tetrahydrochinolinyl, isochinolinyl, tetrahydroisochinolinyl, indolyl, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzizoxazolyl, benzothiazolyl, benzithiazolyl, benzotriazolyl, benzoxadiazolyl, pyrrolopyridinyl; R6 means halogen, CN, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, OH, C1-6-fluoroalkyl, C1-6-fluoroalkoxy, or cycle selected from pyrrolidine and piperidine cycle, besides this cycle is unnecessarily substituted with C1-6-alkyl group; R7 means phenyl group, besides group or groups R7 may be substituted with one or several groups R6, identical or differing from each other, selected from halogen, C1-6-alkyl and C1-6-fluoroalkyl, C1-6-alkoxy, in the form of pharmaceutically acceptable base or acid-additive salt.

EFFECT: compounds are applicable as inhibitors of FAAH ferment.

10 cl, 1 tbl, 7 ex

 

The object of the invention are derivatives of aryl - and heteroarylboronic, obtaining them and their use in therapy.

Known derivatives phenylalkylamines, dioxane-2-allylcarbamate and type aryloxyalkanoic described respectively in documents FR2850377 A, WO2004/020430 A2 and PCT/FR2005/00028, are inhibitors of the enzyme FAAH (Fatty Acid Amido Hydrolase).

The need to identify and develop inhibitors of the enzyme FAAH always exists. Compounds according to the invention meet this goal.

Compounds according to the invention correspond to General formula (I):

in which

m and n denote integers from 1 to 3 such that m+n is an integer from 2 to 5,

p is an integer from 1 to 7,

A simple means bond or is selected from one or more groups X, Y and/or Z,

X represents a methylene group, optionally substituted by one or two groups representing C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylen,

Y represents C2-alkynylamino group, optionally substituted by one or two groups representing C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene; or C2-alkynylamino group;

Z means a group of the formula:

o is an integer from 1 to 5,

r and s denote integers and are defined such that r+s is a number from 1 to 5

R1means the group R5, optionally substituted by one or more groups R6and/or R7,

R2means a hydrogen atom or fluorine, a hydroxyl group, a C1-6-alkoxy or NR8R9,

R3means a hydrogen atom or a C1-6is an alkyl group,

R4means a hydrogen atom or a group that represents C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl;

R5means a group selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, teinila, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazoline, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, chinoline, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, heatline, khinoksalinona, phthalazine, cinnoline, naphthyridine, benzofuranyl, dihydrobenzofuranyl, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazole, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, benzotriazolyl, benzoxadiazole, benzothiadiazole, pyrrolopyridine, properidine, thienopyridine, imidazopyridine, oxazolopyridine, enous is iloperidone, pyrazolopyrimidine, isoxazolidine, isothiazolinone,

R6means a halogen atom or a group that represents cyano, nitro, C1-6-alkyl,

C3-7-cycloalkyl, C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-foralkyl, C1-6-feralcode, C1-6-vertially, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, COR8, CO2R8, CONR8R9, SO2R8, SO2NR8R9, -O-(C1-3-alkylen)or cycle selected from azetidine, pyrolidine, piperidino, morpholino, thiomorpholine, azepino, pieperazinove cycle, and this cycle is optionally substituted C1-6is an alkyl or benzyl group;

R7means phenyl group, phenyloxy, benzyloxy, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, and the group or groups R7can be substituted by one or more groups R6the same or different from each other;

R8and R9independently from each other mean a hydrogen atom or a C1-6is an alkyl group.

Thus, in the framework of the invention compounds of General formula (I) can contain multiple groups A, same or different from each other.

Of the compounds of General formula (I) first subgroup of compounds of clicks the comfort connection, in which:

m and n denote integers of 1 or 2 such that m+n is an integer from 2 to 4

p is an integer equal to from 1 to 3,

A simple means of communication, a methylene group or a C2-akinyan;

R1means the group R5, optionally substituted by one or more groups R6and/or R7,

R2means a hydrogen atom or a hydroxyl group,

R3means a hydrogen atom or a C1-6is an alkyl group,

R4means a hydrogen atom or a group C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl,

R5means a group selected from phenyl, pyridinyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, indoline, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridine;

R6means a halogen atom, in particular bromine, chlorine, fluorine, or a group that represents cyano, C1-6-alkyl, in particular methyl, butyl, isobutyl, C3-7-cycloalkyl, in particular cyclopentyl, C1-6-alkoxy, in particular methoxy or ethoxy, C1-6-foralkyl, in particular trifluoromethyl, or pyrolidine or piperidinyl cycle, and this cycle is optionally substituted C1-6-alkyl the Oh group, in particular isopropyl;

R7means a phenyl group which may be substituted by one or more groups R6the same or different from each other.

Of the compounds of General formula (I), a second subgroup of compounds is formed by compounds in which:

m and n denote integers of 1 or 2 such that m+n is an integer from 2 to 4;

p is an integer from 1 to 3,

A simple means of communication, a methylene group or a C2-akinyan;

R1means the group R5, optionally substituted by one or more groups R6and/or R7,

R2means a hydrogen atom or a hydroxyl group,

R3means a hydrogen atom or a C1-6is an alkyl group,

R4means a hydrogen atom or a group that represents C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl,

R5means a group selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, isoxazolyl, naphthyl, izochinolina,

R6means a halogen atom, in particular bromine, chlorine, fluorine, or a group that represents cyano, C1-6-alkyl, in particular methyl, butyl, isobutyl, C3-7-cycloalkyl, in particular cyclopentyl, C1-6-alkoxy, in particular methoxy or ethoxy, C1-6-foralkyl, in particular, trifluoromethyl, or pyrolidine or p is peridynamic cycle, moreover, this cycle is optionally substituted C1-6-alkyl group, in particular isopropyl,

R7means a phenyl group which may be substituted by one or more groups R6the same or different from each other.

Of the compounds of General formula (I) third subgroup of compounds is formed by compounds in which:

m, n, p, A, R1such as defined in the first subgroup, defined above,

R3means a hydrogen atom,

R4means a hydrogen atom or a C1-6-alkyl group, in particular methyl.

Of the compounds defined above subgroups include the following compounds:

- [2-(methylamino)-2-oxoethyl]-4-{5-[4-(trifluoromethyl)phenyl]pyridine-2-yl}piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4'-chlorobiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4'-ethoxymethyl-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3',4'-dichlorobiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3'-chloro-4'-forbiden-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[(6-cyclopentenopyridine-2-yl)methyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[2-(3-chlorophenyl)ethyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[2-(4-chlorophenyl)ethyl]piperidine-1-carbox the lat,

- [2-(methylamino)-2-oxoethyl]-4-{2-[3-(trifluoromethyl)phenyl]ethyl}piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-{2-[4-(trifluoromethyl)phenyl]ethyl}piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(2-biphenyl-3-retil)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[2-(1-naphthyl)ethyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[2-(2-naphthyl)ethyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[2-(6-cyclopentenopyridine-2-yl)ethyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[2-(6-pyrrolidin-1-espiridion-2-yl)ethyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(2-isoquinoline-1-retil)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(3-chlorophenyl)propyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(4-chlorophenyl)propyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-{3-[3-(trifluoromethyl)phenyl]propyl}piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-{3-[4-(trifluoromethyl)phenyl]propyl}piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(3-cyanophenyl)propyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3-biphenyl-2-ylpropyl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3-biphenyl-3-ylpropyl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(1-naphthyl)propyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(2-n is ftil)propyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(1,3-thiazol-2-yl)propyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[(3-chlorophenyl)ethinyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[(4-chlorophenyl)ethinyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(biphenyl-3-ylethynyl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(1-naphthylamine)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(2-naphthylamine)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3-biphenyl-2-rprop-2-in-1-yl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[(6-pyrrolidin-1-espiridion-2-yl)methyl]piperidine-1-carboxylate.

Of the compounds of General formula (I) one subfamily of compounds is formed by compounds corresponding to General formula (I'):

in which

m and n denote integers from 1 to 3 such that m+n is an integer from 2 to 5,

p is an integer from 1 to 7,

A simple means bond or is selected from one or more groups X, Y and/or Z,

X represents a methylene group, optionally substituted by one or two groups representing C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkylen,

Y denotes either C2-alkynylamino group, optionally substituted by one or two groups representing C1-6-alkyl, C3-7 -cycloalkyl or C3-7-cycloalkyl-C1-3-alkylene; or C2-alkynylamino group,

Z means a group of the formula:

o is an integer from 1 to 5,

r and s denote integers and are defined such that r+s is a number from 1 to 5

R1means the group R5, optionally substituted by one or more groups R6and/or R7,

R2means a hydrogen atom or a fluorine, a hydroxyl group, a C1-6-alkoxy or NR8R9,

R3means a hydrogen atom or a C1-6is an alkyl group,

R4means a hydrogen atom or a group that represents C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl,

R5means a group selected from phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, pyrrolyl, furanyl, teinila, imidazolyl, oxazolyl, thiazolyl, pyrazolyl, isoxazolyl, isothiazoline, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, naphthyl, chinoline, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, heatline, khinoksalinona, phthalazine, cinnoline, naphthyridine, benzofuranyl, dihydrobenzofuranyl, benzothiazyl, dihydrobenzofuranyl, indolyl, indolinyl, indazole, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazole,benzothiazole, benzisothiazole, benzotriazolyl, benzoxadiazole, benzothiadiazole, pyrrolopyridine, properidine, thienopyridine, imidazopyridine, oxazolopyridine, triazolopyridine, pyrazolopyrimidine, isoxazolidine, isothiazolinone,

R6means a halogen atom or a group that represents cyano, nitro, C1-6-alkyl,

C1-6-alkoxy, hydroxyl, C1-6-thioalkyl, C1-6-foralkyl, C1-6-feralcode, C1-6-vertially, NR8R9, NR8COR9, NR8CO2R9, NR8SO2R9, COR8, CO2R8, CONR8R9,

SO2R8, SO2NR8R9or-O-(C1-3-alkylene)-Oh,

R7means phenyl group, phenyloxy, benzyloxy, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl or pyrazinyl, and the group or groups R7can be substituted by one or more groups R6the same or different from each other,

R8and R9independently from each other mean a hydrogen atom or a C1-6is an alkyl group, or together with the atom or atoms to which they are linked, form a cycle selected from azetidine, pyrolidine, piperidino, morpholino, thiomorpholine, azepino, pieperazinove cycle, optionally substituted C1-6-alkyl or benzyl the Noah group.

