HK1097250B

HK1097250B - Arylalkylcarbamate derivatives, preparation method thereof and use of same in therapeutics

Info

Publication number: HK1097250B
Application number: HK07104181.4A
Authority: HK
Inventors: Ahmed Abouabdellah; Antonio Almario Garcia
Original assignee: 赛诺菲-安万特
Priority date: 2003-10-03
Filing date: 2004-10-01
Publication date: 2011-12-09

Description

Arylalkylcarbamate derivatives, preparation thereof and use thereof in therapeutics

The present invention relates to arylalkyl carbamate derivatives, to a process for their preparation and to their use in therapeutics.

The compounds of the invention correspond to the following general formula (I):

wherein

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

x represents C_1-2An alkylene radical, optionally substituted by one or more C_1-12-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkylene group substitution;

y represents C₂An alkenylene group optionally substituted by one or more C_1-12Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkylene group substitution; or a-C.ident.C-group;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₁represents a hydrogen atom, halogenAtom, hydroxy, cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group;

R₂represents a hydrogen atom, a halogen atom, or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group; or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl (phenylthynyl), naphthylvinyl (naphthylvinyl), pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, naphthyridinyl (phthalazinyl), cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl (furylpyridinyl), thienopyridyl, imidazopyridinyl, oxazolopyridinyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenoxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy and isoquinolinyloxy, and optionally substituted with one or more substituents selected from the group consisting of: halogen atom, hydroxy group, cyano group, nitro group, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidineAlkyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, 4-piperazinyl optionally substituted by C_1-3-alkyl or benzyl substitution;

R₃represents a 2, 2, 2-trifluoroethyl group, or a phenyl group, optionally substituted by one or more halogen atoms or cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethyl or trifluoromethyloxy groups,

and

R₆and R₇Independently of one another represent C_1-3-an alkyl group or a phenyl group.

In the present invention, the general formula (I) may contain a plurality of groups A which may be the same as or different from each other.

The following compounds are not part of the present invention:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-4-chloro-2-nitrophenyl 2- (4- (chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ] pyridin-3-yl) phenyl ] ethylcarbamate;

-phenyl 2- [4- (3-thienyl) phenyl ] propylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

In the compounds of general formula (I), the first group of compounds consists of the following compounds:

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

x represents C_1-2An alkylene radical, optionally substituted by one or more C_1-12-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6Substituted by alkylene groups

Y represents C₂An alkenylene group optionally substituted by one or more C_1-12Alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkylene radicalSubstituted by groups; or a-C.ident.C-group;

z represents formula C_3-7-cycloalkyl radical

m represents an integer of 1 to 5;

p and q represent integers defined such that P + q is a number from 1 to 5;

R₁represents a hydrogen atom, a halogen atom, or a hydroxyl group, a cyano group, a nitro group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group;

R₂represents a halogen atom, or nitro, hydroxy, C_1-3-alkyl or C_1-3-an alkoxy group; and

R₃represents a 2, 2, 2-trifluoroethyl group, or a phenyl group, optionally substituted by one or more halogen atoms or cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethyl or trifluoromethyloxy groups.

The following compounds are not part of the above first family of compounds:

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-chloro-2-nitrophenyl 2- (4-chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-4-chloro-p-benzylcarbamic acid phenyl ester;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

In the compounds of formula (I), the compounds of group II consist of:

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

z represents formula C_3-7-cycloalkyl radical

m represents an integer of 1 to 5;

p and q represent integers defined such that P + q is a number from 1 to 5;

R₂represents a hydrogen atom, or a cyano group, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy and isoquinolinyloxy groups, optionally substituted with a halogen atom and optionally substituted with one or more halogen atomsSubstituted with one or more substituents of the following groups: hydroxy, cyano, nitro, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, 4-piperazinyl optionally substituted by C_1-3-alkyl or substituted by benzyl;

and

R₆and R₇Each represents C_1-3-an alkyl group or a phenyl group.

The following compounds are not part of the above-mentioned second group compounds:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-phenyl 2- [4- (3-thienyl) phenyl ] propylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate.

In the compounds of formula (I), the first group of compounds consists of the following compounds:

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

y represents C₂An alkenylene group optionally substituted by one or more C_1-12-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkylene group substitution; or a group-C ≡ C-;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that P + q is a number from 1 to 5;

R₂represents a hydrogen atom, a halogen atom, or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, diazanaphthyl, cinnolinyl, thiopheneA group, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy and isoquinolinyloxy, and which is optionally substituted by one or more substituents selected from halogen atoms and the following: hydroxy, cyano, nitro, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, 4-piperazinyl optionally substituted by C_1-3-alkyl or benzyl substitution;

and

R₆and R₇Each represents C_1-3-an alkyl group or a phenyl group;

with the proviso that when R₃When representing a phenyl group, e.g.Fruit A represents propylene, R₂And do not represent thienyl.

