Arylalkylcarbamate derivatives, synthesis and use thereof in therapy

FIELD: chemistry.

SUBSTANCE: invention relates to a compound which exhibits inhibitory effect on the FAAH enzyme having formula I , where n denotes an integer from 1 to 6; A denotes a group X; where when n equals an integer from 2 to 6, groups A are identical or different; X denotes C1-2-alkylene; R1 denotes a hydrogen atom; R2 denotes a hydrogen atom or a group selected from the following groups: phenyl, phenyloxy; R3 denotes either 2,2,2-trifluoroethyl or phenyl, if necessary substituted with one or more halogen atoms or C1-3-alkyl, C1-3-alkoxy, trifluoromethyl; provided that: the formula 1 compound is not 2,2,2-trifluoroethyl benzylcarbamate, when R3 denotes 2,2,2-trifluoroethyl and group -[A]n- denotes a -CH2- group, when R3 denotes phenyl, if necessary substituted, and group -[A]n-denotes a -CH2-, -CH2CH2-,-CH2CH2CH2- group, then R2 is not a hydrogen atom and is in form of a base, an addition salt with a pharmaceutically acceptable acid, as well as to a method for synthesis of the formula I compound and a pharmaceutical composition having inhibitory effect on FAAH, containing at least one formula I compound.

EFFECT: improved method.

5 cl, 6 ex, 1 tbl

 

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

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

in which

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, Cl-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, halogen

or group of cyano, nitro, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3 -vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, p is rolidone, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline;

and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl.

In the framework of the invention, compounds of General formula (I) may include thus more identical or different groups A.

The following connections are not part of the invention:

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

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

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

p> - phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

Among the compounds of General formula (I) first subgroup of compounds consists of the compounds for which:

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q are integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3the FPO is alkoxy, C1-3-vertially;

R2means

halogen atom or a nitro-group, hydroxyl, C1-3-alkyl, C1-3-alkoxy; and

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline.

The following connections are not part of the first sub-group of the above compounds:

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

Among the compounds of General formula (I), a second subgroup of compounds consists of the compounds for which:

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q are integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom or a cyano, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, ideasall, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary, replaced With1-3-alkyl or benzyl;

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or groups is cyano, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline;

and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl.

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

- 2,2,2-cryptgethashparam;

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

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

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

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

Among the compounds of General formula (I) the first family of compounds consists of compounds in which:

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q) is scored from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, halogen

or group of cyano, nitro, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, n is italinox, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline;

and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl;

provided that

when R3denotes phenyl,

if A denotes propylene, then R2doesn't mean thienyl.

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

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

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

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

Among the compounds of General formula (I) the second family of compounds consists of the compounds for which:

when R3means 2,2,2-triptorelin, then

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C-12 -alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, halogen

or group of cyano, nitro, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, t is inoperational, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl; and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl;

when R3denotes phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline, then

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C -alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, halogen

or the group of cyano, nitro, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, TIA is alil, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, groups, cyano, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl; and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl.

The following compounds of the e are part of a second family of compounds, defined above:

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

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

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

Among the compounds of General formula (I) third family of compounds consists of the compounds for which:

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C 2-albaniles, if necessary substituted by one or more groups selected from Cl-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, halogen

or group of cyano, nitro, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxa is poured, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline,

and

R6and R7represent, independently one from the other, C1-3-alkyl, phenyl;

provided that

when R3means 2,2,2-triptorelin,

if a denotes a methylene, and if R1denotes hydrogen,

then R2is not hydrogen or a methoxy group;

if a denotes a methylene, and if R2denotes hydrogen,

then R1is not hydrogen or a methoxy group;

when R3denotes phenyl,

if a denotes a methylene, then neither R1or R2not represent a chlorine atom, methoxy or nitro - group;

if a denotes ethylene, then

neither R1or R2not denote a methoxy group;

R2means neither 2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine-3-yl or 2-amino-4-thiazolyl;

if A denotes propylene, then R2doesn't mean 3-thienyl;

when R3denotes phenyl, substituted by one to five chlorine atoms, fluorine or nitro groups, cyano,

if A denotes a methylene, then neither R1or R2not denote a methoxy group or a bromine atom;

if A stands for the ethylene, then

neither R1or R2not represent a chlorine atom, a hydroxyl, methyl or methoxy group;

R2doesn't mean phenylmethoxy.

Among the compounds of General formula (I) fourth family of compounds consists of the compounds for which:

when R3means 2,2,2-triptorelin, then

n Ref is no integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

halogen atom

or group of cyano, nitro, hydroxyl, C1-3-alkyl, C2-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phtalate the sludge, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from halogen atoms, hydroxyl groups, cyano, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

and

R6and R7about who appoints, independently of one another, C1-3-alkyl, phenyl;

when R3denotes phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline, then

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, iodine or cyano, C2-3-alkyl, C2-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, iodine

or cyano, C2-3-alkyl, C2-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-floral is hydroxy, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahydroisoquinoline, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6 , NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl.

Among the compounds of General formula (I) fifth family of compounds consists of the compounds for which:

n denotes an integer from 1 to 6;

And are selected from one or more groups X, Y and/or Z;

X represents C1-2-alkylen, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

Y represents C2-albaniles, if necessary substituted by one or more groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene; or the group-C≡C-;

Z represents C3-7-cycloalkyl formula:

m denotes an integer from 1 to 5;

p and q denote integers such that p + q is from 1 to 5;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

the atom is odorata, phenyl group, or fenoxaprop, and this group can be, if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline;

and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl;

this 2,2,2-cryptgethashparam excluded.

