Piperidine alkyl carbamate derivatives, production thereof and use thereof as faah enzyme inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) and their acid-additive and basic salts as FAAH enzyme inhibitors, method of producing said compounds, a pharmaceutical composition based on said compounds and their use, as well as to intermediate compounds of formula (IIa). In general formula (I) , m is an integer ranging from 1 to 4; n is equal to 1 or 2; o is equal to 1 or 2; A is selected from one or several groups X, Y; X denotes a methylene group optionally substituted with one group which is C1-6-alkyl; Y denotes a C2-alkynylene group; B denotes a covalent bond or C1-6-alkylene group; G denotes a covalent bond, an oxygen atom; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, quinolinyl, isoquinolinyl; R5 denotes a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-fluoroalkyl, C1-6-fluroalkoxy, NR7R8; R6 denotes a phenyl group, phenyloxy or pyrimidinyloxy; where R6 group(s) can be substituted with one or two R5 groups which are identical or different from each other; R7 and R8 independently denote a C1-6-alkyl group; R2 denotes a hydrogen atom; R3 denotes a hydrogen atom or C1-C6-alkyl group. In general formula (IIa) , m is an integer ranging from 1 to 2; n equals 2, o equals 2; A denotes X, X denotes a methylene group; B denotes a C1-6-alkylene group; G denotes a covalent bond; R1 denotes an R4 group optionally substituted with one or more R5 and/or R6 groups; R4 denotes phenyl; R5 denotes a halogen atom, C1-6alkoxy; R6 denotes a phenyl group; R2 denotes a hydrogen atom.

EFFECT: compounds can be used for treating and preventing diseases mediated by FAAH enzyme activity, such as acute and chronic pain, dizziness, vomiting, nausea, disrupted eating behaviour, neurologic and psychiatric pathologies, acute and chronic neurodegenerative diseases etc.

 

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

Already known derivatives phenylalkylamines, dioxane-2-allylcarbamate and piperidinyl and piperazinylcarbonyl described respectively in documents WO 2004/067498 A, WO 2004/020430 and WO 2004/099176, are inhibitors of the enzyme FAAH (Fatty Acid Amido Hydrolase).

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

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

in which m denotes an integer from 1 to 4;

n means an integer equal to 1, 2 or 3;

means an integer equal to 1 or 2;

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

X represents a methylene group, optionally substituted by one or two1-6-alkyl, C3-7-cycloalkyl or C3-7-cycloalkyl-C1-3-alkionovymi groups;

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

Z means a group of the formula:

p is an integer from 1 to 5;

q and r are integers and determine the Lena so, that r+q is a number from 1 to 5;

B means a covalent bond or C1-6-alkylenes group;

G means a covalent bond, oxygen atom or sulfur, or a group-CH(OH)-, CO, SO or SO2;

R1means the group R4, optionally substituted by one or more groups R5and/or R6;

R4means a group selected from furanyl, pyrrolyl, teinila, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, imidazolyl, pyrazolyl, thiadiazolyl, isothiazoline, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, naphthyl, chinoline, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, phthalazine, heatline, khinoksalinona, cinnoline, naphthyridine, imidazopyrimidines, thienopyrimidine, benzofuranyl, dihydrobenzofuranyl, benzothiazyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, indolyl, isoindolyl, indazole, pyrrolopyridine, properidine, dihydropyrimidine, thienopyridine, dihydrotriazine, imidazopyridine, pyrazolopyrimidine, oxazolopyridine, isoxazolidine, triazolopyridine;

R5means halogen atom, cyano group, nitro, hydroxyl, C1-6-alkyl, C -alkoxy, C1-6-thioalkyl,1-6-foralkyl,1-6-feralcode,1-6-vertially, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylen, NR7R8, NR7COR8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, CONR7R8, SO2R7, SO2NR7R8or-O-(C1-3-alkylene)-O-;

R6means the group: phenyl, phenyloxy, benzyloxy, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl or pyrimidinone, and the group or groups R6can be substituted by one or more groups R5the same or different from each other;

R7and R8independently from each other mean a hydrogen atom or a C1-6is an alkyl group, or together with the atom or atoms to which they are linked, form a cycle selected from azetidine, pyrolidine, piperidino, morpholino, thiomorpholine, azepino or pieperazinove cycle, and this cycle is optionally substituted C1-6is an alkyl or benzyl group;

R2means a hydrogen atom or a C1-6is an alkyl group;

R3means a hydrogen atom or a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylen.

In the framework of the invention compounds of General formula (I) can, thus, the soda is to press several groups And, the same or different from each other.

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

m means an integer from 1 to 4;

n means an integer equal to 1 or 2;

means an integer equal to 1 or 2;

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

X indicates a methylene group, optionally substituted by one or two C1-6-alkyl groups, in particular methyl;

Y means With2-alkynylamino group;

In the mean covalent bond or C1-6-alkylenes group, in particular methylene or ethylene;

G means a covalent bond or an oxygen atom;

R1means the group R4, optionally substituted by one or more groups R5and/or R6in particular one or two groups R5and/or R6;

R4means a group selected from oxazolyl, isoxazolyl, thiazolyl, phenyl, pyridinyl, naphthyl, chinoline, izochinolina;

R5means a halogen atom, in particular chlorine, bromine or fluorine, a cyano group, NR7R8C1-6-alkyl group, in particular methyl or isopropyl, C1-6-alkoxy, in particular methoxy or ethoxy, C1-6-foralkyl, in particular trifluoromethyl, or C1-6-feralcode, in particular triptoreline;

R6means phenyl group, phenyloxy is whether pyrimidinone, moreover, the group or groups R6can be substituted by one or more groups R5the same or different from each other;

R7and R8independently from each other mean With1-6-alkyl group, in particular methyl;

R2means a hydrogen atom or a C1-6is an alkyl group;

R3means a hydrogen atom or a group1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylen.

Of the compounds of General formula (I) and the first subgroup and the second subgroup is formed connections

n, o, A, B, G, R1, R2and R3such as defined in formula (I) or in the above range;

m means an integer equal to 1 or 2, in particular equal to 1.

Of the compounds of General formula (I) and the above subgroups third subgroup form a connection that

m, A, B, G, R1, R2and R3such as defined in formula (I) or the above-mentioned groups;

n = 2;

o is 2.

Of the compounds of General formula (I) and the above subgroups of the fourth group consists of compounds in which

m, n, o, A, B, G, R2and R3such as defined in formula (I) or the above-mentioned groups;

R1means the group R4optionally substituted by one or more groups R5and/or R6in particular one or two of the groups R 5and/or R6;

R4means a group selected from oxazolyl, isoxazolyl, phenyl or naphthyl;

R5means a halogen atom, in particular chlorine, bromine or fluorine, a cyano group, NR7R8or C1-6-alkyl group, in particular methyl or isopropyl, C1-6-alkoxy, in particular methoxy or ethoxy, C1-6-foralkyl, in particular trifluoromethyl, or C1-6-feralcode, in particular triptoreline;

R6means phenyl group, phenyloxy or pyrimidinone, and the group or groups R6can be substituted by one or more groups R5the same or different from each other;

R7and R8independently of one another denote C1-6-alkyl group, in particular methyl.

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

m, n, o, A, B, G and R1such as defined in formula (I) or the above subgroups,

R2means a hydrogen atom;

R3means a hydrogen atom or a C1-6-alkyl group, in particular methyl.

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

-[2-(methylamino)-2-oxoethyl]-{1-[(3,4'-diferuloyl-4-yl)methyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[(3-chloro-4'-forbiden-4-yl)methyl]piperidine-4-yl}methylcarbamate;

-[2-(meth the laminitis)-2-oxoethyl]-{1-[3-(4-pertenece)benzyl]piperidine-4-yl]}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chloro-3-formatosi)benzyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[3-(triptoreline)benzyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[4-(triptoreline)benzyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[-1-(3-tert-butoxybenzoyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(3-tert-butoxybenzoyl)piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(2,4-dichlorobenzyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(2,5-dichlorobenzyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(3,5-dichlorobenzyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(2-chloro-5-terbisil)piperidine-4-yl]

ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(3-chloro-2-terbisil)piperidine-4-yl]

ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(3-chloro-5-methylbenzyl)piperidine-4-yl]

ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[(3,4'-diferuloyl-4-yl)methyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[(3-chloro-4'-forbiden-4-yl)methyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[4-(4-chloro-3-pertenece)benzyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[3-(4-pertenece)benzyl]piperidine-4-yl}

carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[3-(Tr is formatosi)benzyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[4-(triptoreline)benzyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[3-(pyrimidine-2-yloxy)benzyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(2-chloro-4-terbisil)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(3-chloro-4-terbisil)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(3-cyano-5-terbisil)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[3-(4-pertenece)benzyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{[3-(4-chlorophenyl)isoxazol-5-yl]methyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]methyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-({4-[4-(trifluoromethyl)phenyl]-l,3-thiazol-2-yl}methyl)piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-{[3-(4-chlorophenyl)isoxazol-5-yl]methyl}piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]methyl}piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-({4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-{2-[5-(4-chlorophenyl)isoxazol-3-yl]ethyl}piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl}piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxo is Teal]-[1-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl}piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-{3-[5-(4-chlorophenyl)isoxazol-3-yl]propyl}piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[1-(2-chloro-4-forfinal)ethyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-{1-[3-(4-chlorophenoxy)phenyl]ethyl}piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-{1-[2-chloro-3-(4-chlorophenoxy)phenyl]ethyl}piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{1-[3-(triptoreline)phenyl]ethyl}piperidine-4-yl)ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[1-(2-chloro-4-forfinal)ethyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chlorophenyl)but-3-in-1-yl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[5-(4-chlorophenyl)Penta-4-in-1-yl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[5-(2,5-dichlorophenyl)Penta-4-in-1-yl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chlorophenyl)but-3-in-1-yl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chloro-2-forfinal)but-3-in-1-yl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[4-(2,5-dichlorophenyl)but-3-in-1-yl]piperidine-4-yl}methylcarbamate.