The following compounds are not part of the above first family of compounds:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-4-chloro-2-nitrophenyl 2- (4- (chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

In the compounds of formula (I), the compounds of group II consist of:

when R is₃When it represents a 2, 2, 2-trifluoroethyl group,

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₁represents a hydrogen atom, a halogen atom, or a hydroxyl group, a cyano group, a nitro group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxyOr C_1-3-a fluorothioalkyl group;

R₂represents a hydrogen atom, a halogen atom, or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy, and isoquinolinyloxy, and which are optionally substituted by one or more substituents selected from the group consisting of: halogen atom, hydroxy group, cyano group, nitro group, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, optionally substituted by C_1-3-alkyl or4-piperazinyl substituted with benzyl; and

R₆and R₇Each independently represents C_1-3-an alkyl group or a phenyl group;

when R is₃Represents a phenyl group optionally substituted by one or more halogen atoms, or cyano, nitro, C_1-3-alkyl radical, C_1-3When the alkoxy, trifluoromethyl or trifluoromethyloxy radical is substituted, then

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

y represents C₂An alkenylene group optionally substituted by one or more C_1-12-alkyl radical, C_3- ₇-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkylene group substitution; or a group-C ≡ C-;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₂represents

A hydrogen atom, a halogen atom,

or cyano, nitro, hydroxy, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy, and isoquinolinyloxy, and which are optionally substituted by one or more substituents selected from the group consisting of: a halogen atom, and the following groups: hydroxy, cyano, nitro, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, orQuilt selection C_1-3-4-piperazinyl substituted by alkyl or by benzyl; and

R₆and R₇Each independently represents C_1-3-an alkyl group or a phenyl group.

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-4-chloro-2-nitrophenyl 2- (4- (chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

In the compounds of general formula (I), the group iii compounds consist of the following compounds:

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₁represents a hydrogen atom, a halogen atom, or a hydroxyl group, a cyano group, a nitro group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3Thio-alkanesBase, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group;

R₂represents a hydrogen atom, a halogen atom, or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy and isoquinolinyloxy, and which are optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, 4-piperazinyl optionally substituted by C_1-3-alkyl or substituted by benzyl;

R₃represents a 2, 2, 2-trifluoroethyl group, or a phenyl group optionally substituted by one or more halogen atoms, or a cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethyl or trifluoromethyloxy groups,

and

provided that

When R is₃When it represents a 2, 2, 2-trifluoroethyl group,

if A represents methylene and if R₁Represents hydrogen, then R₂Is not hydrogen or methoxy;

if A represents methylene and if R₂Represents hydrogen, then R₁Is not hydrogen or methoxy;

when R is₃When a phenyl group is represented, the phenyl group,

if A represents methylene, R₁And R₂Neither represents a chlorine atom, a methoxy group or a nitro group;

if A represents ethylene, then

R₁And R₂Neither represents methoxy;

R₂does not represent 2-ethyl-5, 7-dimethyl-3H-imidazo [4, 5-b ]]Pyridin-3-yl or 2-amino-4-thiazolyl;

if A represents propylene, R₂Does not represent 3-thienyl;

when R is₃When representing a phenyl group substituted with 1 to 5 chlorine or fluorine atoms or a nitro or cyano group,

if A represents methylene, R₁And R₂Does not represent a methoxy group or a bromine atom;

if A represents ethylene, then

R₁Or R₂Neither represents a chlorine atom, or a hydroxyl, methyl or methoxy group;

R₂and does not represent phenylmethoxy.

In the compounds of formula (I), the compounds of group iv consist of the following compounds:

when R is₃When represents a 2, 2, 2-trifluoroethyl group, then

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₁represents a hydrogen atom, a halogen atom, or a hydroxyl group, a cyano group, a nitro group,C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group;

R₂represents a halogen atom or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_2-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy, and isoquinolinyloxy, and which are optionally substituted by one or more substituents selected from the group consisting of: halogen atom, hydroxy group, cyano group, nitro group, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, optionally substituted by C_1-3-alkyl or 4-piperazinyl substituted by benzyl;

and

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₁represents a hydrogen atom, an iodine atom, or a cyano group, C_2-3-alkyl radical, C_2-3-alkoxy radical, C_1-3-thio groupAlkyl radical, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group;

R₂represents a hydrogen atom, an iodine atom, or a cyano group, C_2-3-alkyl radical, C_2-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3A fluorothioalkyl group, or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolinyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indolinyl, pyrrolopyridyl, furopyridyl, thienopyridyl, oxazolopyridyl, thiazolopyridyl, pyrazolopyridyl, isoxazolopyridyl, isothiazolopyridyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy and isoquinolinyloxy, and which are optionally substituted by one or more substituents selected from the group consisting of: halogen atom, hydroxy group, cyano group, nitro group, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-2Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, optionally substituted by C_1-3-alkyl or by benzylSubstituted 4-piperazinyl;

and

In the compounds of formula (I), the group v compounds consist of the following compounds:

n represents an integer of 1 to 6;

a is selected from one or more groups X, Y and/or Z;

x represents C_1-2An alkylene radical, optionally substituted by one or more C_1-12-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-_1-6-alkylene group substitution;

z represents formula C_3-7-a cycloalkyl group:

m represents an integer of 1 to 5;

p and q represent integers defined such that p + q is a number from 1 to 5;

