Derivatives of n-heterocyclylmethylmenzamides, obtainment and application in therapy

FIELD: chemistry.

SUBSTANCE: invention claims compound of the general formula (I) , where R is hydrogen atom or vinyl group; n is 1, X is a group of the formula CH or nitrogen atom, R1 is either phenyl or naphthyl group, or cyclohexyl group, or heteroaryl group, R2 is either hydrogen atom or one or more substitutes selected out of halogen atoms and trifluoromethyl, alkyl, alkoxyl phenyloxy, hydroxyl groups or group of the general formula -NR4R5, SO2NR4R5, or group of the formula -OCF2O-, each of R4 and R5 groups is hydrogen atom or alkyl group; and method of obtaining compound of the general formula (I), medicine, pharmaceutical composition. Compounds display special effect as specific inhibitors of glycine GlyT1 and/or GlyT2 transmitters and thus are applied in treatment of various diseases.

EFFECT: obtaining compounds with high specific inhibition effect.

13 cl, 2 tbl, 5 ex

 

The object of the present invention are derivatives of N-getprocessimagefilenamew, obtaining them and their use in therapy.

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

in which

R denotes a hydrogen atom or a vinyl group;

n denotes 0 or 1 or 2, if R denotes a hydrogen atom and n denotes 1, if R denotes the vinyl group;

X denotes a group of the formula CH or a nitrogen atom, if R denotes a hydrogen atom, and X denotes a group of the formula CH, where R denotes the vinyl group;

R1means or phenyl or naftalina group, possibly substituted by one or more substituents selected from halogen atoms, groups (C1-C6)-alkyl, hydroxy and (C1-C6)-CNS, straight or branched, triptorelin group or tsiklogeksilnogo group, or heteroaryl group selected from the groups tanila, pyridinyl, oxazolyl, furanyl, thiazolyl, chinoline and ethanolamine;

R2denotes either a hydrogen atom, or one or more substituents selected from halogen atoms and groups triptoreline, (C1-C6)-alkyl, (C1-C6)-CNS, thienyl, phenyloxy, hydroxy, mercapto, thio(C1-C6)-alkyl, cyano or the group total is ormula-NR 4R5, SO2NR4R5, -SO2-(C1-C6)-alkyl, -SO2-phenyl, -CONR4R5, -COOR7, -CO-(C1-C6)-alkyl, -CO - phenyl, -NHCOR8, -NHSO2-(C1-C6)-alkyl, -NHSO2-phenyl, and-NHSO2NR4R5or a group of the formula-OCF2O-related provisions 2 and 3 phenyl groups;

thus groups (1-C6)-alkyl, (C1-C6)-CNS, -SO2-(C1-C6)-alkyl, -CO-(C1-C6)-alkyl and-NHSO2-(C1-C6)-alkyl possibly substituted by one or more groups R3;

group, phenyl, -SO2-phenyl, -CO-phenyl and-NHSO2-phenyl possibly substituted by a group R6;

R3denotes a halogen atom, a phenyl group, (C1-C6)-CNS, -NR4R5;

R4and R5independently from each other represent a hydrogen atom or (C1-C6)-alkyl group, or R4and R5form together with the nitrogen atom to which they relate, pyrolidine cycle, piperidinyl cycle or morpholinyl cycle;

R6denotes a hydrogen atom, halogen atom, triptorelin group, cyano group, hydroxy, mercapto, (C1-C6)-alkyl or (C1-C6)-CNS,

R7denotes a hydrogen atom or (C1-C6)-and kilou group, possibly substituted by one or more groups R3or phenyl group, possibly substituted by a group R6;

R8means (C1-C6)-alkyl group, possibly substituted by one or more groups R3or (C1-C6)-CNS group, or phenyl group, possibly substituted by a group R6.

Of the compounds of General formula (I) allocate a number of subgroups preferred compounds are:

Group 1: connection configuration tree and the General formula (I)in which n denotes 0 or 1;

Group 2: compounds of group 1, in the formula of which X denotes a group of the formula CH;

Group 3: compounds of group 2, in the formula where R represents a hydrogen atom;

Group 4: compounds of group 3, in the formula which n denotes 1;

Group 5: compounds of group 4, in the formula where R1indicates a possibly substituted phenyl group.

The compounds of formula (I) can contain one or more asymmetric centers. Thus, they can be in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as mixtures thereof, including racemic mixtures, belong to the invention. More specifically, the compounds of formula (I)in which R=H, can be in the form of diastereoisomeric Treo ((1S, 2S) and (1R,2R)or Erythro ((1S, 2S) and (1R,2R)), or pure enantiomers, or a mixture of such isomers.

With the unification of the formula (I) can be in the form of bases or of salts of joining with acids. Such salts are joining with acids belong to the invention.

These salts are mainly obtained using pharmaceutically acceptable acids but the salts of other acids used, for example, for cleaning or preparing compounds of formula (I), also belong to the invention. The compounds of formula (I) may also be in the form of a hydrate or of a solvate, namely in the form of associations or combinations with one or more water molecules or with a solvent. Such a hydrate and a solvate also belong to the invention.

Compounds according to the invention have a special activity as specific inhibitors of vectors glycine glyt 1 and/or glyt 2.

The compounds of formula (I) can be obtained by the method shown in the following scheme 1.

Scheme 1

According to the scheme 1 lead in the interaction of the diamine of General formula (II)in which n, X, R and R1those who defined above, and the activated acid or acid chloride of General formula (III)in which Y represents a nucleofuge group, such as halogen atom, and R2the same as defined above, using methods known to the expert.

The diamines of General formula (II)in which R=H and n, X and R1the same as those defined above, can be obtained by the method shown in the following scheme 2.

Scheme 2

Lead interaction ketone of General formula (IV)in which n, X and R1those who defined above, and benzyloxyacetaldehyde at the boiling point of pyridine under reflux and get the oxime of General formula (IV).

Both forms of Z and E of the oxime can be divided well-known specialist techniques, such as chromatography on a column of silica gel.

The oxime (V) is preferably in the form Z hydrochloride, then restore at the temperature of boiling tetrahydrofuran under reflux with double aluminum hydride and lithium to obtain a diamine of the General formula (II), the main tree.

