New 8-aza-bicyclo[3,2,1]octane derivatives applied as monoamine neurotrnsmitter recapture inhibitors

FIELD: chemistry.

SUBSTANCE: invention concerns new 8-aza-bicyclo[3.2.1]octane derivatives of formula I or any its isomer or mixed isomers, or their pharmaceutically acceptable salt, where Ra represents hydrogen; X represents -O-; Rb represents aryl or heteroaryl group chosen from phenyl, naphthyl, pyridyl, quinolinyl, isoquinolinyl or quinazolinyl substituted with one or two substitutes independently chosen from group including: halogeno, trifluoromethyl, trifluoromethoxy, cyano, hydroxy and alkoxy provided that compound is not 3-(3-trifluoromethylphenoxy)-8-azabcyclo[3.2.1]octane, 3-(4-trifluoromethylphenoxy)-8-azabcyclo[3.2.1]octane, 3-(2-bromphenoxy)-8-azabcyclo[3.2.1]octane, 3-(4-chlorophenoxy)-8-azabcyclo[3.2.1]octane or 3-(4-fluorophenoxy)-8-azabcyclo[3.2.1]octane. Besides invention refers to pharmaceutical composition and application thereof.

EFFECT: production of new biologically active compounds characterised with monoamine recapture inhibiting activity.

6 cl, 1 ex, 1 tbl

 

The technical FIELD

This invention relates to new derivatives of 8-Aza-bicyclo[3.2.1]octane, useful as inhibitors of reuptake monoamine neurotransmitters.

In other aspects the invention relates to the use of these compounds in a method of treatment and pharmaceutical compositions containing the compounds according to the invention.

PRIOR art

WO 97/30997 (NeuroSearch A/S) describes Troyanova derivatives active as inhibitors of reuptake of neurotransmitters.

However, there was a continuing significant need in the detection of compounds with optimized pharmacological activity profile in respect of the reverse takeover monoamine neurotransmitters serotonin, dopamine and norepinephrine, such as the degree of serotonin reuptake compared with noradrenaline and dopamine activity.

The INVENTION

According to the first aspect of the invention proposed compound of the formula I

or any of its isomers or any mixture of its isomers, or their pharmaceutically acceptable salt,

where Ra, Rband X are such as defined below.

According to the second aspect of the invention proposed pharmaceutical composition comprising a therapeutically effective amount of soy is inane according to the invention or any of its isomers or any mixture of its isomers or its pharmaceutically acceptable salt together with at least one pharmaceutically acceptable carrier, excipient or diluent.

According to further aspect of the invention the application of the compounds according to the invention or any of its isomers or any mixture of its isomers, or their pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for the treatment, prevention or relief of disease, disorder or condition of a mammal, including humans, which are sensitive to inhibition of reuptake monoamine neurotransmitters in the Central nervous system.

In yet another the next aspect of the invention relates to a method of treating, preventing or alleviating a disease, disorder or condition of the body of an animal, including humans, which are sensitive to inhibition of reuptake monoamine neurotransmitters in the Central nervous system, including the stage of introduction into the organism animal in need thereof a therapeutically effective amount of the compounds according to the invention or any of its isomers or any mixture of its isomers, or their pharmaceutically acceptable salts.

Other objects of the invention will become clear to experts in the art from the following further detailed description and examples.

DETAILED description of the INVENTION

Derivatives of 8-Aza-bicyclo[3.2.1]octane

According to the first aspect of the infusion is his proposed invention the compounds of formula I

or any of their isomers or any mixture of their isomers

or their pharmaceutically acceptable salt,

where

Rarepresents hydrogen or alkyl, which is possibly substituted by one or more substituents independently selected from the group consisting of

halogeno, trifloromethyl, triptoreline, cyano, hydroxy, amino, nitro, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil;

X represents-O-, -S - or-NRc-;

where Rcrepresents hydrogen, alkyl, -C(=O)Rdor-SO2Rd;

where Rdrepresents hydrogen or alkyl;

Rbrepresents an aryl or heteroaryl group which may be substituted by one or more substituents independently selected from the group consisting of

halogeno, trifloromethyl, triptoreline, cyano, hydroxy, amino, nitro, oxo, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil.

In one embodiment Rarepresents hydrogen or alkyl;

X represents-O-, -S - or-NRc-;

where Rcrepresents hydrogen, alkyl, -C(=O)Rdor-SO2Rd;

where Rdrepresents hydrogen or alkyl;

Rbrepresents an aryl or heteroaryl group, to the which may substituted by one or more substituents, independently selected from the group consisting of

halogeno, trifloromethyl, triptoreline, cyano, hydroxy, amino, nitro, alkoxy, cycloalkane, alkyl, cycloalkyl, cycloalkenyl, alkenyl and quinil.

In the following embodiment Rarepresents hydrogen or alkyl. In another embodiment Rarepresents hydrogen. In the following embodiment Rarepresents alkyl, such as methyl. In yet another the next incarnation Rarepresents alkyl, substituted hydroxy, cyano, cycloalkyl or alkenyl. In a specific embodiment Rais hydroxyalkyl, such as hydroxyethyl. In the following embodiment Rais cianelli, such as cyanomethyl. In yet another the next incarnation Rais cycloalkenyl, such as cyclopropylmethyl. In the following embodiment Rais alkenylacyl, such as allyl.

In the following embodiment X represents-O-. In one of the following embodiment X represents-S-. In the following embodiment X represents-NRc-. In a specific embodiment Rcrepresents hydrogen. In the following embodiment Rcrepresents-C(=O)Rd. In a specific embodiment Rdrepresents hydrogen. In a particular embodiment X represents-NH - and-N((C=O)H).

In the following embodiment Rbrepresents an aryl or heteroaryl group which may be substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, oxo, and alkoxy. In yet another the next incarnation Rbrepresents an aryl or heteroaryl group which may be substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano and alkoxy. In the following embodiment Rbrepresents an aryl or heteroaryl group that is substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, oxo, alkyl and alkoxy. In yet another the next incarnation Rbrepresents an aryl or heteroaryl group that is substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, oxo, and alkoxy. In the following embodiment Rbrepresents an aryl or heteroaryl group that is substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano and alkoxy.

In the following embodiment RbPR is dstanley an unsubstituted, monosubstituted or disubstituted aryl or heteroaryl group.

In yet another the next incarnation Rbrepresents a possibly substituted monocyclic heteroaryl group. In the following embodiment Rbrepresents a possibly substituted bicyclic heteroaryl group. In yet another the next incarnation Rbrepresents a possibly substituted polycyclic heteroaryl group.

In a specific embodiment Rbrepresents a possibly substituted heteroaryl group, and a compound of formula I is in the Exo-configuration. In the following embodiment Rarepresents hydrogen, and Rbrepresents a possibly substituted heteroaryl group. In yet another the next incarnation Rarepresents hydrogen, Rbrepresents a possibly substituted heteroaryl group, and a compound of formula I is in the Exo-configuration.

In yet another the next incarnation Rbrepresents a possibly substituted phenyl group. In the following embodiment Rbrepresents a possibly substituted naftalina group. In yet another the next incarnation Rbrepresents a possibly substituted fluorenyl group.

In the following embodiment Rbrepresents a possibly substituted thienyl group is at. In yet another the next incarnation Rbrepresents a possibly substituted benzisothiazolinone group.

In yet another the next incarnation Rbrepresents a phenyl group which may be substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano and alkoxy.

In the following embodiment Rbrepresents a phenyl group, possibly substituted by one or two halogeno, such as chloro. In a specific embodiment Rbrepresents phenyl. In the following embodiment Rbrepresents a monosubstituted phenyl. In a specific embodiment Rbrepresents chlorophenyl, such as 3-chlorophenyl. In the following embodiment Rbrepresents disubstituted phenyl. In another specific embodiment Rbrepresents dichlorophenyl, such as 2,3-dichlorophenyl or 3,4-dichlorophenyl. In the following embodiment Rbrepresents phenyl, substituted chloro, fluorescent, such as 4-chloro-3-forfinal or 4-fluoro-3-chlorophenyl. In yet another the next incarnation Rbrepresents phenyl, substituted chloro and trifluoromethyl, such as 2-chloro-3-triptoreline or 4-chloro-3-triptoreline. In yet another the next incarnation Rbrepresents phenyl, substituted with fluorescent and triptorelin is, such as 4-fluoro-3-triptoreline. In the following embodiment Rbrepresents phenyl, substituted chloro and cyano, such as 3-chloro-4-cyanophenyl. In yet another the next incarnation Rbrepresents phenyl, substituted chloro and stands, such as 4-chloro-3-were. In yet another the next incarnation Rbrepresents phenyl, substituted chloro and bromo, such as 4-bromo-3-chlorophenyl. In the following embodiment Rbrepresents a monosubstituted phenyl. In yet another the next incarnation Rbrepresents chlorophenyl, such as 3-chlorophenyl or 4-chlorophenyl. In the following embodiment Rbis trifloromethyl, such as 3-trifloromethyl or 4-trifloromethyl. In yet another the next incarnation Rbis triptoreline, such as 4-triptoreline. In the following embodiment Rbis a were, such as 4-were. In yet another the next incarnation Rbrepresents methoxyphenyl, such as 3-methoxyphenyl or 4-methoxyphenyl. In yet another the next incarnation Rbis cyanophenyl, such as 4-cyanophenyl.

In the following embodiment Rarepresents hydrogen, and Rbrepresents a phenyl group which is substituted twice by substituents independently selected from the group is s, consisting of halogeno, trifloromethyl, triptoreline, cyano and alkoxy.

In the following embodiment Rbrepresents naftalina group such as 1-naphthyl or 2-naphthyl. In yet another the next incarnation Rbrepresents naftalina group, substituted by one or two halogeno, such as chloro or bromo. In a specific embodiment Rbrepresents chloronaphthyl, such as 4-chloronaphthalene-1-yl. In the following embodiment Rbrepresents panaftel, such as 6 does not depend-2-yl. In yet another the next incarnation Rbrepresents naftalina group, substituted by one or two alkoxy, such as methoxy. In a specific embodiment Rbrepresents methoxymethyl, such as 4-methoxynaphthalene-1-yl, 6-methoxynaphthalene-2-yl or 7-methoxynaphthalene-2-yl. In yet another the next incarnation Rbrepresents naftalina group, substituted by one or two cyano. In a specific embodiment Rbrepresents canonette, such as 6-cyanonaphthalene-2-yl.