Among the compounds of General formula (I) sixth family of compounds consists of the compounds for which:

n denotes an integer from 1 to 6;

And X denotes a group;

and the groups A are the same or different, when n denotes an integer from 2 to 6;

X represents C1-2-alkylen, if necessary substituted od is Oh or several groups selected from C1-12-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-6-alkylene;

R1denotes a hydrogen atom, halogen or hydroxyl, cyano group, nitro, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially;

R2means

a hydrogen atom, halogen

or group of cyano, nitro, hydroxyl, C1-3-alkyl, C1-3-alkoxy, C1-3-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-vertially,

or a group selected from the following groups: phenyl, naphthalenyl, biphenyl, phenylethylene, naphthylethylene, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, indanyl, indenyl, chinoline, ethenolysis, hintline, honokalani, phthalazine, cinnoline, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolin, thiadiazolyl, oxadiazolyl, triazolyl, benzothiazyl, benzofuranyl, dibenzofurans, benzimidazolyl, benzotriazolyl, indolyl, isoindolyl, indazoles, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, dihydroindole, pyrrolopyridine, properidine, thienopyridines, imidazopyridines, oxazolopyridine, triazolopyridines, pyrazolopyrimidines, isoxazolidine, isothiazolinones, tetrahydroquinoline, tetrahedrite oliner, phenyloxy, phenylthio, phenylsulfonyl, benzoyl, phenylmethoxy, venlafaxi, phenylpropoxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, naphthalenyloxy, himalayense, ethanolamines, and if necessary substituted by one or more substituents selected from a halogen atom, hydroxyl, cyano groups, nitro, C1-4-alkyl, C1-4-alkoxy, C1-4-thioalkyl, C1-3-foralkyl, C1-3-feralcode, C1-3-portyankina, phenyloxy, benzyloxy, piperidinyl, pyrrolidinyl, morpholinyl, NH2, Other6, NR6R7, NHCOR6, COR6, CO2R6, SO2R6, -O-(C1-3-alkylene)-O-, 4-piperazinil, if necessary substituted C1-3-alkyl or benzyl;

R3means

or 2,2,2-triptorelin,

or phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline,

and

R6and R7denote, independently of one another, C1-3-alkyl, phenyl;

provided that:

when R3means 2,2,2-triptorelin and group -[A]n- represents the group-CH2-,

then R1is different from a hydrogen atom or metoxygroup;

when R3denotes phenyl, in case of need, Sames the config, and the group[A]n- represents the group-CH2-, -CH2CH2-, -CH(CH3)-, -CH(CH3)-CH2-,

then R1different from an atom of hydrogen or chlorine or a methyl group or metoxygroup and R2different from the hydrogen atom.

Compounds of General formula (I) may include one or more asymmetric carbon atoms. They can exist as enantiomers or diastereoisomers. These enantiomers and diastereoisomers, as well as mixtures thereof, including racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases or of salts of joining with acids. Such salts accession are part of the invention.

These salts preferably get with pharmaceutically acceptable acids but the salts of other acids that are suitable, for example, for the purification or separation of compounds of formula (I)are also 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 combinations or combinations with one or several molecules of water or with a solvent. Such hydrate and solvate are also part of the invention.

In the framework of the invention understand:

under Ct-zwhere t and z can take values from 1 to 12, carbon chain which can have from t to z carbon atoms, for example C1-3/sub> -carbon chain which may have 1-3 carbon atoms;

under the alkyl aliphatic saturated, straight or branched group; for example, C1-3-alkyl represents a carbon chain of 1-3 carbon atoms, straight or branched, in particular methyl, ethyl, propyl, 1-methylethyl;

under alkylene saturated, straight or branched divalent alkyl, for example, C1-3-alkylene denotes a divalent carbon chain containing from 1 to 3 carbon atoms, straight or branched, in particular, methylene, ethylene, 1-mutilation, propylene;

under cycloalkyl cyclic alkyl group, for example, C3-5-cycloalkyl means cyclic carbon-containing group having 3-5 carbon atoms, in particular, cyclopropyl, cyclobutyl, cyclopentyl;

under Alcanena unsaturated divalent aliphatic group, in particular, ethylene;

under alkoxy-O-alkyl group with a saturated, straight or branched aliphatic chain;

under thioalkyl-S-alkyl group with a saturated, straight or branched aliphatic chain;

under perakyla alkyl group in which one or more hydrogen atoms replaced by fluorine atom;

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

under portyankina thioalkyl group in which one or more hydrogen atoms replaced by fluorine atom;

under the halogen atom are a fluorine, chlorine, bromine or iodine.

Compounds according to the invention can be obtained according to various methods, illustrated by the following schema.

So, the first method (scheme 1) obtain the compounds of General formula (I) is that introduced into the reaction of the amine of General formula (II)in which R1, R2n and A, such as defined above, with a carbonate of General formula (III), where U denotes a hydrogen atom or a nitro-group, and R3such as defined above, in a solvent such as toluene or dichloroethane, at a temperature of from 0 to 80°C.