R₂represents a hydrogen atom, or a phenyl or phenyloxy group, optionally substituted by oneSubstituted with one or more substituents selected from: halogen atom, hydroxy group, cyano group, nitro group, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, optionally substituted by C_1-3-alkyl or 4-piperazinyl substituted by benzyl;

R₃represents a 2, 2, 2-trifluoroethyl group, or a phenyl group, optionally substituted by one or more halogen atoms, or a cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethyl or trifluoromethyloxy groups,

and

benzyl carbamic acid 2, 2, 2-trifluoroethyl ester is excluded.

Among the compounds of general formula (I), the compounds of group six consist of the following compounds:

n represents an integer of 1 to 6;

a is a group X;

the radicals A being identical or different from one another, when n is from 2 to 6;

R₂represents a hydrogen atom, a halogen atom, or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3-a fluorothioalkyl group, or a group selected from phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, dihydroindenyl, indenyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, diazanaphthyl, cinnolinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, triazolyl, benzothienyl, benzofuranyl, dibenzofuranyl, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, dihydroindolyl, pyrrolopyridyl, furopyridyl, thienopyridyl, imidazopyridinyl, oxazolopyridyl, thiazolopyridinyl, pyrazolopyridinyl, isoxazolopyridinyl, isothiazolopyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy, quinolinoxy and isoquinolinyloxy, and which is optionally substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, nitro, C_1-4-alkyl radical, C_1-4-alkoxy radical, C_1-4-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy radical, C_1-3Fluoro-thioalkyl, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH₂，NHR₆，NR₆R₇，NHCOR₆，COR₆，CO₂R₆，SO₂R₆，-O-(C_1-3-alkylene) -O-, optionally substituted by C_1-3-alkyl or 4-piperazinyl substituted by benzyl;

and

with the following conditions:

when R is₃Represents a 2, 2, 2-trifluoroethyl group and a group- [ A]_n-represents-CH₂When the group is a group,

then R is₁Is not a hydrogen atom or a methoxy group;

when R is₃Represents an optionally substituted phenyl group and a group [ A ]]_n-represents-CH₂-，-CH₂CH₂-，-CH(CH₃) -or-CH (CH)₃)-CH₂-when a radical is present;

then R is₁Is not a hydrogen or chlorine atom, or is not a methyl or methoxy group, and R₂Not a hydrogen atom.

The compounds of formula (I) may contain one or more asymmetric carbons. They exist in enantiomeric or diastereomeric forms. These enantiomers and diastereomers, and mixtures thereof, including racemic mixtures, are part of the present invention.

The compounds of formula (I) may be present in the form of a base or an addition salt with an acid. Such addition salts are part of the present invention.

These salts are advantageously prepared with pharmaceutically acceptable acids, while salts of these other useful acids, e.g. for purifying or isolating compounds of formula (I), are also part of the present invention. The compounds of formula (I) may be in the form of hydrates or solvates, i.e. in combination or mixture with one or more moles of water or solvent. Such hydrates and solvates are also part of the present invention.

In the context of the present invention:

the expression "C_t-zWherein t and z may be numbers from 1 to 12 "refers to a carbon-based chain, which may have t-z carbon atoms; for example, "C_1-3"refers to a carbon-based chain that may have 1 to 3 carbon atoms;

the term "alkyl" refers to a straight or branched chain saturated aliphatic group; e.g. C_1-3-the alkyl group represents a linear or branched carbon-based chain having from 1 to 3 carbon atoms, more particularly a methyl, ethyl, propyl or 1-methylethyl group;

the term "alkylene" refers to a linear or branched saturated divalent alkyl group; e.g. C_1-3-the alkylene group represents a linear or branched divalent carbon-based chain having from 1 to 3 carbon atoms, more particularly a methylene, ethylene, 1-methyleneethyl or propylene group;

-the term "cycloalkyl" refers to a cycloalkyl group; e.g. C_3-5-cycloalkyl represents a cyclic carbo-yl group having 3 to 5 carbon atoms, more particularly cyclopropyl, cyclobutyl or cyclopentyl;

the term "alkenylene" refers to a divalent unsaturated aliphatic group, more particularly a vinyl group;

the term "alkoxy" refers to an-O-alkyl group, which includes straight or branched, saturated aliphatic chains;

the term "thioalkyl" refers to an-S-alkyl group, which includes straight or branched, saturated aliphatic chains;

the term "fluoroalkyl" refers to an alkyl group in which one or more hydrogen atoms have been replaced by fluorine atoms;

the term "fluoroalkoxy" refers to an alkoxy group in which one or more hydrogen atoms have been replaced by fluorine atoms;

the term "fluorothioalkyl" refers to a thioalkyl group in which one or more hydrogen atoms have been replaced by fluorine atoms;

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

The compounds of the present invention can be prepared by a variety of methods, specifically as shown below.