Of the compounds of General formula (I') the first subgroup of compounds is formed by compounds in which:

m and n denote integers of 1 or 2 such that m+n is an integer from 2 to 4

p is an integer equal to 1 or 2,

A simple means bond or methylene group;

R1means the group R5, optionally substituted by one or more groups R6and/or R7,

R2means a hydrogen atom or fluorine, a hydroxyl group, a C1-6-alkoxy or NR8R9,

R3means a hydrogen atom or a C1-6is an alkyl group,

R4means a hydrogen atom or a group that represents C1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkyl,

R5means a group selected from phenyl, imidazolyl, naphthyl, tetrahydroquinoline, tetrahydroisoquinoline, indoline, indolinyl, benzimidazolyl, benzotriazolyl, pyrrolopyridine,

R6means a halogen atom, in particular bromine, chlorine, fluorine, or C1-6-alkyl group, in particular methyl, butyl, C1-6-alkoxy, in particular methoxy or ethoxy, C1-6-foralkyl, in particular trifluoromethyl,

R7means a phenyl group which may be substituted by one or more groups R6the same or different from each other.

Of the compounds of the General the th formula (I') the second subgroup of compounds is formed by compounds in which:

m, n, p, A, R1such as defined in the first subgroup, defined above,

R3means a hydrogen atom,

R4means a hydrogen atom or a C1-6-alkyl group, in particular methyl.

Of the compounds of General formula (I') include the following compounds:

- (2-amino-2-oxoethyl)-4-phenylpiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-phenylpiperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[3-(trifluoromethyl)phenyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3-(trifluoromethyl)phenyl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(1H-1,2,3-benzotriazol-1-yl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4'-forbiden-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4'-chlorobiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-hydroxy-4-(4'-methylbiphenyl-4-yl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(4'-butylbiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-hydroxy-4-[4'-(trifluoromethyl)biphenyl-4-yl]piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-hydroxy-4-[4'-(metiloksi)biphenyl-4-yl]piperidine-1-carb is kilat,

- [2-(methylamino)-2-oxoethyl]-4-[4'-(ethyloxy)biphenyl-4-yl]-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3',4'-dichlorobiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-[3'-fluoro-4'-(metiloksi)biphenyl-4-yl]-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(3'-chloro-4'-forbiden-4-yl)-4-hydroxypiperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(naphthalene-2-ylmethyl)piperidine-1-carboxylate,

- [2-(methylamino)-2-oxoethyl]-4-(biphenyl-4-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-(1H-indol-1-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-(2,3-dihydro-1H-indol-1-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-(3,4-dihydroquinoline-1(2H)-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-(3,4-dihydroisoquinoline-2(1H)-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-(1H-pyrrolo[2,3-b]pyridine-1-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-(1H-benzimidazole-1-ylmethyl)piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[(4-phenyl-1H-imidazol-1-yl)methyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-3-(2-phenylethyl)pyrrolidin-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[2-(3,4-dihydroquinoline-1(2H)-yl)ethyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[2-(3,4-dihydroisoquinoline-2(1H)-yl)ethyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)4-[2-(1H-indol-1-yl)ethyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[2-(2,3-dihydro-1H-indol-1-yl)ethyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[2-(1H-pyrrolo[2,3-b]pyridine-1-yl)ethyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[2-(1H-benzimidazole-1-yl)ethyl]piperidine-1-carboxylate,

- (2-amino-2-oxoethyl)-4-[2-(4-phenyl-1H-imidazol-1-yl)ethyl]piperidine-1-carboxylate.

Compounds of General formula (I) may contain one or more asymmetric carbons. They can exist in the form of enantiomers or diastereoisomers. These enantiomers or diastereoisomers, and also mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or acid additive salts. Such additive salts are part of the invention.

These salts are preferably derived from pharmaceutically acceptable acids, but the salts of other acids that are suitable, for example, for the purification or separation of compounds of formula (I), also form part of the invention.

Compounds of General formula (I) can be in the form of a hydrate or of a solvate, namely in the form of aggregates or combinations with one or more water molecules or with a solvent. Such hydrate and solvate are also part of the invention.

In the context of the invention means that:

- Ct-zwhere t and z can take values from 1 to 7, means of plastics technology : turning & is dnow chain, which can have from t to z carbon atoms, for example, C1-3means a carbon chain which can have from 1 to 3 carbon atoms;

- alkyl means saturated aliphatic group, linear or branched; for example, With1-6is an alkyl group means a carbon chain with 1-6 carbon atoms, linear or branched, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl;

- alkylene means a divalent saturated alkyl group, linear or branched, for example, With1-3-Allenova group means a divalent carbon chain of 1-3 carbon atoms, linear or branched, in particular methylene, ethylene, 1-mutilation, propylene;

- cycloalkyl means a cyclic alkyl group, for example, With3-7-cycloalkyl group means a cyclic carbon group having 3-7 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;

- albaniles means a divalent unsaturated aliphatic group with 2 carbon atoms, in particular ethenylene;

- C2-Akinyele means the group-C≡C-;

- alkoxy means an-O-alkyl group with a saturated aliphatic chain, linear or branched;

- thioalkyl means-S-alkyl group with a saturated aliphatic chain, linear or razvetvlenno is;

- foralkyl means an alkyl group in which one or more hydrogen atoms replaced by fluorine atom;

- feralcode means alkoxygroup, in which one or more hydrogen atoms replaced by fluorine atom;

- vertially means thioalkyl group in which one or more hydrogen atoms replaced by fluorine atom;

the halogen atom means fluorine, chlorine, bromine or iodine.

Compounds according to the invention can be obtained by the method shown in the following diagram.

Scheme

Compounds according to the invention can be obtained by introducing in the reaction of the amine of General formula (II)in which R1, A, R2, p, m, and n are defined in the General formula (I), with a carbonate of General formula (III)in which Z means a hydrogen atom or a nitro-group, R3defined in the General formula (I), and R denotes a methyl or ethyl group, in a solvent such as toluene, dichloroethane, acetonitrile, or in mixtures of these solvents, at a temperature of from 0°C to 80°C. the Obtained esters-carbamates of General formula (IV) then convert into compounds of General formula (I) aminolysis an amine of General formula R4NH2where R4defined in the General formula (I). The reaction aminolysis can be carried out in a solvent such as methanol or ethanol, or a mixture of such solvent is th, as methanol and tetrahydrofuran.

Compounds of General formula (I) or (IV)in which R1means a group of the type aryl-aryl, aryl-heteroaryl, heteroaryl-aryl or heteroaryl-heteroaryl, can also be obtained by reaction of the corresponding compounds of General formula (I) or (IV)in which R5substituted by chlorine atom, bromine, iodine or triflate group in the position where should be put in group R7with a derivative of an aryl - or heteroarylboronic acid, following the conditions of the Suzuki reaction (Chem. Rev. 1995, 95, 2457-2483) or a derivative of an aryl - or heteroaryl-trialkylamine, following the reaction conditions Stella (Angew. Chem. Int. Ed. 1986, 25, 504-524).

The carbonates of General formula (III) can be obtained by any method described in the literature, for example, by reaction of the alcohol of General formula HOCHR2COOR, where R is a methyl or ethyl group, with chloroformate phenyl or 4-nitrophenyl, in the presence of such a base as triethylamine or diisopropylethylamine.

Compounds of General formula (II)and amines of General formula R4NH2when the retrieval method is not described, can be purchased in Commerce or described in the literature, or can be obtained by other methods described in the literature or known to the expert.

Compounds of General formula (IV)in which R1, A, R2, R3, p, m, and n are defined in the General formula (I), and R oz is achet methyl or ethyl group, are new and also form part of the invention. They are suitable as intermediates for the synthesis to obtain the compounds of General formula (I).

The following examples illustrate the obtaining of some compounds according to the invention. These examples are not limiting and only illustrate the present invention. Microanalysis, IR and NMR spectra and/or LC-MS (liquid chromatography coupled with mass spectroscopy) confirmed the structure and purity of the obtained compounds.

TPL(°C) mean melting temperature in degrees Celsius.

The numbers indicated in parentheses in the titles of the examples correspond to the numbers shown in the first column in the table below.

To refer to compounds in the following examples was used nomenclature IUPAC (international Union of Pure and Applied Chemistry, English IUPAC). For example, for biphenylenes group observed the following numbering:

Example 1(compound No. 14)

[2-(methylamino)-2-oxoethyl]-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate

1.1. 1,1-dimethylethyl-4-[(methylsulphonyl)oxy]piperidine-1-carboxylate

To a solution of 3.0 g (14.9 mmol) of 1,1-dimethylethyl-4-hydroxypiperidine-1-carboxylate and 2.2 ml (to 17.9 mmol) of triethylamine in 60 ml of dichloromethane, cooled to Le the Jana bath, with stirring, added dropwise to 1.4 ml (to 17.9 mmol) methanesulfonanilide. Continue to stir for one hour at 0°C, then 4 hours at ambient temperature. The reaction mixture is diluted with 100 ml dichloromethane and washed successively with 100 ml of an aqueous solution of sodium bicarbonate, then saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Dried over sodium sulfate and evaporated to dryness. Then the residue is triturated in a 50/50 mixture of cyclohexane and diethyl ether to obtain 3.7 g of product as a white solid substance.