By restoring the shape E of the oxime of General formula (V) receive a mixture of diamine (II) in the form of two diastereoisomers (threo/Erythro).

Diastereoisomer threo and Erythro can be divided well-known specialist techniques, such as chromatography on a column of silica gel.

Another option for obtaining diamines of General formula (II)in which R and R1those who defined above, n is 1 and X denotes CH, shown in the following scheme 3.

Scheme 3

Alcohols of General formula (VI) is converted into amines by Mitsunobu reaction according to the method described in Bull. Soc. Chim. Belg. (106), 1997, 77-84 and in Tetrahedron: Asymmetry, (6), 1995, 1699-1702.

In addition, chiral compounds of General formula (I), corresponding enantio the frames (1R,2R) or (1S,2S) diastereoisomer Treo and enantiomers (1R,2R) or (1S,2S) diastereoisomer eritro, you can also get any separation of racemic compounds by high-performance liquid chromatography (HPLC) on a chiral column, or from a chiral amine, obtained or splitting of racemic amine of General formula (II) using a chiral acid, such as tartaric acid, Camphorosma acid, dibenzoyltartaric acid, N-acetylleucine by fractional recrystallization and preferably salts diastereoisomer in solution type of alcohol, or enantioselective synthesis of chiral Erythro or threo-alcohol using a method similar to those shown in scheme 3. Chiral alcohols can be obtained by a method similar to that described in Tetrahedron (55), 1999, 2795-2810). If R denotes the vinyl group, and R1means hinkleyville group, the diamine of General formula (II) can be obtained according to scheme 3, using the appropriate commercial chiral alcohols.

Racemic ketone of General formula (IV) can be obtained either by deprotonation of the activated complex cyclic United bridging communication amines and interaction with the electrophile, such as an ester or amide Weinrebe according to the method similar to that described in Chem.Commun., 1999, 1927-1928, or interaction organometallics connection with complex ethyl ester 2-hinokitiol acid according to the method similar to the op is sliding in J.Med.Chem., 1980, 180-184, or by oxidation of the corresponding alcohol obtained in various ways, similar to that described in J.Org.Chem., 50, 1985, 29-31 and Chem.Comm., 1999, 1927-1929, oxidants known to the specialist, such as dioxide, magnesium or system oxalicacid-sulfoxide.

Alcohols of General formula (VI) can also be obtained by recovering the corresponding ketones of General formula (IV) under conditions known to the expert.

Acid chlorides of General formula (III) are commercially available or obtained by methods analogous to those known to the expert.

For example, 4-amino-3-chloro-5-triftorperasin acid can be obtained by chlorination of 4-amino-5-triftormetilfosfinov acid with sulfurylchloride in chlorinated solution, such as chloroform, in a way similar to that described in Arzeim.Forsch., 34, 11a, (1984), 1668-1679.

2,6-dichloro-3-triftorperasin acid can be obtained by methods similar to those described in US3 823 134.

Benzoic acid, which is derived from sulfonamides, can be obtained by methods similar to those described in the patents DE-2436263, BE-620741, DE-1158957, US-3112337, GB-915259, US-3203987, DE-642758, EP-68700, FR-2396757, DE-2734270 and J.Pharm.Pharmacol. (1962), 14, 679-685.

Metaconsultancy acid can be obtained by a method similar to that described in J.Chem.Soc.(C), (1968), 13, and in patents US-2273444, DE-19929076, EP-0556674.

Chlorosulfonylisocyanate in the position ortho or para whom you can spend based on diazonium salts by the way, similar to that described in the patent US-3663615 using 4-amino-3-chlorbenzoyl acid.

Sulfonamides get interaction chlorosulfonic derivatives in the presence of excess amine in a solvent such as tetrahydrofuran, at room temperature or at the boiling temperature under reflux.

Secondary sulfonamides can be metilirovanie manner similar to that described in the patent VE-620741.

Primary sulfonamides can result in interaction with the isocyanate in the solution, such as tetrahydrofuran, in the presence of such a base as potassium carbonate.

Some sulfoxide derivatives of benzoic acids described in the patents DE-2056912, DE-2901170 and DE-3953476 or they can be obtained by methods similar to those described in patent BE-872585 and in J.Org.Chem. (1991), 56(1), 4976-4977.

Derivatives of benzoic acids of General formula (III)in which R2denotes a branched alkyl group, can be obtained by methods similar to those described in patent US-4879426 Syn.Lett.(1996), 473-474 and J.Med.Chem.(2001), 44, 1085-1098.

Derivatives of benzoic acid biphenylenes type can be obtained by methods known to the expert.

Finally, carbonyliron benzoic acid can be synthesized by methods similar to those described in patents US-3725417 and GB-913100 and Chem.Pharm.Bull., (1988), 36(9), 3462-3467 and J.Labelled Comp.Radiopharm., (1997), 39(6), 501-508.

Esters or as the IDA can be administered by direct carbonylation strong Foundation in the para-position of the acid conditions, described in Tetrahedron Lett., (2000), 41, 3157-3160.

Finally, cyanoderivatives benzoic acid type, biphenyl is obtained by heating the acid or halogenated complex benzoic ester in the presence of potassium cyanide, catalyst type palladium tetranitroaniline in solvent type tetrahydrofuran by the method similar to that described in J.Org.Chem. (1967) 62, 25, 8634-8639.

Other acids and acid chlorides of General formula (III) can be obtained by methods similar to those described in patents EP-0556672, US-3801636 and in J.Chem.Soc., (1927), 25, Chem.Pharm.Bull., (1992), 1789-1792, Aust.J.Chem., (1984), 1938-1950 and J.O.C., (1980), 527.

The following examples illustrate the production of several compounds according to the invention. Elemental microanalysis and I.R. spectra and NMR and HPLC on a chiral column confirm the enantiomeric structure and purity of the compounds obtained.

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

In the names of compounds hyphen "-" is part of the word and the hyphen "_" is used for reduction at the end of the line, if no reduction, it should not be a substitute for the usual hyphen or a space.