Of the compounds of General formula (I), a subgroup of compounds is formed by compounds corresponding to General formula (I'):

in which m denotes an integer from 1 to 4;

n means an integer equal to 1, 2 or 3;

means an integer equal to 1 or 2;

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

X indicates a methylene group, optionally substituted by one or two groups of C1-6-alkyl, C3-7-cycloalkyl or3-7-cycloalkyl-C1-3-alkylen;

Y means With2-alkynylamino group, optionally substituted by one or two groups of C1-6-alkyl, C3-7-cycloalkyl or3-7-cycloalkyl-C1-3-alkylene; or

C2-alkynylamino group;

Z means a group of the formula

p is an integer from 1 to 5;

q and r denote integer and is defined so that r+q is an integer from 1 to 5;

B means a covalent bond or C1-6-alkylenes group;

G means a covalent bond, oxygen atom or sulfur, or a group-CH(OH)-, CO, SO or SO2;

R1means the group R4optionally substituted by one or more groups R5and/or R6;

R4means a group selected from furanyl, pyrrolyl, teinila, oxazolyl, isoxazolyl, thiazolyl, isothiazoline, imidazolyl, pyrazolyl, thiadiazolyl, isothiazoline, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, phenyl, pyridinyl, pyridazinyl, Piri is Iginla, pyrazinyl, triazinyl, naphthyl, chinoline, tetrahydroquinoline, izochinolina, tetrahydroisoquinoline, phthalazine, heatline, khinoksalinona, cinnoline, naphthyridine, imidazopyrimidines, thienopyrimidine, benzofuranyl, dihydrobenzofuranyl, benzothiazyl, dihydrobenzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazole, benzothiazole, benzisothiazole, indolyl, isoindolyl, indazole, pyrrolopyridine, properidine, dihydropyrimidine, thienopyridine, dihydrotriazine, imidazopyridine, pyrazolopyrimidine, oxazolopyridine, isoxazolidine, triazolopyridine;

R5means halogen atom, cyano group, nitro, hydroxyl, C1-6-alkyl, C1-6-alkoxy, C1-6-thioalkyl, C1-6-foralkyl, C1-6-feralcode, C1-6-vertially,3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkylen, NR7R8, NR7COR8, NR7CO2R8, NR7SO2R8, COR7, CO2R7, CONR7R8, SO2R7, SO2NR7R8or-O- (C1-3-alkylene) -O-;

R6means a phenyl group, phenyloxy, benzyloxy, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl, and the group or groups R6can be substituted by one or more groups R5the same is or are different from each other;

R7and R8independently from each other mean a hydrogen atom or a C1-6is an alkyl group, or together with the atom or atoms to which they are linked, form a cycle selected from azetidine, pyrolidine, piperidino, morpholino, thiomorpholine, azepino or pieperazinove cycle, and this cycle is optionally substituted C1-6is an alkyl or benzyl group;

R2means a hydrogen atom or a C1-6is an alkyl group;

R3means a hydrogen atom or a group C1-6-alkyl, C3-7-cycloalkyl,3-7-cycloalkyl-C1-3-alkylen.

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

m means an integer from 1 to 3;

n means an integer equal to 1 or 2;

means an integer equal to 2;

A is A methylene group;

B means a covalent bond or C1-6-alkylenes group, in particular methylene or ethylene;

G means a covalent bond or an oxygen atom;

R1means the group R4, optionally substituted by one or more groups R5and/or R6in particular one or two groups R5and/or R6;

R4means a group selected from phenyl, pyridinyl, naphthyl, izochinolina;

R5means a halogen atom, in particular chlorine, bromine or fluorine, the group cyano, N,N-dimethylaminopropyl, C1-6-alkyl group, in particular isopropyl, C1-6-alkoxy, in particular methoxy or ethoxy, C1-6-foralkyl, in particular trifluoromethyl;

R6means phenyl group;

R2means a hydrogen atom or a C1-6is an alkyl group;

R3means a hydrogen atom or a group C1-6-alkyl, C3-7-cycloalkyl, C3-7-cycloalkyl-C1-3-alkylen.

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

m, n, o, A, B, G and R1such as defined in subgroup 1;

R2means a hydrogen atom;

R3means a hydrogen atom or a C1-6-alkyl group, in particular methyl.

Of the compounds of General formula (I') can be named the following connections:

-[2-(methylamino)-2-oxoethyl]-{1-[(2-chlorophenyl)methyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[(4-chlorophenyl)methyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[(4-chlorophenyl)methyl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-(1-[4-(1-methylethyl)phenyl]methylpiperidin-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]carbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(biphenyl-4-ylmethyl)piperidine-4-the l]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(2-biphenyl-4-retil)piperidine-4-yl]carbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(naphthalene-2-ylmethyl)piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[(4-bromophenyl)methyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{[3-(trifluoromethyl)phenyl]methyl}piperidine-4-yl)ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{[4-(trifluoromethyl)phenyl]methyl}piperidine-4-yl)ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[(2,3-dichlorophenyl)methyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[(3,4-dichlorophenyl)methyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(naphthalene-1-ylmethyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(naphthalene-2-ylmethyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-[1-(pyridine-2-ylmethyl)piperidine-4-yl]ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(l-{2-[4-fluoro-2-(metiloksi)phenyl]ethyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-forfinal)oxy]ethyl}piperidine-4-yl)carbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-chlorophenyl)oxy]ethyl}piperidine-4-yl)carbamate;

-[2-(methylamino)-2-oxoethyl]-(l-{2-[(2,4-dichlorophenyl)oxy]ethyl}piperidine-4-yl)carbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-chlorophenyl)oxy]ethyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-1-{2-[(2,4-dichlorophenyl)oxy]ethyl}piperidine-4-and the)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{2-[(4-forfinal)oxy]ethyl}piperidine-4-yl)ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{2-[(4-chlorophenyl)oxy]ethyl}piperidine-4-yl)ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-forfinal)oxy]ethyl}pyrrolidin-3-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-chlorophenyl)oxy]ethyl}pyrrolidin-3-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[3-(trifluoromethyl)phenyl]ethyl}piperidine-4-yl)carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[2-(4-chlorophenyl)ethyl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[2-(4-cyanophenyl)ethyl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[(isoquinoline-5-yl)oxy]ethyl}piperidine-4-yl)carbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(2-naphthalene-1-retil)piperidine-4-yl]carbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(2-naphthalene-2-retil)piperidine-4-yl]carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[3-(4-chlorophenyl)propyl]piperidine-4-yl}carbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{3-[4-(metiloksi)phenyl]propyl}piperidine-4-yl)carbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[2-(3-chlorophenyl)ethyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{2-[4-(ethyloxy)phenyl]ethyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-{2-[4-(dimethylamino)phenyl]ethyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-{1-[2-(2,4-dichlorophenyl)ethyl]piperidine-4-yl}methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-[1-(2-naphthalene-2-retil)piperidine-4-yl]methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-(1-{3-[4-(metiloksi)phenyl]propyl}piperidine-4-yl)methylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[2-(2-chlorophenyl)ethyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[2-(4-forfinal)ethyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{2-[4-(ethyloxy)phenyl]ethyl}piperidine-4-yl)ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-{1-[2-(2-chloro-6-forfinal)ethyl]piperidine-4-yl}ethylcarbamate;

-[2-(methylamino)-2-oxoethyl]-2-(1-{3-[4-(metiloksi)phenyl]propyl}piperidine-4-yl)ethylcarbamate.

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

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

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

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

In the context of the invention means that the

- Ct-zwhere t and z can take values from 1 to 7, means a carbon chain which can have from t to z carbon atoms, for example, C1-3is a carbon chain which can have from 1 to 3 carbon atoms;

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

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

- cycloalkyl means a cyclic alkyl group, for example, C3-7-cycloalkyl group means a cyclic carbon group having 3-7 carbon atoms, in particular cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl;

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

- C2-Akinyele means the group-C≡C-;

- alkoxy oz is ACET-O-alkyl group with a saturated aliphatic chain, linear or branched;

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

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

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

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

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

Next, the protective group PG is a group that allows, on the one hand, to protect a reactive functional group such as hydroxy or amino group, during a synthesis and, on the other hand, will activate a sound reactive functional group at the end of the synthesis. Examples of protective groups and methods of protection and removal of protection are given in "Protective Groups in Organic Synthesis", Green et al., 2nd Edition (John Wiley & Sons, Inc., New York).

Compounds according to the invention can be obtained in different ways, shown in the following diagram 1.

So, the first method (scheme 1) is to be introduced into the reaction of compound of General formula (II)in which B, R2, n and o, such as defined in the General formula (I), with a derivative of General formula (III)in which W means mesilat the Yu, tosylate group or a chlorine atom, bromine or iodine, and m, G, A, and R1such as defined in the General formula (I), in the presence of a base, such as triethylamine, sodium hydride, tert-piperonyl sodium or sodium carbonate, in a solvent such as tetrahydrofuran, acetonitrile, dimethylsulfoxide or dimethylformamide, at a temperature of from 0°C to the boiling point of the solvent.

Scheme 1

Then thus obtained oxazolidinedione General formula (IIa) is converted into compound of General formula (I), aminolysis an amine of General formula R3NH2in which R3such as defined in the General formula (I). The reaction aminolysis can be carried out in a solvent such as methanol, ethanol, or a mixture of solvents, such as methanol and tetrahydrofuran, or methanol and dioxane.

One option for obtaining compounds of General formula (I) (scheme 1) consists in the transformation of compounds of General formula (II), as defined above, aminolysis in the above-described conditions by using an amine of General formula R3NH2such as defined above, to obtain the derived carbamate-amide of General formula (Ia)in which B, R2, R3, n and o, such as defined in the General formula (I). Then get the compound of General formula (I) by reaction of the compound (Ia) with a derivative of General forms of the crystals (III), such as defined above, in the above-described conditions.

Derived carbamate-amide of General formula (Ia), such as defined above can be obtained also from the complicated ether carbamate of General formula (Ib)in which B, R2, n and o, such as defined in the General formula (I), PG denotes a protective group, such as Boc (tert-butyloxycarbonyl), and R denotes a methyl or ethyl group, by aminolysis an amine of General formula R3NH2such as defined above, in the above-described conditions, followed by removal of the protection, for example, in the presence of hydrochloric acid (5 BC) in isopropanol.

Esters - carbamates (Ib) can be obtained by the method shown in the following scheme 2.

Scheme 2

According to the scheme 2 ester carbamate of General formula (Ib) obtained by the reaction of an amine of General formula (IV)in which B, n and o, such as defined in the General formula (I), and PG denotes a protective group, such as Boc, with a carbonate of General formula (V), where V denotes a hydrogen atom or a nitro group, R2defined in the General formula (I) and R is a methyl or ethyl group.

If the retrieval method is not described, compounds of General formula (II) can be obtained by methods described in the literature or by methods similar to those described, or by methods known to the expert.

2COOR, where R is a methyl or ethyl group, with chloroformate phenyl or 4-nitrophenyl, in the presence of a base such as triethylamine or diisopropylethylamine.

Compounds of General formula (III), (IV) and the amines of General formula R3NH2commercially available or prepared by methods described in the literature or known to the specialist methods.

Compounds of General formula (Ia)in which B, R2, R3n and o are defined in the General formula (I)are new and also form part of the invention. They are useful as intermediates for the synthesis to obtain the compounds of General formula (I).

Compounds of General formula (IIa)where m, G, A, R1, B, R2n and o are defined in the General formula (I)are new and also form part of the invention, except for the compound 3-[1-(phenylmethyl)-4-piperidinyl]-2,4-oxazolidinedione. They are useful as intermediate compounds for the synthesis to obtain the compounds of General formula (I).