Scheme 1

According to the second method of the compounds of General formula (I)in which R3represents, in particular, phenyl, if appropriate substituted, can be obtained by reaction of the amine of General formula (II), such as defined above, with arillotta General formula (IIIa)

where R3denotes phenyl, if appropriate substituted by one or more halogen atoms or cyano groups, nitro, C1-3-alkyl, C1-3-alkoxy, trifluoromethyl or triptoreline,

in a solvent such as dichloromethane or dichloroethane, in the presence of a base such as triethylamine or diisopropylethylamine, at a temperature from room temperature up to the boiling point of the solvent./p>

The carbonates of General formula (III) can be obtained from any described in the literature by, for example, by reaction of an alcohol of General formula HOR3with phenyl - or p-nitrophenyl-chloroformate, in the presence of a base such as triethylamine or diisopropylethylamine.

Compounds of General formula (II) and (IIIa) are ready-made industrial products or described in the literature, or can be obtained are described in the literature methods or by methods known to the expert.

When R2denotes a group of the type aryl or heteroaryl in the compound of formula (I) or (II)the introduction of R2in the phenyl ring can be carried out by a reaction-derived compounds of General formula (I) or (II)the phenyl ring of which is chlorine atom, bromine, iodine or triflate group in the position where it is desirable to introduce R2with aryl or heteroaryl derivative Bronevoy acid under Suzuki reaction conditions (Chem. Rev. (1995), 95, 2457-2483; Angew. Chem. Int., Ed. (1999), 38, 3387-3388), or with aryl or heteroaryl derivative triamcinolone, under the terms of the Stille reaction (Angew. Chem. Int. Ed. Engl. (1986), 25, 508-524).

The following examples illustrate the obtaining of some compounds according to the invention. They are not restrictive and only to illustrate the invention. Spectra NMR and/or LC-MS (Liquid Chromatography coupled to Mass Spectroscopy) confirmed the structure and purity of the obtained what's connections.

TPL (°C) denotes the melting point in degrees Celsius.

The numbers indicated in parentheses in the titles of the examples correspond to the numbers in the 1st column of the following next table.

Item UICPA (international Union of Pure and Applied Chemistry - IUPAC in English) was used for the names of the compounds in the following examples. For example, for biphenylenes group was observed following numbering:

Example 1 (compound No. 1)

2,2,2-triptorelin-1,1'-biphenyl-4-illecillewaet

To a solution of 0.3 g (1,49 mmol) p-nitrophenylphosphate in 15 ml of methylene chloride is added dropwise and at room temperature, 0,119 ml (1,64 mmol) 2,2,2-triptoreline and 0,306 ml (for 1.49 mmol) of N,N-diisopropylethylamine. The mixture is stirred at room temperature for 2 hours, then add 0,275 g (1.5 mmol) of 4-phenylendiamine. Then add, dropwise and at room temperature, N,N-diisopropylethylamine to the disappearance of the formed precipitate. Thus obtained transparent solution was stirred at room temperature for 1 hour. The reaction medium is diluted with an additional 10 ml of methylene chloride and washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Share phase and the organic phase is dried over sodium sulfate. Filter the comfort, concentrate the filtrate under reduced pressure and purify the residue by chromatography on silica gel with methylene chloride.

Get 0,215 g solid white color.

LC-MS: 310

TPL (°C): 123-125°C

1H-NMR (DMSO-d6) δ (cmln): of 8.25 (t, 1H), 7,75-7,30 (m, N)and 4.65 (square, 2H), 4.25 in (d, 2H).

Example 2 (compound No. 19)

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

Apply analogously to example 1, replacing 4-phenylendiamin 2-(4-biphenyl)ethylamine.

Get 0,311 g solid white color.

LC-MS: 324

TPL (°C): 79-81°C

1H-NMR (DMSO-d6) δ (cmln): 7,80-7,20 (m, 10H)and 4.65 (square, 2H), 3,30 (m, 2H), 2,75 (t, 2H).

Example 3 (compound No. 10)

2,2,2-triptorelin-4-phenylacetylcarbinol

Apply analogously to example 1, replacing 4-phenylendiamin 4-phenoxybenzamine.

Get 0,252 g solid white color.

LC-MS: 326

TPL (°C): 145-148°C

1H-NMR (DMSO-d6) δ (cmln): 8,15 (t, 1H), 7,40-of 6.90 (m, N)and 4.65 (square, 2H), 4,20 (d, 2H).

Example 4 (compound No. 3)

4-forfinal-1,1'-biphenyl-4-illecillewaet

To a solution of 0,107 g (of 0.58 mmol) of 4-phenylaniline in 4 ml of methylene chloride added dropwise and at room temperature, 0,069 ml (0,522 mmol) of 4-ftorhinolonami and 0,149 ml (0.82 mmol) of N,N-diisopropylethylamine. The mixture is stirred at room temperature for 1 hour. The reaction cf the remote control is diluted with an additional 2 ml of methylene chloride and washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. Share phase and filter the organic phase through a hydrophobic filter glass. Concentrate the filtrate under reduced pressure and washed solid residue 5 ml simple diisopropyl ether.

Get 0,136 g solid white color.

LC-MS: 322

TPL (°C): 155-157°C

1H-NMR (DMSO-d6) δ (cmln): 8,30 (t, 1H), 7,70-7,10 (m, 13H), 4,30 (d, 2H).

Example 5 (compound No. 26)

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

Apply analogously to example 4, substituting 4-phenylendiamin 2-(4-biphenyl)ethylamine and 4-forfinal-4-methylphenylcarbinol.

Get 0.126 g solid white color.