In yet another the next incarnation Rbrepresents a 1,2,3,4-tetrahydronaphthalene group, such as 1,2,3,4-tetrahydronaphthalen-6-yl.

In the following embodiment Rbrepresents indenolol group, such as 5-indanyl.

In yet another the next incarnation Rbis fluoren the optimum group, substituted by oxo, such as fluoren-9-one-2-yl.

In yet another the next incarnation Rbrepresents a thienyl group which is substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano and alkoxy.

In the following embodiment Rbrepresents a thienyl group, substituted one or more times, halogeno, such as chloro or bromo. In a specific embodiment Rbrepresents bromanil, such as 4-bromothiophene-2-yl. In the following embodiment Rbrepresents dehalogenation, such as the bromine-chlorine-thienyl, in particular 3-bromo-5-chloro-thiophene-2-yl or 4-bromo-5-chloro-thiophene-2-yl. In the following embodiment Rbrepresents dichlorotris, such as 3,4-dichloro-thiophene-2-yl. The following specific embodiment Rbrepresents trichlorethyl, such as 3,4,5-trichloro-thiophene-2-yl. In one of the following specific embodiment Rbrepresents tribromophenyl, such as 3,4,5-tribromo-thiophene-2-yl.

In yet another the next incarnation Rbrepresents benzisothiazolinone group, such as 1,2-benzisothiazol-3-yl.

In the following embodiment Rbrepresents a possibly substituted benzothiazolyl group. In a specific embodiment Rbrepresents benzothiazolyl, this ka is benzothiazol-2-yl. In the following embodiment Rbrepresents benzothiazolyl group, substituted by one or two halogeno, such as chloro. In a specific embodiment Rbrepresents chlorobenzothiazole, such as 6-chlorobenzothiazole-2-yl.

In the following embodiment Rbrepresents thiazolidine group, substituted by one or two halogen, such as bromo. In a specific embodiment Rbrepresents bromothiazole, such as 5-bromothiazole-2-yl.

In yet another the next incarnation Rbrepresents khinoksalinona group, such as cinoxacin-2-yl.

In the following embodiment Rbrepresents chinazolinei group, such as hinzelin-2-yl.

In the following embodiment Rbrepresents hyalinella group, such as quinoline-2-yl, quinoline-6-yl or quinoline-8-yl.

In the following embodiment Rbrepresents athinodorou group, such as isoquinoline-5-yl.

In yet another the next incarnation Rbrepresents benzoxazolyl group, such as benzoxazol-2-yl.

In the following embodiment Rbrepresents a possibly substituted pyridazinyl group. In yet another the next incarnation Rbrepresents pyridazinyl group, substituted by one or two halogeno, such as chloro. In a specific embodiment Rb represents a chlorine pyridazinyl, such as 6-chloropyridin-3-yl.

In the following embodiment Rbrepresents a possibly substituted pyridyloxy group. In the following embodiment Rbrepresents pyridyloxy group, which is substituted by one or more substituents independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, hydroxy and alkoxy. In yet another the next incarnation Rbrepresents pyridyloxy group, substituted by one or two halogeno, such as chloro or bromo. In a specific embodiment Rbis chloropyridin, such as 5-chloropyridin-2-yl or 6-chloropyridin-2-yl. In the following embodiment Rbis bromperidol, such as 5-bromopyridin-2-yl or 6-bromopyridin-2-yl. In yet another the next incarnation Rbrepresents pyridyloxy group, substituted by one or two alkoxy, such as methoxy or ethoxy. In a specific embodiment Rbis methoxypyridine, such as 6-methoxypyridine-2-yl. The following specific embodiment Rbis ethoxypyridine, such as 6-ethoxypyridine-2-yl. In yet another the next incarnation Rbis a group of pyridine, substituted by one or two trifluoromethyl. In a specific embodiment Rbrepresents trip ornatipinnis, such as 5-triptorelin-2-yl. In the following embodiment Rbis a group of pyridine, substituted by one or two hydroxy. In a specific embodiment Rbis hydroxypyridine, such as 6-hydroxy-pyridine-2-yl.

In the following embodiment Rbrepresents athinodorou group, such as isoquinoline-1-yl.

In the following embodiment Rbrepresents a possibly substituted group of the pyrimidine. In yet another the next incarnation Rbrepresents a group of the pyrimidine substituted by one or two halogen, such as bromo. In a specific embodiment Rbis bromopyrimidine, such as 5-bromopyrimidine-2-yl.

In the following embodiment Rbrepresents dibenzofuranes group, such as dibenzofuran-2-yl.

In yet another the next incarnation Rbrepresents indolenine group, such as 5-indolyl.

In a particular embodiment the chemical compound according to the invention represents:

endo-3-(3,4,5-tripartite-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

endo-3-(3,4-dichlorothiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4,5-tripartite-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(1,2-benzisothiazol-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(5-bromothiazole-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]is CTAN;

Exo-3-(benzothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-chlorobenzothiazole-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(cinoxacin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(quinoline-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(benzoxazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-chloro-pyridazin-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(5-chloro-pyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(isoquinoline-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-chloropyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(5-bromopyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-bromopyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(5-bromopyrimidine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(hinzelin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(5-triptorelin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4,5-tribromide-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-bromothiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

endo-3-(3-bromo-5-chloro-thiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

endo-3-(4-bromo-5-chloro-thiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

endo-3-(3,4,5-tripartite-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(2,3-dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-H-8-azabicyclo[3.2.]octane;

Exo-3-(3,4,5-tripartite-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-4-pertenece)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-pertenece)-8-H-8-azabicyclo[3.2.1 ]octane;

Exo-3-(4-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1 ]octane;

Exo-3-(2-chloro-3-trifluoromethyl-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(fluoren-9-one-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(1,2-benzisothiazol-3-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane;

endo-3-(3,4-dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-triptoreline)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(2-dibenzofurans)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(1-naphthyloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(2-naphthyloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-4-cianfrocca)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-methylphenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloronaphthalene-1-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(quinoline-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(5-chloro-pyridine-2-yl)-8-H-8-azabicyclo[3.2.1 ]octane;

Exo-3-(4-methoxyphenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(isoquinoline-5-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-bromo-naphthalene-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-bromo-3-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

E. the AOR-3-(quinoline-6-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-tryptophanate)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-cianfrocca)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(quinoline-8-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-methylphenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-chloropyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(5-bromopyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-bromopyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(isoquinoline-1-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-methoxypyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(5-triptorelin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-ethoxypyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-fluoro-3-triptoreline)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(2,3-dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-4-pertenece)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-pertenece)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(2-chloro-3-trifluoromethyl-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(fluoren-9-one-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-d is chlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(1-naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(2-naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-trifluoromethyl-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-4-cianfrocca)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(2-dibenzofurans)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloronaphthalene-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-methylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(7-methoxynaphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-methoxynaphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-bromo-3-chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(isoquinoline-5-yl)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-bromo-naphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3-methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-cianfrocca)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(quinoline-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(1,2,3,4-tetrahydronaphthalen-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-triptoreline)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-methylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(8-chinoline)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(5-inanimate)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-methoxynaphthalene-1 yloxy)-8-ethyl-8-azabicyclo[3.2.1]octane;

Exo-3-(indol-5-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3-triftormetilfosfinov)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-triftormetilfosfinov)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(4-fluoro-3-triptoreline)-8-methyl-8-azabicyclo[3.2.1]octane;

endo-3-(3,4-dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-(cyanomethyl)-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-(allyl)-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-(methoxyethyl)-8-azabicyclo[3.2.1]octane;

Exo-3-(6-methoxypyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-ethoxypyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-hydroxy-pyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-3-(6-cyano-naphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane;

Exo-(3,4-dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-amine;

endo-(3,4-dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-formylamino;

Exo-(3,4-dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-formylamino;

or any of its isomers or any mixture of its isomers or its pharmaceutically acceptable salt.

It is assumed that any combination of two or more of the embodiments described above, included webjam of the present invention.

The definition of the substituents

In the context of this invention, halogen is a fluorescent, chloro, bromo or iodo.

In the context of this invention alkyl group means a monovalent saturated straight or branched hydrocarbon chain. This hydrocarbon chain preferably contains from one to six carbon atoms (C1-6alkyl), including pentyl, isopentyl, neopentyl, tertiary of pentyl, hexyl and isohexyl. In the preferred embodiment, the alkyl is a1-4alkyl group, including butyl, isobutyl, secondary butyl and tertiary butyl. In another preferred embodiment of this invention, alkyl is a1-3alkyl group, which may, in particular, represent methyl, ethyl, propyl or isopropyl.

In the context of this invention Alchemilla group means a carbon chain containing one or more double bonds, including di-ENES, three-ENES and poly-ENES. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6alkenyl), including at least one double bond. In the preferred embodiment Alchemilla group according to the invention represents an ethynyl; 1 - or 2-propenyl; 1-, 2 - or 3-butenyl or 1,3-butadienyl; 1-, 2-, 3-, 4 - or 5-hexenyl or 1,3-hexadienyl, or of 1.35-EXTRANEAL.

In the context of this invention Alchemilla group means a carbon chain containing one or more triple relations, including di-ins, three-ins and poly-ins. In the preferred embodiment Alchemilla group according to the invention contains from two to six carbon atoms (C2-6quinil), including at least one triple bond. In its most preferred embodiment Alchemilla group according to the invention is ethinyl; 1 - or 2-PROPYNYL; 1-, 2 - or 3-butenyl or 1,3-butadienyl; 1-, 2-, 3-, 4-pentenyl or 1,3-pentadienyl; 1-, 2-, 3-, 4 - or 5-hexenyl or 1,3-hexadienyl, or 1,3,5-extreinely.

In the context of this invention cycloalkyl group means a cyclic alkyl group, preferably containing from three to seven carbon atoms (C3-7cycloalkyl), including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

Alkoxy represents O-alkyl, where alkyl such as defined above.

Cycloalkane means O-cycloalkyl where cycloalkyl such as defined above.

Cycloalkenyl means cycloalkyl as given above, and the alkyl, as given above, meaning, for example, cyclopropylmethyl.