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

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

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

Example 1 (compound No. 25)

[2-(Methylamino)-2-oxoethyl]-2-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]ethylcarbamate

1.1. Hydrochloride 3-(2-piperidine-4-retil)-1,3-oxazolidin-2,4-dione

To a solution of 10 g (77,40 mmol) 2-piperidine-4-retinol, 22,33 g (85,14 mmol) of triphenylphosphine and 9,39 g (92,88 mmol) of 1,3-oxazolidin-2,4-dione (J. Med. Chem. 1991,34, 1538-1544) in 150 ml of tetrahydrofuran, cooled to about -10°C in inert atmosphere is added dropwise a solution of 15,65 g (77,40 mmol) of diisopropylcarbodiimide (DIAD) in 25 ml of tetrahydrofuran, maintaining the temperature of the reaction medium between -10°C and 0°C. Continue to stir at 0°C for 1 h, then at 25°C for 22 hours. Formed solid phase is separated by filtration, washed several times with tetrahydrofuran, and then dried in vacuum at about 70°C. Then the solid phase is introduced into a solution of hydrochloric acid (5 BC) in isopropanol. The resulting solids are filtered and then washed with ethyl acetate and ether.

After drying in vacuum at about 70°C gain of 6.45 g of the hydrochloride in the form of a white solid.

PF(°C): 178°C.

1.2. 3-{2-[1-(Biphenyl-4-ylmethyl)PIP is ridin-4-yl]ethyl}-1,3-oxazolidin-2,4-dione

A solution of 0.40 g (of 1.61 mmol) of the hydrochloride of 3-(2-piperidine-4-retil)-1,3-oxazolidin-2,4-dione obtained in stage 1.1, 0,326 g (of 1.61 mmol) of 4-(chloromethyl)biphenyl and 0.51 g (4,82 mmol) of sodium carbonate in 3 ml of acetonitrile is refluxed for 17 hours. Brought to ambient temperature, filtered and the filtrate concentrated under reduced pressure. The residue is combined with dichloromethane and water, separating the aqueous phase and extracted twice with dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride and dried over sodium sulfate. After evaporation of the solvent, the obtained residue is purified by chromatography on silica gel, elwira a 97/3 mixture, then 95/5 dichloromethane and methanol.

Receive and 0.46 g of product as a beige solid substance.

1.3. [2-(Methylamino)-2-oxoethyl]-2-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]ethylcarbamate

To a solution of 0.45 g (1,19 mmol) 3-{2-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]ethyl}-1,3-oxazolidin-2,4-dione obtained in stage 1.2, 5 ml of methanol is added 3 ml (5,97 mmol) of a solution of methylamine (2M) in tetrahydrofuran. Continue to stir at ambient temperature for 17 hours. After concentration under reduced pressure, the obtained residue is purified by chromatography on silica gel, elwira mixture 95/5, then 90/10 dichloromethane and methanol. Get will altou pasta, which is crystallized in diisopropyl ether.

Obtain 0.40 g of product as a yellow solid substance.

LC-MS:M+H = 410.

PF(°C) 106-110°C.

1H-NMR (CDCl3) δ (ppm): 1,2-1,50 (wt, 5H); to 1.70 (m, 2H); 2,0 (Shir. t, 2H); 2,90 (d, 3H); 3,0 (m, 2H); 3,30 (quintet, 2H); 3,55 (s, 2H); 4,60 (s, 2H); 4.80 to (Shir. s, 1H); 6,15 (Shir. s, 1H); 7,40 (m, 5H); of 7.60 (m, 4H).

Example 2 (compound No. 52)

[2-(Methylamino)-2-oxoethyl]-(1-{2-[4-fluoro-2-(methoxy)phenyl]ethyl}piperidine-4-yl)methylcarbamate

2.1. 1,1-Dimethylethyl-4-{[(1-methylsulphonyl)oxy]methyl}piperidine-1-carboxylate

To a solution 10,08 g (46.81 / bbl mmol) 1,1-dimethylethyl-4-(hydroxymethyl)piperidine-1-carboxylate and 9,90 ml (70,21 mmol) of triethylamine in 100 ml dichloromethane, cooled to about 0°C dropwise in an inert atmosphere add a solution of 4 ml (51,49 mmol) methylchloride in 10 ml of dichloromethane. Remove bath and continue to stir at ambient temperature for 30 minutes. In the reaction medium was added water, separating the aqueous phase is extracted once with dichloromethane, the combined organic phases are washed with water, dried over sodium sulfate and the filtrate concentrated under reduced pressure.

Gain of 13.7 g of product as an orange oil, used in the next stage.

2.2. 1,1-Dimethylethyl-4-[(2,4-dioxo-1,3-oxazolidin-3-yl)methyl]piperidine-1-carboxylate

Boil to reverse the m refrigerator for 24 hours, the suspension 13,60 g (46,36 mmol) 1,1-dimethylethyl-4-{[(methylsulphonyl)oxy]methyl}piperidine-1-carboxylate, obtained in stage 2.1, 9,37 g (92,72 mmol) of 1,3-oxazolidin-2,4-dione and 16,02 g (139,08 mmol) 1,1,3,3-tetramethylguanidine in a mixture of 180 ml of tetrahydrofuran and 30 ml of dimethylformamide. Brought to ambient temperature and concentrate under reduced pressure. The residue is introduced into dichloromethane and water, separating the aqueous phase is twice extracted with her dichloromethane. The combined organic phases are washed with saturated aqueous sodium chloride and dried over sodium sulfate. After evaporation of the solvent, the obtained residue is purified by chromatography on silica gel, elwira mixture 98/2 then 95/5 dichloromethane and methanol.

Get of 12.53 g of the product as a brown-orange solid substance.

2.3. Hydrochloride 3-(piperidine-4-ylmethyl)-1,3-oxazolidin-2,4-dione

To a suspension 12,51 g (41,95 mmol) 1,1-dimethylethyl-4-[(2,4-dioxo-1,3-oxazolidin-3-yl)methyl]piperidine-1-carboxylate, obtained in stage 2.2, in 65 ml of dioxane add 38,10 ml (209,75 mmol) hydrochloric acid (5 BC) in isopropanol. Continue to mix at about 60°C for 17 hours. Brought to ambient temperature. Solids are filtered, then washed several times with ether and dried in vacuum at about 70°C.

Get to 8.41 g of the product as white solid.

PF(°C): 195-200°C.

2.4. 3-[(1-{2-[4-fluoro-2-(methoxy)phenyl]ethyl}piperidine-4-yl)m is Teal]-1,3-oxazolidin-2,4-dione

Use the method described in example 1 (stage 1.2). Of 0.40 g (1.70 mmol) of 3-(piperidine-4-ylmethyl)-1,3-oxazolidin-2,4-digidroid obtained at the stage 2.3, 0,423 g (1.70 mmol) of 2-[4-fluoro-2-(metiloksi)phenyl]ethylmethanesulfonate (EP 1340761) and 0.54 g (5,11 mmol) of sodium carbonate after treatment receive 0,590 g of the product as a viscous yellow oil, used in the next stage.

2.5. [2-(Methylamino)-2-oxoethyl]-(1-{2-[4-fluoro-2-(methoxy)phenyl]ethyl}piperidine-4-yl)methylcarbamate

Follow the methods of synthesis described in example 1 (stage 1.3). Out of 0.58 g (of 1.66 mmol) of 3-[(1-{2-[4-fluoro-2-(methoxy)phenyl]ethyl}piperidine-4-yl)methyl]-1,3-oxazolidin-2,4-dione obtained in stage 2.4, and of 8.28 ml (16,55 mmol) of a solution of methylamine (2M) in tetrahydrofuran after chromatography on silica gel with elution with a mixture of 95/5/0,5 dichloromethane, methanol and 28%aqueous ammonia followed by washing diisopropyl ether get 0,315 g of the product as white solid.

LC-MS: M+H = 382.

PF(°C): 126-128°C.

1H-NMR (DMSO) δ (ppm): 1,10 (m, 2H); 1,35 (Shir. s, 1H); 1,60 (Shir. d, 2H); 1.85 to (shirt, 2H); 2, 40 (m,2H); 2,60 (m, 5H); 2,90 (m, 4H); of 3.80 (s, 3H); 4,30 (s, 2H); of 6.65 (TD, 1H); to 6.80 (DD, 1H); to 7.15 (m, 2H); 7,70 (Shir. s, 1H).

Example 3 (compound N 68)

[2-(Methylamino)-2-oxoethyl]-(1-{2-[(2,4-dichlorophenyl)oxy]ethyl}piperidine-4-yl)carbamate

3.1. 1,1-Dimethylethyl-4-[({[2-(ethyloxy)-2-oxoethyl]oxy}carbon is l)amino]piperidine-1-carboxylate

Refluxed for 30 hours, the suspension 5,09 g (25,42 mmol) 1,1-dimethylethyl-4-aminopiperidin-1-carboxylate and 13,45 g (59,99 mmol) of ethyl[(phenoxycarbonyl)oxy]acetate (J. Med. Chem., 1999, 42, 277-290) in 300 ml of toluene.

Brought to ambient temperature, the insoluble fraction is separated by filtration and the filtrate concentrated under reduced pressure. Obtained residue purified by chromatography on silica gel, elwira a 30/70 mixture of ethyl acetate and cyclohexane.

In this way receive 6,62 g of the product as a transparent yellow oil.

3.2. 1,1-dimethylethyl-4-[({[2-(methylamino)-2-oxoethyl]oxy}carbonyl)amino]piperidine-1-carboxylate

Act as in example 1 (stage 1.3). From 6,33 g (19,16 mmol) 1,1-dimethylethyl-4-[({[2-(ethyloxy)-2-oxoethyl]oxy}carbonyl)amino]piperidine-1-carboxylate, obtained in stage 3.1, and 47,90 ml (95,81 mmol) of a solution of methylamine (2M) in tetrahydrofuran get 5,90 g of the product in paste form sticky yellow substance.

3.3. Hydrochloride of 2-(methylamino)-2-oxoethylidene-4-ylcarbamate

Use the method described in example 2 (stage 2.3).

From 5,90 g (18,71 mmol) 1,1-dimethylethyl-4-[({[2-(methylamino)-2-oxoethyl]oxy}carbonyl)amino]piperidine-1-carboxylate, obtained in stage 3.2, and 17 ml (93,53 mmol) hydrochloric acid (5 BC) in isopropanol, after washing diisopropyl ether and drying under vacuum in PR is approximately 70°With get a 3.83 g of the hydrochloride in the form of a white solid.

PF(°C): 153°C.