LC-MS: 332

TPL (°C): 172-174°C

1H-NMR (DMSO-d6) δ (cmln): of 7.75 (t, 1H), 7,70-7,30 (m, N), 7,10 (d, 2H), 6.90 to (d, 2H), 3,30 (m, 2H), 2,80 (t, 2H), of 2.25 (s, 3H).

Example 6 (compound No. 16)

4-methoxyphenyl-4-phenylacetylcarbinol

Apply analogously to example 4, substituting 4-phenylendiamin 4-phenoxybenzamine, and 4-ftorhinolonami-4-methoxyphenylacetamide.

Get 0,137 g solid white color.

LC-MS: 350

TPL (°C): 89-91°C

1H-NMR (DMSO-d6) δ (cmln): to 8.20 (t, 1H), 7,45-7,25 (m, 4H), 7,20-to 6.80 (m, N), 4,25 (d, 2H in), 3.75 (s, 3H).

The following table illustrates the chemical structures and physical properties of some compounds according to the invention. In this table, "n.d." means that lockplate has not been defined (for example, the compound obtained in the form of resin).

No.[A]nR1R2R3TPL (°C)
1CH2N4-phenylCH2CF3123-125
2CH2N4-phenylphenyl158-162
3CH2N4-phenyl4-F-phenyl155-157
4CH2N4-phenyl2-Cl-phenyl128-130
5CH N4-phenyl4-Cl-phenyl161-164
6CH2N4-phenyl2-CH3O-phenyl186-188
7CH2N4-phenyl4-CH3O-phenyl153-156
8CH2N4-phenyl4-CH3-phenyl153 to 155
9CH2N4-phenyl3-CF3-phenyln.d.
10CH2N4 phenyloxyCH2CF3145-148
11CH2N4 phenyloxy/td> phenyl99-101
12CH2N4 phenyloxy4-F-phenyl82-84
13CH2N4 phenyloxy2-Cl-phenyl106-109
14CH2N4 phenyloxy4-Cl-phenyl90-93
15CH2N4 phenyloxy2-CH3O-phenyl84-86
16CH2N4 phenyloxy4-CH3O-phenyl89-91
17CH2N4 phenyloxy4-CH3-phenyl105-107
18CH2N4 phenyloxy3-CF3-phenyln.d.
19CH2CH2N4-phenylCH2CF379-81
20CH2CH2N4-phenylphenyl150-152
21CH2CH2N4-phenyl4-F-phenyl160-163
22CH2CH2N4-phenyl2-Cl-phenyl131-133
23CH2CH2N4-phenyl4-Cl-phenyl167-169
24 CH2CH2N4-phenyl2-CH3O-phenyl116-119
25CH2CH2N4-phenyl4-CH3O-phenyl158-160
26CH2CH2N4-phenyl4-CH3-phenyl172-174
27CH2CH2N4-phenyl3-CF3-phenyl132-135
28CH2CH2CH2NNphenyl62-65
29CH2CH2CH2NN4-F-phenyl61-63
30CH2CH CH2NN4-Cl-phenyl53-56
31CH2CH2CH2NN4-CH3-phenyl79-81
32CH2CH2CH2CH2NNphenyl76-78
33CH2CH2CH2CH2NN4-F-phenyl91-93
34CH2CH2CH2CH2NN4-Cl-phenyl95-97
35CH2CH2CH2CH2NN4-CH3-phenyl91-93

Compounds according to the invention was the subject of the m pharmacological tests to determine their inhibitory effect on the enzyme FAAH (Fatty Acid amido Hydrolase).

Inhibitory activity was detected in radioterminal test based on measuring the product of hydrolysis (ethanolamine [1-3H]) of anandamide [ethanolamine 1-3H] FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimented Therapeutics (1997, 283, 729-734). So, the brains of mice (without cerebellum) was collected and kept at -80°C. Homogenizate membranes received extemporal by homogenization of tissue in the transmitter station in a buffer of Tris-HCl 10 mm (pH 8.0)containing 150 mm NaCl and 1 mm EDTA. Then the enzymatic reaction was performed in 70 μl of buffer containing bovine serum albumin without fatty acids (1 mg/ml). Consistently add test compounds in different concentrations of anandamide [ethanolamine 1-3H] (specific activity 15-20 Ci/mmol)in a dilution of 10 μm cold anandamide and preparation of membranes (400 g frozen tissue on the test). After 15 minutes at 25°C. the enzymatic reaction stopped by the addition of 140 μl of a mixture of chloroform/methanol (2:1). The mixture is stirred for 10 minutes, then centrifuged for 15 minutes at 3500 g. An aliquot (30 μl) of the aqueous phase containing ethanolamine [1-3H], counting liquid scintillation.

In these conditions, the most active compounds according to the invention represent CI50(concentration inhibiting 50% of the control enzyme and the activity of FAAH) from 0.001 to 1 μm.

It seems thus that the compounds according to the invention have an inhibitory effect on the enzyme FAAH.

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. These derivatives have various pharmacological activities, interacting, inter alia, with cannabinoid and vanilloid receptors.

Compounds of the invention block the path of degradation and increase the levels of these endogenous substances in the tissues. They can be used in this capacity in the prevention and treatment of pathologies involving endogenous cannabinoids and/or any other substances, metabolisable enzyme FAAH.