1.2. 1,1-dimethylethyl-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate

To a suspension of 1.1 g (of 27.9 mmol) of sodium hydride (60%suspension in oil) in 30 ml of N,N-dimethylformamide, cooled in an ice bath, is added dropwise a solution of 4.0 g (of 27.9 mmol) of 4-phenylimidazole in 40 ml of N,N-dimethylformamide. Then stirred for one hour at ambient temperature, then cooled to 0°C and added dropwise 2.6 g (9.3 mmol) of 1,1-dimethylethyl-4-[(methylsulphonyl)oxy]piperidine-1-carboxylate, obtained in stage 1.1, in solution in 20 ml of N,N-dimethylformamide. Then heated to 80°C for 2 hours. The reaction mixture was cooled to ambient temperature and diluted with 150 ml water and 150 ml ethyl acetate. The aqueous phase is decanted and extracted twice with 00 ml of ethyl acetate. The organic phase is twice washed with 100 ml of water, then 100 ml of a saturated aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel, elwira a 98/2 mixture of dichloromethane and methanol, to obtain 1.0 g of product as a yellow oil.

1.3. 4-(4-phenyl-1H-imidazol-1-yl)piperidine

To a solution of 1.0 g (3,05 mmol) 1,1-dimethylethyl-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate, obtained in stage 1.2, in 60 ml of dichloromethane, cooled in an ice bath, is added dropwise 5.6 ml (76,3 mmol) triperoxonane acid. Then stirred for one hour at ambient temperature and evaporated to dryness. The residue is introduced into 25 ml of water and add 2 ml of 30%aqueous sodium hydroxide solution. Stirred for 30 minutes, then extracted four times with 80 ml of dichloromethane. Then the organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness to obtain 0.7 g of product as a yellow oil, used in the next stage.

1.4. [2-(ethyloxy)-2-oxoethyl]-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate

A solution of 1.0 g (4.4 mmol) of 4-(4-phenyl-1H-imidazol-1-yl)piperidine obtained in stage 1.3, and 1.18 g (5.2 mmol) of ethyl[(phenoxycarbonyl)oxy]acetate (J. Med. Chem, 1999, 42, 277-290) in 50 ml of toluene is heated Ave is 60°C during the night. Then is evaporated to dryness and the residue is introduced into 80 ml of ethyl acetate and 80 ml of water. Decanted and the aqueous phase is extracted three times with 80 ml of ethyl acetate. Then the organic phase is washed with 80 ml of a saturated aqueous solution of sodium chloride. Dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel, elwira a 98/2 mixture of dichloromethane and methanol, to obtain 0.35 g of the product.

1.5. [2-(methylamino)-2-oxoethyl]-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate

Dissolve 0.35 g (0.98 mmol) [2-(ethyloxy)-2-oxoethyl]-4-(4-phenyl-1H-imidazol-1-yl)piperidine-1-carboxylate, obtained in stage 1.4, in 7 ml of methanol. Add 1.5 ml (3 mmol) of a 2 M solution of methylamine in tetrahydrofuran. After 16 hours at ambient temperature was added 1 ml (2 mmol) of a solution of methylamine (2m) in tetrahydrofuran and allowed to interact for another 6 hours. Is evaporated to dryness and the residue purified by chromatography on silica gel, elwira mixture 98/2 then 97/3, 96/4 and 95/5 dichloromethane and methanol. Then triturated in diethyl ether to obtain 0.20 g of product as a white solid substance.

Melting point (°C): 192-194

LC-MS: M+H=343

1H-NMR (CDCl3) δ (ppm): of 7.75 (d, 2H), 7,60 (s, 1H), 7,40 (m, 2H), 7,25 (m, 2H), 6,05 (Shir. s, 1H)and 4.65 (s, 2H), 4,35 (m, 2H), 4,15 (m, 1H), 3,05 (m, 2H), 2,90 (d, 3H), of 2.20 (m, 2H), 2.05 is-of 1.85 (m, 2H).

Example 2(compound No. 32)

[2-(methyl) - Rev. Mino)-2-oxoethyl]-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

2.1. [2-(ethyloxy)-2-oxoethyl]-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

A mixture of 2.24 g (10 mmol) of ethyl[(phenoxycarbonyl)oxy]acetate and of 2.56 g (10 mmol) of 4-(4-bromophenyl)-4-piperidinol in solution in 40 ml of toluene is heated at 50°C for 20 hours. The solution is evaporated to dryness on a water bath under reduced pressure. Get the oil, which is directly used in the next stage.

2.2. [2-(methylamino)-2-oxoethyl]-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate

[2-(ethyloxy)-2-oxoethyl]-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate, obtained in stage 2.1, stirred for 3 hours at 33%solution of methylamine in methanol. The solution is concentrated on a water bath under reduced pressure. The residue is purified by chromatography on silica gel, elwira with ethyl acetate. Obtain 2.6 g of the product in the form of oil, which gradually solidifies.

Melting point (°C): 57-60

LC-MS: M+H=371

1H-NMR (DMSO-d6) δ (ppm): 1.55V (Shir. s, 1H), 7,50 (d, 2H), 7,40 (d, 2H), 5,20 (s, 1H), and 4.40 (s, 2H), 3,80 (m, 2H), 3,20 (m, 2H), 2,60 (d, 3H), 1,90 of 1.50 (m, 4H).

Example 3(compound No. 40)

[2-(methylamino)-2-oxoethyl]-4-(3',4'-dichlorobiphenyl-4-yl)-4-hydroxypiperidine-1-carboxylate

Mix 0.1 g (0.27 mmol) of [2-(methylamino)-2-oxoethyl]-4-(4-bromophenyl)-4-hydroxypiperidine-1-carboxylate, poluchennogo is according to example 2, 0,077 g (0.4 mmol) of 3,4-dichlorophenylamino acid, 10 mg of tetrakis-(triphenylphosphine)palladium(0), 2 ml of an aqueous solution (2 M) of sodium carbonate, 0.5 ml of ethanol and 4 ml of toluene and purged with nitrogen. Heated at 80°C under stirring for 20 hours. Filtered at high temperature through a hydrophobic cartridge, washed with tetrahydrofuran (THF) and evaporated to dryness. The residue is purified by chromatography LC-MS phase of silicon oxide, elwira with a gradient of mixtures of cyclohexane/ethyl acetate/methanol to obtain 0,069 g of crystallized product.

Melting point (°C): 156-158

LC-MS: M+H=438

1H-NMR (DMSO-d6) δ (ppm): to 7.95 (s, 1H), 7,80 (m, 1H), of 7.70 (m, 4H), 7,60 (m, 2H), 5,20 (s, 1H), of 4.45 (s, 2H), 4.00 points (m, 2H), 3,25 (m, 2H), 2,60 (d, 3H), of 1.95 (m, 2H), 1,65 (m, 2H).

Example 4(compound No. 43)

[2-(methylamino)-2-oxoethyl]-4-(naphthalene-2-ylmethyl)piperidine-1-carboxylate

4.1. 1,1-dimethylethyl-4-(naphthalene-2-ylmethyl)piperidine-l-carboxylate

In the atmosphere of argon added to 8.0 ml of 0.5 N. (4 mmol) of 9-borabicyclo[3.3.1]nonane in tetrahydrofuran to a solution of 0,789 g (4 mmol) of 1,1-dimethylethyl-4-metiletilpiridin-1-carboxylate (Tetrahedron Letters 1996, 37(30), 5233-5234) in solution in 5 ml of tetrahydrofuran. Refluxed for 3 hours. Cool at ambient temperature and add 0,787 g (3.8 mmol) of 2-bromonaphthalene in rest the re in 9 ml of N,N-dimethylformamide, 0,829 g (6.0 mmol) of potassium carbonate in solution in 1 ml of water and 0.16 g (0.20 mmol) of the complex [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II)-dichloromethane). Refluxed over night. The reaction mixture is diluted with 150 ml ethyl acetate and 50 ml of water. The organic phase is decanted and washed with 25 ml of water, then with 25 ml of a saturated aqueous solution of sodium chloride. Dried over magnesium sulfate and evaporated in vacuum. The residue is purified by chromatography on silica gel, elwira a 99/1 mixture, then 95/5 and 90/10 cyclohexane and ethyl acetate to obtain 0,79 g of the product as a colourless viscous liquid.

4.2. 4-(naphthalene-2-ylmethyl)piperidine

Dissolve 0,79 g (2,43 mmol) 1,1-dimethylethyl-4-(naphthalene-2-ylmethyl)piperidine-1-carboxylate, obtained in stage 4.1, in 10 ml of dichloromethane and add 2 ml (25 mmol) triperoxonane acid. Stirred for 3 hours at ambient temperature. Is evaporated under reduced pressure, then add 4 ml of 1,2-dichloroethane and again evaporated. The residue is introduced into a mixture of 50 ml of dichloromethane and 15 ml of 10%aqueous sodium hydroxide solution. The organic phase is decanted and the aqueous phase is extracted twice with 25 ml dichloromethane. The organic phase was washed with 15 ml saturated aqueous solution of sodium chloride, then dried over sodium sulfate and evaporated in vacuum to obtain 0.52 g of the product VI is e orange oil, used in the next stage.