Thus, the first process (Scheme 1) for preparing the compounds of formula (I) consists in reacting an amine of formula (II) in which R is₁，R₂N and A are as defined above) with a carbonate of the general formula (III) in which U represents a hydrogen atom or a nitro group and R₃As defined above) in a solvent such as toluene or dichloroethanol at a temperature of 0-80 ℃.

Scheme 1

According to a second method, the compound of formula (I) (wherein R is R) is in the presence of a base such as triethylamine or diisopropylethylamine in a solvent such as dichloromethane or dichloroethane at a temperature of 0 ℃ to the reflux temperature of the solvent₃More particularly representing an optionally substituted phenyl group) can be obtained by reacting an amine of formula (II) as defined above with an aryl chloroformate of formula (IIIa):

wherein R is₃Represents a phenyl group, optionally substituted with one or more substituents selected from: halogen atoms, or cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethyl or trifluoromethyloxyAnd (4) clustering.

The carbonates of formula (III) can be prepared by any of the methods described in the literature, for example by the formula HOR₃With phenylchloroformate or p-nitrophenylchloroformate in the presence of a base such as triethylamine or diisopropylethylamine.

The compounds of the general formulae (II) and (IIIa) are commercially available or described in the literature or can also be prepared according to the methods described in the literature or known to the person skilled in the art.

When in the compounds of the general formula (I) or (II), R₂Represents a radical of the aryl or heteroaryl type, R₂The introduction onto the phenyl ring can be achieved as follows: the derivatives of the compounds of the general formula (I) or (II) in which the phenyl ring bears a chlorine, bromine or iodine atom or a triflate group are introduced where appropriate into R according to the Suzuki reaction conditions (chem. Rev. (1995), 95, 2457-2483; Angew. chem. int., Ed. (1999), 38, 3387-3388)₂With an aryl-or heteroaryl boronic acid derivative or with an aryl-or heteroaryl trialkyltin derivative according to the Stille reaction conditions (Angew. chem. int. Ed. Engl. (1986), 25, 508-.

The following examples illustrate the preparation of certain compounds of the present invention. They are only illustrative and not restrictive of the invention. NMR spectroscopy and/or LC-MS (liquid chromatography coupled with mass spectrometry) determine the structure and purity of the resulting compound.

Mp (. degree. C.) represents the melting point in degrees Celsius.

The numbers shown in parentheses in the example headings correspond to those in the first column of the table below.

The compounds in the following examples are named using IUPAC nomenclature (International Union of Pure and Applied Chemistry). For example, biphenyl groups, numbered as follows:

1-3 example 1 (Compound No.1)

1, 1' -Biphenyl-4-ylmethyl-carbamic acid 2, 2, 2-trifluoro-ethyl ester

0.119ml (1.64mmol) of 2, 2, 2-trifluoroethanol and 0.306ml (1.49mmol) of N, N-diisopropylethylamine are added dropwise at room temperature to a solution of 0.3g (1.49mmol) of p-nitrophenyl chloroformate in 15ml of dichloromethane. The mixture was stirred at room temperature for 2 hours, then 0.275g (1.5mmol) of 4-phenylbenzylamine was added. N, N-diisopropylethylamine was then added dropwise at room temperature until the precipitate which had formed disappeared. Thus, a clear solution was obtained, and stirred at room temperature for 1 hour. The reaction medium is further diluted with 10ml of dichloromethane and washed with saturated aqueous ammonium chloride and with aqueous sodium chloride. The phases were separated and the organic phase was dried over sodium sulfate. The product was filtered, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography with dichloromethane. 0.215g of a white solid was obtained.

LC-MS：310

Mp(℃)：123-125℃

¹H NMR(DMSO-d₆)δ(ppm)：8.25(t，1H)；7.75-7.30(m，9H)；4.65(q，2H)；4.25(d，2H)。

Example 2 (Compound No.19)

2- (1, 1' -Biphenyl-4-yl) ethylcarbamic acid 2, 2, 2-trifluoroethyl ester

The procedure is analogous to example 1, except that 2- (4-biphenylyl) ethylamine is used instead of 4-phenylbenzylamine. 0.311g of a white solid was obtained.

LC-MS：324

Mp(℃)：79-81℃

¹H NMR(DMSO-d₆)δ(ppm)：7.80-7.20(m，10H)；4.65(q，2H)；3.30(m，2H)；2.75(t，2H)。

Example 3 (Compound No.10)

4-Phenyloxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester

The procedure is carried out in analogy to example 1, except that 4-phenylbenzylamine is replaced by 4-phenyloxybenzylamine. 0.252g of a white solid was obtained.