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

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 inflammatory diseases: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, symptoms of irritation of the colon;

acute or chronic peripheral b is;

dizziness, vomiting, nausea, in particular, due to chemotherapy;

eating disorders, particularly anorexia and cachexia of various nature;

neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasms, compulsive and obsessive behavior, Tourette's syndrome, all forms of depression and anxiety of any kind and origin, mood disorders, psychoses;

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

epilepsy;

sleep disorders, including sleep apnea;

cardiovascular disease, in particular hypertension, cardiac arrhythmia, arteriosclerosis, heart attack, coronary heart disease;

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, neuroepithelioma, a tumor of the pineal gland, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanoma, sanomi);

castroist is and the immune system, in particular, autoimmune diseases: psoriasis, erythematous lupus erythematosus, connective tissue disease or connectivity syndrome Sjogren, ankylosing spondylitis, undifferentiated spondylitis, Behcet's disease, autoimmune hemolytic anemia, multiple sclerosis, amyotrophic lateral sclerosis, amyloidosis, graft rejection, diseases affecting plasmacytoma line;

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

parasitic, viral or bacterial infectious diseases: AIDS, meningitis;

inflammatory diseases, particularly diseases of the joints: arthritis, rheumatoid arthritis, osteoarthritis, spondylitis, gout, vasculitis, Crohn's disease, symptoms of irritation of the colon;

osteoporosis;

eye disorders: ocular hypertension, glaucoma;

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

gastrointestinal disease: a syndrome of irritated large intestine, intestinal inflammatory disorders, ulcers, diarrhea;

urinary incontinence and bladder inflammation.

The use of compounds according to the invention for the floor of the treatment drugs designed for treatment of the above mentioned pathologies, is an integral part of the invention.

The use of the following compounds to obtain a medicinal product intended for the treatment of the above mentioned pathologies, is also an integral part of the invention:

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

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

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

It is also an object of the invention are medicaments that include a compound of formula (I) or salt, or pharmaceutically acceptable hydrate is whether the MES of the compounds of formula (I). These drugs are used in therapy, in particular in the treatment of these pathologies.

It is also an object of the invention are medicaments that include a compound selected from the following list of compounds, or salt, or pharmaceutically acceptable hydrate or MES this connection:

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

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

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

These drugs are used in therapy, particularly in treatment for these pathologies.

According to another aspect of the present invention relates to pharmaceutical compositions containing as an active beginning at least one compound according to the invention. These pharmaceutical compositions contain an effective dose of a compound according to the invention or salts or pharmaceutically acceptable hydrate or MES specified connection, and if necessary one or more pharmaceutically acceptable excipients.

According to another aspect of the present invention relates to pharmaceutical compositions containing as an active beginning at least one compound selected from the following list of compounds. These pharmaceutical compositions contain an effective dose of a compound selected from the following list of compounds, or salts, or pharmaceutically acceptable hydrate or MES specified connection, and if necessary one or more pharmaceutically acceptable excipients:

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

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

- 2,4,5-trichlorophenyl--(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

- 2,3,4,5,6-pentafluorophenyl-4-bromobenzylamine.

These excipients chosen, depending on the pharmaceutical form and the desired method of administration, from the usual well-known specialist of the excipients.

In the pharmaceutical compositions according to the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intermembranous, intranasal, transdermal, pulmonary, ocular or rectal administration, the active principle of the above formula (I) or one of the following connections:

- 2,2,2-cryptgethashparam;

- 2,2,2-triptorelin-4-methoxybenzylamine;

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

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

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

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

- 4-cyanophenyl-2-(4-were)Amilcar the Amat;

- 2,4,5-trichlorophenyl-2-(4-chlorophenyl)ethylcarbamate;

- phenyl-4-chlorobenzylidene;

- phenyl-4-methoxybenzylamine;

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

- phenyl-3-nitrobenzylamine;

- 4-cyanophenyl-4-methoxybenzylamine;

- phenyl-3-chlorobenzylidene;

- phenyl-3,4-dichloraniline;

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

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

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

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

or if it needs salt, MES or hydrate, can be introduced in the form of a single dosage form, mixed with conventional pharmaceutical excipients, to animals and to humans for the prophylaxis or treatment of the above disorders or diseases.

The appropriate common dosage forms include oral forms such as tablets, soft or hard gelatin capsules, powders, granules, chewing gum and oral solutions or suspensions, sublingual, oral, intratracheal, intraocular, intranasal, inhalation dosage forms, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration. For topical application it is possible to use the compounds according to the invention in creams, ointments or lotions.

As an example, a single dosage form of the compounds according to the invention in tablet form can include the following components:

The connection according to the invention50.0 mg
Mannitol223,75 mg
Croscarmellose sodium6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

The above-mentioned single dosage form designed to provide daily administration of 0.01-20 mg of active start per kg of body weight, in galenical form.

Can be private when you want a lower or higher dose; this dose also belong to the invention. According to usual practice, the dosage appropriate to each patient is determined by the doctor depending on the method of administration, body weight and individual sensitivity of the specified patient.

The invention in another aspect relates to a method of treatment of the above pathologies, which which includes the introduction of 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 n denotes an integer from 1 to 6;
And X denotes a group;
moreover, when n denotes an integer from 2 to 6, group And are the same or different;
X denotes a1-2-alkylen;
R1denotes a hydrogen atom;
R2denotes a hydrogen atom,
or a group selected from the following groups: phenyl, phenyloxy;
R3does
or 2,2,2-triptorelin,
or phenyl, if appropriate substituted by one or more halogen atoms or C1-3-alkyl, C1-3-alkoxy, trifluoromethyl;
provided that
the compound of formula 1 is not 2,2,2-cryptgethashparam,
when R3means 2,2,2-triptorelin and group -[A]n- represents the group-CH2-,
when R3denotes phenyl, if necessary replaced, and the group[A]n- represents the group-CH2-, -CH2CH2-, -CH2CH2CH2-,
then R2is different from a hydrogen atom
a base, the salt of the merger with pharmaceutically acceptable acid.