3.4. [2-(Methylamino)-2-oxoethyl]-(1-{2-[(2,4-dichlorophenyl)oxy]ethyl}piperidine-4-yl)carbamate

Use the method described in example 1 (stage 1.2). From 0.51 g (1,89 mmol) of the hydrochloride [2-(methylamino)-2-oxoethyl]piperidine-4-ylcarbamate obtained at stage 3.3, 0.50 g (1,99 mmol) 1-[(2-bromacil)oxy]-2,4-dichlorobenzene and of 0.60 g (of 5.68 mmol) of sodium carbonate after chromatography on silica gel with elution with a mixture 94/6/0,6, then 95/5/0,5 dichloromethane, methanol and 28%aqueous ammonia and then rinse diisopropyl ether gain of 0.44 g of product as a white solid.

LC-MS: M+H = 404.

PF(°C) 115-119°C.

1H-NMR (CDCl3) δ (ppm): 1.50 in (m, 2H); 2,0 (Shir. d, 2H); 2,35 (Shir. t, 2H); 2,90 (d, 3H); 3,0 (m, 4H); of 3.60 (m, 1H); 4,15 (t, 2H); 4,60 (s, 2H); 4.75 in (lat. d, 1H); 6,15 (Shir. s, 1H); 6,85 (d, 1H); 7,20 (DD, 1H); 7,40 (d, 1H).

Example 4 (compound No. 4)

Hydrochloride [2-(methylamino)-2-oxoethyl]-{1-[(4-chlorophenyl)methyl]piperidine-4-yl}methylcarbamate

4.1. Hydrochloride [2-(methylamino)-2-oxoethyl]-(piperidine-4-yl)methylcarbamate

When the ambient temperature is stirred for 15 hours a solution of 0.50 g (2,13 mmol) of the hydrochloride of 3-(piperidine-4-ylmethyl)-1,3-oxazolidin-2,4-dione obtained in stage 2.3, and 5.30 ml (10,65 mmol) of a solution of methylamine (2M) in tetrahydrofuran 10 ml of methanol. After concentration under reduced pressure, the obtained residue processing the feed solution of hydrochloric acid (5 BC) in isopropanol. The obtained hydrochloride are filtered, washed his diisopropyl ether and dried under vacuum at about 70°C.

Get 0,49 g of white powder.

4.2. Hydrochloride [2-(methylamino)-2-oxoethyl]-{1-[(4-chlorophenyl)methyl]piperidine-4-yl}methylcarbamate

When the ambient temperature is stirred mixture amount of 0.118 g (0.44 mmol) of the hydrochloride [2-(methylamino)-2-oxoethyl]-(piperidine-4-yl)methylcarbamate, 0,283 g (1,33 mmol) triacetoxyborohydride sodium and 0,626 g (of 4.45 mmol) of 4-chlorobenzaldehyde in 5 ml of 1%aqueous solution of acetic acid in N,N-dimethylformamide. After 24 hours stirring 2 g of the acid resin DOWEX50WX2 (Fluka) and continue to stir at ambient temperature for one hour. The resin is filtered and washed 3 times with 5 ml of N,N-dimethylformamide, 3 times 5 ml of dichloromethane and 3 times 5 ml of methanol. Then the resin is treated for one hour at ambient temperature 8 ml (2M ammonia in methanol. Filtered and the filtrate concentrated in vacuo. The product was then purified by chromatography on silica gel, elwira a 94/6 mixture of dichloromethane and methanol containing 2% aqueous solution of 28%aqueous ammonia. The obtained oily residue is treated with 5 ml of hydrochloric acid (0.1 N.) in isopropanol. Concentrate and get 0,067 g of white powder.

PF (°C): 220-222°C.

LC-MS: M+H = 354.

1H-NMR (DMSO-d6/D2O): δ(ppm): 1,20 (m, 2H); of 1.40 (m, 1H)and 1.60 (m, 2H); 1,90 (t, 2H); 2,70 (s, 3H); 2,75 (d, 2H); 2,90 (d, 2H); 3.40 in (s, 2H); 4,30 (s, 2H); to 7.95 (m, 4H).

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

In this table,

- in the column "base or salt" basis means that the connection is in the form of a free base and HCl connection means in the form of hydrochloride, and the ratio in parentheses is the ratio of the (acid:base),

- t-BuO, Me, Et and i-Pr means, respectively, of the group of tert-butoxy, methyl, ethyl and isopropyl and

- Ph means phenyl group.

Table 1

40. 2 H
R1G[A]mnaboutBR2R3base or saltPF(°C)
1.4-Cl-phenyllinkCH222SV is z HCH3base144-146
2.4-Phenyl-phenyllinkCH222linkHCH3base165-167
3.2-Cl-phenyllinkCH222CH2HCH3HCl (1/1)173-175
4.4-Cl-phenyllinkCH222CH2HCH3HCl (1/1)220-222
5.4-iPr-phenyl linkCH222CH2HCH3HCl (1/1)159-161
6.4-Phenyl-phenyllinkCH222CH2HCH3HCl (1/1)205-207
7.[2-F,4-(4-F-phenyl)]-phenyllinkCH222CH2HCH3base156-158
8.[2-Cl,4-(4-F-phenyl)]-phenyllinkCH222CH2HC 3HCl (1/1)163-169
9.3-(4-F-phenyloxy)-phenyllinkCH222CH2HCH3HCl (1/1)163-165
10.4-[(3-F,4-Cl)-phenyloxy]-phenyllinkCH222CH2HCH3base96-104
11.naphthalene-2-yllinkCH222CH2HCH3HCl (1/1)156-157
12.4-Br-phenyllink CH222(CH2)2HCH3base107-111
13.3-CF3-phenyllinkCH222(CH2)2HCH3base90-92
14.4-CF3-phenyllinkCH222(CH2)2HCH3base116-12O
15.3-CF3O-phenyllinkCH222(CH2)2H CH3base418*
16.4-CF3O-phenyllinkCH222(CH2)2HCH3base109-111
17.(2-Cl,3-Cl)-phenyllinkCH222(CH2)2HCH3base114-116
18.(2-Cl,4-Cl)-phenyllinkCH222(CH2)2HCH3base117-119
19.(2-Cl,5-Cl)-phenyl linkCH222(CH2)2HCH3base125-127
20.(3-Cl,4-Cl)-phenyllinkCH222(CH2)2HCH3base101-105
21.(3-Cl,5-Cl)-phenyllinkCH222(CH2)2HCH3base124-126
22.(2-Cl,5-F-phenyllinkCH222(CH2)2 HCH3base102-104
23.(2-F,3-Cl)-phenyllinkCH222(CH2)2HCH3base104-106
24.(3-Cl,5-CH3)-phenyllinkCH222(CH2)2HCH3base79-81
25.4-Phenyl-phenyllinkCH222(CH2)2HCH3base106-110
26. [2-F,4-(4-F-phenyl)]-phenyllinkCH222(CH2)2HCH3base143-145
27.[2-Cl,4-(4-F-phenyl)]-phenyllinkCH222(CH2)2HCH3base98-102
28.4-[(3-F,4-Cl)-phenyloxy]-phenyllinkCH222(CH2)2HCH3base109-111
29.naphthalene-1-yllinkCH222/td> (CH2)2HCH3base86-88
30.naphthalene-2-yllinkCH222(CH2)2HCH3base87-93
31.pyridine-2-yllinkCH222(CH2)2HCH3base104-106
32.3-CF3-phenyllink(CH2)222linkHCH3HCl (1/1)136-138
33.4-Cl-phenyllink(CH2)222linkHCH3HCl (1/1)168-170
34.4-CN-phenyllink(CH2)222linkHCH3base179-181
35.(2-Cl,3-Cl)-phenyllink(CH2)222linkHCH3base117-123
36.(2-Cl,4-Cl)-phenyllink(CH2)22 2linkHCH3base134-138
37.(2-Cl,6-Cl)-phenyllink(CH2)222linkHCH3base163-167
38.(3-Cl,4-Cl)-phenyllink(CH2)222linkHCH3base130-132
39.4-Phenyl-phenyllink(CH2)222linkHCH3base174-178
4 phenyloxy-phenyllink(CH2)222linkHCH3base144-146
41.naphthalene-1-yllink(CH2)222linkHCH3HCl (1/1)185-187
42.4-F-naphthalene-1-yllink(CH2)222linkHCH3base124-130
43.naphthalene-2-yllink(CH2)22 2linkHCH3HCl (1/1)198-202
44.3-Cl-phenyllink(CH2)222CH2HCH3base93-95
45.4-EtO-phenyllink(CH2)222CH2HCH3base134-136
46.4-Me2N-phenyllink(CH2)222CH2HCH3base130-132
47.2-Cl,3-Cl)-phenyllink(CH2)222CH2HCH3base81-87
48.(2-Cl,4-Cl)-phenyllink(CH2)222CH2HCH3base125-127
49.(2-Cl,4-Cl)-phenyllink(CH2)222CH2HHbase115-119
50.(2-Cl,6-Cl)-phenyllink(CH2)22CH2HCH3base144-148
51.(3-Cl,4-Cl)-phenyllink(CH2)222CH2HCH3base123-127
52.(2-MeO,4-F-phenyllink(CH2)222CH2HCH3base126-128
53.4 phenyloxy-phenyllink(CH2)222CH2HCH3base 120-124
54.naphthalene-1-yllink(CH2)222CH2HCH3HCl (1/1)148-150
55.4-F-naphthalene-1-yllink(CH2)222CH2HCH3base120-124
56.naphthalene-2-yllink(CH2)222CH2HCH3base163-166
57.2-Cl-phenyllink(CH2)2 22(CH2)2HCH3HCl (1/1)121-123
58.4-F-phenyllink(CH2)222(CH2)2HCH3base122-124
59.4-EtO-phenyllink(CH2)222(CH2)2HCH3base118-120
60.(2-Cl,6-F)-phenyllink(CH2)222(CH2)2HCH3 base88-90
61.4-Cl-phenyllink(CH2)322linkHCH3HCl (1/1)132-134
62.4-MeO-phenyllink(CH2)322linkHCH3HCl (1/1)175-177
63.4-MeO-phenyllink(CH2)322CH2HCH3HCl (1/1)155-157
64.4-MeO-phenyllink(CH2)3 22(CH2)2HCH3HCl (1/1)118-120
65.4-F-phenylO(CH2)222linkHCH3base135-137
66.4-Cl-phenylO(CH2)222linkHCH3base141-145
67.(2-Cl,3-Cl)-phenylO(CH2)222linkHCH3base68.2-Cl,4-Cl}-phenylO(CH2)222linkHCH3base115-119
69.2-Cl,4-Cl)-phenylOCH(CH3)CH222linkHCH3HCl (1/1)141-143
70.3-Cl,4-Cl)-phenylO(CH2)222linkHCH3base146-148
71.4-Cl-naphthalene-1-ylO(CH2)22 2linkHCH3base136-140
72.4-C1-naphthalene-1-ylO(CH2)222linkHHbase141-143
73.the quinoline-5-yl-O(CH2)222linkHCH3base140-142
74.isoquinoline-5-ylO(CH2)222linkHCH3base149-153
75.4-Cl-phenylO(CH2)222CH2HCH3base115-119
76.(2-Cl,3-Cl)-phenylO(CH2)222CH2HCH3base117-119
77.(2-Cl,4-Cl)-phenylO(CH2)222CH2HCH3HCl (1/1)137-139
78.(2-Cl,4-Cl)-phenylOCH(CH3)CH222 CH2HCH3HCl (1/1)194-196
79.(3-Cl,4-Cl)-phenylO(CH2)222CH2HCH3base98-100
80.4-C1-naphthalene-1-ylO(CH2)222CH2HCH3base116-120
81.the quinoline-5-ylO(CH2)222CH2HCH3HCl (1/1)220-224
82. isoquinoline-5-ylO(CH2)222CH2HCH3HCl (1/1)74-78
83.4-F-phenylO(CH2)222(CH2)2HCH3base125-129
84.4-Cl-phenylO(CH2)222(CH2)2HCH3base109-113
85.4-Cl-phenylO(CH2)322linkCH3base133-137
86.4-F-phenylO(CH2)212CH2HCH3HCl (1/1)354*
87.4-Cl-phenylO(CH2)212CH2HCH3base67-69
88.3-(4-F-phenyloxy)-phenyllinkCH222linkHCH3base107-109
89.5-(4-Cl-phenyl)-isoxazol-3-yl link(CH2)322linkHCH3base151-153
90.3-CF3O-phenyllinkCH222CH2HCH3base73-75
91.4-CF3O-phenyllinkCH222CH2HCH3base104-106
92.3-
(pyrimidine-2-yloxy)-phenyl
linkCH222CH2 HCH3HCl (1/1)196-200
93.3-(4-Cl-phenyl)-isoxazol-5-yllinkCH222CH2HCH3base148-150
94.5-(4-Cl-phenyl)-1,3-oxazol-2-yllinkCH222CH2HCH3base143-145
95.4-(4-CF3-phenyl)-1,3-thiazol-2-yllinkCH222CH2HCH3base172-174
96.5-(4-Cl-phenyl)-isoxazol-3-yllink(CH2)222CH2HCH3base165-167
97.3-(4-Cl-phenyl)-isoxazol-5-yllink(CH2)222CH2HCH3base146-148
98.3-(4-Cl-phenyl)-isoxazol-5-yllink(CH2)322CH2HCH3base134-136
99.5-(4-Cl-phenyl)-isoxazol-3-yllink(CH2)3 22CH2HCH3base160-162
100.(2-Cl,4-F-phenyllinkCH222(CH2)2HCH3base108-110
101.(3-Cl,4-F-phenyllinkCH222(CH2)2HCH3base112-114
102.(3-CN 5-F-phenyllinkCH222(CH2)2HCH3 base132-134
103.3-(4-F-phenyloxy)-phenyllinkCH222(CH2)2HCH3base79-81
104.3-(4-Cl-phenyl)-isoxazol-5-yllinkCH222(CH2)2HCH3base169-171
105.5-(4-Cl-phenyl)-1,3-oxazol-2-yllinkCH222(CH2)2HCH3base124-126
106.4-(4-CF3-phenyl)-1,3-thiazo the-2-yl linkCH222(CH2)2HCH3base161-163
107.2-Cl,4-F-phenyllinkCH(CH3)22CH2HCH3HCl (1/1)386*
108.3-(4-Cl-phenyloxy)-phenyllinkCH(CH3)22CH2HCH3HC1 (1/1)130-134
109.[2-Cl,3-(4-Cl-phenyloxy)]-phenyllinkCH(CH3)22CH2 HCH3base115-119
110.3-CF3O-phenyllinkCH(CH3)22(CH2)2HCH3HCl (1/1)169-171
111.(2-Cl,4-F-phenyllinkCH(CH3)22(CH2)2HCH3HCl (1/1)400*
112.4-Cl-phenyllinkC≡C-(CH2)222linkHCH3base189-191
113.4Cl-phenyl linkC≡C-(CH2)322linkHCH3base137-139
114.(2-Cl,5-Cl)-phenyllinkC≡C-(CH2)322linkHCH3base426*
115.(2-Cl,4-F-phenyllinkC≡C-(CH2)322linkHCH3base410*
116.4-Cl-phenyllinkC≡C-(CH2)222CH2 HCH3base151-153
117.(2-Cl,3-Cl)-phenylAbout(CH2)211linkHCH3base138-140
118.(2-F,4-Cl)-phenyllinkC≡C-(CH2)222CH2HCH3base144-146
119.(2-Cl,5-Cl)-phenyllinkC≡C-(CH2)222CH2HCH3base128-130
20. 3-(4-Cl-phenyl)-isoxazol-5-yllink(CH2)222(CH2)2HCH3base135-137
121.3-t-BuO-phenyllinkCH222CH2HCH3base392*
122.3-t-BuO-phenyllinkCH222(CH2)2HCH3base66-70