4.3. [2-(ethoxy)-2-oxoethyl]-4-(naphthalene-2-ylmethyl)piperidine-1-carboxylate

During the night heated at 60°C a mixture of 0.52 g (2.3 mmol) of 4-(naphthalene-2-ylmethyl)piperidine obtained in stage 4.2, and 0.69 g (3.11 mmol) of ethyl[(phenoxycarbonyl)oxy]acetate in 10 ml of toluene and 5 ml of acetonitrile. Is evaporated in vacuum. The residue is purified by chromatography on silica gel, elwira mixture 90/10, then 85/15 and 80/20 cyclohexane and ethyl acetate to obtain 0.56 g of product as a colorless viscous liquid.

4.4. [2-(methylamino)-2-oxoethyl]-4-(naphthalene-2-ylmethyl)piperidine-1-carboxylate

In 3 ml of methanol is dissolved 0,54 g (of 1.52 mmol) [2-(ethoxy)-2-oxoethyl]-4-(naphthalene-2-ylmethyl)piperidine-1-carboxylate, obtained in stage 4.3, and add 3 ml (6.0 mmol) of a 2 M solution of methylamine in tetrahydrofuran. Left to react overnight at ambient temperature, then add 1.5 g of silicon oxide and evaporated. The residue is purified by chromatography on silica gel, elwira mixture of 98.5/1.5 a, then 97/3 dichloromethane and methanol. Then recrystallized in a mixture of ethyl acetate and diisopropyl ether to obtain of 0.43 g of product as a white solid substance.

Melting point (°C): 150-152

LC-MS: M+H 341

1H-NMR (CDCl3) δ (ppm): 7,80 (m, 3H), 7,60 (s, 1H), 7,45 (m, 2H), 7,30 (d, 1H), 6,10 (m, 1H), 4,60 (s, 2H), 4,15 (m, 2H), 2,85 (d, 3H), 2,85-2,75 (m+d, 4H, 1,90 is 1.70 (m, 3H), 1,35-of 1.15 (m, 2H).

Example 5(compound No. 107)

[2-(methylamino)-2-oxoethyl]-4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine-1-carboxylate

5.1. Tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate

To a solution of 30.4 g (132 mmol) of tert-butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate in 150 ml of dichloromethane, cooled to 0°C, added in several portions to 70.9 g (167 mmol) of (1,1,1-Tris(atomic charges)-1,1-dihydro-1,2-benzodioxol-3-(1H)-she (reagent dess-Martin). Stirred for 2 hours at ambient temperature, then add 150 ml of 10%aqueous solution of sodium thiosulfate (Na2S2O3and additionally continue to mix for another 30 minutes. The organic phase is decanted, washed with saturated aqueous sodium carbonate, dried over sodium sulfate and evaporated to dryness to obtain 30.1 g (132 mmol) of the product as a colourless oil, used in the next stage.

5.2. Tert-butyl 4-(3,3-dibromo-2-EN-1-yl)piperidine-1-carboxylate

To a solution of 139,4 g (531 mmol) of triphenylphosphine in 440 ml of toluene, cooled to -20°C, add 47,6 ml (531 mmol) tribromomethane, then to 59.6 g (531 mmol) of potassium tert-butylate. Continue to mix at -20°C for 15 minutes, then add a solution of 30.1 g (131 mmol) of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate obtained in stud and 5.1, in 240 ml of toluene. Then stirred at ambient temperature for 3 hours. Add 300 ml of diethyl ether, filter the resulting solid phase and the filtrate is evaporated. The residue is purified by chromatography on silica gel, elwira dichloromethane, to obtain a 32.6 g (85 mmol) of the product as a yellow oil.

5.3. Tert-butyl-4-prop-2-in-1-reparacin-1-carboxylate

Dissolve 32,6 g (85 mmol) of tert-butyl 4-(3,3-dibromo-2-EN-1-yl)piperidine-1-carboxylate, obtained in stage 5.2, in 420 ml of anhydrous tetrahydrofuran. Cooled to -78°C and with vigorous stirring, added dropwise 106 ml (1,6 M) n-utility (170 mmol) in hexane, dissolved in 100 ml of anhydrous tetrahydrofuran. Continue to stir at -78°C for 3 hours, and then at -20°C for 1 hour. Cooled to -78°C and add 130 ml of a 1.25 M solution of hydrochloric acid in ethanol. Then again heated to ambient temperature over one hour. Add water and ethyl acetate. The organic phase is decanted, washed her saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel, elwira dichloromethane, then with a 98/2 mixture of dichloromethane and methanol, to obtain 32,4 g (of 85.2 mmol) of the product as a colourless oil.

5.4. Tert-butyl 4-[3-(4-chlorophenyl)prop-2-the-1-yl]piperidine-1-carboxylate

Dissolve to 2.29 g (9.6 mmol) of 1-chloro-4-yogashala and 1.7 ml (12 mmol) of triethylamine in 5 ml of tetrahydrofuran. In an argon atmosphere add 0,076 g (0.40 mmol) of copper iodide and has 0.168 g (0.24 mmol) of the complex dichloride bis(triphenylphosphine)palladium, and then added dropwise a solution of 1.78 g (8 mmol) of tert-butyl-4-prop-2-in-1-reparacin-1-carboxylate, obtained in stage 5.3, in 3 ml of tetrahydrofuran. Continue to stir over night. Add 25 ml of water and 100 ml of ethyl acetate. The organic phase is decanted, washed successively with 25 ml 10%ammonium, 25 ml water and 25 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to dryness. The residue is purified by chromatography on silica gel, elwira mixture 95/5, then 90/10 cyclohexane and ethyl acetate to obtain 2.15 g (6,44 mmol) of the product as a yellow oil.

5.5. 4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine

Dissolve to 2.13 g (6.38 mmol) of tert-butyl 4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine-1-carboxylate, obtained in stage 5.4, in 15 ml of dichloromethane. Added dropwise a solution of 4.9 ml (63,8 mmol) triperoxonane acid in 5 ml of dichloromethane. Leave to communicate over night at ambient temperature, then evaporated to dryness. Add 25 ml of dichloroethane and again evaporated to dryness. Then the residue is introduced into a mixture of 70 ml of ethyl acetate, 10 ml of 1 N. aqueous solution of hydrocyanate and 10 ml of 30%ammonium. The organic phase is decanted, washed with 2 times 10 ml of water, then 10 ml of a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness to obtain 1.39 g (5,94 mmol) of the product as a brown oil, used in the next stage.

5.6. (2 ethoxy-2-oxoethyl)-4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine-1-carboxylate

A solution of 1.39 g (5,94 mmol) 4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine obtained in stage 5.5, and 1.86 g (8,33 mmol) of ethyl[(phenoxycarbonyl)oxy]acetate in 12 ml of toluene is heated at 70°C for 5 hours. Is evaporated to dryness and the residue purified by chromatography on silica gel, elwira mixture 90/10 then 80/20 cyclohexane and ethyl acetate to obtain 1.89 g (5,19 mmol) of the product as a viscous oil.

5.7. [2-(methylamino)-2-oxoethyl]-4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine-1-carboxylate

Dissolve 0,91 g (2.51 mmol) (2-ethoxy-2-oxoethyl)-4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine-1-carboxylate, obtained in stage 5.6, 4 ml of methanol. Add 2.5 ml (25 mmol) of a 33%solution of methylamine in ethanol and left overnight at ambient temperature. Is evaporated to dryness and the residue purified by chromatography on silica gel, elwira mixture of 99.5/0.5 to then 98/2 and 96/4 dichloromethane and methanol. Crystallized in hexane, then dried in vacuum to obtain 0.50 g (1,43 mmol) of the product as a white powder is A.

Melting point (°C): 101-103

LC-MS: M+H=349

1H-NMR (CDCl3) δ (ppm): 7,20 (m, 4H), 6.30-in (m, 1H), 4,50 (Shir. s, 2H), 4,10 (Shir. d, 2H), 2,75 (m+d, 5H), 2,30 (d, 2H), 1.85 to to 1.60 (m, 3H), 1,35-of 1.15 (m, 2H).

Example 6(compound No. 83)

[2-(methylamino)-2-oxoethyl]-4-[3-(4-chlorophenyl)propyl]piperidine-1-carboxylate

Dissolve 0.156 g (0,448 mmol) [2-(methylamino)-2-oxoethyl]-4-[3-(4-chlorophenyl)prop-2-in-1-yl]piperidine-1-carboxylate obtained in example 5, in 2 ml of ethanol. Add 16 mg of platinum dioxide. Stirred in hydrogen atmosphere at a pressure and ambient temperature for 2 hours, then at 40°C for another 2 hours. Filtered through celite and the filtrate is evaporated. The residue is purified HPLC-chromatography on a gel Nucleosil, elwira gradient from 70/30/0 to 0/80/20 hexane, ethyl acetate and methanol, to obtain 0.108 mg (0,306 mmol) of product as a white solid substance.

Melting point (°C): 118-120

LC-MS: M+H=353

1H-NMR (CDCl3) δ (ppm): to 7.25 (d, 2H), 7,10 (d, 2H), equal to 6.05 (m, 1H), 4,60 (s, 2H), 4,10 (Shir. d, 2H), 2,90 (d, 3H), 2,80 (Shir. t, 2H), 2,60 (t, 2H), 1,75-of 1.55 (m, 4H), of 1.45 (m, 1H), 1,35-of 1.05 (m, 4H).

Example 7(compound No. 74)

[2-(methylamino)-2-oxoethyl]-4-(2-isoquinoline-1-retil)-1-piperidinecarboxylate

7.1. Tert-butyl 4-(iodomethyl)-1-piperidinecarboxylate

To a solution of 10 g (46,45 mmol) of tert-butyl 4-(hydroxymethyl-1-piperidinecarboxylate, 15,84 g (60,38 mmol) of triphenylphosphine and 4,74 g (69,67 mmol) of imidazole in 200 ml of dichloromethane, cooled to about 0°C in small portions add 14,15 g (is 55.74 mmol) of iodine (I2), maintaining the temperature of the reaction environment between 0°C and 5°C. Continue to stir at 0°C for 1 hour, then at ambient temperature for 4 hours.