2. The method of obtaining compounds of General formula (I) according to claim 1

in which R1, R2And n have meant what I defined in claim 1, and R3denotes phenyl, if appropriate substituted by one or more halogen atoms or With1-3-alkyl, C1-3-alkoxy, trifluoromethyl,
including the state, namely, that
injected into the reaction amine of General formula (II),

in which R1, R2, n and a have the meanings defined in General formula (I), with arillotta General formula (IIIa)

where R3denotes phenyl, if appropriate substituted by one or more halogen atoms or With1-3-alkyl, C1-3-alkoxy, trifluoromethyl.

3. Pharmaceutical composition having inhibitory effect on the enzyme FAAH, containing an effective dose of at least one of the compounds of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt, and if necessary one or more pharmaceutically acceptable excipients.

4. The compound of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt for use as drugs having inhibitory action on the enzyme FAAH.

5. The use of the compounds of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt to obtain drugs having inhibitory action on the enzyme FAAH, pre is scheduled 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, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular disorders, pulmonary disorders, gastrointestinal diseases or urinary incontinence.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: present invention pertains to novel pyrrolo[3,2-b]pyridine derivatives of formula I , where values of radicals R1-R5 are given in the description. The invention also covers pharmaceutically acceptable salts of these compounds, methods of producing these compounds and pharmaceutical compositions containing these compounds. Pyrrolo[3,2-b]pyridine derivatives and their pharmaceutically acceptable salts can provide proton pump reversible inhibitory effect.

EFFECT: obtaining novel pharmaceutically acceptable salts which can provide proton pump reversible inhibitory effect.

5 cl, 2 tbl, 289 ex

FIELD: medicine.

SUBSTANCE: invention refers to compounds having anxiolytic and antidepressant activity, which are derivatives of the formula 1 (a-b), or formula 2 (a-b) at that compounds of formula 2 (a-b) are intermediate products in synthesis of compounds of the formula , where R-Cl is a compound 1a or R'=COOC2H5 - compound 1b, , where R=COOC2H5 and R'=C1 - compound 2a; R=R-COOC2H5 - compound 2b.

EFFECT: obtaining new biologically active compounds that differ from analogues as intended in low toxicity and lack of side effects.

5 cl, 3 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. The disclosed compounds have CDK1 and/or CDK2 kinase inhibiting activity. In formula R1 is selected from hydrogen, hydroxy-lower alkyl, C3-C6 cycloalkyl and R2-(X)n; X is selected from lower alkylene, hydroxy-lower alkylene, lower cycloalkylene or lower alkanoyloxy-lower alkylene; R2 is and is selected from phenyl and a 5- or 6-member heteroaromatic ring containing 1 or 2 heteroatoms selected from a group consisting of sulphur and nitrogen; R5 and R6 are independently selected from a group consisting of hydrogen, lower alkyl, halogen and lower alkoxy; and n equals 0 or 1.

EFFECT: design of a pharmaceutical composition for treating and preventing diseases whose condition can be improved by inhibiting CDK1 and/or CDK2 kinase, containing an effective amount of formula I compounds.

47 cl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula I. In general formula I A is C or N; B, D and E independently represent CR4, NR5, N, O or S; and a ring containing groups A, B, D, E, selected from thienyl, furan, imidazole, oxazole, isothiazole, thiazole, pyrrol, pyrazole; provided that: b) when A is N, not any of B, D, E can be O or S; and c) when A is C, B is CR4 and one of D or E is N or NR5, when any of D or E cannot be NR5 or N; G is N or C; R1 represents one or more substitutes selected from H, Ra halogen, -OH and -ORa; R2 represents one or more substitutes selected from H, halogen and C1-6-alkyl, and also one of substitutes R2 can be -ORb' , -NRb' Rb', -SRb', -SORb', -SO2Rb', -SO2NRb' Rb'; R3 is H, or Cy, selected from phenyl optionally substituted with one or more substitutes selected from Rc , where Rc independently represents halogen, -ORg', where Rg' independently represents a Rg group, where Rg is C1-6-alkyl; each R4 independently represents H, Re, halogen, -CORe', -CO2Re', -CONRe'Re', -NRe'Re'; R5 independently represents H, Re, -CORe, -CONReRe, -SORe or -SO2Re; each Ra independently represents C1-6-alkyl or halogen- C1-6-alkyl; each R independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rb' independently represents H or Rb; each Rc independently represents halogen, -ORg', -CONRg'Rg', -NRg'Rg'; Rd is Cy optionally substituted with one or more Rf substitutes; each Rc independently represents C1-6-alkyl optionally substituted with one or more substitutes selected from Rc and Cy*, or Re is Cy, where any of the groups Cy or Cy* can optionally be substituted with one or more substitutes selected from Rc and Rg ; each Re' independently represents H or Re; each Rf independently represents a halogen, -ORh', -CO2Rh; each Rg independently represents Rd or C1-6-alkyl optionally substituted with one or more substitutes selected from Rd and Rf; each Rg' independently represents H or Rg; each Rh independently represents C1-6-alkyl, halogen-C1-6-alkyl or hydroxy- C1-6-alkyl; each Rh' independently represents H or Rh; and Cy or Cy* given in definitions above is a partially saturated, saturated or aromatic 3-7-member monocyclic carbocyclic ring which optionally contains 1-2 heteroatoms selected from N and O, and where the ring or rings can be bonded to the remaining part of the molecule through a carbon or nitrogen atom.