LC-MS：326

Mp(℃)：145-148℃

¹HNMR(DMSO-d₆)δ(ppm)：8.15(t，1H)；7.40-6.90(m，9H)；4.65(q，2H)；4.20(d，2H)。

Example 4 (Compound No.3)

4-fluorophenyl 1, 1' -biphenyl-4-ylmethylcarbamate

0.069ml (0.522mmol) of 4-fluorophenyl chloroformate and 0.149ml (0.82mmol) of N, N-diisopropylethylamine are added dropwise at room temperature to a solution of 0.107g (0.58mmol) of 4-phenylbenzylamine in 4ml of dichloromethane. The mixture was stirred at room temperature for 1 hour. The reaction medium is further diluted with 2ml of dichloromethane and washed with saturated aqueous ammonium chloride and with aqueous sodium chloride. The phases were separated and the organic phase was dried over sodium sulfate. The organic phase was filtered using a hydrophobic fritted funnel. The filtrate was concentrated under reduced pressure and the solid residue was washed with 5ml diisopropyl ether. 0.136g of a white solid was obtained.

LC-MS：322

Mp(℃)：155-157℃

¹H NMR(DMSO-d₆)δ(ppm)：8.30(t，1H)；7.70-7.10(m，13H)；4.30(d，2H)。

Example 5 (Compound No.26)

4-methylphenyl 2- (1, 1' -biphenyl-4-yl) ethylcarbamate

The procedure was carried out in analogy to example 4, except for replacing 4-phenylbenzylamine by 2- (4-biphenylyl) ethylamine and 4-fluorophenylchloroformate by 4-methylphenylchloroformate.

0.126g of a white solid was obtained.

LC-MS：332

Mp(℃)：172-174℃

¹H NMR(DMSO-d₆)δ(ppm)：7.75(t，1H)；7.70-7.30(m，9H)；7.10(d，2H)；6.90(d，2H)；3.30(m，2H)；2.80(t，2H)；2.25(s，3H)。

Example 6 (Compound No.16)

4-Methoxyphenyl 4-phenoxybenzylcarbamate

The procedure was carried out in analogy to example 4, except that 4-phenylbenzylamine was used instead of 4-phenylbenzylamine and 4-methoxyphenyl chloroformate was used instead of 4-fluorophenyl chloroformate.

0.137g of a white solid was obtained.

LC-MS：350

Mp(℃)：89-91℃

¹H NMR(DMSO-d₆)δ(ppm)：8.20(t，1H)；7.45-7.25(m，4H)；7.20-6.80(m，9H)；4.25(d，2H)；3.75(s，3H)。

The following table illustrates the chemical structures and physical properties of some of the compounds of the present invention. In this table, "n.d." means that its melting point cannot be measured (e.g. the product is in the form of a gum).

Watch (A)

No.	[A]_n	R₁	R₂	R₃	Mp(℃)
						1.	CH₂	H	4-phenyl radical	CH₂CF₃	123-125
2.	CH₂	H	4-phenyl radical	Phenyl radical	158-162
						3.	CH₂	H	4-phenyl radical	4-F-phenyl	155-157
4.	CH₂	H	4-phenyl radical	2-Cl-phenyl	128-130
						5.	CH₂	H	4-phenyl radical	4-Cl-phenyl	161-164
6.	CH₂	H	4-phenyl radical	2-CH₃O-phenyl	186-188
						7.	CH₂	H	4-phenyl radical	4-CH₃O-phenyl	153-156
8.	CH₂	H	4-phenyl radical	4-CH₃-phenyl radical	153-155
						9.	CH₂	H	4-phenyl radical	3-CF₃-phenyl radical	n.d.
10.	CH₂	H	4-Phenyloxy	CH₂CF₃	145-148
						11.	CH₂	H	4-Phenyloxy	Phenyl radical	99-101
12.	CH₂	H	4-Phenyloxy	4-F-phenyl	82-84
						13.	CH₂	H	4-Phenyloxy	2-Cl phenyl	106-109
14.	CH₂	H	4-Phenyloxy	4-Cl-phenyl	90-93
						15.	CH₂	H	4-Phenyloxy	2-CH₃O-phenyl	84-86
16.	CH₂	H	4-Phenyloxy	4-CH₃O-phenyl	89-91

17.	CH₂	H	4-Phenyloxy	4-CH₃-phenyl radical	105-107
						18.	CH₂	H	4-Phenyloxy	3-CF₃-phenyl radical	n.d.
19.	CH₂CH₂	H	4-phenyl radical	CH₂CF₃	79-81
						20.	CH₂CH₂	H	4-phenyl radical	Phenyl radical	150-152
21.	CH₂CH₂	H	4-phenyl radical	4-F-phenyl	160-163
						22.	CH₂CH₂	H	4-phenyl radical	2-Cl-phenyl	131-133
23.	CH₂CH₂	H	4-phenyl radical	4-Cl-phenyl	167-169
						24.	CH₂CH₂	H	4-phenyl radical	2-CH₃O-phenyl	116-119
25.	CH₂CH₂	H	4-phenyl radical	4-CH₃O-phenyl	158-160