Add 100 ml of water and 300 ml of ethyl acetate. The organic phase is decanted, washed her consistently saturated aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on silica gel, elwira a 90/10 mixture of cyclohexane and ethyl acetate. Get 13,70 g (42,13 mmol) of the product as a colourless oil.

7.2. Tert-butyl 4-(2-isoquinoline-1-retil)-1-piperidinecarboxylate

To a solution of 2,202 g (15,38 mmol) of 1-methylisoquinoline in 150 ml of tetrahydrofuran, cooled to about -70°C, are added dropwise 10 ml (20 mmol) of a solution (2 M) diisopropylamide lithium (LDA) in a mixture of tetrahydrofuran and n-hexane. Continue to stir at -70°C for 10 minutes, then slowly add a solution of 5 g (15,38 mmol) of tert-butyl 4-(iodomethyl)-1-piperidinecarboxylate obtained at the stage 7.1, in 30 ml of tetrahydrofuran. After 30 minutes of stirring at -70°C add 100 ml saturated in the aqueous solution of ammonium chloride. Brought to ambient temperature, separating the aqueous phase is then extracted 3 times its ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrate under reduced pressure. The resulting residue is purified by chromatography on silica gel, elwira a 99/1 mixture, then 98/2 dichloromethane and methanol. Gain of 1.80 g (from 5.29 mmol) of the product as a yellow oil.

7.3. (2-piperidine-4-retil)-1-isoquinoline

To a solution of 1.60 g (4,70 mmol) of tert-butyl 4-(2-isoquinoline-1-retil)-1-piperidinecarboxylate obtained at the stage 7.2, in 15 ml of 1,4-dioxane was added when the temperature of the environment, 3,90 ml (23,50 mmol) solution (6 BC) of hydrochloric acid in isopropanol. Then the reaction mixture is kept at about 60°C for 12 hours.

Concentrate to dryness under reduced pressure. The resulting hydrochloride is introduced into 5 ml of water, then while mixing, slowly add 20%aqueous sodium hydroxide solution to pH 9. The aqueous phase is extracted twice with chloroform, the combined organic phases are washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrate under reduced pressure. Get 0.400 g (of 1.66 mmol) of the product as a brown oil.

7.4. (2 ethoxy-2-oxoethyl)-4-(2-isoquinoline-1-retil)-1-piperidinecarboxylate

Rest the R 0,320 g (of 1.33 mmol) (2-piperidine-4-retil)-1-isoquinoline, obtained at the stage of 7.3, and 0,388 g (1,73 mmol) of ethyl[(phenoxycarbonyl)oxy]acetate in 10 ml of toluene is heated at 70°C for 18 hours. Brought to ambient temperature, concentrated under reduced pressure, then the residue purified by chromatography on silica gel, elwira a 40/60 mixture of ethyl acetate and cyclohexane. So get 0,390 g (1.05 mmol) of the product as a viscous oil.

7.5. [2-(methylamino)-2-oxoethyl]-4-(2-isoquinoline-1-retil)-1-piperidinecarboxylate

To a solution of 0,380 g (1,03 mmol) (2-ethoxy-2-oxoethyl)-4-(2-isoquinoline-1-retil)-1-piperidinecarboxylate obtained at the stage of 7.4, 10 ml of methanol, add 2,60 ml (5,13 mmol) of a solution of methylamine (2 M in tetrahydrofuran. Continue to stir at ambient temperature for 12 hours.

After concentration under reduced pressure, the obtained residue is purified by chromatography on silica gel, elwira a 95/5 mixture of dichloromethane and methanol. Get a solid substance that will recrystallized in a mixture of ethyl acetate and diisopropyl ether. In this way receive 0,315 g (0.88 mmol) of product as a white solid substance.

LC-MS: M+H=356

Melting point (°C): 126-128

1H-NMR (CDCl3) δ (ppm): 8,50 (d, 1H), 8,15 (d, 1H), of 7.90 (d, 1H), of 7.70 (m, 2H), 7,55 (d, 1H), 6,10 (Shir. s, 1H), 4,60 (Shir. s, 2H), 4,20 (m, 2H), 3,35 (DD, 2H), 2,90 (m+d, 5H), 1,90 (m, 4H), of 1.65 (m, 1H), 1,30 (m, 2H).

In shadowmania table 1 shows the chemical structure and physical properties of some compounds according to the invention.

In this table:

- all connections are in the form of a free base,

- n-butyl mean linear boutelou group.

2
No.R1[A]pR2nmR3R4TPL °C (M+H)
1.phenyllinkH22HH160-162
2.phenyllinkH22HCH376-78
3. 3-CF3-phenyllinkH22HH(331)
4.3-CF3-phenyllinkH22HCH3(345)
5.5-isobutylidene-2-yllinkH22HCH398-100
6.6-isobutylpyrazine-2-yllinkH22HCH3(334)
7. 6-cyclopentenopyridine-2-yllinkH22HCH3(346)
8.5-(4-F-phenyl)-pyridine-2-yllinkH22HCH3151-153
9.6-(4-F-phenyl)-pyridine-2-yllinkH22HCH3104-106
10.6-(4-Cl-phenyl)-pyridine-2-yllinkH22HCH3136-138
11.5-(4-CF3-phenyl)-pyridine-2-yllinkH22HCH3203-205
12.6-(4-CF3-phenyl)-pyridine-2-yllinkH22HCH3128-130
13.5-(3-CF3-phenyl)-1-methylpyrazole-3-yllinkH22HCH3160-162
14.4-phenylimidazol-1-yllinkH22HCH3 192-194
15.5-phenyl-1,3,4-oxadiazol-2-yllinkH22HH152-154
16.5-phenyl-1,3,4-oxadiazol-2-yllinkH22HCH3114-116
17.5-(4-F-phenyl)-1,3,4-oxadiazol-2-yllinkH22HH158-160
18.5-(4-F-phenyl)-1,3,4-oxadiazol-2-yllinkH22HCH3 163-165
19.5-(3-CF3-phenyl)-1,3,4-oxadiazol-2-yllinkH22HH130-130
20.5-(3-CF3-phenyl)-1,3,4-oxadiazol-2-yllinkH22HCH3123-125
21.3-(3-CF3-phenyl)-1,2,4-oxadiazol-5-yllinkH22HH133-135
22.3-(3-CF3-phenyl)-1,2,4-oxadiazol-5-yllinkH2 HCH3119-121
23.benzoxazol-2-yllinkH22HCH3137-139
24.benzothiazol-2-yllinkH22HH148-150
25.benzothiazol-2-yllinkH22HCH3120-122
26.the benzimidazole-2-yllinkH2 2HCH3213-215
27.the benzimidazole-1-yllinkH22HH206-208
28.2-phenylbenzimidazol-1-yllinkH22HCH3193-195
29.benzotriazol-1-yllinkH22HCH3129-131
30.5-CF3-benzotriazol-1-yllinkH2 2HH152-154
31.indol-1-yllinkH22HH178-180
32.4-Br-phenyllinkOH22HCH357-60
33.4-(4-F-phenyl)phenyllinkOH22HCH3212-214
34.4-(4-Cl-phenyl)phenyllinkOH2 2HCH3223-225
35.4-(4-CH3-phenyl)phenyllinkOH22HCH3179-181
36.4-(4-n-butylphenyl)phenyllinkOH22HCH3(425)
37.4-(4-CF3-phenyl)phenyllinkOH22HCH3191-193
38.4-(4-CH3About-phenyl)phenyllinkOH 22HCH3175-176
39.4-(4-C2H5About-phenyl)phenyllinkOH22HCH3165-167
40.4-(3-CL,4-Cl-phenyl)phenyllinkOH22HCH3156-158
41.4-(3-F,4-CH3About-phenyl)phenyllinkOH22HCH3(417)
42.4-(3-Cl,4-F-phenyl)phenyllink OH22HCH3123-125
43.naphthalene-2-ylCH2H22HCH3150-152
44.4-phenylphenylCH2H22HCH3115-117
45.6-cyclopentenopyridine-2-ylCH2H22HCH3(360)
46.6-(4-F-phenyl)-pyridine-2-ylC 2H22HCH3112-114
47.indol-1-ylCH2H22HH158-159
48.indolin-1-ylCH2H22HH115-116
49.1,2,3,4-tetrahydroquinolin-1-ylCH2H22HH158-159
50.1,2,3,4-tetrahydroisoquinoline-2-yl CH2H22HH(332)
51.pyrrolo[2,3-b]pyridine-1-ylCH2H22HH(317)
52.the benzimidazole-1-ylCH2H22HH(317)
53.4-phenylimidazol-1-ylCH2H22HH124-125
54.phenyl(CH2 )2H12HCH3(291)
55.4-F-phenyl(CH2)2H22HCH3150-152
56.3-Cl-phenyl(CH2)2H22HCH386-88
57.4-Cl-phenyl(CH2)2H22HCH3150-152
58.3-CF3-FeNi is (CH2)2H22HCH3103-105
59.4-CF3-phenyl(CH2)2H22HCH3131-133
60.3-CN-phenyl(CH2)2H22HCH3(330)
61.4-CH3-phenyl(CH2)2H22HH125-127
62 4-CH3-phenyl(CH2)2H22HCH3117-119
63.4-CH3O-phenyl(CH2)2H22HH123-125
64.4-CH3O-phenyl(CH2)2H22HCH3122-124
65.2-phenylphenyl(CH2)2H22HCH3 (381)
66.3-phenylphenyl(CH2)2H22HCH3113-115
67.naphthalene-1-yl(CH2)2H22HCH3112-114
68.naphthalene-2-yl(CH2)2H22HCH3106-108
69.pyrimidine-2-yl(CH2)2H22HCHsub> 3160-170
70.pyrimidine-5-yl(CH2)2H22HCH3123-125
71.6-cyclopentenopyridine-2-yl(CH2)2H22HCH3(374)
72.6-pyrrolidin-1-espiridion-2-yl(CH2)2H22HCH3130-132
73.the thiazole-2-yl(CH2)2H2 HCH397-99
74.isoquinoline-1-yl(CH2)2H22HCH3126-128
75.1,2,3,4-tetrahydroquinolin-1-yl(CH2)2H22HH(346)
76.1,2,3,4-tetrahydroisoquinoline-2-yl(CH2)2H22HH112-114
77.indol-1-yl(CH2)2H 22HH(330)
78.indolin-1-yl(CH2)2H22HH92-93
79.pyrrolo[2,3-b]pyridine-1-yl(CH2)2H22HH(331)
80.the benzimidazole-1-yl(CH2)2H22HH181-182
81.4-phenylimidazol-1-yl(CH2)2H 22HH183-184
82.3-Cl-phenyl(CH2)3H22HCH392-94
83.4-Cl-phenyl(CH2)3H22HCH3118-120
84.3-CF3-phenyl(CH2)3H22HCH3106-108
85.4-CF3-phenyl(CH2)3H2HCH3111-113
86.3-CN-phenyl(CH2)3H22HCH3118-120
87.2-phenylphenyl(CH2)3H22HCH3(395)
88.3-phenylphenyl(CH2)3H22HCH3116-118
89.naphthalene-1-yl(CH2)3 H22HCH3(369)
90.naphthalene-2-yl(CH2)3H22HCH3112-114
91.pyrimidine-2-yl(CH2)3H22HCH3105-107
92.pyrimidine-5-yl(CH2)3H22HCH3105-107
93.the thiazole-2-yl (CH2)3H22HCH3(326)
94.3-Cl-phenylC≡CH22HCH385-87
95.4-Cl-phenylC≡CH22HCH3122-124
96.3-CF3-phenylC≡CH22HCH3(369)
97.4-CF3-phenylC≡C H22HCH3134-136
98.3-CN-phenylC≡CH22HCH3(326)
99.2-phenylphenylC≡CH22HCH3(377)
100.3-phenylphenylC≡CH22HCH3(377)
101.naphthalene-1-ylC≡CH22 HCH3(351)
102.naphthalene-2-ylC≡CH22HCH3(351)
103.pyrimidine-2-ylC≡CH22HCH3(303)
104.pyrimidine-5-ylC≡CH22HCH3136-138
105.the thiazole-2-ylC≡CH22HCH3 (308)
106.3-Cl-phenylC≡CCH2H22HCH391-93
107.4-Cl-phenylC≡CCH2H22HCH3101-103
108.3-CF3-phenylC≡CCH2H22HCH3113-115
109.4-CF3-phenylC≡CCH2H22HCH3112-114
110.3-CN-phenylC≡CCH2H22HCH3112-114
111.2-phenylphenylC≡CCH2H22HCH399-101
112.3-phenylphenylC≡CCH2H22HCH3(391)
113.naphthalene-1-ylC≡CCH2H22HCH398-100
114.Naftal the h-2-yl C≡CCH2H22HCH399-101
115.pyrimidine-2-ylC≡CCH2H22HCH391-93
116.pyrimidine-5-ylC≡CCH2H22HCH3113-115
117.the thiazole-2-ylC≡CCH2H22HCH3112-114
118.6-pyrrolidin-1-espiridion-2-yl CH2H22HCH3119-121
119.6-(1-isopropylpiperazine-4-yl)pyridine-2-yl(CH2)2H22HCH3(431)