Amino represents NH2or NH-alkyl or N-(alkyl)2where alkyl such as defined above.

In the context of this invention, the aryl group sachetsealing aromatic ring system, such as phenyl, naphthyl (1-naphthyl or 2-naphthyl) or fluorenyl. This also implies that the term "aryl" includes partially gidrirovannoe carbocyclic aromatic ring system such as indanyl or 1,2,3,4-tetrahydronaphthyl.

In the context of this invention, the heteroaryl group means an aromatic mono - or bicyclic heterocyclic group which contains one or more heteroatoms in its ring structure. Preferred heteroatoms include nitrogen (N), oxygen (O) and sulfur (S).

Preferred monocyclic heteroaryl groups of the invention include aromatic 5 - and 6-membered monocyclic heterocyclic group including, for example, oxazolyl (oxazol-2-yl, -4-yl or-5-yl), isoxazolyl (isoxazol-3-yl, -4-yl or-5-yl), thiazolyl (thiazol-2-yl, -4-yl or-5-yl), isothiazole (isothiazol-3-yl, -4-yl or-5-yl), 1,2,4-oxadiazolyl (1,2,4-oxadiazol-3-yl or-5-yl), 1,2,4-thiadiazolyl (1,2,4-thiadiazole-3-yl or-5-yl), 1,2,5-oxadiazolyl (1,2,5-oxadiazol-3-yl or-4-yl), 1,2,5-thiadiazolyl (1,2,5-thiadiazole-3-yl or-4-yl), imidazolyl (2-, 4 - or 5-imidazolyl), pyrrolyl (2 - or 3-pyrrolyl), furanyl (2 - or 3-furanyl), thienyl (2 - or 3-thienyl), pyridyl (2-, 3 - or 4-pyridyl), pyrimidyl (2-, 4-, 5 - or 6-pyrimidyl) or pyridazinyl (3 - or 4-pyridazinyl), but are not limited to.

Preferred bicyclic heteroaryl groups of p the invention include indolizinyl, in particular 2-, 5 - or 6-indolizinyl; indolyl, in particular 2-, 5 - or 6-indolyl; isoindolyl, in particular 2-, 5 - or 6-isoindolyl; indazoles, in particular 1 - or 3-indazole; benzo[b]furanyl, in particular 2-, 5 - or 6-benzofuranyl; benzo[b]thienyl, in particular 2-, 5 - or 6-benzothiazyl; benzimidazolyl, in particular 2-, 5 - or 6-benzimidazolyl; benzoxazolyl, in particular 2-, 5 - or 6-benzoxazolyl; benzothiazolyl, in particular 2-, 5 - or 6-benzothiazolyl; benzisothiazolin (1,2-benzisothiazolin or 2.1-benzisothiazolin), in particular 1,2-benzisothiazol-3-yl; purinol, in particular 2 - or 8-purinol; chinoline, in particular 2-, 3-, 6-, 7 - or 8-chinoline; ethenolysis, in particular 1-, 3-, 5-, 6 - or 7-ethenolysis; indolinyl, in particular 6 - or 7-indolinyl; phthalazines, in particular 6 - or 7-phthalazine; hintline, in particular 2-, 6 - or 7-hintline; honokalani, in particular 2 - or 6-honokalani; 1,8-naphthyridines, in particular 1,8-naphthiridine-2-, -3-, -6 - or-7-yl; pteridinyl, in particular 2-, 6 - or 7-pteridinyl; and indenyl, in particular 1-, 2-, 3-, 5 -, or 5-indanyl.

Preferred polycyclic heteroaryl groups of the invention include dibenzofurans, in particular 2-dibenzofuran.

Pharmaceutically acceptable salt

Chemical compound according to the invention can be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. the EU is ü physiologically) acceptable salts, and pre - or proletarienne form chemical compounds according to the invention.

Examples of pharmaceutically acceptable salts of joining include salts of joining non-toxic inorganic and organic acids, such as hydrochloride, obtained with hydrochloric acid, the hydrobromide obtained with Hydrobromic acid, nitrate, obtained with nitric acid, perchlorate obtained perchloro acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, formate obtained with formic acid, acetate derived from acetic acid, aconitic obtained amanitowoc acid, the ascorbate derived from ascorbic acid, bansilalpet obtained with benzosulfimide acid, the benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, the citrate derived from citric acid, embanet obtained monowai acid, enanthate, derived from enanthic acid, the fumarate derived from fumaric acid, the glutamate derived from glutamic acid, the glycolate derived from glycolic acid, the lactate derived from lactic acid, the maleate derived from maleic acid, malonate obtained from malonic acid, mandelate obtained with almond acid, methanesulfonate, obtained methanesulfonic acid, naphthalene-2-sulfonate obtained from naphthalene-2-sulfonic acid, phthalate obtained paleoecology, the salicylate derived from salicylic acid, sorbate derived from sorbic acid, stearate derived from stearic acid, succinate obtained from succinic acid, tartrate derived from tartaric acid, toluene-p-sulfonate obtained with toluene-p-sulfonic acid, and the like, but do not stop there. Such salts can be formed using methods that are well known and described in this technical field.

Other acids, such as oxalic acid, which can not be considered pharmaceutically acceptable, may be useful in obtaining salts useful as intermediates in obtaining chemical compounds according to the invention and its salts attaching a pharmaceutically acceptable acid.

Examples of pharmaceutically acceptable cationic salts chemical compounds according to the invention include sodium, potassium, calcium, magnesium, zinc, aluminum, lithium, Kalinovo, lysine and ammonium salt and the like, chemical compounds according to the invention containing an anionic group, but do not stop there. Such cationic salts can be formed by methods well known and described in the art.

In the context of this invention "onevia salt" N-containing compounds are also considered as the pharmaceutical is acceptable salt. Preferred "onevia salts include alkyl-onieva salt, cycloalkyl-onieva salt and cycloalkenyl-onieva salt.

Examples of pre - or proletarienne forms of chemical compounds according to the invention include examples of suitable prodrugs of the substances according to the invention, which include compounds which are modified by one or more reactive or capable in the formation of derivative groups of the original connection. Of particular interest are compounds modified at the carboxyl group, hydroxyl group or amino group. Examples of suitable derivatives are the esters or amides.

Chemical compound according to the invention can be offered in a soluble or insoluble forms with pharmaceutically acceptable solvents such as water, ethanol and the like. Soluble forms may also include hydrated forms, such as the monohydrate, dihydrate, hemihydrate, trihydrate, tetrahydrate and the like. In General, soluble forms are considered equivalent insoluble forms in the framework of the objectives of this invention.

Spatial isomers

Specialists in this field will be obvious that the compounds of the present invention can contain one or more chiral centres, and that such compounds exist in the form of isomers.

moreover, Deputy-X-Rb3-position 8-Aza-bicyclo[3.2.1]octane skeleton of the formula I may, in particular, to be in Exo or endo configuration. In one embodiment of the invention the Deputy position 3 is in the Exo-configuration. In another embodiment of the invention the Deputy position 3 is in the endo-configuration.

The invention includes all such isomers and any mixtures thereof, including racemic mixtures.

The racemic forms can be separated into the optical antipodes by known methods and techniques. One method of separation of isomeric salts using an optically active acid and liberation of the optically active amino compounds as a result of processing the substrate. Another method of separation of racemates on the optical antipodes is based on the use of chromatography on optically active matrix. Thus, racemic compounds of the present invention can be separated into their optical antipodes, for example, by fractional crystallization of d - or I-salts (tartratami, mandelate or camphorsulfonate).

Chemical compounds of the present invention can also be separated through the formation of diastereomeric amides by the interaction of chemical compounds of the present invention with an optically active enabled the carboxylic acid, such as acid, derived from (+)- or (-)phenylalanine, (+)- or (-)phenylglycine, (+)- or (-)-campanulas acid or by the formation of diastereomeric carbamates by the interaction of chemical compounds of the present invention with an optically active chloroformate or the like.

Other methods of separation of optical isomers are known in this field. Such methods include the methods described Jaques J, Collet A & Wilen S "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, New York (1981).

In addition, optically active compounds can be obtained from optically active starting materials.

Labeled compounds

Compounds according to the invention can be used in their labeled or unlabeled form. In the context of this invention "label" means associating a token with interest the connection that makes it easy to determine quantitatively the specified connection.

Labeled compounds according to the invention can be useful as diagnostic agents, radioactive labels or agents for monitoring in different diagnostic methods for the visualization of receptors in vivo.

Labeled isomer according to the invention preferably contains at least one radionuclide as a label. Positron-emitting radionuclides are candidates for use. In the context of this is subramania the radionuclide is preferably selected from 2H (deuterium),3H (tritium),13C,14C,131I125I123I and18F.

Physical detection of labeled isomer of the present invention can be selected from positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance spectroscopy (MRS)imaging method for nuclear magnetic resonance (MRI) and computed (transaxial) tomography (CAT) using x-rays or combinations thereof.

Ways to get

Chemical compounds according to the invention can be obtained by traditional methods of chemical synthesis, for example by the methods described in the working examples. Starting materials for the methods described in this application are known or can be obtained by conventional methods from commercially available chemicals.

In addition, one connection according to the invention can be converted into another compound according to the invention, using conventional methods.

The final products of the reactions described in this description, you can select traditional methods, such as extraction, crystallization, distillation, chromatography and so on.

Biological activity

Compounds according to the invention can be tested for their ability to inhibit the reuptake of the monoamines dopamine, Nora is renaline and serotonin in the uptake, for example, as described in WO 97/30997. On the basis of balanced activity detected in these tests, the compounds according to the invention are considered useful for treatment, prevention or relief of a disease, disorder, or condition of a mammal, including humans, and the disease, disorder or condition responsive to the inhibition of the reuptake monoamine neurotransmitters in the Central nervous system.