EFFECT: obtaining formula I compounds with p38-kinase inhibitory properties which can be used in making drugs for treating such diseases as tumour immune and autoimmune diseases etc.

21 cl, 10 dwg, 8 tbl, 57 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula where L1 and L2 independently denote a bond, -S-, -NH- or unsubstituted C1-C5alkylene; A1 denotes a 6-member substituted aryl or unsubstituted heteroaryl; A2 denotes aryl or heteroaryl; R1 denotes halogen, -OR5, -NR6R7, -C(Z)R8, -S(O)wR9, -CN, -NO2, -S(O)2NH2, alkyl, aryl or heteroaryl; X1 denotes -C(R2)=, -C(R2)(R3)-, -N(R4)- or -O-; R2 and R3 independently denote hydrogen, -OR5 or alkyl; R4 denotes hydrogen or alkyl; Z denotes O or NH; w is integer from 0 to 2; R5 independently denotes hydrogen or alkyl; R6 and R7 independently denote hydrogen, -S(O)2R11 alkyl or heteroalkyl; R11 denotes hydrogen or alkyl; R8 independently denotes hydrogen, -NR14R15, -OR16, heteroalkyl or cycloalkyl; R14, R15 and R16 independently denote hydrogen, alkyl, cycloalkyl, heteroalkyl or heterocycloalkyl; R9 independently denotes hydrogen or alkyl; and where R6 and R7, R14 and R15 independently and optionally together with the nitrogen atom to which they are bonded form a substituted or unsubstituted heterocycloalkyl. The invention also relates to a method of modulating protein kinase activity, as well as to use of compounds in paragraph 1 and a pharmaceutical composition based on the said compounds.

EFFECT: new compounds which can be useful in treating diseases mediated by kinase activity are obtained and described.

47 cl, 2 ex, 40 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) and their pharmaceutically acceptable salts of formula (I) where n equals 0, 1 or 2, A is a five- or six-member aromatic ring which optionally contains one or two heteroatoms independently selected from nitrogen, oxygen or sulphur, B is a 5-9-member ring containing 0 or 1 double bonds and optionally contains an additional heteroatom selected from nitrogen and oxygen; where the ring optionally contains one or two substitutes independently selected from a group comprising C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkyl, carboxy, cyano, hydroxy, hydroxy-C1-C6-alkyl, di-C1-C6-alkylamino-C1-C6-alkyl, (NR4R5)-carbonyl or oxo; R1 is selected from -C(O)NR4R5 - CO2R4, 5-tetrazolyl, cyano; each R2 is independently selected from a group comprising C1-C6-alkyl, amino, benzyloxy, halogen, hydroxyl; R3 is a 5-7-member cycloalkyl ring; values of the rest of the radicals are given in the formula of invention. The invention also relates to a method for synthesis of the said compounds, a method of inhibiting HCV replicon function and a method of inhibiting functioning of the HCV NS5B protein.

EFFECT: wider field of use of the compounds.

16 cl, 4 tbl, 29 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel condensed heterocylic protein kinase modulators of formula I where L1 and L2 independently denote a bond, and R1 and R2 denote a substituted or unsubstituted heteroaryl or a substituted or unsubstituted aryl, as well as to pharmaceutical compositions containing such compounds, and methods of using the compounds to prepare medicine for diseases mediated by protein kinase activity.

EFFECT: increased effectiveness of using the compounds.

24 cl, 20 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds selected from compounds of formulae Ia, lb and Ic, which have protein kinase activity on kinase selected from CDKs, Aurora, Jak2. Rock, CAMKI, FLT3, Tie2, TrkB, FGFR3 and KDR, abnormal activity of which is observed in pathological conditions such as nonmalignant and malignant proliferative diseases. In compounds of formulae , and : n equals 0 or 1, R1 is selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted CpC6alkyl and halogen-substituted C1-C6alkoxy, R2 is selected from a group comprising phenyl, 6-member heteroaryl containing 1-2 nitrogen atoms in the heteroaryl ring as heteroatoms, and phenyl(C0-C4)alkyl, where the said phenyl and heteroaryl in R2 are optionally substituted with 1-3 radicals independently selected from a group comprising halogen, C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl, halogen-substituted C1-C6alkoxy, -S(O)0-2R5, -COOR5 and -NR5C(O)R6, where R5 is selected from C1-C6alkyl, and R6 is selected from phenyl, where the said phenyl in R6 is optionally substituted with 1-3 radicals independently selected from a group comprising C1-C6alkyl, C1-C6alkoxy, halogen-substituted C1-C6alkyl and halogen-substituted C1-C6alkoxy, X is selected from CR7 and N, where R7 is selected from hydrogen or C1-C6alkyl.

EFFECT: increased effectiveness of using the compounds.

7 cl, 3 dwg, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 2-amino-5-methylthiazole used as an intermediate compound in synthesis of drugs. Method for synthesis of 2-amino-5-methylthiazole involves the following steps: chlorination reaction of propionic aldehyde with sulfuryl chloride, successive addition of lower alcohol and alkali aqueous solution to alkaline pH value of medium, separation of organic phase containing 2-chloropropionic aldehyde acetal, condensation of acetal with thiourea. Organic phase is added directly to thiourea in acid aqueous solution. Method provides increasing yield of the end product and to simplify the process.