Example 1(Compound No. 3)

Threo-2-chloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-triftormetilfullerenov 1:1

1.1.(Z)-1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methanon 0-benzyloxyaniline is.

Into a flask of 100 ml equipped with a magnetic stir bar, enter 2.2 g (a 9.35 mmol) of 1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methanone (Chem.Commun., 1999, 1927-1928) and 3 g (18,69 mmol) benzyloxycarbonylglycine in 50 ml of pyridine and heat the mixture under reflux for 20 hours.

After evaporation of the solvents under reduced pressure, the residue diluted with water and chloroform, separating the aqueous phase and extracted with chloroform. Washed the combined organic phases are dried on sodium sulfate and the solvent is evaporated under reduced pressure, then the residue purified by chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol.

Obtain 0.5 g of a fraction, the corresponding (E)-1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methanon 0-benzyloxy and 2.25 g of another faction, the corresponding (Z)-1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methanon 0-benzyloxypyrrolidine

The melting point 195-197°C.

Tio-[1-azabicyclo[2.2.2.]Oct-2-yl(phenyl)methyl]amine

In a three-neck flask with a volume of 250 ml, equipped with a magnetic stirrer, under nitrogen atmosphere injected 1.3 g (34,32 mmole) double hydride of aluminium and lithium, suspended in 10 ml of tetrahydrofuran, add portions of 2.2 g (6,16 mmol) of (Z)-1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methanon 0-benzyloxypyrrolidine and heated under reflux for 2 hours.

After cooling, the solution is subjected guide is oliso at 0° With using sequentially 1.3 ml of water, then 1.3 ml of 15%aqueous sodium hydroxide solution and 3.9 ml of water. Filter heterogeneous mixture on celite®concentrate the filtrate under reduced pressure, then the residue was diluted with 1N-sulfuric acid and chloroform. Separate the organic phase and the aqueous phase is alkalinized with ammonia. Twice extracted with chloroform. The combined organic phases are washed, dried on sodium sulfate and the solvent is evaporated under reduced pressure and earn 1.25 g Treo-[1-azabicyclo[2.2.2.]Oct-2-yl(phenyl)methyl]amine in the form of oil, which crystallized and used as such in the next stage.

Melting point: 120-140°C.

Tio-2-chloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-triftormetilfullerenov 1:1

Into a flask of 100 ml equipped with a magnetic stir bar, enter 0.51 g (2,12 mmol) of the chloride of 2-chloro-3-triftorperasin acid in solution in 5 ml of chloroform in the presence of 0.29 g (2,12 mmol) of potassium carbonate at 0°and pour in a solution of 0.42 g (1,93 mmol) threo-[1-azabicyclo[2.2.2.]Oct-2-yl(phenyl)methyl]amine in solution in 5 ml of chloroform and the mixture is shaken for 6 hours at room temperature.

Carry out the hydrolysis with water, diluted with chloroform, then separated from the aqueous phase and extracted with her chloroform. Washed the combined organic phases are dried on sodium sulfate and the solvent is evaporated under reduced pressure, then the resulting residue is purified by chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol.

Obtain 0.18 g of oily product.

The latter is dissolved in a few ml of propan-2-ol, add 6 ml of a solution of 0.1 G. of hydrochloric acid in propan-2-OLE and concentrate the mixture under reduced pressure to reduce the volume of the solvent. After grinding obtain 0.15 g of the hydrochloride in the form of solids.

Melting point: 257-262°C.

Example 2(Compound No. 4)

Tree-2,6-dichloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-triftormetilfullerenov 1:1

Into a flask of 100 ml equipped with a magnetic stir bar, enter 0.36 g (1.38 mmol) of 2,6-dichloro-3-triftorperasin acid, 0.187 g (1.38 mmol) of hydroxybenzotriazole, 0,264 g (1.38 mmol) of 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide in solution in 5 ml of chloroform and stirred at room temperature overnight.

Carry out the hydrolysis with water, diluted with chloroform, then separated from the aqueous phase and extracted with her chloroform. Washed the combined organic phases are dried on sodium sulfate and the solvent is evaporated under reduced pressure, then the residue purified by chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol.

Get 0,37 g of oily product.

The latter is dissolved in not is how many ml of propan-2-ol, add 20 ml of a solution of 0.1 G. of hydrochloric acid in propan-2-OLE and concentrate the mixture under reduced pressure to reduce the volume of the solvent. After grinding obtain 0.35 g of the hydrochloride in the form of solids.

Melting point: 270-273°C.

Example 3(Compound No. 14)

2-chloro-N-(8α9S-Cinchona-9-yl)-3-triftormetilfullerenov 2:1

3.1. 8α9S-Cinchona-9-amine

In a three-neck flask with a volume of 100 ml, equipped with a magnetic stirrer, under nitrogen atmosphere enter 0.74 g (2.5 mmol) of 8α9S-Cinchona-9-ol (cinchonidine) and 0.79 g (3 mmole) of triphenylphosphine, suspended in 15 ml of tetrahydrofuran, and added 3.5 ml of a solution of 0.9 M acid hydrazoique in benzene (3 mmole). This solution is injected dropwise a solution of 0.55 ml (2,75 mmol) diisopropylcarbodiimide in 1.5 ml of tetrahydrofuran and heated to 40°C for 16 hours.

Add 0.65 g (2.5 mmol) of triphenylphosphine and shaken for 30 min, injected with 0.5 ml of water and shaken for 6 hours.

Carry out the hydrolysis with 1 N. hydrochloric acid and diluted with chloroform. The aqueous phase is alkalinized with ammonia and extracted several times its chloroform. Washed the combined organic phases are dried on sodium sulfate and the solvent is evaporated under reduced pressure to obtain 0.97 g of an orange oil containing 8α9S-Cinchona-9-amine, which was used without education is ODI at the next stage.