* M+N

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

Inhibitory activity was confirmed in radioterminal test based on measuring the product of hydrolysis (ethanolamine [1-3H]) of anandamide [ethanolamine 1-3H] by FAAH (Life Sciences (1995), 56, 1999-2005 and Journal of Pharmacology and Experimental Therapeutics (1997), 283, 729-734). So, you removed the mouse brain (without cerebellum) and kept at -80°C. Membrane homogenates were prepared immediately before the experiment by homogenization of tissue in Polytrone in buffer Tris-HCl 10 mm (pH 8.0)containing 150 mm NaCl and 1 mm EDTA. Then he carried out the enzymatic reaction in 70 μl of buffer containing bovine serum albumin without fatty acids (1 mg/ml). Consistently added test compound in various concentrations: anandamide [ethanolamine 1-3H] (specific activity 15-20 Ci/mmol)diluted to 10 μm cold anandamide, and the membrane preparation (400 µg frozen tissue on experience). After 15 minutes at 25°C. the enzymatic reaction was stopped by adding 140 μl of a mixture of chloroform/methanol (2:1). The mixture was stirred for 10 minutes, then centrifuged for 15 minutes at 3500 rpm/min an Aliquot (30 μl) of the aqueous phase containing ethanolamine [1-3H], calculated by the scintillation fluid.

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

In the following table 2 shows CI50some compounds according to the invention.

Table 2

Connection # CI50
250,225 mcm
770,049 mcm

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

The activity in vivo of the compounds according to the invention was evaluated in the test for analgesia.

So, intraperitoneal (I.P. Pavlova.) introduction PBQ (phenylbenzophenone, 2 mg/kg in 0.9%sodium chloride solution containing 5% ethanol) male OF1 mice weighing 25-30 g, causes spasm of the peritoneum, on average, 30 Perekrestov or reductions for the period from 5 to 15 minutes after injection. The test compounds were administered orally (p/o) or intraperitoneally (I.P. Pavlova.) suspension of Tween-80 concentration of 0.5% for 60 or 120 minutes prior to the introduction of PBQ. Under these conditions, the most potent compounds according to the invention at 35-70% reduce the number of spasms caused PBQ, in the dose range of 1 to 30 mg/kg

For example, compound No. 26 of table reduces the number of sprains caused PBQ, 56% of the oral dose of 10 mg/kg over 60 minutes.

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

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

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

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

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

acute or chronic peripheral pain;

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

eating disorders, particularly anorexia and cachexia of various nature;

neurological and psychiatric pathologies: tremor, dyskinesia, dystonia, spasticity, obsessive-compul the Toms disorders, Tourette syndrome, all forms of depression and anxiety of any nature and origin, mood disorders, psychoses;

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

epilepsy;

sleep disorders, including stopping of breathing during sleep;

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

renal ischemia;

cancer: superficial skin tumors, papillomas and brain tumors, prostate tumors, brain tumors (glioblastomas, medulloepithelioma, Protocol, neuroblastomas, tumors of embryonic origin, astrocytomas, astroblastoma, ependyma, oligodendrogliomas, plexus tumors in, neuroepithelioma, tumor epiphysis, ependymoblastomas, malignant meningiomas, sarcomatosis, malignant melanoma, sanomi);

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

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

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

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

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

urinary incontinence and bladder inflammation.

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

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

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

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

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

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

For example, a single form of the introduction of the compounds according to the invention in the form of tablets may contain the following components:

Connection in accordance with the invention50.0 mg
Mannitol223,75 mg
Crosscarmellose sodium6.0 mg
Corn starch15,0 mg
The hypromellose2.25 mg
Magnesium stearate3.0 mg

These single forms can be dosed to allow a daily intake of 0.01 to 20 mg acting is about substance per 1 kg of body weight, according to the galenical form.

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

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

1. The compound corresponding to the formula (I)

in which
m means an integer from 1 to 4;
n means an integer equal to 1 or 2;
about an integer equal to 1 or 2;
And selected from one or more groups X, Y;
X indicates a methylene group, optionally substituted with one group that represents C1-6-alkyl;
Y means With2-alkynylamino group;
In the mean covalent bond or C1-6-alkylenes group;
G means a covalent bond, oxygen atom;
R1means the group R4, optionally substituted by one or more groups R5and/or R6;
R4means a group selected from oxazolyl, from cazalilla, thiazolyl, phenyl, pyridinyl, naphthyl, chinoline, izochinolina;
R5means a halogen atom, a cyano group, C1-6-alkyl, C1-6-alkoxy, C1-6-foralkyl, C1-6-feralcode, NR7R8;
R6means phenyl group, phenyloxy or pyrimidinone, and the group or groups R6can be substituted by one or two groups R5the same or different from each other;
R7and R8independently of one another denote C1-6is an alkyl group;
R2means a hydrogen atom;
R3means a hydrogen atom or a C1-C6alkyl group;
in the base condition, the acid additive salt.

2. The compound of formula (I) according to claim 1 or 2, characterized in that:
m means an integer equal to 1 or 2;
in the base condition, the acid additive salt.

3. The compound of formula (I) according to claim 1 or 2, characterized in that:
n = 2;
about equal to 2;
in the base condition, the acid additive salt.

4. The compound of formula (I) according to claim 1 or 2, characterized in that:
R1means the group R4, optionally substituted by one or more groups R5and/or R6;
R4means a group selected from oxazolyl, isoxazolyl, phenyl or naphthyl;
R5means a halogen atom, a cyano group, NR7R8group C1-6-alkyl, C 1-6-alkoxy,
C1-6-foralkyl or C1-6-feralcode;
R6means phenyl group, phenyloxy or pyrimidinone, and the group or groups R6can be substituted by one or two groups R6the same or different from each other;
R7and R8independently of one another denote C1-6is an alkyl group;
in the base condition, the acid additive salt.