In a particular embodiment of the compounds according to the invention are considered useful for treatment, prevention or relief of the following: mood disorders, depression, atypical depression, severe depressive disorder, estimatesare disorder, bipolar disorder, bipolar disorder type I, bipolar II disorder, cyclothymic disorder, mood disorders due to a General medical condition, induced by substances mood disorders, pseudodementia, syndrome Ganzera, obsessive-compulsive disorder, panic disorder, panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without panic disorder in disorder, panic attack, memory deficits, memory loss, hyperactivity attention deficit, obesity, anxiety, generalized tre is one of the disorders, eating disorders, Parkinson's disease, parkinsonism, dementia, dementia of ageing, senile dementia, Alzheimer's disease, acquired immunodeficiency syndrome and dementia, memory impairment during aging, specific phobia, social phobia, posttraumatic stress disorder, acute stress disorder, addiction to the excessive use of drugs, abuse drugs, abuse, cocaine abuse, nicotine abuse, tobacco, addiction to alcohol, alcoholism, pain, chronic pain, inflammatory pain, neuropathic pain, migraine, headaches, stress, chronic headaches tension associated with depression, pain, fibromyalgia, arthritis, osteoarthritis, rheumatoid arthritis, back pain, pain in cancer and pain in irritable bowels, irritable bowel syndrome, post-operative pain, pain after stroke-induced medication neuropathy, diabetic neuropathy, simpaticeskii supported pain, trigeminal neuralgia, dental pain, musculoskeletal facial pain, phantom pain, bulimia, premenstrual syndrome, syndrome, late luteal phase, post-traumatic syndrome, chronic fatigue syndrome, urinary incontinence, incontinence when the voltage incontinence when the urge is, nocturnal incontinence, sexual dysfunction, premature ejaculation, erectile difficulties, errectile dysfunction, eating disorders, anorexia nervosa, disorders of sleep, autism, mutism, trichotillomania, narcolepsy, depression after stroke caused by stroke, cerebral disorders caused by stroke, neural injury or disease, Gilles de La Tourette. In the preferred embodiment the compounds are useful to treat, prevent or alleviate depression.

Currently, it is assumed that a suitable dosage of the active pharmaceutical ingredient (API) is in the range from about 0.1 to about 1000 mg API per day, more preferably from about 10 to about 500 mg API per day, most preferably from about 30 to about 100 mg API per day, depending, however, on the particular method of administration, the form in which it is introduced, the proposed testimony of the subject and in particular the weight of the affected entity, and further the preference and experience of the responsible physician or veterinarian.

Preferred compounds according to the invention show a biological activity in submicromolar and micromolar range, i.e. of from below 1 to about 100 microns.

The pharmaceutical composition

In another aspect, with the according to the invention proposed new pharmaceutical compositions containing a therapeutically effective amount of a chemical compound according to the invention.

Despite the fact that a chemical compound according to the invention for use in therapy can be introduced in the form of the raw chemical compound, it is preferable to introduce the active ingredient, possibly in the form of a physiologically acceptable salt, in a pharmaceutical composition together with one or more than one adjuvant, excipient, carrier, buffer, diluent and/or other commercially available pharmaceutical auxiliary substances.

In the preferred embodiment according to the invention proposed pharmaceutical composition comprising a chemical compound according to the invention or its pharmaceutically acceptable salt or derivative, together with one or more pharmaceutically acceptable carriers and, possibly, other therapeutic and/or prophylactic ingredients, known and used in the field. The carrier(s) need(s) to be acceptable(and)" in the sense of its compatibility with other ingredients of the drug and safety for the recipient.

The pharmaceutical compositions according to the invention can provide a composition suitable for oral, rectal, bronchial, nasal, pulmonary, local (including transbukkalno and sublingual), transderm is high, vaginal or parenteral (including cutaneous, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular injection or infusion) administration, or compositions in a form suitable for administration by inhalation or insufflation, including the introduction of powders or liquid aerosol, or via continuous release. Suitable examples of systems of continuous release include semi-permeable matrices of solid hydrophobic polymers containing a compound according to the invention, which can be represented as products of a certain shape, e.g. films, or microcapsules.

Thus, the chemical compound according to the invention together with a conventional adjuvant, carrier or diluent may be moulded into the form of pharmaceutical compositions and their standard dosage forms. Such forms include solid forms, in particular tablets, filled capsules, powder and granulated forms, and liquids, in particular aqueous or nonaqueous solutions, suspensions, emulsions, elixirs, or capsules filled with them intended for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral use. Such pharmaceutical compositions and their standard drug is army may contain conventional ingredients in conventional proportions, with an additional active compounds or principles, or without them, and such a standard dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended for use by the range of the daily dosage.

Chemical compound according to the present invention can be introduced in a wide variety of oral and parenteral dosage forms. Specialists in this field will be obvious that the following dosage forms may contain as an active ingredient or chemical compound according to the invention, or pharmaceutically acceptable salt of a chemical compound according to the invention.

For preparing pharmaceutical compositions from a chemical compound according to the present invention, pharmaceutically acceptable carriers can be either solid or liquid. Drugs in solid form include powders, tablets, pills, capsules, pills, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, corrigentov, soljubilizatory, lubricants, suspendresume agents, binders, preservatives, leavening tablets or encapsulating material.

In powders, the carrier is a finely ground solid material, which is mixed with finely ground active what omponents.

In tablets, the active component is mixed in suitable proportions with the carrier having the necessary binding capacity, and skompanovan with obtaining the desired shape and size.

The powders and tablets preferably contain from five or ten to about seventy percent of the active compounds. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragakant, methylcellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. The term "preparation" includes the preparation of the active compound with encapsulating material as carrier providing a capsule in which the active ingredient with the carriers, or without them, surrounded by carrier, which thus turns out to be associated with him. Similarly included are wafers and cakes. Tablets, powders, capsules, pills, wafers and cakes can be used as solid dosage forms suitable for oral administration.

For preparing suppositories first melted low-melting wax such as a mixture of glycerides of fatty acids or cocoa butter, and it is homogeneous dispersed active component, for example, by stirring. Molten homoge the ing the mixture is then poured into forms convenient size, leave to cool and, accordingly, to harden.

Compositions suitable for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers, which are suitable according to experts in this field.

Liquid preparations include solutions, suspensions and emulsions, such as solutions in water or in a mixture of water-propylene glycol. For example, liquid preparations for parenteral injection may be made in the form of solutions in an aqueous solution of polyethylene glycol.

Thus, a chemical compound according to the present invention can be prepared for parenteral administration (e.g. by injection, in particular bolus injection or continuous infusion) and may be presented in a standard dosage form in ampoules, pre-filled syringes, containers for small volume infusion or in multi-dose containers with an added preservative. These songs can have such forms as suspensions, solutions or emulsions in oily or aqueous carriers, and may contain such auxiliary agents, as suspendida, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, p is obtained by release of sterile solids in aseptic conditions or by lyophilization from solution, for reverse engineering before use with a suitable diluent, such as sterile pyrogen-free water.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding, if desired, a suitable dye, corrigentov, stabilizing and thickening agents.

Aqueous suspensions suitable for oral use can be prepared by dispersing finely ground active component in water with viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose or other well-known suspendresume agents.

Also included preparations in solid form, designed to turn them into liquid form before oral administration. Such liquid forms include solutions, suspensions and emulsions. In addition to the active ingredient such preparations may contain colouring agents, corrigentov, stabilizers, buffers, artificial and natural sweeteners, dispersing agents, thickeners, solubilizing agents and the like.

For local injection into the epidermis chemical compound according to the invention can be prepared in the form of ointments, creams or lotions, or as a transdermal patch. Ointments and criminoso, for example be prepared using an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Lotions can be prepared using water or oil base, and in General they will also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspendida agents, thickening agents, or dyes.

Compositions suitable for local injection in the mouth include pellet containing the active agent in the corrected basis, usually sucrose and Arabian gum or tragakant; tablets containing the active ingredient in an inert basis such as gelatin and glycerin or sucrose and Arabian gum; and liquid mouth rinse containing the active ingredient in a suitable liquid carrier.

The solutions or suspensions are injected directly into the nasal cavity by conventional methods, for example, using a dropper, pipette or spray. Song data can be represented in a single form or in aldosivi form.

Introduction to the respiratory tract can also be realized by means of the aerosol formulation, the active ingredient which is present in a pressurized pack with a suitable propellant, such as chlorofluorocarbon (CFC), for example DICHLORODIFLUOROMETHANE, Trichlorofluoromethane or dig iteratortag, the carbon dioxide or other suitable gas. The aerosol may also conveniently contain a surfactant such as lecithin. The dose can be controlled by providing a metering valve.

Alternatively, the active ingredients can be represented in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, derivatives of starch, hypromellose and polyvinylpyrrolidone (PVP). Convenient to powder carrier formed a gel in the nasal cavity. The powder composition may be presented in a standard dosage form, for example, capsules or cartridges, in particular, from gelatin or blister packs from which the powder can be introduced through the inhaler.

Particles of compound in compositions intended for administration to the respiratory tract, including intranasal compositions, in the General case will be small, for example of the order of 5 microns or less. This particle size can be achieved using well-known specialists in the field of methods, for example by micronization.

If desired, can be used compositions adapted for continuous release of the active ingredient.

The pharmaceutical preparations are preferably presented in the article is Hartig dosage forms. In such form the preparation is divided into standard doses containing appropriate quantities of the active component. Standard dosage form can be a packaged preparation, the package contains discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. In addition, a standard dosage form itself can be a capsule, tablet, wafer or pellet, or it can represent an appropriate number of any of these packaged forms.

Tablets or capsules for oral administration and fluids for intravenous injection and continuous infusion are preferred compositions.

Additional details of methods of preparation and introduction can be found in the latest edition Remington''s Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

A therapeutically effective dose refers to that amount of active ingredient which reduces the intensity of symptoms or condition. Therapeutic efficacy and toxicity, such as ED50and LD50you can define a standard pharmaceutical procedures in cell cultures or experimental animals. The dose ratio between therapeutic and toxic effects is therapeutic index and it can be expressed with the relation LD 50/ED50. Preferred are pharmaceutical compositions that demonstrate a high therapeutic index.

Enter the dose should be, of course, carefully chosen depending on age, weight and condition being treated the individual as well as route of administration dosage form and regimen and the desired result, and the exact dosage must surely be determined by a medical practitioner.

The actual dosage depends on the nature and severity of the subject to treatment of the disease and is at the discretion of the physician, it can be varied by titration of the dosage to the specific cases in this invention in order to obtain the desired therapeutic effect. However, it is currently envisioned that a pharmaceutical composition containing from about 0.1 to about 500 mg of the active ingredient on the individual dose, preferably from about 1 to about 100 mg, most preferably from about 1 to about 10 mg, are suitable for therapeutic applications.