3.2. 2-chloro-N-(8α9S-Cinchona-9-yl)-3-triftormetilfullerenov 2:1

The method described in example 1.3, using as starting substances 0.97 g (3.3 mmol) of 8α9S-Cinchona-9-amine, 0.84 g (3.4 mmol) of 2-chloro-3-triftorperasin acid and 0.5 g (3.63 mmol) of potassium carbonate, get 0,360 g of oil which was dissolved in 30 ml of 1 N. hydrochloric acid. The aqueous phase is extracted with chloroform, and then the solvent is evaporated under reduced pressure. Thus obtain 0.26 g of the hydrochloride as a white solid.

Melting point: 185-205°; [αD25=-5,4 (c=0,986, Meon).

Example 4(Compound No. 17)

2,6-dichloro-N-[(1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamidophenyl 1:1

4.1 (1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methyl]amine D-tartrate

Dissolving 9.4 g (43,45 mmol) threo-[1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methyl]amine in 150 ml of ethanol. Pour in a solution of 6.52 g (43,45 mmol) of D-tartaric acid in solution in 200 ml of ethanol. After evaporation of the solvent under reduced pressure the residue is introduced into 500 ml of a solution of ethanol and water (9/1), then heated to dissolution. After 3 consecutive precrystallization get of 5.39 g of (1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methyl]amine D-tartrate.

Melting point: 125-135 mA°C;

D25=-46,1 (c=0,616, Meon).

4.2. 2,6-dichloro-N-[(1S)-[(2S)(1-Aza-bicyclo[2.22]Oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamidophenyl 1:1

In a flask with a volume of 100 ml, equipped with a magnetic stirrer, enter 3.33 g (12,02 mmol) chloride 2,6-dichloro-3-(trifluoromethyl)benzoic acid in solution in 30 ml of chloroform in the presence 1,82 g (13,22 mmol) of potassium carbonate at 0°and pour in a solution of 2.6 g (12,02 mmol) of (1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methyl]amine (obtained by alkalizing salts described in 4.1, with subsequent extraction) in solution in 40 ml of chloroform and shake the mixture at room temperature for 6 hours.

Carry out the hydrolysis with water, diluted with chloroform, then separated from the aqueous phase and extracted with her chloroform. Washed the combined organic phases are dried on sodium sulfate and the solvent is evaporated under reduced pressure, then the residue purified by chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol.

Gain of 5.4 g of oily product.

The latter is dissolved in a few ml of chloroform, add 600 ml of simple ether saturated with hydrochloric acid, and concentrating the mixture under reduced pressure. The remainder will recrystallized in ethyl acetate. Thus obtain 4.7 g of 2,6-dichloro-N-[(1S)-[(2S)(1-Aza-bicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamidopiperidine.

Melting point: 264-268°C;

D25=+61,1° (c=0,32, Meon).

Example 5(Connect the tion No. 26)

Threo-N-[(1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methyl]-2,6-dichloro-3-(trifluoromethyl)benzamidophenyl 1:1.

5.1 1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methanol

In a three-neck flask with a volume of 100 ml in the atmosphere of argon is injected to 1.11 g (10 mmol) of hinoklidina in 40 ml of dry tetrahydrofuran at 0°C. Enter dropwise to 1.33 ml (10.5 mmol) of complex simple ether-boron TRIFLUORIDE and shaken at 0°C for 30 minutes (solution A). In parallel in the three-neck flask with a volume of 250 ml in the atmosphere of argon injected 2,47 g (22 mmol) of dry tertiobutyl potassium in 60 ml of dry tetragidrofurana. Cooled to -70°and poured dropwise 22 ml of a 1M solution of second-utility in a mixture of cyclohexane/hexane (22 mmol), keeping the temperature below -60°With (solution B). After the introduction of the solution And injected into the solution, while maintaining a temperature of about -70°C. Stirred for 2 hours.

In a three-neck flask objelem 50 ml in an atmosphere of argon is injected at 2.36 ml (22 mmol) of distilled 4-forventelige in solution in 20 ml of tetrahydrofuran at -70°C. the Solution is injected while maintaining a temperature of about -70°C. the resulting solution was left for 30 min at -70°C, then the temperature is raised to -20°C. followed by hydrolysis using a solution of 10%hydrochloric acid. Extracted with simple ether, then the aqueous phase obrabatyvati alkalinized with ammonia. Ekstragiruyut chloroform, and then the solvent is evaporated under reduced pressure. The residue is purified flash chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol. So get of 0.53 g of 1-azabicyclo[2.2.2]Oct-2-yl(forfinal)methanol in the form of a yellowish solid.

Melting point: 69-70°C.

5.2 1-azabicyclo[2.2.2]Oct-2-yl(forfinal)metano

In a three-neck flask with a volume of 250 ml in a nitrogen atmosphere injected 1.3 ml of dimethyl sulfoxide in 40 ml of tetrahydrofuran at -70°add dropwise 0.9 ml oxalicacid (11 mmol) and stirred for 30 min at this temperature. Injected dropwise a solution of 1 g (4.6 mmol) of 1-azabicyclo[2.2.2]Oct-2-yl(forfinal)methanol in 40 ml of tetrahydrofuran. After 30 min injected 4 ml (27.6 mmol) of triethylamine at -70°C. the Reaction mixture was then shaken at -70°C for 30 minutes, at 0°C for 30 minutes, then for 1 hour at room temperature.

A mixture of tilt in the ammonia solution, and then extracted several times with chloroform. The organic phase is dried on sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel, elwira with a mixture of chloroform and methanol. Thus get 1 g of 1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methanone.

Melting point: 68-69°C.

5.3. (Z)-1-azabicyclo[2.2.2]Oct-yl(4-f is arvanil)methanon 0-benzyloxyaniline.

According to the method described in example 1.1, from of 1.17 g (5 mmol) of ketone obtain 1.4 g (Z)-1-azabicyclo[2.2.2]Oct-yl(4-forfinal)methanon 0-benzyloxypyrrolidine after grinding in a simple ether residue obtained after the reaction processing.

Melting point: 202-203°C.

5.4 Trio 1-azabicyclo[2.2.2]Oct-yl(4-forfinal)methanamine.

According to the method described in example 1.2 of 1.47 g (of 4.54 mmol) of (Z)-1-azabicyclo[2.2.2]Oct-yl(4-forfinal)methanon 0-benzyloxypyrrolidine receive 1 g of 1-azabicyclo[2.2.2]Oct-yl(4-forfinal)methanamine Treo (excess diastereoisomer, de=90%).