No.	[A]_n	R₁	R₂	R₃	Mp(℃)
						26.	CH₂CH₂	H	4-phenyl radical	4-CH₃-phenyl radical	172-174
27.	CH₂CH₂	H	4-phenyl radical	3-CF₃-phenyl radical	132-135
						28.	CH₂CH₂CH₂	H	H	Phenyl radical	62-65
29.	CH₂CH₂CH₂	H	H	4-F-phenyl	61-63
						30.	CH₂CH₂CH₂	H	H	4-Cl-phenyl	53-56
31.	CH₂CH₂CH₂	H	H	4-CH₃-phenyl radical	79-81
						32.	CH₂CH₂CH₂CH₂	H	H	Phenyl radical	76-78
33.	CH₂CH₂CH₂CH₂	H	H	4-F-phenyl	91-93
						34.	CH₂CH₂CH₂CH₂	H	H	4-Cl-phenyl	95-97
35.	CH₂CH₂CH₂CH₂	H	H	4-CH₃-phenyl radical	91-93

The compounds of the present invention were subjected to pharmacological tests to determine their inhibitory effect on the FAAH enzyme (fatty acid amidohydrolase).

Anandamide hydrolysate (ethanolamine [1-³H]) Their inhibitory activity in the radioactive enzyme assay was determined (Life Sciences (1995), 56, 1999) 2005 and (Journal of Pharmacology and Experimental therapeutics (1997), 283, 729) 734). Thus, mouse brains (without cerebellum) were removed and stored at-80 ℃. Immediately by mixing a 10mM Tris-HCl buffer solution containing 150mM NaCl and 1mM EDTA (A)Tissue homogenization of Polytron in pH 8.0) to prepare a membrane homogenate. The enzymatic reaction was then carried out in 70. mu.l of bovine serum albumin containing no fatty acids (1 mg/ml). Subsequently, the test compound was added at various concentrations, and anandamide [ ethanolamine [1-³H](specific activity of 15-20 Ci/mmol) and the membrane preparation (400. mu.g frozen tissue per experiment). After 15 minutes at 25 ℃ the enzyme reaction was stopped by adding 140. mu.l chloroform/methanol (2: 1). The mixture was stirred for 10 minutes and then centrifuged at 3500g for 15 minutes. Comprising ethanolamine [1-³H]The aqueous fraction (30. mu.l) was counted by liquid scintillation.

Under these conditions, the majority of the active compounds IC according to the invention₅₀The value (concentration inhibiting 50% of the FAAH control enzyme activity) was 0.001-1. mu.M.

This shows that the compounds of the present invention inhibit FAAH enzymatic activity.

The FAAH enzyme (Chemistry and Physics of Lipids, (2000), 108, 107-. These derivatives exert various pharmacological activities through interactions, in particular with cannabinoid and vanilloid (vanilloides) receptors.

The compounds of the present invention block this degradation pathway and increase the tissue content of these endogenous substances. They may be used in the prevention and treatment of pathologies, including endogenous cannabinoids and/or any other substrates metabolized by the FAAH enzyme.

The following diseases and conditions may be mentioned, for example:

pain, in particular acute or chronic pain of the neuropathic type: migraine, neuropathic pain, which includes forms of pain associated with herpes viruses and with diabetes;

acute or chronic pain associated with inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, crohn's disease, irritable bowel syndrome;

acute or chronic peripheral pain:

vertigo, vomiting, retching, and especially those following chemotherapy;

eating disorders, in particular anorexia and illnesses of various natures;

neurological and psychiatric pathology: shaking, movement disorders, dystonia, spasticity, obsessive compulsive disorder, tourette's syndrome, all forms of depression and anxiety of any nature and any origin, affective disorders, psychosis; acute and chronic neurodegenerative diseases: parkinson's disease, alzheimer's disease, senile dementia, nyctalopia of huntington, and brain injury and ischemic skull and trauma; epilepsy;

sleep disorders including sleep apnea;

cardiovascular diseases, especially hypertension, arrhythmia, arteriosclerosis, heart attack,

Ischemia of the heart; renal ischemia;

cancer: benign skin tumors, papilloma and brain tumors, prostate tumors, brain tumors (glioblastoma, medulloblastoma, neuroblastoma, tumor embryonic origin, astrocytoma, Ependomymas, oligodendroglioma, plexus tumors, retinal neuroepithelial tumors, epiphyseal tumors, ependymoma, malignant meningioma, sarcomas, malignant melanoma, schwannoma),

diseases of the immune system, in particular autoimmune diseases: psoriasis, lupus erythematosus, connective tissue disease or connectivities,the syndrome of (a) is,

ankylosing spondyloarthritis, undifferentiated spondyloarthritis, Behcet's disease, autoimmune anemia, multiple sclerosis, amyotrophic lateral sclerosis of the spinal cord, amyotrophy, transplant rejection, disease affecting the plasma cell line;

allergic reaction: hypersensitive or delayed, allergic rhinitis, conjunctivitis, contact dermatitis; parasitic, viral, bacterial or viral infections: AIDS, meningitis;

inflammation, especially joint diseases: arthritis, rheumatoid arthritis, hypertrophic osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, irritable bowel syndrome;

osteoporosis;

eye diseases: hypertensive eyes, glaucoma;

pulmonary disorders: respiratory system infection diseases, motor bronchospasm, cough, asthma, chronic bronchitis, chronic airway obstruction, and emphysema;

gastrointestinal diseases: irritable bowel syndrome, gastrointestinal disease, ulcers, diarrhea; urinary incontinence and cystitis.