5. The compound of formula (I) according to claim 1 or 2, characterized in that:
R2means a hydrogen atom;
R3means a hydrogen atom or a C1-6is an alkyl group;
in the base condition, the acid additive salt.

6. The compounds of formula (I) according to claim 1, selected from the group including:
-[2-(methylamino)-2-oxoethyl]-{1-[(3,4'-diferuloyl-4-yl)methyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1[(3-chloro-4'-forbiden-4-yl)methyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[3-(4-pertenece)benzyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chloro-3-formatosi)benzyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[3-(triptoreline)benzyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[4-(triptoreline)benzyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[-1-(3-tert-butoxybenzoyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoe the yl]-2-[1-(3-tert-butoxybenzoyl)piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(2,4-dichlorobenzyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(2,5-dichlorobenzyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(3,5-dichlorobenzyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(2-chloro-5-terbisil)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(3-chloro-2-terbisil)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(3-chloro-5-methylbenzyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[(3,4'-diferuloyl-4-yl)methyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[(3-chloro-4'-forbiden-4-yl)methyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[4-(4-chloro-3-pertenece)benzyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[3-(4-pertenece)benzyl]piperidine-4-yl}carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[3-(triptoreline)benzyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[4-(triptoreline)benzyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[3-(pyrimidine-2-yloxy)benzyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(2-chloro-4-terbisil)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(3-chloro-4-terbisil)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(3-cyano-5-terbisil)piperidine-4-yl]ethylcarbamate;
-[2-(IU is ylamino)-2-oxoethyl]-2-{1-[3-(4-pertenece)benzyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{[3-(4-chlorophenyl)isoxazol-5-yl]methyl}piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]methyl}piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-({4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-{[3-(4-chlorophenyl)isoxazol-5-yl]methyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]methyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-({4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}methyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{2-[5-(4-chlorophenyl)isoxazol-3-yl]ethyl}piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{2-[3-(4-chlorophenyl)isoxazol-5-yl]ethyl]piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{3-[3-(4-chlorophenyl)isoxazol-5-yl]propyl}piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{3-[5-(4-chlorophenyl)isoxazol-3-yl]propyl}piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[1-(2-chloro-4-forfinal)ethyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{1-[3-(4-chlorophenoxy)phenyl]ethyl}piperidine-4-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{1-[2-chloro-3-(4-chlorophenoxy)phenyl]ethyl}piperidine-4-yl]IU is ylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-{1-[3-(triptoreline)phenyl]ethyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[1-(2-chloro-4-forfinal)ethyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chlorophenyl)but-3-in-1-yl]piperidine-4-yl}carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[5-(4-chlorophenyl)Penta-4-in-1-yl]piperidine-4-yl}carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[5-(2,5-dichlorophenyl)Penta-4-in-1-yl]piperidine-4-yl}carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chlorophenyl)but-3-in-1-yl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[4-(4-chloro-2-forfinal)but-3-in-1-yl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[4-(2,5-dichlorophenyl)
but-3-in-1-yl]piperidine-4-yl}methylcarbamate.

7. The compounds of formula (I) according to claim 1, selected from the group including
-[2-(methylamino)-2-oxoethyl]-{1-[(2-chlorophenyl)methyl]piperidine-
4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[(4-chlorophenyl)methyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[(4-chlorophenyl)methyl]piperidine-4-yl}carbamate;
-[2-(methylamino)-2-oxoethyl]-(1-[4-[1-methylethyl)phenyl]methylpiperidin-4-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]carbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(biphenyl-4-ylmethyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino-2-oxoethyl]-[1-(2-biphenyl-4-retil)piperidine-4-yl]carbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(naphthalene-2-ylmethyl)piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[(4-bromophenyl)methyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-{[3-(trifluoromethyl)phenyl]methyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-{[4-(trifluoromethyl)phenyl]methyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[(2,3-dichlorophenyl)methyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[(3,4-dichlorophenyl)methyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(naphthalene-1-ylmethyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(naphthalene-2-ylmethyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-[1-(pyridine-2-ylmethyl)piperidine-4-yl]ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[4-fluoro-2-(metiloksi)phenyl]ethyl}piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-forfinal)oxy]ethyl}piperidine-4-yl)carbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-chlorophenyl)oxy]ethyl}piperidine-4-yl)carbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(2,4-dichlorophenyl)oxy]ethyl}piperidine-4-yl)carbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-chlorophenyl)oxy]ethyl}piperidine-4-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-1-{2-[(2,4-dichlorophenyl)oxy]ethyl}piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-{2-[(4-forfinal)oxy]ethyl}piperidine-4-yl)ethylcarbamate is;
-[2-(methylamino)-2-oxoethyl]-2-(1-{2-[(4-chlorophenyl)oxy]ethyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-forfinal)oxy]ethyl}pyrrolidin-3-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(4-chlorophenyl)oxy]ethyl}pyrrolidin-3-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[3-(trifluoromethyl)phenyl]ethyl}piperidine-4-yl)carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[2-(4-chlorophenyl)ethyl]piperidine-4-yl} carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[2-(4-cyanophenyl)ethyl]piperidine-4-yl} carbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[(isoquinoline-5-yl)oxy]ethyl}piperidine-4-yl)carbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(2-naphthalene-1-retil)piperidine-4-yl]carbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(2-naphthalene-2-retil)piperidine-4-yl]carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[3-(4-chlorophenyl)propyl]piperidine-4-yl}carbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{3-[4-(metiloksi)phenyl]propyl}piperidine-4-yl)carbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[(3-chlorophenyl)ethyl]piperidine-4-yl }methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{2-[4-(ethyloxy)phenyl]ethyl }piperidine-4-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-{2-[4-(dimethylamino)phenyl]ethyl} piperidine-4-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-{1-[2-(2,4-dichlorophenyl)ethyl]piperidine-4-yl}methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(2-naphthalene-1-retil)piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-[1-(2-n is Talin-2-retil)piperidine-4-yl]methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-(1-{3-[4-(metiloksi)phenyl]propyl}piperidine-4-yl)methylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[2-(2-chlorophenyl)ethyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-{1-[2-(4-forfinal)ethyl]piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-{2-[4-(ethyloxy)phenyl]ethyl}piperidine-4-yl)ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-[2-(2-chloro-6-forfinal)ethyl]
piperidine-4-yl}ethylcarbamate;
-[2-(methylamino)-2-oxoethyl]-2-(1-{3-[4-(metiloksi)phenyl]propyl} piperidine-4-yl)ethylcarbamate.

8. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 7, comprising a stage consisting in the transformation of oxazolidinedione General formula (IIa)

in which a, b, G, R1, R2, m, n and o are defined in formula (I) according to claim 1,
taking place during the ammonolysis of an amine of General formula R3NH2in which R3defined in formula (I) according to claim 1.

9. The method of obtaining the compounds of formula (I) according to any one of claims 1 to 7, comprising a stage consisting in the transformation of the derived carbamate-amide of General formula (Ia)

in which, R2, R3, n and o are defined in the formula (1) according to claim 1,
occurring during the reaction with a derivative of General formula (III)

in which W means mesilate, tosylate group or a chlorine atom, bromine or iodine and m, G, a and R1about is defined in formula (I) according to claim 1.

10. The connection that meets the General formula (IIa)

in which m denotes an integer from 1 to 2; n represents 2; o represents 2; And X denotes That X is methylene group; means C1-6-alkylenes group; G means a covalent bond; R1means the group R4, optionally substituted by one or more groups R5and/or R6; R4denotes phenyl; R5means a halogen atom, a C1-6-alkoxy; R6means phenyl group; R2means a hydrogen atom,
with 3-[1-(phenylmethyl)-4-piperidinyl]-2,4-oxazolidinedione excluded.

11. The connection that meets the General formula (Ia),

in which, R2, R3, n and o are defined in formula (I) according to claim 1.

12. Pharmaceutical composition having the property of inhibitor of FAAH enzyme containing at least one compound of formula (I) according to any one of claims 1 to 7 in the state of pharmaceutically acceptable base salts, optionally one or more pharmaceutically acceptable excipients.

13. The compound of formula (I) according to any one of claims 1 to 7 in the form of a pharmaceutically acceptable base, salt for its use as a medicinal product having the property of inhibiting FAAH enzyme.

14. The use of the compounds of formula (I) according to any one of claims 1 to 7 in the state of pharmace is almost acceptable base, salt for a medicinal product intended for the prevention or treatment of acute or chronic pain, dizziness, vomiting, nausea, eating disorders, neurological and psychiatric pathologies, acute or chronic neurodegenerative diseases, epilepsy, sleep disorders, cardiovascular disease, renal ischemia, cancers, disorders of the immune system, allergic diseases, infectious parasitic, viral or bacterial diseases, inflammatory diseases, osteoporosis, eye diseases, lung diseases, gastrointestinal diseases or urinary incontinence.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel compound N-(1-{(3R)-3-(3,5-difluorophenyl)-3-[1-(methylsulfonyl) piperidin-4-yl]propyl}piperidin-4-yl)-N-ethyl-2-[4- (methylsufonyl)phenyl]acetamide or its pharmaceutically acceptable salts. The invention also relates to a method for synthesis of the compound in paragraph 1, as well as to a pharmaceutical composition.

EFFECT: obtaining a novel biologically active compound with activity towards CCR5 (chemokine receptor 5).

6 cl, 6 ex, 2 tbl

FIELD: medicine.