5.5 N-[(S)-(2S)(1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methyl]-2,6-dichloro-3-(trifluoromethyl)benzamidophenyl 1:1

According to the method described in example 1.3, from 0.39 g (of 1.66 mmol) tree 1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methanamine, 0.5 g (1,83 mmol) chloride 2,6-dichloro-3-triftorperasin acid, 0.25 g (1,83 mmol) of potassium carbonate, obtained after purification by chromatography 0,79 g trio N-[1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methyl]-2,6-dichloro-3-(trifluoromethyl)benzamide in the form of oil that turned into salt with a solution of gaseous hydrochloric acid in a simple ethyl ether.

Melting point: 290-291°C.

Other compounds get by the methods described in examples 1, 2 and 5 of their other functionalized aldehydes.

In the following table 1 shows the chemical structures of several connect the deposits according to the invention.

In column "R", CH-CH2denotes the vinyl group in the column "R1" C6H5denotes a phenyl group and 4-C9H6N denotes the group chinolin-4-yl. In the column "salt" denotes a compound in the ground state, "HCL" denotes a hydrochloride and "tfa" refers to triptorelin.

Compounds 14, 19-23, 24, presented in table are in the form of hydrochloride or dichlorhydrate (see table), solvated by one or more water molecules.

Compounds 15 and 16 in the table represent a pair of enantiomers, which are separated by preparative HPLC using a column CHIRALCEL® AD 20 μm, and the solvent is a mixture of isohexane/propan-2-ol 95/5, also relates to compounds 17 and 18.

Table 2 shows the physical properties melting point and rotation capabilities compounds represented at the table, "(d)" refers to melting point with decomposition.

Table 1
No.R1RXnR2SolStereochemistry
1With6H5NSN13-SO2N(CH3 )2,4-Cl-Treo (1R,2R;1S,2S)
2With6H5NSN12-Cl,5-CF3HClTreo (1R,2R;1S,2S)
3With6H5NSN12-Cl,3-CF3HClTreo (1R,2R;1S,2S)
4With6H5NSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
5With6H5NSN12-Cl,3-CF3,6-FHClTreo (1R,2R;1S,2S)
6With6H5NSN12-Cl,3-CH3HClTreo (1R,2R;1S,2S)
7With6H5NSN12,4,6-(Cl)3HClTreo (1R,2R;1S,2S)
8With6H5NSN12-Cl,3-CF3HClTreo (1R,2R;1S,2S)
9With6H5N 12,6-(Cl)2HClTreo (1R,2R;1S,2S)
10With6H5NSN12,5-(CF)2HClTreo (1R,2R;1S,2S)
11With6H5NSN12-F, 3-Cl, 6-CF3HClTreo (1R,2R;1S,2S)

No.R1RXnR2SolStereochemistry
12With6H5NSN12-CH3, 3-ClHClTreo (1R,2R;1S,2S)
13With6H5CH=CH2SN12,3-(Cl)2HClTreo (1R,2R;1S,2S)
144-C9H6NNSN12-Cl,3-CF32HCl(1S,2S)
15With6H5NSN12-Cl,3-CF3tfa(1R,2R)
16 With6H5NSN12-Cl,3-CF3tfa(1S,2S)
17With6H5NSN12,6-(Cl)2,3-CF3HCl(1S,2S)
18With6H5NSN12,6-(Cl)2,3-CF3HCl(1R,2R)
19With6H5NN12-Cl,3-CF32HClTreo (1R,2R;1S,2S)
20With6H5NN12,6-(Cl)2,3-CF32HClTreo (1R,2R;1S,2S)
21With6H5NN12,6-(Cl)22HClTreo (1R,2R;1S,2S)
22With6H5NN12-CH3, 3-CF32HClTreo (1R,2R;1S,2S)
23With6H5NN12-CH3, 3-Cl2HClTreo (1R,2R;1S,2S)
24With6H5NSN13,5(Cl)2,4-NH2HClTreo (1R,2R;1S,2S)
254-F-C6H4NSN12-Cl,3-CF3HClTreo (1R,2R;1S,2S)
264-F-C6H4NSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
271-naphtyleNSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
281-naphtyleNSN12-Cl,3-CF3HClTreo (1R,2R;1S,2S)
291-naphtyleNSN12-CH3, 3-ClHClTreo (1R,2R;1S,2S)
302-CH3-C6H4NSN12-Cl,3-CF3HClTreo (1R,2R;1S,2S)
312-CH3-C6H4NSN12,6-(Cl)2, 3-CF3HClTreo (1R,2R;1S,2S)

3-F-C6H4
No.R1RXnR2SolStereochemistry
32With6H5NSN16-CH3,3-Cl,2-NH2HClTreo (1R,2R;1S,2S)
33With6H5NSN13,6-(Cl)2,2-NH2HClTreo (1R,2R;1S,2S)
34With6H5NSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
35With6H5NSN12-CH3, 3-ClHCl(1S,2S)
36With6H5NSN12-Cl, 3-CF3HClerythro (1S,2R,1R,2S)
374-F-C6H4NSN12-CH3, 3-ClHClthreo/erythro: 9/1
38NSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
393-F-C6H4NSN12,6-(Cl)2,3-CF3HClerythro (1S,2R,1R,2S)
404-F,3-CH3-C6H3NSN12-CH3,3-OCH3HClthreo/erythro: 1/1
414-F,3-CH3-C6H3NSN13,5-(OCH3)2HClthreo/erythro: 1/1
424-F,3-CH3-C6H3NSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
433-F-C6H4NSN12-CH3,3-OCH3HClTreo (1R,2R;1S,2S)
44With6H5NSN12-OCH3,5-ClHCl(1S,2S)
45With6H5NCH/td> 12-Br,5-OCH3HCl(1S,2S)
46With6H5NSN12,3-(OCF2O)HCl(1S,2S)
47With6H5NSN12,6-(OCH3)2HCl(1S,2S)
48With6H5NSN13,5-(OCH3)2HCl(1S,2S)
49With6H5NSN12,3-(OCH3)2HCl(1S,2S)
50With6H5NSN12-NH2,3-CH3HCl(1S,2S)
51With6H5NSN12-OCH3,3,6-(Cl)2HCl(1S,2S)
52With6H5NSN13-(O-C6H5)HCl(1S,2S)