The use of the compounds of the invention for the preparation of a medicament for the treatment of the above pathologies is an integral part of the present invention.

The use of the following compounds for the preparation of a medicament for the treatment of the above pathologies is also part of the invention:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [ 4-phenylmethoxy) phenyl ] ethylcarbamate,

-4-chloro-2-nitrophenyl 2- (4-chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

A subject of the invention is also a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I), or a hydrate or solvate thereof. These medicaments have their use in therapy, in particular in the treatment of the pathologies mentioned above.

A subject of the present invention is also a pharmaceutical product comprising a compound selected from the following, or a pharmaceutically acceptable salt of the following, or a hydrate or solvate thereof:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [ 4-phenylmethoxy) phenyl ] ethylcarbamate,

-4-chloro-2-nitrophenyl 2- (4-chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

These medicaments have their use in therapy, in particular in the treatment of the pathologies mentioned above.

According to another aspect of the invention, the invention relates to a pharmaceutical composition comprising at least one compound of the invention as active ingredient.

These pharmaceutical compositions comprise an effective dose of a compound of the present invention, or a pharmaceutically acceptable salt of said compound, or a hydrate or solvate thereof, and optionally one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention, the present invention relates to a pharmaceutical composition comprising at least one compound selected from the group consisting of the following as an active ingredient. These pharmaceutical compositions comprise an effective dose of a compound selected from the following, or a pharmaceutically acceptable salt of said compound, or a hydrate or solvate thereof, and optionally one or more pharmaceutically acceptable excipients:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [ 4-phenylmethoxy) phenyl ] ethylcarbamate,

-4-chloro-2-nitrophenyl 2- (4-chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

The excipients are selected from the usual excipients known to the person skilled in the art according to the pharmaceutical form and the desired method of administration.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical (locale), intrathecal (intrarate), intranasal, transdermal, pulmonary, ocular or rectal administration, the active ingredient of formula (I) above or the following compounds or their possible salts, or hydrates or solvates thereof, can be administered in unit administration form (water for free administration) in admixture with conventional pharmaceutical excipients to animals and humans for the prevention or treatment of the above-mentioned conditions or diseases:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [ 4-phenylmethoxy) phenyl ] ethylcarbamate,

-4-chloro-2-nitrophenyl 2- (4-chlorophenyl) ethylcarbamate;

-4-nitrophenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-4-cyanophenyl 2- (4-methylphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

4-bromo-benzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

Suitable unit administration forms include oral administration forms such as tablets, soft or hard capsules, powders, granules, chewing gums (chewing gums) and oral solutions or suspensions, sublingual, buccal, intratracheal, intraocular and intranasal administration forms, administration forms by inhalation, subcutaneous administration, intramuscular or intravenous administration forms, and rectal or vaginal administration forms. For topical application, the compounds of the invention may be used in the form of creams, ointments or lotions.

By way of example, where the unit dosage form of a compound of the invention is a tablet form, it comprises the following components:

compound of the invention 50.0mg

Mannitol 223.75mg

Croscarmellose sodium 6.0mg

Corn starch 15.0mg

Hydroxypropyl methylcellulose 2.25mg

Magnesium stearate 3.0mg

Depending on the pharmaceutical form, the unit form comprises a dose such that 0.01 to 20mg of active ingredient per kg body weight per day is administered.

Such dosages are also part of the invention for special cases where higher or lower dosages are required. The appropriate dosage for each patient is determined by the physician according to the method of administration and its weight and the response of the patient, according to routine experimentation.

According to another aspect of the invention, the invention also relates to a method for treating the pathologies described above, which comprises the administration of an effective dose of a compound according to the invention, of a pharmaceutically acceptable salt thereof or of a solvate of said compound or of a hydrate thereof.