The active ingredient can be entered in one or more doses per day. In some cases, satisfactory results can be obtained at a dosage lower than 0.1 μg/kg I.V. and 1 mcg/kg orally. The upper boundary of the range dosiro the deposits at the present time is equal to approximately 10 mg/kg I.V. and 100 mg/kg orally. Preferred ranges are from about 0.1 μg/kg to about 10 mg/kg/day intravenously and from about 1 μg/kg to about 100 mg/kg/day orally.

Methods of treatment

In another aspect according to the invention, a method for treatment, prevention or relief of disease, disorder or condition of the body of an animal, including humans, which are sensitive to inhibition of reuptake monoamine neurotransmitters in the Central nervous system, including the introduction in an organism in need thereof an animal, including humans, an effective amount of a chemical compound according to the invention.

Currently, it is assumed that appropriate dosing ranges are from 0.1 to 1000 milligrams per day, 10-500 milligrams daily, and especially 30-100 milligrams per day depending, as usual, on the particular method of administration, form in which the introduction, readings, directed the introduction of the affected subject, and body mass of the affected entity, and further the preference and experience of the responsible physician or veterinarian.

EXAMPLES

The invention is additionally illustrated with reference to the following examples which are not intended to limit in any way the scope of the invention as represented in the Les of the invention.

General: all reactions involving sensitive to air reagents or intermediates were performed under nitrogen atmosphere and anhydrous solvents. In the processing procedures as a drying agent used magnesium sulfate and the solvents evaporated under reduced pressure.

Method And

endo-3-(3,4,5-Tripartite-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

A mixture of tetrachloroethene (5,48 g; 24,69 mmol), tropine (endo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol) (3,48 g; 24,69 mmol), of potassium tert-butylate (4,16 g; 37,04 mmol), 18-crown-6-ether (6,53 g; 24,69 mmol) and DMF (N,N-dimethylformamide (50 ml) was stirred at 100°C for 15 hours To the mixture was added aqueous hydrochloric acid (50 ml; 4 M). The mixture was washed with diethyl ether (2×100 ml). Was added aqueous sodium hydroxide (100 ml, 4 M). The mixture was extracted with ethyl acetate (3×100 ml). The organic phase is washed with aqueous sodium chloride (3×50 ml). Yield 2.65 g (33%). The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. TPL 200,4-206,4°C.

endo-3-(3,4-Dichlorothiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with the method And 2,3,4-trichlorotoluene and tropine (enbo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol), was isolated as free base and oil.

endo-3-(3,4,5-Tripartite-2-ilok and)-8-methyl-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with the method And tetrachlormethane and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 249-250°C.

Exo-3-(1,2-Benzisothiazol-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Was obtained according to method a from 3-chloro-1,2-benzisothiazole and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 259,4-261,2°C.

Exo-3-(5-Bromothiazole-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with the method And of the 2.5-dibromothiazole and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). Was isolated as the free base. TPL 104-106°C.

Exo-3-(Benzothiazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 2-chlorobenzothiazole and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 160-162°C.

Exo-3-(6-Chlorobenzothiazole-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method And 2,6-dichlorobenzothiazole and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 163-164,5°C.

Exo-3-(Cinoxacin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 2-chlorphenoxamine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 208-210°C.

ek is about-3-(Quinoline-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 2-chlorhydrin and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 192.5 kg-195°C.

Exo-3-(Benzoxazol-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 2-chlorobenzoxazole and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 141-144°C.

Exo-3-(6-Chloro-pyridazin-3-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method And of 3,6-dichloropyridazine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 181-183°C.

Exo-3-(5-Chloro-pyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method And of the 2.5-dichloropyridine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 214-216°C.

Exo-3-(Isoquinoline-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 1-chloroisoquinoline and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 180-181,5°C.

Exo-3-(6-Chloropyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method And 2,6-dichloropyridine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 202-204°C.

Exo-3-(5-Bromopyridin-2-yloxy)-8-ethyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method And of the 2.5-dibromopyridine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 213-215°C.

Exo-3-(6-Bromopyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method And 2,6-dibromopyridine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 198-200°C.

Exo-3-(5-Bromopyrimidine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 5-bromo-2-chloropyrimidine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 198-200°C.

Exo-3-(Hinzelin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 2-chlorination and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 209-211°C.

Exo-3-(5-Triptorelin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 2-chloro-5-triptoreline and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 190-191,5°C.

Exo-3-(3,4,5-Tribromide-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with the method And tetrabromoethane and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 223,3-223,9°C.

ind is-3-(4-Bromothiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received from Exo-3-(3,4,5-tribromide-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane by mixing with 5 equivalents of zinc powder in concentrated acetic acid at 75°C for 15 p.m Procedure was carried out according to method A. TPL 222,1°C.

endo-3-(3-Bromo-5-chloro-thiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 3-bromo-2,5-dichlorothiophene and tropine (endo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 171-173°C.

endo-3-(4-Bromo-5-chloro-thiophene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method a from 3-bromo-2,5-dichlorothiophene and tropine (endo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 136-139°C.

Method In

endo-3-(3,4,5-Tripartite-2-yloxy)-8-H-8-azabicyclo[3.2.1]Octan

A mixture of endo-3-(3,4,5-tripartite-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane (0.50 g; 1.53 mmol), 1-chloroethylphosphonic (1,27 ml; 11.5 mmol) and toluene (20 ml) was stirred at the boil under reflux for 15 hours was Added water (10 ml) and the mixture was stirred at the temperature of reflux distilled within 3.5 hours the Mixture was evaporated. Was added sodium methylate in methanol (5 ml, 1 M) and silica gel 60 (2 g) and then was evaporated. Chromatography of the crude mixture on silica gel with dichloromethane, methanol and conc the form of ammonia (89:10:1) gave specified in the title compound in quantitative yield in the form of a free base and oil.

Exo-3-(2,3-Dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base. TPL 62,3-65,4°C.

Exo-3-(3,4-Dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with method C. TPL 160,1°C.

Exo-3-(3,4,5-Tripartite-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with method C. TPL 255-256°C.

Exo-3-(3-Chloro-4-pertenece)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 151-154°C.

Exo-3-(3-Chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 195-196°C.

Exo-3-(4-Chloro-3-pertenece)-8-H-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base and oil.

Exo-3-(4-Chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 188-188,5°C.

Exo-3-(2-Chloro-3-trifluoromethyl-phenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 190-193°C.

Exo-3-(Fluoren-9-one-2-yloxy)-8-H-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base. TPL 242,8-256,3°C.

Exo-3-(1,2-Benzisothiazol-3 is hydroxy)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with the method of 3-chloro-1,2-benzisothiazole and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 252,5°C.

Exo-3-(3,4-Dichlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 194-196°C.

endo-3-(3,4-Dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with method C. TPL 287°C;

Exo-3-(4-Chloro-3-triptoreline)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 215-217°C.

Exo-3-(2-Dibenzofurans)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 217-221°With.

Exo-3-(1-Naphthyloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL p.223-224°With.

Exo-3-(2-Naphthyloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 202-204°With.

Exo-3-(3-Chloro-4-cianfrocca)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 176,3-178,9°With.

Exo-3-(4-Chloro-3-methylphenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 192.5 kg-194,5°With.

Exo-3-(4-chlorine is naphthalene-1-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 226-227 of the°With.

Exo-3-(Quinoline-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 211-213°With.

Exo-3-(5-Chloro-pyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 196-198°With.

Exo-3-(4-Methoxyphenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 137-147°With.

Exo-3-(Isoquinoline-5-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 192-194°With.

Exo-3-(6-Bromo-naphthalene-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with method C. was Isolated as free base. TPL 270-274°C.

Exo-3-(4-Bromo-3-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 207-209°C.

Exo-3-(Quinoline-6-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 237-239°C.

Exo-3-(4-Tryptophanate)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with method C. TPL 178-180°C.

Exo-3-(4-Cianfrocca)-8-H-8-azabicyclo[3.2.1]octane, salt of fumarola the acid

Received in accordance with method C. TPL 188,9 to 191.6°C.

Exo-3-(Quinoline-8-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 182-184,5°C.

Exo-3-(4-Methylphenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 174-177°C.

Exo-3-(6-Chloropyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method of 2,6-dichloropyridine and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 202-204°C.

Exo-3-(5-Bromopyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 216-218°C.

Exo-3-(6-Bromopyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 218-220°C.

Exo-3-(Isoquinoline-1-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method of the 1-chloroisoquinoline and pseudo-tropine (Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol). TPL 215-217°C.

Exo-3-(3-Triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base. TPL 185-187°C.

Exo-3-(4-Triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. You shall elali in the form of free base. TPL 192.5 kg-194°C.

Exo-3-(6-Methoxypyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 200-202°C.

Exo-3-(5-Triptorelin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 196,5-198,5°C.

Exo-3-(6-Ethoxypyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 192.5 kg-194,5°C.

Exo-3-(4-Fluoro-3-triptoreline)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 182-185°C.

Way

Exo-3-(2,3-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Diethylazodicarboxylate (at 8.36 ml; 53,1 mmol) was added dropwise at room temperature to a mixture of tropine (enbo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol) (5.0 g; of 35.4 mmol), 2,3-dichlorophenol (6,93 g; 42,5 mmol), triphenylphosphine (13,9 g; 53,1 mmol) and dioxane (55 ml). The mixture was stirred for 40 h at 100°C. To the mixture was added aqueous sodium hydroxide (100 ml, 1 M). The mixture was extracted with dichloromethane (2×100 ml). Chromatography on silica gel with methanol, dichloromethane and acetone (1:4:1) gave specified in the header connection. The output from 6.22 g (61%).

The corresponding salt was obtained by adding a mixture of diethyl ether and methanol (9:1, rich fumaric acid. TPL is 171.3-194,7°C.

Exo-3-(3,4-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL of 225.6°C.

Exo-3-(3-Chloro-4-pertenece)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base and oil.

Exo-3-(4-Chloro-3-pertenece)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base and oil.

Exo-3-(2-Chloro-3-triptoreline)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base and oil.

Exo-3-(3-Chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of oxalic acid

Received in accordance with method C. TPL 208-209°C.