R1
No.RXnR2SolStereochemistry
53With6H5NSN12,5-(OCH3)2HCl(1S,2S)
54With6H5NSN12-CH3,3-OCH3HCl(1S,2S)
55With6H5NSN12-OCH3,3,5-(Cl)2HCl(1S,2S)
56With6H5NSN12-Cl,6-CH3HCl(1S,2S)
57With6H5NSN12-NH2,6-CH32HCl(1S,2S)
58With6H5NSN12-NH2,5-Br2HCl(1S,2S)
59With6H5NSN12-NH2,5-CH32HCl(1S,2S)
60the 6H5NSN12-OCH3,3-CH3HCl(1S,2S)
61With6H5NSN12-NH2A 5-OCH32HCl(1S,2S)
62With6H5NSN12-NH2,3-OCH32HCl(1S,2S)
63With6H5NSN12-Cl, 5-CH3HCl(1S,2S)
64With6H5NSN12-OCH3,5-CH3HCl(1S,2S)
65With6H5NSN12-CH3, 3-OHHCl(1S,2S)
66With6H5NSN12-CH3,5-ClHCl(1S,2S)
674-OCH3-C6H4NSN12,6-(Cl)2,3-CF3HClTreo (1R,2R;1S,2S)
684-OH-C6H4NSN12,6-(Cl)2,3-CF3-Treo (1R,2R;1S,2S)
693-F-C6H4NSN12-CH3,3-ClHClTreo (1R,2R;1S,2S)

37
Table 2
No.F (°C)[α]25(°)
1233-235-
2267-269-
3257-262-
4270-273-
5315-316-
6319-320-
7>300-
8281-283-
9359-361-
10281-283-
11347-349-
12311-313-
13316-318-
14185-205-5,4 (c=0,986; MeOH)
15196-197 -51,3 (c=1,03; MeOH)
16214-215+48,2 (c=0,618; MeOH)
17264-268°C+61,1 (c=0,32; MeOH)
18265-268-58,9 (c=0,3; MeOH)
19207-208-
20214-215-
21210-211-
22215-217-
23210-212-
24336-339-
25271-273-
26290-291-
27317-318-
28314-315-
29315-316-
30215-230-
31210-220-
No.F (°C)[α]25(°)
32238-330-
33275-330
34338-344
35295-300+55,2 (c=0,3; MeOH)
36287-291
>300
38232-234
39289-291
40124-126
41154-156
42254-256
43280-282
44162-164+87,4 (c=0,32; MeOH)
45275-277+43,8 (c=0,32; MeOH)
46191-193+42,4 (c=0,32; MeOH)
47234-236+53,2 (c=0,30; MeOH)
48297-299+21,3 (c=0,31; MeOH)
49284-286+68,6 (c=0,32; MeOH)
50244-246+41,1 (c=0,30; MeOH)
51194-196+73,9 (c=0,29; MeOH)
52105-108+26,7 (c=0,30; MeOH)
53169-171+82,3 (c=0,30; MeOH)
54298-300+46,6 (c=0,31; MeOH)
55213-215+75,9 (c=0,30; MeOH)
56331-333+67,9 (c=0,31; MeOH)
57295-297+79,4 (c=0,30; MeOH)
58 244-246+16,1 (c=0,30; MeOH)
59282-284+26,4 (c=0,31; MeOH)
60235-237+116,6 (c=0,29; MeOH)
61278-280+14,2 (c=0,30; MeOH)
62264-266+40,5 (c=0,30; MeOH)
63128-130+61,9 (c=0,32; MeOH)
64185-187+81,9 (c=0,30; MeOH)
No.F (°C)[α]25(°)
65329-331+45,9 (c=0,29; MeOH)
66242-244+8,4 (c=0,31; MeOH)
67284-286-
68-
69291-293-

Compounds according to the invention was subjected to a series of pharmacological studies that have shown that they are of interest as substances with therapeutic effect.

Study of transport of glycine in cells SK-N-MC with the expression of native human carrier of glyt1.

The capture of [14C]glycine was investigated in cells SK-N-MC (neuroepithelial cells), expression of native human vector glyt 1 by measuring incorporated radioactive the th substance in the presence or in the absence of the test compound. Cells were cultured in monolayer for 48 hours in tablets, pre-treated with 0.02% fibronectin. On the day of the experiment, culture medium was removed and cells were washed with buffer solution of Krebs-HEPES ([4-(2-hydroxyethyl)piperazine-1-econsultancy acid) with a pH of 7.4. After 10 min from the beginning of pre-incubation at 37°in the presence of buffer solution (control sample) or test compounds at different concentrations or 10 mm glycine (definition of nonspecific capture)were added followed by 10 μm [14C]glycine (specific activity 112 mCi/mmol). Incubation continued for 10 min at 37°and the reaction was stopped by 2 washes with buffer solution of Krebs-HEPES with pH 7.4. Incorporated into the cells of the radioactive substance was assessed after addition of 100 μm shimmering liquid substances and mixing for 1 hour. The computation was carried out using a counter Microbeta Tri-luxtm. The effectiveness of the compounds was determined using CI50the concentration of compounds decreasing the specific capture of glycine by 50%, which was determined by the difference of incorporated radioactivity control sample and the sample that received the glycine at a concentration of 10 mm.

In this test, the most active compounds according to the invention have CI50the order of 0.001-10 μm.

Individual cut is ltati several compounds of the following (CI 50in microns):

Connection # 3 0,017

Connection # 4 0,004

Connection # 14 0,07

Connection # 17 0,001

Connection # 26 0,07

The study ex vivo inhibitory activity of compounds against capture [14C]glycine homogenate of the cells of the cerebral cortex of the mouse.