Claims

1. A compound of formula (I):

wherein

n represents an integer of 1 to 6;

a is a group X;

when n is an integer from 2 to 6, the radicals A are identical or different from one another;

x represents C_1-2An alkylene group, whichOptionally substituted by one or more C_1-12-alkyl radical, C_3-7-cycloalkyl or C_3-7-cycloalkyl-C_1-6-alkylene group substitution;

R₂represents a hydrogen atom, a halogen atom, or a cyano group, a nitro group, a hydroxyl group, C_1-3-alkyl radical, C_1-3-alkoxy radical, C_1-3-thioalkyl, C_1-3-fluoroalkyl, C_1-3-fluoroalkoxy or C_1-3-a fluorothioalkyl group;

or a group selected from: phenyl, naphthyl, biphenyl, phenylvinyl, naphthylvinyl, indenyl, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, phenylethoxy, phenylpropoxy, naphthyloxy, naphthylmethoxy, naphthylethoxy, naphthylpropoxy;

and

with the following conditions:

when R is₃Represents a 2, 2, 2-trifluoroethyl group and a group- [ A]n-represents-CH₂When the group is a group,

then R is₁Is not a hydrogen atom or a methoxy group;

when R is₃Represents an optionally substituted phenyl group and a group [ A ]]_n-represents-CH₂-，-CH₂CH₂-，-CH(CH₃) -or-CH (CH)₃)-CH₂When the group is a group,

then R is₁Not being hydrogen or chlorine atomsOr is not a methyl or methoxy group and R₂Is not a hydrogen atom;

the compounds are in the form of base, acid addition salts.

2. A process for the preparation of a compound of the general formula (I),

wherein R is₁，R₂，R₃A and n are as defined in claim 1,

the method comprises the following steps:

reacting an amine of the general formula (II) with a carbonate of the general formula (III)

Wherein R is₁，R₂N and A are as defined in formula (I),

wherein U represents a hydrogen atom or a nitro group and R₃As defined in formula (I).

3. A process for the preparation of a compound of the general formula (I),

wherein

R₁，R₂A and n are as defined in claim 1, and

R₃represents a phenyl group optionally substituted by one or more halogen atoms, or cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethylSubstituted by a group or a trifluoromethyl group,

the method comprises the following steps:

reacting an amine of the general formula (II) with an aryl chloroformate of the general formula (IIIa),

wherein R is₁，R₂N and A are as defined in formula (I),

wherein R is₃Represents a phenyl group optionally substituted by one or more halogen atoms, or cyano, nitro, C_1-3-alkyl radical, C_1-3-alkoxy, trifluoromethyl or trifluoromethyloxy groups.

4. A pharmaceutical composition comprising at least one compound of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base, a salt thereof, and optionally one or more pharmaceutically acceptable excipients.

5. A pharmaceutical composition comprising at least one of the following compounds:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-4-chloro-2-nitrophenyl 2- (4- (chlorophenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-2, 3, 4, 5, 6-pentafluorophenyl 4-bromobenzylcarbamate;

-wherein the compound is in the form of a pharmaceutically acceptable base, a salt thereof, and optionally comprises one or more pharmaceutically acceptable excipients.

6. Use of a compound of formula (I) as defined in claim 1, in the manufacture of a medicament for the prevention and treatment of pathologies involving endogenous cannabinoids and/or any other substrates metabolized by fatty acid amidohydrolases, wherein the compound is in the form of a pharmaceutically acceptable base, a salt thereof.

7. A compound selected from the group consisting of:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-4-chloro-2-nitrophenyl 2- (4- (chlorophenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-4-bromobenzylcarbamic acid 2, 3, 4, 5, 6-pentafluorophenyl ester.

8. Use of a compound of formula (I) as defined in claim 1 in the manufacture of a medicament for the prevention or treatment of acute or chronic pain, vertigo, emesis, retching, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular diseases, renal ischemia, cancer, immune system disorders, allergies, parasitic, viral or bacterial infections, inflammatory diseases, osteoporosis, ocular disorders, pulmonary disorders, gastrointestinal diseases or urinary incontinence, wherein the compound is in the form of a pharmaceutically acceptable base, a salt thereof.

9. Use of a compound according to any one of claims 1 to 5, selected from the group consisting of:

-benzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-methoxybenzylcarbamic acid 2, 2, 2-trifluoroethyl ester;

-4-nitrophenyl 2- [4- (phenylmethoxy) phenyl ] ethylcarbamate;

-4-chloro-2-nitrophenyl 2- (4- (chlorophenyl) ethylcarbamate;

-phenyl 2- (3, 4-dimethoxyphenyl) ethylcarbamate;

-2- (4-chlorophenyl) ethylcarbamic acid 2, 4, 5-trichlorophenyl ester;

-phenyl 4-chlorobenzylcarbamate;

-4-methoxybenzylcarbamic acid phenyl ester;

-4-fluorophenyl 2- (4-methoxyphenyl) ethylcarbamate;

-3-nitrobenzyl carbamic acid phenyl ester;

-4-cyanobiphenyl 4-methoxybenzylcarbamate;

-phenyl 3-chlorobenzylcarbamate;

-phenyl 3, 4-dichlorobenzylcarbamate;

-4-nitrophenyl 2- (4-hydroxyphenyl) ethylcarbamate;

-phenyl 2- [4- (2-amino-4-thiazolyl) phenyl ] ethylcarbamate;

-2, 3, 4, 5, 6-pentafluorophenyl 4-bromobenzylcarbamate;

wherein the compound is in the form of a pharmaceutically acceptable base, a salt thereof.