EFFECT: improved method of synthesis.

1 cl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel crystalline forms that can be used as components in preparing a solid pharmaceutical antidiabetic composition and antidiabetic medicinal agent. Invention relates to α-form of crystal and β-form of crystal of (R)-2-(2-aminothiazol-4-yl)-4'-{2-(2-hydroxy-2-phenylethyl)amino)]ethyl}acetanilide. α-Form of crystal shows the heat-absorption peak at 142-146°C in DSC-analysis and main peaks of X-rays powdery diffraction 5.32, 8.08, 15.28, 17.88, 19.04, 20.20, 23.16 and 24.34 in 2θ(°) units, it doesn't show hygroscopicity but possesses stability and therefore can be used as a medicinal agent. β-Form of crystal shows heat-absorbing peaks at 90-110°C and 142-146°C in DSC-analysis and main peaks in X-rays powdery diffraction 9.68, 19.76, 20.72, 22.10 and 23.52, it doesn't show hygroscopicity relatively and useful as an intermediate substance in preparing α-form of crystal also.

EFFECT: valuable properties of crystal.

8 cl, 2 tbl, 9 dwg, 4 ex

The invention relates to a method for producing acid salt of (Z)-2-aminothiazole the compounds of formula (I), where R1and R2independently represent an alkyl group having 1-5 carbon atoms, Y represents a halogen atom, m represents the valency of the inorganic acid of the formula (III) and n represents the integer 1 or 2, including the interaction of the acid salt of 2-aminothiazoline the compounds of formula (II), where R1and R2independently represent an alkyl group having 1-5 carbon atoms, X represents a bromine atom or an iodine atom and the wavy line indicates that this compound is a mixture of E - and Z-isomers, with an inorganic acid of the formula HY (III), where Y represents a halogen atom, and where the acid salt of 2-aminothiazoline the compounds of formula (II) is a compound obtained by the interaction of thiourea and halogenated compounds of the formula (VI), where R1, R2X and the wavy line have the same meanings as defined above

The invention relates to new amide derivatives of General formula (I) or their salts, where a means thiazolidin, imidazoline, triazoline, benzimidazolyl, benzothiazolyl, thiadiazolyl, imidazopyridine or imidazothiazole; X is a bond, -NR5-, -NR5CO-, -NR5CONH-, NR5SO2-, -NR5C(= NH)NH-; R1means H, lower alkyl, aryl, pyridyl, thienyl, furyl, thiazolyl, benzimidazolyl, imidazopyridine, triazolyl, thiadiazolyl, imidazolyl, imidazothiazoles, benzothiazolyl, cyclohexyl, which may be optionally substituted with halogen, lower alkyl, -OH, -CN, -NO2, -CF3, -NH2, -O-lower alkyl, and the Deputy of the lower alkyl may be substituted by phenyl, naphthyl, fullam, tanila or pyridium;2a, R2bmean H or lower alkyl; R3means hydrogen or lower alkyl; R4a, R4bmean H or HE, or taken together form a group =O or =N-O-lower alkyl; R5means H or lower alkyl

The invention relates to organic chemistry, and more specifically to new connections - hydrochloridum 2-aminoimidazole and 2-aminothiazole General formula (1),

< / BR>
aryl, the substituent in position 4 and a disulfide bridge in the position 5, where X is alkylamino, for example, methylamino, and R1-R2is hydrogen; X-methylaminopropyl, and R1-alkyl, for example methyl and R2is hydrogen; X-methylaminopropyl, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X-methylaminopropyl, and R1-ethoxypropan and R2is hydrogen; X-methylaminopropyl, and R1halogen, for example chlorine and RF2is hydrogen; X-methylaminopropyl, and R1-R2-alkoxygroup, for example, methoxy; X-atramentaria, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-alkoxygroup, for example, methoxy and R2is hydrogen; X is sulfur, and R1-R2-alkoxygroup, for example, methoxy; X is sulfur, and R1halogen, for example fluorine and R2-hydrogen

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of formula (I) , in which Ar is furanyl, thiophenyl, thiazolyl, pyridinyl; R1 is independently chosen from a group consisting of hydrogen, lower alkyl, lower alkoxy, halogen and nitro; R2 is independently chosen from a group consisting of hydrogen and halogen; R4 is hydroxyl or residue of pyrrolidine-2-carboxylic acid, piperidine-2-carboxylic acid or 1-aminocyclopentane carboxylic acid, bonded through a nitrogen atom of an amino acid residue; n is 0, 1, 2, 3, 4 or 5; m is 0, 1, 2, 3 or 4; p is 0, and s is 0, or to their pharmaceutically acceptable salts, under the condition that, the compound is not S-1- [5-(biphenyl-4-yloxymethyl)furan-2-carbonyl]pyrrolidin-2-carboxylic acid, 5-(biphenyl-4-yloxymethyl)furan-2-carboxylic acid, 3-(biphenyl-4-yloxymethyl)benzoic acid, 2-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-3-yloxymethyl)benzoic acid, 4-(biphenyl-4-yloxymethyl)benzoic acid, 5-(biphenyl-4-yloxymethyl)thiophene-2-carboxylic acid. Invention also relates to a pharmaceutical composition based on formula (I) compounds, which stimulates glycogen synthase activity.

EFFECT: wider range of use of the compounds.

27 cl, 34 ex, 8 dwg

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

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