Compounds according to the invention were the subject of pharmacological tests to determine their inhibitory effect on the enzyme FAAH (hydrolase fatty acid amides).

Inhibitory activity was confirmed in radioterminal test based on measuring the product of hydrolysis (ethanolamine [1-3H]) of anandamide [ethanolamine 1-3H] by FAAH (Life Sciences (1.995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). So, the mouse brain (without cerebellum) was removed and kept at -80°C. Membrane homogenates were prepared immediately before the experiment by homogenization of tissue in Polytron'e in buffer Tris-HCl 10 mm (pH 8.0)containing 150 mm NaCl and 1 mm EDTA. Then carried out the enzymatic reaction in 70 μl of buffer content is the future bovine serum albumin without fatty acids (1 mg/ml). Consistently added test compounds in different concentrations: anandamide [ethanolamine 1-3H] (specific activity 15-20 CI/mmol)diluted to 10 μm cold anandamide, and the membrane preparation (400 µg frozen tissue on experience). After 15 minutes at 25°C. the enzymatic reaction was stopped by adding 140 μl of a mixture of chloroform/methanol (2:1). The mixture was stirred for 10 minutes, then centrifuged for 15 minutes at 3500 rpm/min an Aliquot (30 μl) of the aqueous phase containing ethanolamine [1-3H] calculated by scintillation fluid.

Under these conditions, the most active compounds according to the invention have CI50(concentration inhibiting 50% of the enzymatic activity of the control FAAH) is from 0.001 to 1 μm.

For example, compound No. 39 and 40 tables have CI50accordingly 0,095 and 0,098 microns.

Thus, it is seen that the compounds according to the invention have inhibitory activity against the enzyme FAAH.

Activityin vivocompounds according to the invention was evaluated in the test for analgesia.

So, intraperitoneal (I.P. Pavlova.) introduction PBQ (phenylbenzophenone, 2 mg/kg in 0.9%sodium chloride solution containing 5% ethanol) to male mice series OF1 weighing 25-30 g, causes spasm of the peritoneum, on average, 30 Perekrestov or reductions for the period from 5 to 15 minutes after injection. Test compounds were introduced peroral what about the (p.o.) or intraperitoneally (I.P. Pavlova.) suspension of Tween-80 concentration of 0.5%, for 60 or 120 minutes prior to the introduction of PBQ. Under these conditions, the most potent compounds according to the invention at 35-70% reduce the number of sprains caused PBQ, in the dose range of 1 to 30 mg/kg, for Example, compound No. 57 table reduces the number of sprains caused PBQ, 37% and 74% at the dose of 3 mg/kg, respectively, after 60 minutes and 120 minutes.

The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107-121) catalyzes the hydrolysis of endogenous derivatives of amides and esters of various fatty acids, such as N-arachidonoylethanolamine (anandamide), N-palmitoylethanolamide, N-oleoylethanolamide, oleamide or 2-arachidonoylglycerol. In addition, these derivatives exhibit different pharmacological activity in interaction with cannabioids and vanilloid receptors.

Compounds of the invention block the path decomposition and increase tissue portion of these endogenous substances. They can be used for this purpose in the prevention and treatment of pathologies involving endogenous cannabinoid and/or any other substrate metabolized by the enzyme FAAH.

Can be called, for example, the following diseases and ailments:

pain, in particular acute or chronic pain of neurogenic type: migraine, neuropathic pain, including forms associated with the herpes virus and diabetes;

acute or chronic pain associated with vospalitelnaya: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularity, Crohn's disease, irritable bowel syndrome;

acute or chronic peripheral pain;

dizziness, vomiting, nausea, in particular resulting from chemotherapy;

eating disorders, particularly anorexia and cachexia of various nature;

neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, obsessive-compulsive disorder, Tourette's syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, psychoses;

acute and chronic neurodegenerative diseases: Parkinson's disease, Alzheimer's disease, senile dementia, Huntington's chorea, lesions associated with cerebral ischemia and traumatic brain injury;

epilepsy;

sleep disorders, including stopping of breathing during sleep;

cardiovascular disease, in particular hypertension, cardiac arrhythmia, arteriosclerosis, heart attacks, ischemia of the heart;

renal ischemia;

cancer: benign skin tumors, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulla-epithelioma, Protocol, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastoma, ependyma, oligodendrogliomas, plexus tumor in, neuro is epithelioma, tumor epiphysis, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanoma, sanomi);

disorders of the immune system, in particular autoimmune diseases: psoriasis, lupus erythematosus, diseases of the connective or connective tissue syndromes Segren, Ancylostoma spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, amylose, rejection of transplants, disease, acting on plasmaatomic series;

allergic diseases: immediate or delayed hypersensitivity, allergic rhinitis or conjunctivitis, contact dermatitis;

infectious parasitic, viral or bacterial diseases: AIDS, meningitis; inflammatory diseases, in particular diseases of the joints: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vascularity, Crohn's disease, irritable bowel syndrome; osteoporosis; eye disease: ocular hypertension, glaucoma;

lung diseases: diseases of the respiratory tract, bronchial constriction, cough, asthma, chronic bronchitis, chronic airway obstruction, emphysema;

gastrointestinal diseases: irritable bowel syndrome, inflammatory intestinal disorders, ulcers, diarrhea;

incontinence is the eyes and inflammation of the urinary bladder.

The use of the compounds of formula (I) pharmaceutically acceptable base, salt, hydrate or MES for obtaining a medicinal product intended for the treatment of the above mentioned pathologies, are an integral part of the invention.

The object of the invention are also medicines that contain the compound of formula (I) or salt, and pharmaceutically acceptable hydrate or MES the compounds of formula (I). These drugs are used in therapy, in particular in the treatment of the aforementioned disorders.

According to another of its aspects the present invention relates to pharmaceutical compositions containing as active ingredient at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention, or a pharmaceutically acceptable salt, MES or hydrates of the compounds, and optionally one or more pharmaceutically acceptable excipients.

These excipients are chosen according to the pharmaceutical form and the desired method of administration, from the usual excipients which are specialist known.