Increasing doses of the compounds administered orally (obtained by grinding of the test molecule in a mortar in a 0.5%solution of Tween/MethocelTMin distilled water) or IPR (dissolution test molecules in physiological serum or receipt by grinding in a mortar in a 0.5%solution of Tween/MethcelTMin water, depending on the solubility of the molecule) OF1 male mice Iffa Crédo, weighing 20 to 25 g per day of the experiment. The control group is treated with a filler. Dose in mg/kg, route of administration and the processing time is determined depending on the investigated molecule.

After euthanasia by cutting off the heads of the animals at a certain time after the introduction, the cerebral cortex of each animal quickly seized on ice, weighed and stored at 4°or frozen at -80°With (in both cases, the samples are stored for a maximum period of 1 day). Each sample is homogenized in a buffer solution of Krebs-HEPES at pH 7.4 at a rate of 10 ml/g of tissue. 20 μm of each homogenate incubated for 10 minutes at on the th temperature in the presence of 10 mm L-alanine and buffer solution. Nonspecific capture is determined by injection of 10 mm glycine in the control group. The reaction is stopped by filtration under vacuum and the remaining radioactivity determined by solid shimmering material by counting using a Microbeta counter Tri-luxTM.

Inhibitor capture [14C]glycine decreases the number of radio incorporated in each homogenate.

The potency of the compound is evaluated according to its DE50the dose which inhibits 50% capture [14C]glycine relative to the control group.

Possessing the greatest activity of the compounds according to the invention in this test have DE50from 0.1 to 5 mg/kg intraperitoneally the introduction or by oral administration.

Study of transport of glycine in the spinal cord homogenate mouse

The capture of [14C]glycine vector glyt 2 are examined in the spinal cord homogenate of mouse brain by measuring the radioactivity incorporated in the presence or absence of the compounds.

After euthanasia of the animals (male OF1 mice Iffa Crédo, weighing 20 to 25 g per day of the experiment) the spinal cord of each animal quickly withdrawn, weighed and stored on ice. Samples homogenized in buffer solution Krebes-HEPES ([4-(2-hydroxyethyl)piperazine-1-econsultancy acid), pH 7.4 at the rate of 25 ml/g of tissue. 50 μl of homogenate previously cuberoot for 10 min at 25° In the presence of buffer solution Krebes-HEPES, pH 7.4, and the compounds in different concentrations, or 10 mm glycine to determine nonspecific capture. Then enter [14C]glycine (specific activity=MS/mmol) for 10 min at 25°With a final concentration of 10 μm. The reaction is stopped by filtration under vacuum and the radioactivity determined by solid shimmering material by counting using a Microbeta counter Tri-luxTM.

The potency of the compound is estimated by the concentration CI50able to inhibit 50% of specific capture glycine, defined by the difference of radioactivity incorporated in the control group and the group receiving the glycine at a concentration of 10 mm.

Possessing the greatest activity of the compounds according to the invention in this test have CI50order from 0.02 to 10 microns.

CI50compound No. 17 0.69 microns.

The results of experimental tests carried out on the compounds according to the invention of General formula (I), show that they are inhibitors of vectors glycine glyt 1, present mainly in the brain, and vectors glycine glyt 2, present mainly in the spinal cord.

Compounds according to the invention can thus be used to obtain drugs, particularly drugs which s means, are inhibitors vector glycine glyt 1 and/or glyt 2.

Thus, in accordance with another aspect of the object inventions are the drugs, which contain the compound of formula (I) or its salt affiliations with a pharmaceutically acceptable acid or hydrate, or MES the compounds of formula (I).

Compounds according to the invention can be used, in particular, for the treatment of behavioral disturbances associated with dementia, psychoses, in particular schizophrenia (deficient form and productive form)and acute or chronic extrapyramidal symptoms induced by neuroleptics, for the treatment of various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders, for the treatment of various forms of depression, including psychotic depression, for treating disorders associated with alcohol abuse or alcohol dependence, disorders of sexual behaviour, eating disorders and for treatment of migraine.

In addition, the compounds according to the invention can be used for treatment of painful muscle cramps in rheumatology and in acute spinal pathology, for the treatment of spastic convulsions States of spinal or cerebral origin, for symptomatic treatment of acute and subacute pain from mild to moderate and is tensively, for the treatment of intense and/or chronic pain, neurogenic pain and persistent pain, for the treatment of Parkinson's disease and symptoms of Parkinson's disease neurodegenerative origin or induced by neuroleptics, for the treatment of generalized primary and secondary partial epilepsy with simple or complex symptomatology, mixed forms and other epileptic syndromes in addition to another anti-epileptic treatment, or as monotherapy for the treatment of sleep apnea and to neurotoxity.

The object of the present invention are also pharmaceutical compositions containing an effective dose of at least one compound according to the invention in the form of a base or salt, or pharmaceutically acceptable MES, and in the mixture, if necessary, with one or more acceptable excipients.

These excipients are chosen according to the pharmaceutical form or the desired method of administration.

The pharmaceutical compositions according to the invention can also be used for oral, sublingual, subcutaneous, intramuscular, intravenous, topical application, intratracheal, intranasal, crescendo, rectal, intraocular injection.

The dosage form can, for example, be represented as tablets, gelatin capsules, granules, powders, rest the market or suspension for oral administration or for injection, plasters for percutaneous actions, suppositories. For local use, you can use ointments, lotions, lotions for the eyes.

As an example of a single form for administration of the compounds according to the invention in the form of tablets may contain the following components:

The connection according to the invention 50.0 mg

Mannitol 223,75 mg

Sodium croscarmelose 6.0 mg

Corn starch 15,0 mg

The hypromellose of 2.25 mg

Magnesium stearate 3.0 mg

These one-forms, therefore, to provide a daily dose of from 0.01 to 20 mg of active substance per kg of body weight depending on the galenical form.

In some cases it is necessary to decrease or increase the dosage; these dosage is not beyond the scope of the invention. In accordance with the usual practice, the dosage for each patient is determined by the physician depending on the method of administration, body weight and individual sensitivity of the specified patient.

In accordance with another aspect of the present invention relates also to a method of treatment of the above pathologies, which includes the introduction to the patient an effective dose of the compounds according to the invention or one of its pharmaceutically acceptable salt or hydrate or solvate.