SUBSTANCE: invention is related to new compounds of formula (I): , in which: Ra and Ra', identical or different, mean atom of hydrogen or alkyl, R1 means atom of hydrogen or alkyl, cycloalkyl, heterocycloalkyl or aryl, R2 means group of formula -(CH2)x-(CO)y-Y or -(CO)y-(CH2)x-Y, in which, x = 0, 1, 2, 3 or 4, y = 0 or 1, Y means atom of hydrogen or the following group: hydroxyl, alkyl, cycloalkyl, alkyloxyl, aryl, heteroaryl or -NR11R12, besides, Y is not an atom of hydrogen, when x=y=0, R11 and R12, identical or different, mean atom of hydrogen or the following group: alkyl, cycloalkyl, alkyloxyl or -NR13R14, or R11 and R12 together with atom of nitrogen, to which they are connected, create mono- or bicyclic structure, which contains 4-10 links and unnecessarily contain additionally 1-3 heteroatoms and/or 1-3 ethylene unsaturated links, besides this cycle is not necessarily substituted in any of positions with 1-3 groups, selected from atoms of halogen and hydroxyl, alkyl, cycloalkyl and alkyloxygroups; R13 and R14, identical or different, mean atom of hydrogen or alkyl, R3 means 1-3 groups, identical or different, available in any position of cyclic structure, to which they are connected, and selected from atoms of halogen; R5 means atom of hydrogen, R4 is selected from groups of formulae (a), (b), (c), which are not necessarily substituted with aryl group, described below: (a), (b), (c), in which p=0,1,2 or 3; m=0,1 or 2, and either a) X means link -N(R10)-, in which R10 is selected from: -CO-alkyl, -CO-cycloalkyl, -CO-heterocycloalkyl, -CO-aryl, -CO-heteroaryl, - or R10 with atom of nitrogen, with which it is connected, and with atom of carbon, available in any position of cyclic structure of formula (a), but not with neighboring to mentioned atom of nitrogen, creates bridge, containing 3-5 links, or, b) X means link -C(R6)(R7)-, where R6 is selected from the following: atom of hydrogen, atom of halogen, group -(CH2)x-OR8, -(CH2)x-NR8R9, -(CH2)x-CO-NR8R9 or -(CH2)x-NR8-COR9, in which x=0,1,2,3 or 4, alkyl, cycloalkyl, heterocycloalkyl, aryl, heterocycloalkyl, condensed with aryl, besides, alkyl, cycloalkyl or aryl groups are not necessarily substituted with 1 or several groups, selected from groups: R, R', -OR, -NRR', -COR; R7 is selected from atoms of hydrogen and halogen and the following groups: alkyls, -OR, -NRR', -NR-CO-R', -NR-COOR', -R8 and R9 are selected, independently from each other, from atom of hydrogen and the following groups: alkyls, cycloalkyls, aryls, -CO-alkyls, besides, alkyls and aryls are unnecessarily substituted with one or several groups, selected from groups: R, R', -OR, or R8 and R9 together create heterocycloalkyl,- R and R' mean, independently from each other, atom of hydrogen or alkyl, cycloalkyl, besides, mentioned hetero aryl groups represent aromatic groups, including from 5 to 10 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen and/or sulfur; besides mentioned heterocycloalkyl groups represent cycloalkyl groups, including from 5 to 6 links and including from 1 to 4 heteroatoms, such as atom of nitrogen, oxygen or sulfur; in the form of base or acid-additive salt, and also in the form of hydrate or solvate. Invention is also related to medicinal agent, to pharmaceutical composition, to application, to method of production, and also to compounds of formulas (VI), (XVIII), (XIX).

EFFECT: new biologically active compounds have activity of agonists of melanocortin receptors.

27 cl, 16 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: present invention refers to the new compounds of formula (I): whereat R1 is -SO2NR102R103, -NR101SO2R104 or -COOR105 whereat R101 is hydrogen atom, R102 and R103 each independently represents hydrogen atom or C1-4 alkyl, R104 is C1-4 alkyl and R105 is hydrogen atom or C1-4 alkyl ; X is bond, -CH2- or -O-; Y is -CH2-; ring A and ring B, which are same or different, each independently is benzene, pyridine, pyrazol or piperidine which can have the following substituents: C1-4 alkyl or halogen; ring D is piperidine; R2 is whereat the arrow shows the position of the bond with the ring D; R51 is (1) hydrogen atom a, (2) C1-6alkyl, which can have the following substituents: (a) hydroxy, (b) methoxy, (c) cyano, (d) carboxy, (e) halogen, (f) methyl sulphonylamino, (g) C3-8cycloalkyl or phenyl, which can have the following substituents: methyl, halogen, hydroxy or methoxy, (h) thienyl, pyrazolyl, tetrahydropyranyl, thiazolyl, isooxalyl, imidazolyl, tetraazolyl, pyridyl, pyrimidinyl which can have the following substituents: methyl, trifluoromethyl or hydroxy, (3) C2-10alkenyl, (4) C2-10alkynyl, (5) phenyl which can have the following substituents: C1-4alkyl or halogen, or (6) pyridine or tetrahydropyran; R52 is (1) hydrogen atom a, (2) C1-6alkyl which can have the following substituents: (a) hydroxy, (b) methoxy, (c) carboxy, (d) C3-8cycloalkyl, (e) phenyl or (f) oxo, (3) C3-8cycloalkyl or phenyl which can have the following substituents: C1-4alkyl, hydroxy, cyano, oxo, carbamoyl, N-methyl aminocarbonyl, carboxy, halogen, methoxy, trifluoromethoxy, methythio, methylsulphonyl, acetylamino, dimethylamino, acetyl, tetraazolyl, trifluoromethyl or methylsulphonylamino (4) C3-10cycloalkenyl, (5) adamantyl, (6) thienyl, pyrazolyl, tetrahydropyranyl, isoxaazolyl, isothiazolyl, thiadiazolyl, piperidinyl, pyridyl, pyrimidinyl, pyridazinyl, quinolyl, indolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, dioxaindanyl, benzodioxaindanyl which can have the following substituents: C1-4alkyl, hydroxy, oxo, halogen, azido or trifluoromethyl or (7) benzyloxy groups; and R53 is hydrogen atom or C1-6alkyl; to its salts or its solvates. The invention refers also to the regulator CCR5, to the agent of prevention and/or treatment of HIV infection, immunological or inflammatory diseases, to the pharmaceutical composition, to the medicinal preparation, to the method of disease treatment or prevention as well as to the application of compound as in claim 1.

EFFECT: obtaining of new bioactive compounds possessing anti CCR5 receptor activity.

23 cl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the general formula: , where R1 is an inferior alkyl, -(CH2)n-aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluormethyl, or pyridine; R2 is an inferior alkyl, -(CH2)n- aryl, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl, inferior alkoxy-, halogen or trifluoromethyl, nitro-, cyano-, -NR'R", hydroxy-, or heteroaryl group that is a monovalent heterocyclic 5- or 6-membered aromatic radical with N atoms, either R2 is a heteroaryl that is monovalent heterocyclic 5- or 6-membered aromatic radical where heteroatoms are chosen from N, O or S group, unsubstituted or substituted by one or two substitutes from the group of inferior alkyl or halogen; R3 is pyridine or aryl, unsubstituted or substituted by a halogen or inferior alkyl; R4 is hydrogen or hydroxy-. A is -S(O)2- or -C(O)-; X, Y are -CH2- or -O- independently from each other, though both X and Y should not be -O- at the same time; R'R" are hydrogen or inferior alkyl independently from each other; n is 0, 1 or 2. Also the invention concerns pharmaceutically acceptable additive salts and acids of the compounds, and a medicine based on it.

EFFECT: new biologically active compounds show inhibition effect in glycine absorption.

21 cl, 214 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula I: , where: a is 0 or whole number of 1 to 3; each R1 is selected independently out of the halogens; b is 0 or whole number of 1 to 3; each R2 is selected independently out of the halogens; W is linked in 3 or 4 position against the nitrogen atom in piperidine ring and is O; c is 0 or whole number of 1 to 4; each R3 is selected independently out of (1-4C)alkyls; or two groups of R3 are linked together forming (1-3C)alkylene or oxyrane-2,3-diyl; R4 is a bivalent group of the formula: -(R4a)d-(A1)e-(R4b)t-Q-(R4c)g-(A2)h-(R4d)i-, where each of d, e, f, g, h and i is selected independently out of 0 or 1; each of R4a, R4b, R4c and R4d is selected independently out of (1-10C)alkylene, where each alkylene group is unsubstituted or substituted by 1-5 substitutes selected independently out of (1-4C)alkyl, fluorine and hydroxy-; each of A1 and A2 is selected independently out of (3-7C)cycloalkylene, (6-10C)arylene, -O-(6-10C)arylene, (6-10C)arylene-O-, (2-9C)heteroarylene and (3-6C)heterocyclene where each cycloalkylene is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each arylene, heteroarylene or heterocyclene group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogens, (1-4C)alkyl, (1-4C)alkoxy-, -S(O)2-(1-4C)alkyl, hydroxy-, nitro- and trifluormethoxy; Q is selected out of -O-, -S(O)2-, -N(Qa)C(O)-, -C(O)N(Qb)-; -N(QC)S(O)2-, -S(O)2N(Qd)-, -N(Qe)C(O)N(Qf)- and -N(Qk) links; each of Qa, Qb, Qc, Qd, Qe, Qf and Qk is selected independently out of hydrogen, (1-6C)alkyl and A3, where alkyl group is unsubstituted or substituted by 1-3 substitutes selected independently out of fluorine, hydroxy- and (1-4C)alkoxy-; or together with nitrogen atom and R4b or R4c group to which they are linked they form 4-6-membered azacycloalkylene group; A3 is selected independently out of (3-6C)cycloalkyl, (6-10C)aryl, (2-9C)heteroalkyl and (3-6C)heterocyclyl, where each cycloalkyl is unsubstituted or substituted by 1-4 substitutes selected independently out of (1-4C)alkyl, and each aryl, heteroaryl or heterocyclyl group is unsubstituted or substituted by 1-4 substitutes selected independently out of halogen, (1-4C)alkyl and (1-4C)alkoxy-, if the number of adjacent atoms in the shortest chain between two nitrogen atoms, to which R4 is linked, lies within 4 to 16; R5 is hydrogen or (1-4C)alkyl; R6 is -NR6aCR6b(O), and R7 is hydrogen; either R6 and R7 together form -NR7aC(O)-CR7b=CR7c-; each of R6a and R6b is hydrogen or (1-4C)alkyl independently; and each of R7a, R7b and R7c is hydrogen or (1-4C)alkyl independently; or the pharmaceutically acceptable salts, solvates or stereoisomers of the claimed compounds. The invention also concerns compounds of the formula I, 1-[2-(2-chlor-4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinoline-5-yl)ethylamino]methyl}-5-methoxuphenylcarbamoyl)ethyl] piperidine-4-yl ether of biphenyl-2-ylcarbamine acid or its pharmaceutically acceptable salt or solvate, pharmaceutical composition, method of pulmonary disease treatment, method of bronchial lumen dilation for a patient, method of treatment of chronic obstructive pulmonary disease or asthma, method of obtaining the compound of the formula I, medicine based on it, and application of compounds described in any of the paragraphs 1, 13, 14, 24, 25, 26, 27 or 28.

EFFECT: obtaining of new biologically active compounds with high activity rate of both antagonist of muscarine receptors and β2 agonist of adrenergic receptors.

42 cl, 186 ex

FIELD: chemistry.

SUBSTANCE: description is given of amides of piperazinyl- or piperidinylaminesulphoamic acid with genera formula (I) , in which R1 and R2 together with a nitrogen atom, to which they are bonded, represent a 6-member aliphatic heterocyclyl, containing two atoms of nitrogen as heteroatoms. The indicated extra atom of nitrogen is substituted with radical R, where R represents COOR', and R' represents (C1-C6)alkyl or benzyl, or phenyl, substituted with trifluoromethyl and aminocarbonyl, or R1 represents hydrogen, and R2 represents a group with formula , in which R9 represents (C1-C8)alkoxycarbonyl or phenyl, substituted with haloid(C1-C6)alkyl or aminocarbonyl; R3 represents phenyl or phenyl(C1-C4)alkyl, containing two substitutes, chosen from halogen and haloid(C1-C6)alkyl. Description is given of the use of formula (I) compounds as inhibitors of steroid sulphatase.