In the pharmaceutical compositions according to the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal, rectal injection or injection through the lungs and eyes, the active substance of the above formula (I) or its possible salt, MES or hydrate can be administered to animals and humans for the prophylaxis or treatment of the above disorders or diseases in a single form of introducing mixed with classical pharmaceutical excipients.

The appropriate common forms of introduction include forms for oral administration such as tablets, soft or hard gelatin capsules, powders, granules, chewing gum and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular, intranasal, administration by inhalation, forms for subcutaneous, intramuscular or intravenous, and rectal or vaginal forms of introduction. For topical administration the compounds according to the invention can be used in creams, gels, lipsticks or lotions.

For example, the common form of the reception of the connection according to the invention in the form of tablets may contain the following components:

The connection according to the present invention:50.0 mg
Mannitol: 223,75 mg
Crosscarmellose sodium:6.0 mg
Corn starch:15,0 mg
The hypromellose:2.25 mg
Magnesium stearate:3.0 mg

These single forms can be dosed to allow a daily intake of 0.01 to 20 mg of active substance per kg of body weight, according to the galenical form.

May be special cases when suitable higher or lower dosages; these dosages are also not beyond the scope of the invention. According to usual practice, the dosage appropriate for each patient is determined by the physician in accordance with the method of administration, the weight and susceptibility of the specified patient.

The present invention according to another of its aspects, also relates to method of treating the above disorders, which includes the patient an effective dose of the compounds according to the invention, one of its pharmaceutically acceptable salts, MES or hydrate specified connection.

1. The compound corresponding to the formula (I)

in which m and n denote integers from 1 to 3 such that m+n is the integer is m a number from 2 to 5,
p means an integer from 1 to 7,
A represents a simple bond or is selected from one or more groups X, Y,
X indicates a methylene group,
Y means With2-alkynylamino group,
R1means the group R5substituted by one or more groups R6and/or R7,
R2means a hydrogen atom or fluorine, a hydroxyl group,
R3means a hydrogen atom,
R4means a hydrogen atom or a group that represents C1-6-alkyl,
R5means a group selected from phenyl, pyridinyl, pyrimidinyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, chinoline, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, indoline, indolinyl, isoindolyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, benzotriazolyl, benzoxadiazole, pyrrolopyridine,
R6means a halogen atom or a group that represents cyano, C1-6-alkyl, C3-7-cycloalkyl,1-6-alkoxy, hydroxyl, C1-6-foralkyl,1-6-feralcode, or cycle, is selected from pyrolidine and piperidino cycle, and this cycle is optionally substituted C1-6is an alkyl group,
R7means phenyl group, and the group or groups R7can be substituted by one or a number of the groups R 6the same or different from each other, selected from halogen, C1-6-alkyl and C1-6-foralkyl,1-6alkoxy.
in the form of a pharmaceutically acceptable base or acid additive salt.

2. The compound of formula (I) according to claim 1, characterized in that:
m and n denote integers of 1 or 2 such that m+n is an integer from 2 to 4,
p denotes an integer equal to from 1 to 3,
A represents a simple bond, a methylene group or2-akinyan;
R1means the group R5, optionally substituted by one or more groups R6and/or R7,
R2means a hydrogen atom or a hydroxyl group,
R3means a hydrogen atom,
R4means a hydrogen atom or a group C1-6-alkyl,
R5means a group selected from phenyl, pyridinyl, pyrimidinyl, imidazolyl, thiazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphthyl, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, indoline, indolinyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridine,
R6means a halogen atom or a group that represents cyano, C1-6-alkyl, C3-7-cycloalkyl, C1-6-alkoxy, C1-6-foralkyl or pyrolidine or piperidinyl cycle, and this cycle is optionally substituted C1-6and Kilroy group,
R7means a phenyl group which may be substituted by one or more groups R6the same or different from each other, selected from halogen, C1-6-alkyl, C1-6-foralkyl, C1-6alkoxy. in the form of a pharmaceutically acceptable base or acid additive salt.

3. The compound of formula (I) according to claim 1 or 2, characterized in that:
m and n denote integers of 1 or 2 such that m+n is an integer from 2 to 4,
p means an integer from 1 to 3,
A represents a simple bond, a methylene group or2-akinyan;
R1means the group R5, optionally substituted by one or more groups R6and/or R7,
R2means a hydrogen atom or a hydroxyl group,
R3means a hydrogen atom,
R4means a hydrogen atom or a group C1-6-alkyl,
R5means a group selected from phenyl, pyridinyl, pyrimidinyl, thiazolyl, isoxazolyl, naphthyl, izochinolina,
R6means a halogen atom or a group that represents cyano, C1-6-alkyl, C3-7-cycloalkyl,1-6-alkoxy, C1-6-foralkyl or pyrolidine or piperidinyl cycle, and this cycle is optionally substituted C1-6is an alkyl group,
R7means a phenyl group which may be substituted by one or some of the groups and R 6the same or different from each other, selected from halogen, C1-6-alkyl, C1-6-foralkyl,1-6alkoxy.

4. The compound of formula (I) according to claim 1 or 2, characterized in that:
R3means a hydrogen atom,
R4means a hydrogen atom or a C1-6is an alkyl group,
able pharmaceutically acceptable base or acid additive salt.

5. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 4, comprising the step consisting in the transformation of the ether-carbamate of General formula (IV)

in which R1, A, R2, R3, p, m and n are such as defined in formula (I) according to claim 1, and R is a methyl or ethyl group,
aminolysis using an amine of General formula R4NH2.in which R4defined in formula (I) according to claim 1.

6. The connection that meets the General formula (IV),

in which R1, A, R2, R3, p, m and n are such as defined in formula (I) according to claim 1, and R is a methyl or ethyl group.

7. The pharmaceutical composition inhibiting FAAH enzymes containing at least one compound of formula (I) according to any one of claims 1 to 4, in the state of pharmaceutically acceptable base or salt, and optionally one or more pharmaceutically acceptable excipients.

8. The use of the connection form is s (I) according to any one of claims 1 to 4, able pharmaceutically acceptable base or salt, as inhibiting FAAH enzymes medicines.

9. The use of the compounds of formula (I) according to any one of claims 1 to 4, in the state of pharmaceutically acceptable base or salt, to obtain FAAH inhibition of a medicinal product intended for the prevention or treatment of pathologies involving the substrates metabolized by the enzyme FAAH.

10. The use of the compounds of formula (I) according to any one of claims 1 to 4, in the state of pharmaceutically acceptable base or salt, to obtain a medicinal product intended for the prevention or treatment of acute or chronic pain, dizziness, vomiting, nausea, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular disease, renal ischemia, cancers, disorders of the immune system, allergic diseases, infectious parasitic, viral or bacterial diseases, inflammatory diseases, osteoporosis, eye diseases, lung diseases, gastrointestinal intestinal diseases or urinary incontinence.



 

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FIELD: medicine.

SUBSTANCE: invention is related to monohydrate of sodium salt S-tenatoprazol, which complies with the following formula: . Invention is also related to method for production of monohydrate of sodium salt of S-tenatoprazol, to application and pharmaceutical composition on its basis for treatment of gastrointestinal pathologies.

EFFECT: production of new compound and pharmaceutical composition on its basis, which may be used in medicine for production of medicinal agents for treatment of gastrointestinal pathologies, gastroesophageal reflux and gastrointestinal haemorrhages in patients, which are prescribed polymedicamental therapy.

19 cl, 9 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of hydantoin with common formula I , where R1 represents cyclobutyl or cyclopropyl; where mentioned group cyclopropyl may be additionally substituted with CH3; R2 represents C1-3alkyl or cyclopropyl; and A, A1 and B independently represent CH or N. Invention is also related to method for production of compounds of formula I, pharmaceutical composition on its basis, its use for making of medicinal agent and to method for inhibition of metal proteinases, based on use of compound of formula I.

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11 cl, 1 tbl, 9 ex

FIELD: medicine.

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6 cl, 3 ex

FIELD: medicine.

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17 cl, 1 tbl, 41 ex

FIELD: medicine.

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7 cl, 45 ex, 2 tbl

FIELD: chemistry.

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5 cl, 1 tbl, 39 ex

FIELD: chemistry.

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7 cl, 6 tbl, 29 ex

FIELD: chemistry.

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18 cl, 32 ex

FIELD: pharmacology.

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26 cl, 49 ex, 2 tbl

FIELD: pharmacology.

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13 cl, 1 tbl, 103 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives (indole-3-yl)heterocyclic compounds of formula 1: , where: A represents 5-member aromatic heterocyclic ring, where X1, X2 and X3 are independently selected from N, O, S, CR; R means H, (C1-4)alkyl; or R, when it is available in X2 or X3, may form 5-8-member ring together with R3; R1 means 5-8-member saturated carbocyclic ring, which unnecessarily contains heteroatom O; R2 means H; or R2 is connected to R7 with creation of 6-member ring, which unnecessarily contains heteroatom O, or where mentioned heteroatom is connected to position 7 of indole ring; R3 and R4 independently mean H, (C1-6)alkyl, which is unnecessarily substituted with OH, (C1-4)alkyloxy; or R3 together with R4 and N, with which they are connected, creates 4-8-member ring, which unnecessarily contains additional heteroatom, selected from O and S, and unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy or (C1-4)alkyloxy-(C1-4)alkyl; or R3 together with R5 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; or R3 together with R, when present in X2 or X3, creates 5-8-member ring; R5 means H; or R5 together with R3 creates 4-8-member ring, unnecessarily substituted with OH, (C1-4)alkyl, (C1-4)alkyloxy; R5' means H; R6 means one substituent selected from H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; R7 means H, (C1-4)alkyl, (C1-4)alkyloxy, halogen; or R7 is connected to R2 with creation of 6-member ring, which unnecessarily contains additional heteroatom O, and where heteroatom is connected to position 7 of indole ring; or its pharmaceutically acceptable salt. Compounds of formula I display activity of agonists to cannabinoid receptor CB1.