Exo-3-(4-Chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of oxalic acid

Received in accordance with method C. TPL 150,5-154,0°C.

Exo-3-(Fluoren-9-one-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid

Received in accordance with method C. the Decomposition at TPL

Exo-3-(3,4-Dichlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method of 3,4-dichlorothiophene. TPL 179-181°C.

Exo-3-(1-Naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in compliance and with the way With. Was isolated as the free base. TPL 72-74°C.

Exo-3-(2-Naphthyloxy)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base. TPL 83-86°C.

Exo-3-(4-Chloro-3-triptoreline)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method.TPL 172,3-174,2°With.

Exo-3-(3-Chloro-4-cianfrocca)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 191,7-for 194.3°With.

Exo-3-(2-Dibenzofurans)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL of 199, 9-202,0°With.

Exo-3-(4-Chloronaphthalene-1-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C.TPL 198-199°With.

Exo-3-(4-Chloro-3-methylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 230-232°With.

Exo-3-(4-Methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 164,5-KZT 166.5°With.

Exo-3-(7-Methoxynaphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 143-145°With.

Exo-3-(6-Methoxynaphthalene-2-ylox the)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 78.5 to 81.5 to°C.

Exo-3-(4-Bromo-3-chloro-phenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 218-220°C.

Exo-3-(Isoquinoline-5-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 193-196°C.

Exo-3-(6-Bromo-naphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 227-229°C.

Exo-3-(3-Methoxyphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 144-147°C.

Exo-3-(4-Cianfrocca)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 177, 9mm-181,9°C.

Exo-3-(Quinoline-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid was Obtained in accordance with method C.TPL 221-223°C.

Exo-3-(1,2,3,4-Tetrahydronaphthalen-6-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 165,9-of 167.2°C.

Exo-3-(4-Triptoreline)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 184,1-186,5°C.

Exo-3-(4-Methylphenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of f is mirovoi acid

Received in accordance with method C. TPL 178-181°C.

Exo-3-(Quinoline-8-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 158-160°C.

Exo-3-(5-Inanimate)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C.TPL 184,7-185,9°C.

Exo-3-(4-Methoxynaphthalene-1 yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 185-188°C.

Exo-3-(Indol-5-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 176,3-178,3°C.

Exo-3-(3-Triftormetilfosfinov)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base. Butter.

Exo-3-(4-Triftormetilfosfinov)-8-methyl-8-azabicyclo[3.2.1]Octan

Received in accordance with method C. was Isolated as free base. Butter.

Exo-3-(4-Fluoro-3-triptoreline)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with method C. TPL 167-169°C.

Method D

endo-3-(3,4-Dichlorophenoxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

A mixture of endo-3-chloro-8-methyl-8-azabicyclo[3.2.1]octane (3,9 g; 24 mmol) (obtained from Exo-8-methyl-8-azabicyclo[3.2.1]Octan-3-ol and thionyl orida boiling under reflux for 3 h), 3,4-dichlorophenol (5.9 g; 36 mmol), sodium hydride 60% (1.2 g; 36 mmol) and ethanol (30 ml) was stirred at the boil under reflux for 15 hours To the mixture was added aqueous hydrochloric acid (50 ml, 4 M). The ethanol evaporated. The mixture was washed with diethyl ether (3×50 ml). Was added aqueous sodium hydroxide (50 ml, 4M). The mixture was extracted with diethyl ether (3×50 ml). Chromatography of the crude mixture on silica gel with dichloromethane, methanol and concentrated ammonia (89:10:1) gave specified in the header connection. The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. The output of 0.90 g (9%). TPL 198,0-207,7°C.

Method E

Exo-3-(3,4-Dichlorophenoxy)-8-(2-hydroxyethyl)-8-azabicyclo[3.2.1]Octan

A mixture of Exo-3-(3,4-dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane (2.2 g; 8.1 mmol), 2-bromoethanol (0.6 ml; 8.9 mmol), potassium carbonate (1.1 g; 8.1 mmol) and ethanol (20 ml) was stirred at the boil under reflux for 15 hours was Added aqueous sodium hydroxide (50 ml, 4 M). The mixture was extracted with dichloromethane (3×50 ml). Chromatography of the crude mixture on silica gel with dichloromethane, methanol and concentrated ammonia (89:10:1) gave specified in the title compound in the form of the free bases and oils. Yield 0.40 g (16%).

Exo-3-(3,4-Dichlorophenoxy)-8-(cyanomethyl)-8-azabicyclo[3.2.1]octane, salt of fumare the second acid

Received in accordance with the method that is TPL 79-82°C.

Exo-3-(3,4-Dichlorophenoxy)-8-(cyclopropylmethyl)-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method that is TPL 187-189,5°C.

Exo-3-(3,4-Dichlorophenoxy)-8-(allyl)-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method that is TPL 202-206°C.

Exo-3-(3,4-Dichlorophenoxy)-8-(methoxyethyl)-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received in accordance with the method that is TPL of 177.8-179,5°C.

Method F

Exo-3-(6-Methoxypyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

A mixture of Exo-3-(6-chloropyridin-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]-octane (6.5 g; and 25.8 mmol), sodium methylate (6.5 g; 0.12 mol) and NMP (N-organic (30 ml) was stirred at 130°C for 15 h was Added water (300 ml). The mixture was extracted with diethyl ether (3×150 ml). The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. Yield 3.0 g (32%). TPL 176-177,5°C.

Exo-3-(6-Ethoxypyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Was obtained according to method F. TPL 177-179°C.

Exo-3-(6-Hydroxy-pyridine-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

Received from Exo-3-(6-(CIS-methylphenoxy)-pyridine-2-yloxy)-8-met the l-8-azabicyclo[3.2.1]octane by mixing with concentrated hydrochloric acid and boiled under reflux for 0.5 hours Processing was carried out according to method F. TPL 196,5-200°C.

Method G

Exo-3-(6-Cyano-naphthalene-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane, salt of fumaric acid

A mixture of Exo-3-(6-bromo-naphthas-2-yloxy)-8-methyl-8-azabicyclo[3.2.1]octane (2.6 g; 7.5 mmol), Zn(CN)2(2.2 g; 18 mmol), palladacycles (50 mg) and dioxane (30 ml) was stirred at the boil under reflux for 70 hours To the mixture was added aqueous sodium hydroxide (50 ml, 1 M). The mixture was extracted with dichloromethane (2×50 ml). Chromatography on silica gel with methanol, dichloromethane and aqueous ammonia (1:9:1%) gave specified in the header connection. The output of 2.06 g (94%). The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. TPL 230-232°C.

Way N

Exo-(3,4-Dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-amine salt of fumaric acid

A mixture of 3,4-dichloroaniline (0.6 g; 3,17 mmol), tropine methansulfonate, salt toluensulfonate acid (1.24 g; 3,17 mmol) [S.Archer et. al., JACS 80, 4677-4691 (1958)], sodium hydride (0.17 g; 6,97 mmol) and DMF (5 ml) was prepared at 0°C. the Mixture was stirred for 15 h at room temperature. To the mixture was added aqueous sodium hydroxide (5 ml, 1 M). The mixture was extracted with dichloromethane (2×5 ml). Chromatography on silica gel with methanol, dichloromethane and aqueous ammonia (10:89:1) gave specified in the header with the Association. The corresponding salt was obtained by addition of a mixture of diethyl ether and methanol (9:1), saturated fumaric acid. Yield 23 mg (2%). TPL of 193.5-202,0°C.

endo-(3,4-Dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-formylamino, salt fumaric acid

Was isolated from the reaction mixture (above) in accordance with method I. the Yield 32 mg (3%). TPL 206,3°C.

Exo-(3,4-Dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-formylamino, salt fumaric acid

Received by formirovaniya concentrated formic acid from Exo-(3,4-dichloro-phenyl)-(8-methyl-8-Aza-bicyclo[3.2.1]Oct-3-yl)-amine. Processing was carried out according to method I. TPL 150,5-153,0°C.

Inhibitory activity in vitro

Compounds were tested for their ability to inhibit the reuptake monoamine neurotransmitters dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake, as described in WO 97/30997.

Inhibition of in vitro capture3H-dopamine (3H-DA) veins in the uptake.

The tissue preparations: Preparations prepared at 0-4°C, unless otherwise noted. Corpi striate male Wistar rats (150-200 g) homogenized for 5-10 sec in 100 volumes of chilled in people of 0.32 M sucrose containing 1 mm of pargyline, homogenizer Ultra-Turrax. The monoamine oxidase activity must be inhibited in the presence of pargyline. The homogenate was centrifuged at 1000ggfor 50 min and the supernatant discarded. The remainder (P2again suspended in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 min) incubation buffer Krebs-ringer (8000 ml per g of original tissue) with rn,2, containing 122 mm NaCl, 0.16 mm EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis: K. 100 μl of test solution and 100 µl of the3H-DA (final concentration 1 nm) add aliquots at 4,0 ml tissue suspension are mixed and incubated for 25 min at 37°C. Nonspecific capture determined using benztropine (final concentration 10 μm). After incubation the sample is poured directly on the filters glass fiber Whatman GF/C under suction. Then the filters are washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the standard account liquid scintillation. Specific capture is calculated as the difference between total and nonspecific capture.

Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

Inhibition of in vitro capture3H-norepinephrine (3H-NA) uptake g is pacana.

The tissue preparations: Preparations prepared at 0-4°C, unless otherwise noted. Hippocampi of male Wistar rats (150-200 g) homogenized for 5-10 sec in 100 volumes of the cooled in ice of 0.32 M sucrose containing 1 mm of pargyline, homogenizer Ultra-Turrax. The monoamine oxidase activity must be inhibited in the presence of pargyline. The homogenate was centrifuged at 1000 g for 10 minutes Obtained supernatant is then centrifuged at 27000 g for 50 min and the supernatant discarded. The remainder (P2again suspended in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 min) incubation buffer Krebs-ringer (2000 ml per g of original tissue) with a pH of 7.2, containing 122 mm NaCl, 0.16 mm EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis: K. 100 μl of test solution and 100 µl of the3H-NA (final concentration 1 nm) add aliquots at 4,0 ml tissue suspension are mixed and incubated for 90 min at 37°C. Nonspecific capture determined using desipramine (final concentration 1 μm). After incubation the sample is poured directly on the filters glass fiber Whatman GF/C under suction. Then the filters are washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The number of happy is aktivnosti on the filters define the standard account liquid scintillation. Specific capture is calculated as the difference between total and nonspecific capture.

Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

Inhibition of in vitro capture3H-hydroxytryptamine (3H-5-HT, serotonin) in cortical uptake.

The tissue preparations: Preparations prepared at 0-4°C, unless otherwise noted. The cerebral cortex of male Wistar rats (150-200 g) homogenized for 5-10 sec in 100 volumes of the cooled in ice of 0.32 M sucrose containing 1 mm of pargyline, homogenizer Ultra-Turrax. The monoamine oxidase activity must be inhibited in the presence of pargyline. The homogenate was centrifuged at 1000 g for 10 minutes Obtained supernatant is then centrifuged at 27000 g for 50 min and the supernatant discarded. The remainder (P2again suspended in oxygendemand (balanced in an atmosphere of 96% O2: 4% CO2for at least 30 min) incubation buffer Krebs-ringer (2000 ml per g of original tissue) with a pH of 7.2, containing 122 mm NaCl, 0.16 mm EDTA, 4.8 mm KCl, 12.7 mm Na2HPO4, 3.0 mm NaH2PO4, 1.2 mm MgSO4, 1 mm CaCl2, 10 mm glucose and 1 mm ascorbic acid.

Analysis: K. 100 μl of test solution and 100 µl of the3H-5-HT (final concentration 1 nm) add aliquots at 4,0 ml tissue suspension are mixed and cuberoot for 30 min at 37° C. Nonspecific capture is determined with the use of citalopram (final concentration 1 μm). After incubation the sample is poured directly on the filters glass fiber Whatman GF/C under suction. Then the filters are washed three times with 5 ml chilled in ice with 0.9% (wt./about.) NaCl solution. The amount of radioactivity on the filters define the standard account liquid scintillation. Specific capture is calculated as the difference between total and nonspecific capture.

Before the calculation of the IC50must be received 25-75% inhibition of specific binding.

The obtained values are given in the table below in the form of the IC50(the concentration (μm) test substance which inhibits the specific capture3H-DA,3H-NA or3H-5-HT by 50%).

ConnectionStructureGrip DA IC50(µm)Capture NA IC50(µm)Capture 5-HT IC50(µm)
Exo-3-(2,3-dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]Octan0,0560,00380,0052
Exo-3-(4-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid1,80,0570,0064
Exo-3-(4-chloro-3-trifluoromethyl-phenoxy)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid130,0180,0054
Exo-3-(3-Triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]Octan1,90,100,014
Exo-3-(5-chloro-pyridine-2-yl)-8-H-8-azabicyclo[3.2.1]octane, salt of fumaric acid2,10,0720,031
Exo-3-(6-bromo-naphthalene-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane, salt of hydrochloric acid0,760,120,016

1. Derived 8-Aza-bicyclo[3.2.1]octane of formula I

or any of its isomers or any mixture of its isomers,

or their pharmaceutically acceptable salt,

where Rarepresents hydrogen;

X represents-O-;

Rbrepresents an aryl or heteroaryl group selected from phenyl, naphthyl, pyridyl, chinoline, izochinolina or hintline, which is substituted by one or two substituents, independently selected from the group consisting of halogeno, trifloromethyl, is reformatory, cyano, hydroxy and alkoxy, provided that the compound is not 3-(3-triptoreline)-8-azabicyclo[3.2.1]octane, 3-(4-triptoreline)-8-azabicyclo[3.2.1]octane, 3-(2-bromophenoxy)-8-azabicyclo[3.2.1]octane, 3-(4-chlorphenoxy)-8-azabicyclo[3.2.1]octane or 3-(4-pertenece)-8-azabicyclo[3.2.1]octane.

2. Chemical compound according to claim 1,

where Rbrepresents a phenyl group which is substituted by one or two substituents, independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano and alkoxy.

3. Chemical compound according to claim 1,

where Rbrepresents pyridyloxy group, which is substituted by one or two substituents, independently selected from the group consisting of halogeno, trifloromethyl, triptoreline, cyano, hydroxy and alkoxy.

4. Chemical compound according to claim 1, which represents the

Exo-3-(2,3-dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3,4-dichlorophenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-4-pertenece)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-pertenece)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(2-chloro-3-trifluoromethyl-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

endo-3-(3,4-dichlorophenoxy the)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-triptoreline)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-chloro-4-cianfrocca)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloro-3-methylphenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-chloronaphthalene-1-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(5-chloro-pyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-methoxyphenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-bromo-naphthalene-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-bromo-3-chloro-phenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-cianfrocca)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-methylphenoxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-chloropyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(5-bromopyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-bromopyridin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(3-triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-triftormetilfosfinov)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-methoxypyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(5-triptorelin-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(6-ethoxypyridine-2-yloxy)-8-H-8-azabicyclo[3.2.1]octane;

Exo-3-(4-fluoro-3-triptoreline)-8-H-8-azabicyclo[3.2.1]octane;

or any of its isomers or any mixture of its isomers, or a pharmacist who Cesky acceptable salt.

5. Pharmaceutical composition having inhibitory activity against reuptake of monoamines containing a therapeutically effective amount of a compound according to claim 1 or any of its isomers or any mixture of its isomers, or pharmaceutically acceptable salts together with at least one pharmaceutically acceptable carrier, excipient or diluent.

6. The use of chemical compounds according to claim 1 or any of its isomers or any mixture of its isomers, or their pharmaceutically acceptable salts for the manufacture of pharmaceutical compositions for the treatment or relief of symptoms of the disease, disorder or condition of a mammal, including humans, which are sensitive to inhibition of reuptake monoamine neurotransmitters in the Central nervous system.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention pertains to new hetero-aryl derivatives of 8-azabicyclo-[3.2.1]-octan-3-ol with general formula I where R-R4 represent hetero-aryl. The hetero-aryl is in form of a cyclic aromatic group with C5-C6 or a bicyclic group with C9-C10, which contain 1, 2 or 3 hetero atoms, independently O, S or N, or a residue of , R1-H, C1-C6-akyl, R2 and R3 independently CH3, -OCH3, F, Cl, Br, J, R4 - from 1 to 4 substitutes, -H, halogen, C1-C6alkyl, -CF3, -OCF3, -(CH2)n-OR5, -(CH2)n-NR5R6, -(CH2)n-NHSO2R5, -(CH2)n-NH(CH2)2NR5R6, -(CH2)n-NHC(O)NR5R7, -(CH2)n-NH(CH2)2OR5, or 1-piperazinyl; n - 0, 1, 2, 3; R5 and R6 - H, C1C3alkyl, R7-H, C1-C3alkyl, aminoalkyl C1-C3, or to their pharmaceutical salts. The compounds are antagonists of the nociceptin ORL-1 receptor.

EFFECT: obtaining of compounds that are useful in the treatment of cough.

10 cl, 22 ex, 1 tbl

Novel benzodioxols // 2304580

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzodioxol of the formula (I): wherein R1, R2, R3, R4, R5, R6, R7 and X are given in the description and the invention claim, and to their pharmaceutically acceptable salts. Also, invention relates to pharmaceutical compositions based on compounds of the formula (I) and their using for preparing medicinal agents used in treatment and/or prophylaxis of diseases associated with modulation of CB1 receptors.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

19 cl, 279 ex

The invention relates to therapeutic active usacycling or azabicyclic compounds, method of their preparation and to pharmaceutical compositions comprising these compounds

The invention relates to a derivative (azetidin-1-illlil)lactams of the formula (I) and their pharmaceutically acceptable salts, where R - (C1-C6)-alkyl, optionally substituted by-COOH, -COO((C1-C4)-alkyl), (C3-C7-cycloalkyl, aryl or het1and (C3-C7-cycloalkyl, optionally substituted with 1-2 substituents selected from (C1-C4)-alkyl and fluorine; R1is phenyl, optionally substituted by 1-2 halosubstituted; R2- -CONR3R4, -CONR5((C3-C7-cycloalkyl), -NR3R4that gets3or a group of formula (a), (b), (C); X - (C1-C4-alkylene; X1- directional communication, X2- directional communication or CO; m = 1; used in the treatment of diseases by producing antagonistic action on tachykinin, working in human NK1-, NK2- and NK3the receptor or in their combinations

The invention relates to derivatives of 3-(piperidinyl-1)-chroman-5,7-diol and 1-(4-hydroxyphenyl)-2-(piperidinyl-1)alkanol General formula I or their pharmaceutically acceptable salts accession acid, in which (a) R2and R5taken individually and R1, R2, R3and R4independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7and R5represents methyl; or (b) R2and R5taken together form a ring chroman-4-ol, a R1, R3and R4each independently represent hydrogen, (C1-C6)-alkyl, halogen, HE or or7; R7represents methyl; and R6represents a substituted piperidinyl or 8-azabicyclo[3,2,1]octenidine derived; provided that (a) if R2and R5taken separately, at least one of R1, R2, R3and R4is not hydrogen; and (b) if R2and R5taken together, at least one of R1, R3and R4is not hydrogen, with the property that the NMDA antagonist

FIELD: medicine.

SUBSTANCE: specified acid strengthens an alcohol metabolism and by that prevents adverse consequences from the alcohol use. D-glyceric acid enter simultaneously with alcohol to accelerate elimination of alcohol from an organism. The D-glyceric acid turns in D-glyceride and then to Glycerinum in reactions, catalysed by NADH-aldehyde dehydrogenase complexes which are produced much during ethanol oxidation in the cells of alcohol-metabolising tissues. In these reactions NADH-complexes become NADH-aldehyde dehydrogenased and NADH-alcohol dehydrogenased. These complexes in turn accelerate oxidation of ethanol which occurs in parallel due to intensifying of oxidation of an acetaldehyde to metabolically harmless acetic acid.

EFFECT: increase of alcohol metabolism.

6 cl, 4 dwg, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: agent for prevention and alcoholism treatment contains admixture of amidocyanogen and polylactide in the ratio (wt) from 10:90 till 40:60. The method of prevention and alcoholism treatment consists that to the patient, as a rule, enter intramusculary a solution containing an admixture amidocyanogen and polylactide in a single dose of 0.5-1.5 g once a month.