EFFECT: compound has inhibition effect to steroid sulphatase.

7 cl, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds, namely, to N-substituted derivatives of piperidine of the formula (I): or their pharmaceutically acceptable salts, amides, esters wherein values R1, R, R3, m, X, n, W, Ar1 and Ar2 are disclosed in the invention claim. Also, invention relates to methods for inhibition of activity and methods for inhibition of activation of monoamine receptors. Methods involve contacting monoamine receptors or system comprising monoamine receptors with the effective amount of one or some compounds of the formula (I). Except for, invention relates to using compounds of the formula (I) in treatment of psychotic diseases.

EFFECT: valuable medicinal properties of compounds.

35 cl, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of aminotetraline of the formula (I) wherein R1 means (C1-C6)-alkyl; R2 means halogen atom or -OR'; R3 means hydrogen atom (H) or -OR' wherein R' means (C1-C6)-alkyl or -SO2R'' wherein R'' means phenyl, thienyl, isoxazolyl; R4 means (C1-C6)-alkyl, phenyl, piperidinyl, pyrrolidinyl, morpholinyl, piperazinyl, diazepinyl, furanyl, isoxazolyl, imidazolyl and pyrazolyl that can be substituted optionally, and pharmaceutical compositions containing derivatives of aminotetraline. Proposed compounds are selective antagonists of M2/M3 muscarinic receptors and designated for treatment and prophylaxis of diseases associated with smooth muscle disorder.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

23 cl, 1 tbl, 16 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel 4-(dipeptidylamino)-piperidine-1-carboxamidines of the general formula (1): or their optical isomers or pharmaceutical acceptable salts wherein R1 is chosen from hydrogen atom (H), lower alkyl, R4-CO wherein R4 means -OCCH2, R5-OCO wherein R means -SO2; R2 is chosen from lower alkyl, cycloalkyl, (C5-C12)-cycloalkylalkyl, phenylalkyl and others; R3 is chosen from H, -OH and group O-lower alkyl; R4 is chosen from H, lower alkyl and phenyl; R5 is chosen from lower alkyl, phenyl and benzyl. Proposed compounds are inhibitors of kallikrein and can be used in treatment of intestine inflammatory disease, arthritis, septic shock, hypotension or cancer.

EFFECT: valuable medicinal properties of compounds.

12 cl, 2 tbl, 60 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts or solvates wherein m represents 0, 1, 2 or 3; each R1 represents halogen atom or (C1-C6)-alkylcarbonyl; Z1 represents a bond or group -(CH2)q wherein q represents 1 or 2; Z2 represents a bond or group -CH2 under condition that both Z1 and Z2 don't represent a bond simultaneously; Q represents oxygen or sulfur atom or group -CH2 or -NH; R2 represents group of the formula: ; n = 0; each R4, R5, R6 and R7 represents hydrogen atom; R8 represents hydrogen atom or (C1-C6)-alkyl group; R15 represents -C(O)NR17R18 or -NHC(O)R20; t represents 0, 1, 2 or 3; each R16 represents halogen atom, cyano-group, hydroxyl, (C3-C6)-cycloalkyl, (C1-C6)-alkoxy-group, phenyl or (C1-C6)-alkyl; each R17 and R18 represents hydrogen atom or (C1-C6)-alkyl; R20 represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, phenyl or 5-6-membered heterocyclic system that can be substituted with (C1-C6)-alkyl. Compounds of the formula (I), their salts and solvates possess a modulating activity with respect to chemokine MIP-1α receptors and can be used in medicine.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

19 cl, 64 ex

The invention relates to derivatives of cyclic amines and their use as pharmaceuticals, particularly to a compound represented by the General formula (I), its pharmaceutically acceptable acid additive salts or its pharmaceutically acceptable C1-C6alcaldicios salt, R1-phenyl, C3-8-cycloalkyl, aromatic heterocycle with 1-3 heteroatoms selected from O, S, N, or combinations thereof, and these groups may be condensed with benzene ring or an aromatic heterocyclic group with heteroatoms, selected from O, S or N, or combinations thereof, and may also have different substituents

The invention relates to 1,4-disubstituted the piperazines of General formula (I), which means the group-CO - or-CH2-OCO; D - heteroaryl selected from a range including 1, 3, 5-triazinyl, pyrimidinyl and pyridinyl, possibly substituted by one or two substituents selected from a range, including mono-(C1-C6)-alkylamino, mono-(C3-C7)- alkynylamino-, di-(C1-C6)-alkylamino-,

(C1-C6)-alkyl-(C3-C7)-alkylamino and pyrrolidin-I-yl group; Raand Rbis a hydrogen atom or (C1-C3)-alkyl; n is an integer from 1 to 4; their enantiomers, racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to heterocyclic amines of formula I:

,

in which

X represents-CH2-group or-S-group;

B denotes a group selected from a number containing-CO -, - CH2OCO-, -CH2OCS-, -CH2NHCO - CH2NHCS-group;

D represents benzhydryl or phenyl group, optionally substituted by halogen atoms, and heterocyclic group, selected from a number containing 1,3,5-triazine-2-yl, pyridin-2-yl and pyrimidine-4-yl, and optionally substituted by one or two substituents selected from the group comprising amino, mono - or di-(C1C6) alkylamino, mono- (C3-C7)-alkynylamino, mono-(C3-C7)-quinil-amino group and pyrrolidin-1-yl group;

The is a simple carbon-carbon bond or a group of the formula: -CH2CH2or CRaRb-, where Raand Rbis a hydrogen atom, (C1-C3)alkyl, or taken together with the carbon atom to which they are attached, form a (C3-C6) cycloalkyl;

A is selected from the group comprising (a) carboxyl group optionally esterified (C1-C4) Ukrspirt the crystals: -CОNHRgOH, where Rcand Rdidentical or different, represent a hydrogen atom, (C1-C6) alkyl, benzyl, pyridin-2-yl, or taken together with the nitrogen atom to which they are bound, form piperidino, morpholino-, 4-thiomorpholine-, 4,5-diazepino, 4-(C1-C4)alkylpiperazine; Rfis a tolyl; Rgis a (C1-C4) alkyl;

(b) (C1-C3) alkyl;

(c) the group-NRcRdwhere Rcand Rddefined above,

(d) a cyano, if "y" does not mean a simple carbon-carbon bond

in the form of S-enantiomers, diastereomers, in the form of various racemic mixtures and their salts with pharmaceutically acceptable acids and bases

The invention relates to a process for the catalytic hydrogenation of nitro-derivatives of pyrrolidine to the corresponding amines, which are used as intermediates for the synthesis of pharmaceuticals, in particular to a process for the hydrogenation of 1-ethyl-2-micrometeorology 1-ethyl-2-aminomethylpyrrolidine is an intermediate in the synthesis of the drug Sulpiride"

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

FIELD: chemistry.

SUBSTANCE: present invention refers to the new naphtylene derivative having general formula (I-A) and to their pharmaceutically acceptable salts having the property of inhibition of the cytochrome ferment P450RAI (Cyp26) activity, to the pharmaceutic composition thereof and to the method of inhibition of cytochrome ferment P450RAI (Cyp26). , wherein X is selected from imidasolyl or triasolyl; R2 and R3, independently represent H, C1-10-alkyl; G1 is -NR72R82 or G1 and R3 taken together with attached carbon atom form 3-10-membered saturated ring or heterocyclic saturated ring containing N as heteroatom which is optionally substituted with substituting group R72, Z, R4b, R5b, Q1, R72, n2, n3 and n4 values are indicated in the formula of the invention.

EFFECT: present invention refers to the intermediates for compounds with general formula (I-A) and to their pharmaceutic salts thereof.

37 cl, 30 dwg, 7 tbl

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for purifying racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol that involves the following stages: (a) suspending racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethoxy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol in ethanol and tetrahydrofuran mixture to form suspension wherein indicated mixture of ethanol and tetrahydrofuran has the volume ratio from 4:1 to 1:1; (b) stirring and heating the indicated suspension; (c) cooling the indicated suspension from the stage (b), and (d) collection of solid purified racemic cis-6-phenyl-5-[4-(2-pyrrolidine-1-ylethocy)phenyl]-5,6,7,8-tetrahydronaphthalene-2-ol. Method provides preparing the end product containing less 0.1% of impurities.

EFFECT: improved purifying method.

11 cl, 11 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein R1 and R2 can be similar or different and mean branched or direct (C1-C6)-alkyl chain; R3 and R4 form in common a ring chosen from the group including pyrrolyl, imidazolyl, pyrazolyl, indolyl, indolinyl, pyrrolidinyl, piperazinyl and piperidyl and comprising nitrogen atom to which they are bound, and to their pharmaceutically acceptable salts also. Also, invention relates to a pharmaceutical composition possessing anti-hyperglycemic activity. Pharmaceutical composition comprises compound of the formula (I) as an active substance and an inert excipient. Invention provides using derivatives of biguanide possessing anti-hyperglycemic activity.

EFFECT: valuable medicinal property of derivatives.

9 cl, 2 tbl, 11 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

FIELD: pharmaceutical chemistry, medicine.

SUBSTANCE: invention relates to new compounds of formula I ,

solvates or pharmaceutically acceptable salts having antiarrhythmic activity, including ventrical fibrillation, as well as pharmaceutical compositions containing the same. Compounds of present invention are useful in treatment or prevention of arrhythmia, modulation of ion channel activity, for topic or local anesthesia, etc. In formula I X is direct bond, -C(R6,R14)-Y- and C(R13)=CH-; Y is direct bond, O, S, and C1-C4-alkylene; R13 is hydrogen, C1-C6-alkyl, C3-C8-cycloalkyl, unsubstituted aryl or benzyl; R1 and R2 are independently C3-C8-alkoxyalkyl, C1-C8-hydroxyalkyl and C7-C12-aralkyl; or R1 and R2 together with nitrogen atom directly attached thereto form ring of formula II ,

wherein said ring is formed by nitrogen and 3-9 ring atoms selected independently from carbon, sulfur, nitrogen and oxygen, etc; R3 and R4 are independently attached to cyclohexane ring in 3-, 4-, 5-, or 6-position and represent independently hydrogen, hydroxyl, C1-C6-alkyl and C1-C6-alkoxy; and when R3 and R4 are bound with the same atom of cyclohexane ring they may form together 5- or 6-membered spiroheterocycle ring containing one or two heteroatoms selected from oxygen and sulfur; A is C5-C12-alkyl, C3-C13-carbocyclic ring, or ring structure as defined herein.

EFFECT: new antiarrhythmic drugs.

30 cl, 12 dwg, 34 ex

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