EFFECT: possibility to use them for treatment of pains of various nature.

10 cl, 1 tbl, 42 ex

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

FIELD: medicine.

SUBSTANCE: invention is related to new derivatives of benzoindazole of formula I , where radicals A1, A2, A3, R1, R2, R3, R4 and n have values mentioned in formula of invention, and their pharmaceutically acceptable salts, and also to application of these compounds for production of medicinal agent intended for modulation of α2-subsort of GABA receptor, and pharmaceutical composition that contains it.

EFFECT: application of compounds for preparation of medicinal agent intended for treatment of depression, disorder in the form of anxiety, psychic disorder, disturbed ability to learning and cognition, sleep disturbance, disorder in the form of cramps or fits or pain.

16 cl, 5 tbl, 40 ex

FIELD: medicine.

SUBSTANCE: compounds can be used for treatment and prevention of diseases associated with activity of specified enzyme, such as diabetes, obesity, diseases associated with food intake, dyslipidemia and hypertension. In general formula (I) , R1 represents methyl, ethyl, cyclopropyl, cyclobutyl, isopropyl, tert-butyl, methoxymethyl, cyclopropyl methoxymethyl, 2-methyl thiazolyl, morpholinyl methyl or phenyl; R2 represents hydrogen, C1-4alkyl or phenyl; R3 represents hydrogen, C1-4alkyl or phenyl; R4 represents phenyl, naphthyl, thiophenyl, quinolyl or piperidyl where phenyl, naphthyl, thiophenyl, quinolyl and piperidyl are optionally substituted with one to three substitutes independently chosen of C1-4alkyl, halogen, C1-4alkoxy, cyano, trifluoromethyl, phenyl, phenyls C1-4alkyl, phenyloxy, oxasolyl and pyridinyl; R5 represents hydrogen, C1-4alkyl, phenyl-C1-4alkyl, C3-6dicloalkyl-C1-4alkyl or aminocarbonylC1-4alkyl.

EFFECT: higher clinical effectiveness.

17 cl, 2 dwg, 72 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new substituted phenoxy-aceitic acids (I), in which: X is halogen, cyano, nitro or C1-4alkyl, which is substituted with one or more halogen atoms; Y is chosen from hydrogen, halogen or C1-C6alkyl, Z is phenyl, naphthyl or ring A, where A is a six-member heterocyclic aromatic ring containing one or two nitrogen atoms, or can be 6,6- or 6,5-condensed bicycle which contains one O, N or S atoms, or can be 6,5-condensed bicycle which contains two O atoms, where phenyl, naphthyl or ring A can all be substituted with one or more substitutes, independently chosen from halogen, CN, OH, nitro, COR9, CO2R6, SO2R9, OR9, SR9, SO2NR10R11, CONR10R11, NR10R11, NHSO2R9, NR9SO2R9, NR6CO2R6, NR9COR9, NR6CONR4R5, NR6SO2NR4R5, phenyl or C1-6alkyl, where the last group can possibly be substituted with one or more substitutes, independently chosen from halogen; R1 and R2 independently represent a hydrogen atom or C1-6alkyl group, R4 and R5 independently represent hydrogen, C3-C7cycloalkyl or C1-6alkyl, R6 is a hydrogen atom of C1-6alkyl; R8 is C1-4alkyl; R9 is C1-6alkyl, possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; R10 and R11 independently represent phenyl, 5-member aromatic ring which contains two heteroatoms, chosen from N or S, hydrogen, C3-C7cycloalkyl or C1-6alkyl, where the last two groups are possibly substituted with one or more substitutes, independently chosen from halogen or phenyl; or R10 and R11 together with the nitrogen atom to which they are bonded, can form a 3- to 8-member saturated heterocyclic ring, which possibly contains one or more atoms chosen from O, S(O)n (where n= 0, 1 or 2), NR8.

EFFECT: invention relates to a method of modulating activity of CRTh2 receptors, involving administration of therapeutically effective amount of formula compound or its pharmaceutically acceptable salt to a patient.

9 cl, 170 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 2-heteroaryl derivatives of benzothiazole and benzoxazole of formula by boiling amine with general formula with acid chloride of general formula , where R=2-furyl or 2-thienyl, X = S or O, in 1-methyl-2-pyrrolidone.

EFFECT: method increases output of product to 78 to 90% and environmental friendliness of the process.

1 cl, 2 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: medicine.

SUBSTANCE: invention covers thaizole derivatives of formula (I) and to their pharmaceutically acceptable salts. In formula I: X1 and X2 differ from each other and represent sulphur atom or carbon atom; R1 represents phenyl group; phenyl group substituted by 1-2 members chosen from the group including halogen atoms, alkoxygroup with 1-6 carbon atoms, hydroxygroup, phenylalkoxygroup with 7-12 carbon atoms; phenyl group fused with 5-7-membered heteroaromatic or nonaromatic ring with at least one heteroatom consisting of N, O and S; pyridyl group; R2 represents hydrogen atom, halogen atom, alkyl group with 1-6 carbon atoms, alkyl group with 1-6 carbon atoms substituted by 1-5 halogen atoms, alkoxygroup with 1-6 carbon atoms, or hydroxyalkyl group with 1-5 carbon atoms; A represents group which is presented by formula or . Also, the invention concerns ALK5 inhibitor containing compound of the invention as an active component, stimulators of hair follicles proliferation and hair growth, and also to thiazole derivative of formula where A1 represents .

EFFECT: higher efficiency.

12 cl, 2 tbl, 50 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: new 5-sulphanyl-4H-1,2,4-triazole derivatives of general formula I (meaning of radicals R1-R3 are indicated in the description of the invention), methods of their preparation by liquid-phase parallel synthesis and pharmaceutical composition are claimed.

EFFECT: claimed compounds display high affinity to some subtypes of somostatin receptors of the SST2 and SST5 subtypes and possibility of their usage for treatment of pathological states or diseases involving one or more of the given somostatin receptors

9 cl, 708 ex

FIELD: chemistry.

SUBSTANCE: in new compounds with general formula (I): , R1 stands for a naphthyl group, which can be substituted with a halogen atom, W represents a bond, a equals 0, 1 or 2, X1 represents C1-4alkylene, which can be substituted with a hydroxy group, Y1 represents -C(O)-,A represents a piperazine ring or piperidine ring, X2 represents a bond, Y2 represents -C(O)-, -S(O)2- or -C(=NR7)- (where R7 represents a hydrogen atom), X3 represents C1-4alkylene, which can be substituted with a hydroxyl group, oxo group or C1-6alkyl group; or C2-4alkylene, which can be substituted with a C1-6alkyl group, where two alkyl groups can be bonded to each other forming, together with carbon atoms to which they are bonded, an aryl ring when X3 represents C2-4alkylene, substituted with two alkyl groups, Z3 represents -N(R4)- or a bond (where R4 represents a hydrogen atom, C1-6alkyl group, which can be substituted with a hydroxy group or methoxy group, or acyl group), represents a single or double bond, where if represents a single bond, then Z1 represents -C(R2)(R2')-, -N(R2)- or -O- and Z2 represents C(R3)(R3')-, -N(R3)-, -O- or a bond (under the condition that, when Z2 represents -O-, then Z is different from -O-), and when represents a double bond, then Z1 represents -C(R3)= or a nitrogen atom and Z2 represents =C(R3)- or a nitrogen atom, each of R2, R2', R3 and R3' represents a hydrogen atom or C1-6alkylene. The invention also relates to salts of the given new compounds. The invention also relates to compounds, chosen from the group, to pharmaceutical compositions, to use of compounds in sub-paragraph 1 or 2, to prevention or treatment methods, as well as to the method of obtaining compounds in paragraph 1.

EFFECT: obtaining new biologically active compounds, which inhibit activated factor X of blood clotting and have anticoagulation activity and antithrombotic activity.

33 cl, 46 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new heterocyclic compounds of common formula (I), and also their pharmaceutically acceptable salts, hydrates and/or solvates, possessing properties of human neutrophil elastase. In common formula (I) , A means phenyl or pyridyl cycle, R1 and R3 each means atom of hydrogen, R2 means atom of fluorine, chlorine, bromine, nitro group or cyano group, R4 means cyano group, alkyl carbonyl group with number of carbon atoms in alkyl residue from one to four, or alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, besides alkoxycarbonyk group with number of carbon items in alkoxyl residue from one to four, may be substituted with substituent, which is selected from the group that includes hydroxyl group, alkoxygroup with number of carbon atoms from one to four, alkoxycarbonyl group with number of carbon atoms in alkoxyl residue from one to four, mono- or dialkylaminogroup, with number of carbon atoms in each of alkyl residues from one to four, 5-6-member heteroaryl group, which contains from 1 to 4 heteroatoms in heteroaryl ring, selected from nitrogen, oxygen or sulfur, possibly susbstituted with alkyl group, which contains from 1 to 4 atoms of carbon and possibly condensed with benzene ring, and 5-8 member heterocyclyl group, which contains from 1 to 3 heteroatoms from group of nitrogen, oxygen or sulfur, or SO, SO2 possibly substituted with ketogroup, R5 means methyl group, R6 means atom of hydrogen, alkyl group with number of carbon atoms from one to four, mono- or dialkylaminocarbonyl group with number of carbon atoms in each of alkyl residues from one to four, etc., Y1, Y2, Y3, Y4 and Y5 each means CH-group. Invention is also related to pharmaceutical composition.

EFFECT: possibility of application for treatment of chronic obstructive lung diseases, acute coronary syndrome, acute myocardial infarction and progressing cardiac decompensation.

8 cl, 1 dwg, 111 ex

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