EFFECT: appreciable effect of delay and slow liberation of the operating beginning.

4 cl, 3 dwg, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: novel derivatives of 4-phenyltetrahydroisoquinolines have total formula I: , in which R1, R2, R3 and R4 independently on each other represent H, F, CI, Br, I, alkyl with 1, 2, 3 or 4 C-atoms; R5 represents H, alkyl with 1, 2, 3 or 4 C-atoms; R6 represents H, alkyl with 1, 2, 3 or 4 C-atoms; R7, R8 and R9 independently on each other represent H, COOR60, -L-G; R60 represents H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; L represents -NR30CO-, -CONR30-, -NR30CONR31-, -NR30COO-; and R30 and R31 independently on each other represent H; G represents groups Ca(OR32)xH2a+1-x, and one or more CH2-groups can be substituted with O; Cb(OR32)yH2b-1-y,and one or more CH2-groups can be substituted with O; CcH2c+1 and two or more CH2- groups can be substituted with O; -(CH2)z-COOR34, where atom of H group -(CH2)z - can be substituted with group OR32; -CR38R39-COOR40, -(CH2)Z-SO3R34; -(CH2)z-N+R35R36R37; -CR38R39NR41R42; a is equal 2, 3, 4, 5 or 6; x is equal 2, 3, 4, or 5 R32 represents H; b is equal 6; y is equal 4; c is equal 5; z is equal 1 or 2; R34, R35, R36 and R37 independently on each other represent H or alkyl with 1, 2, 3, 4, 5 or 6 C-atoms; R38 represents -(CH2)n-Y; n is equal 1 or 3; Y represents H, -COOR44, -CONR45R46, -NHC(NH)NH2, imidazole -4-yl; R44, R45 and R46 independently on each other represent H; R39 represents H; R40 represents H, alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 C-atoms; R41 and R42 independently on each other represent H; and, at least, one of residues of R7, R8 or R9 must represent group -L-G, as well as their pharmaceutically acceptable salts and salts of trifluoroacetic acid. Invention also relates to medication and its application for treatment and prevention of number of diseases.

EFFECT: novel derivatives of 4-phenyltetrahydroisoquinalines, which have inhibiting effect on NHE3.

14 cl, 2 tbl, 47 ex

FIELD: medicine; gastroenterology.

SUBSTANCE: orally appoint administration of thioridazine preparation, in amount of 10-20 mg once a day daily within a month. Perform psychorelaxation therapy according the RESURS method: Relaxation, Suggestion, Operated imagination, Condition Restoration, for achievement of a condition of a psychological relaxation with the help of autologous training with elements of suggestive influence which is remembered and reproduced further by means of use of operated imagination. Thus the suggestive component of influence is directed on strengthening of sensation of slackness, heat and ease in a body, especially in the field of a stomach. Propose the patient to remember relaxation and rest condition, and at the moment of occurrence of the most pleasant sensations to visualise sensation of slackness, associating it with colour in itself. Effect strengthen the suggestive formula directed on storing of sensation of ease and slackness then suggest some time to spend in this condition for storing and fastening of the received sensation and reconstruction of a condition of a relaxation and health to the patient, then to begin an exit from relaxation condition considering to five. Thus psychotherapeutic sessions are spent individually or in small groups in a day. Duration of one session makes 40-50 minutes, a course of 10-12 sessions.

EFFECT: an exception of collateral reactions from application of psychotropic preparations, reduction of pharmacological loading by an organism, strengthening vemicular movements, removal of painful sensation, decrease in level of uneasiness, dream improvement, removal asthenohypochondriac semiology, increase of medical effect, increase in term of remission, considerable reduction of terms of treatment.

2 ex

FIELD: medicine; pharmacology.

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31 cl, 6 dwg, 5 tbl, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition is used for treatment of by-effects and idiphatic syndromes caused by opioids, contains a matrix and a pharmaceutically active substance, and the matrix is executed from ethyl cellulose or polymer on a basis of ethyl cellulose and at least one acyclic spirit; thereat the matrix is diffused and practically not bulking up, and contains naloxone as a pharmaceutically active substance, released from the matrix invariant and prolonged, in amount of 1-50 mg, 5-30 mg preferably, and the most preferably in amount of 5-20 mg.

EFFECT: composition is tolerant at storage.

19 dwg, 16 ex, 2 cl

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition is used for treatment of by-effects and idiphatic syndromes caused by opioids, contains a matrix and a pharmaceutically active substance, and the matrix is executed from ethyl cellulose or polymer on a basis of ethyl cellulose and at least one acyclic spirit; thereat the matrix is diffused and practically not bulking up, and contains naloxone as a pharmaceutically active substance, released from the matrix invariant and prolonged, in amount of 1-50 mg, 5-30 mg preferably, and the most preferably in amount of 5-20 mg.

EFFECT: composition is tolerant at storage.

19 dwg, 16 ex, 2 cl

FIELD: medicine; pharmacology.

SUBSTANCE: pharmaceutical composition contains aripiprazole and in the form of a complex of inclusion with β-cyclodextrin, preferably, sulphonic-propyl carbinol aether of β-cyclodextrin (SBECD). The method of treatment of schizophrenia includes introduction of the specified composition to the patient requiring treatment.

EFFECT: irritation decrease in the place of an intramuscular injection.

18 cl, 6 tbl, 1 ex

FIELD: medicine; pharmacology.

SUBSTANCE: are offered application of Safinamid from 0.5 to 1,2,3,4 or 5 mg/kg/day, in a combination with levodopa/PDI (peripheral antioxidant of decarboxylase: levodopa plus carbidopa (SINEMET®), levodopa plus carbidopa of controlled release (SINEMET-CR®), levodopa plus benserazide (MADOPAR®), levodopa plus benserazide of controlled release (MADOPAR-HBS) for treatment of Parkinson's disease, the corresponding set and the pharmaceutical composition.

EFFECT: additional effect of increase in frequency of revealing of the patients reacting to treatment with dopamine agonist.

8 cl, 2 tbl

FIELD: medicine; pharmacology.

SUBSTANCE: sterile aripiprazole compound for injections with controllable elution in the form of sterile suspension provides aripiprazole release after an injection within at least one week, including: (a) aripiprazole which has the average size of particles approximately from 1 to 10 micron, (b) aripiprazole carrier, and (c) water for injections, and the specified structure for injections contains aripiprazole in amount from approximately 1% to 40% wt in relation to the total amount of the specified sterile compound for injections.

EFFECT: increase of adaptable ability of patients and decrease in frequency of relapses at schizophrenia treatment.

27 cl, 2 tbl, 3 dwg, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: ways of obtaining and pharmaceutical compositions of lipophile association (LA) of ionised pharmaceutical means and one or several lipophile substances are described. LA is in a liquid condition at a room temperature or soluble in solvent with smaller, than at water, dielectric permeability, in the form of solution LA at a room temperature. Solvent, preferably, ethanol, dimethyl carbinol spirit, isopropyl myristate, isopropyl palmitate or glyceride is, LA can be adsorbed or absorbed on the carrier. The carrier is preferably silicified microcrystalline cellulose and-or silicon dioxide. Pharmaceutical means is preferably represented by nicotine.

EFFECT: fast liberation of pharmaceutical means at contact to water at pH, close to physiological and its subsequent delivery in the big circle of blood circulation.

31 cl, 6 dwg, 5 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: described is device for transcutaneous introduction of nicotine, which ensures basic as well as additional introduction of nicotine activated by user. Invention also describes device for combined basic and additional transcutaneous delivery of nicotine activated by user ensuring different rates of nicotine delivery to individual.

EFFECT: increase in means efficiency.

13 cl, 6 dwg, 3 tbl, 6 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to pharmaceutical composition for treatment of disease, condition or disturbance requiring application of the antagonist of the neurokinin receptor containing therapeutically effective quantity of compound of the formula I or its pharmaceutically acceptable salt where the composition contains sulphopropyl ether of β-cyclodextrin, meta-cresol preservative and pharmaceutically acceptable medium. Also, the invention refers to application of the said composition and a method for treatment way of diseases requiring application of the antagonist of the neurokinin receptor.

EFFECT: maintenance of stability of a compounding and acceptable tolerance in the place of the product injection when using preservative for prevention of bacteriemic and fungoid growth in a compounding.

11 cl, 4 dwg, 9 tbl, 4 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention concerns medicine inhalation composition including antiholynergic substance of the formula 1 where X- is single-charged anion, as well as corticosteroid and betamimetic. Additionally, the invention concerns application of the claimed medicine composition in treatment of inflammatarory and/or obstructive respiratory diseases.

EFFECT: positive therapeutic and synergetic effect.

25 cl, 3 dwg, 5 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: premedication by suprastin is performed in the dose of 0.25 mg/kg, in 15 minutes before anesthetic induction intravenous injection of 6-7.5 ml/kg of plasmalyte solution. Anesthesis induction is performed with 0.013 mg/kg of atropine and 1.33 mcg/kg of fentanil, then 2.5-3 mg/kg of propofol followed by 0.6 mg/kg of atracurium is injected. In 2 minutes after achievement of adequate mioplegia laryngoscopy and trachea intubation are performed. Anesthesia is sustained by low-flow anesthesia based on sevoflurane with minimum alveolar concentration of 1.2-0.6 in air and oxygen mix flow of 1.2-1.4 l/min via half-closed circuit in the IPPV mode, with tidal volume (TV)=7-8 ml/kg and minute tidal volume (MTV)=78-85 ml/kg, FiO2=40% under control of SpO2 and EtCO2. During anesthesia mioplegia is sustained by infusion of 0.36 mg/kg/hour of atracurium. If the operation should involve collapsed lung expansion, then sevoflurane feed is stopped at the moment of toracal drainage installation, in 8-10 min before the expansion, and fresh air and oxygen mix feed reaches 1.2-1.4 l/min in half-closed circuit with FiO2=40% with previous breath parametres. In 2 minutes before the collapse lung expansion anesthesia is deepened by injection of 1.25-1.5 mcg/kg of fentanil. If the operation is performed for a patient with complicated spine trauma, additionally 30 dose units of ingitryl is applied.

EFFECT: reduced surgical stress for patient and prevention of stress-induced response to surgical aggression.

1 ex, 3 cl

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