1. The compound of General formula (I)

in the cat the Roy R denotes a hydrogen atom or a vinyl group;

n denotes 0 or 1 or 2, if R denotes a hydrogen atom and n denotes 1, if R denotes the vinyl group;

X denotes a group of the formula CH or a nitrogen atom, if R denotes a hydrogen atom, and X denotes a group of the formula CH, where R denotes the vinyl group;

R1indicates either phenyl or naftalina group, possibly substituted by one or more substituents selected from halogen atoms, (C1-C6)-alkyl, hydroxy and (C1-C6)-CNS group, linear or branched, or tsiklogeksilnogo group, or heteroaryl group selected from tanila, pyridinyl, chinoline;

R2denotes either a hydrogen atom, or one or more substituents selected from halogen atoms and triptoreline, (C1-C6)-alkyl, (C1-C6)-CNS, phenyloxy, hydroxy groups, or a group of General formula-NR4R5, SO2NR4R5or a group of the formula-OCF2O-related provisions 2 and 3 phenyl groups;

R4and R5independently from each other represent a hydrogen atom or a (C1-C6)-alkyl group;

in the form of free base or salt accession acid, hydrate or MES.

2. The compound according to claim 1, characterized in that it has the configuration of tree./p>

3. The compound according to claim 1 or 2, characterized in that X denotes a group of the formula CH.

4. The compound according to claim 3, characterized in that R denotes a hydrogen atom.

5. The compound according to claim 4, wherein R1indicates a possibly substituted phenyl group.

6. The compound according to claim 1, characterized in that it is chosen from the following compounds:

threo-2-chloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-cryptomelane;

threo-2-chloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-cryptomelane hydrochloride;

tree-2,6-dichloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-cryptomelane;

tree-2,6-dichloro-N-[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-cryptomelane hydrochloride;

2-chloro-N-(8α,9S-Cinchona-9-yl)-3-cryptomelane;

2-chloro-N-(8α,9S-Cinchona-9-yl)-3-cryptomelane hydrochloride;

2,6-dichloro-N-[(1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamide;

2,6-dichloro-N - [(1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]-3-(trifluoromethyl)benzamide hydrochloride;

threo-N-[(1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methyl]-2,6-dichloro-3-(trifluoromethyl)benzamide;

threo-N-[(1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methyl]-2,6-dichloro-3-(trifluoromethyl)benzamide hydrochloride.

7. Drug for inhibition of vectors of the GlyT1 glycine and/or GlyT2, ex is different, however, it consists of a compound according to any one of claims 1 to 6.

8. Pharmaceutical composition for inhibiting vectors of the GlyT1 glycine and/or GlyT2, characterized in that it contains a compound according to any one of claims 1 to 6, and at least one pharmaceutically acceptable excipient.

9. A method of obtaining a compound according to claim 1, wherein the diamine of General formula (II)

in which n, R and R1have the meanings defined in claim 1, is introduced into reaction with an activated acid or a compound of General formula (III)

in which Y represents a group to delete.

10. A method of obtaining a compound according to claim 1, characterized in that the deleted group is halogen.

11. A method of obtaining a compound according to claim 9, characterized in that it comprises a compound selected from the following compounds:

(Z)-1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methanon 0-benzyloxy hydrochloride;

Treo-[1-azabicyclo[2.2.2.]Oct-2-yl(phenyl)methyl]amine;

threo-2-chloro-N[(1-azabicyclo[2.2.2]Oct-2-yl)phenylmethyl]amine hydrochloride;

8α,9S-Cinchona-9-amine;

2-chloro-N-(8α,9S-Cinchona-9-yl)-3-cryptomelane hydrochloride;

(1S)-[(2S)(1-azabicyclo[2.2.2]Oct-2-yl(phenyl)methyl]amine D-tartrate;

1-azabicyclo[2.2.2]Oct-2-yl(4-forfinal)methanol;

1 asabis the CLO [2.2.2] Oct-2-yl(forfinal)methanon;

(Z)-1-azabicyclo[2.2.2]Oct-yl(4-forfinal)methanon 0-benzyloxy hydrochloride;

threo-1-azabicyclo[2.2.2]Oct-yl(4-forfinal)methanamine.

12. The use of the compounds of formula (1) according to any one of claims 1 to 6 to obtain a medicinal product intended for the treatment of behavioral disturbances associated with dementia, psychosis, various forms of anxiety, panic attacks, phobias, obsessive-compulsive disorders, various forms of depression, disorders related to alcohol abuse or alcohol dependence, disorders of sexual behavior, eating disorders, and migraine headaches.

13. The use of the compounds of formula (1) according to any one of claims 1 to 6 to obtain a medicinal product intended for the treatment of seizures, pain, Parkinson's disease and symptoms of Parkinson's disease, epilepsy, mixed forms and other epileptic symptoms, in combination with other antiepileptic treatment or as monotherapy, sleep apnea and neurotoxity.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: organic chemistry.

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4 cl, 1 tbl, 3 ex

FIELD: organic chemistry, chemical technology, medicine.

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EFFECT: improved preparing and treatment methods.

33 cl, 69 ex

FIELD: organic chemistry, chemical technology.

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wherein R means hydrogen atom; Ar means phenyl; or R means benzyl and Ar means p-methoxyphenyl group. Also, the invention describes a method for preparing these compounds. Invention provides preparing new compounds that can be used as the parent substances for synthesis of new heterocyclic systems.

EFFECT: improved preparing method, valuable chemical properties of compounds.

4 cl, 1 tbl, 3 ex

The invention relates to a single-stage process for the preparation of new chemical compounds - cyclocarbonate

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The invention relates to new compounds which can be used as inhibitors of matrix metalloprotease, in particular interstitial collagenases, and which is effective for the treatment of painful condition caused by excessive activity of matrix metalloprotease

FIELD: chemistry.

SUBSTANCE: derivatives of 7-aryl-3,9-diazabicyclo(3.3.1)non-6-ene of general formula I , general formula I, where X and W or both represent -CH-, or one of them represents -CH-, and the other -N. V represents -A-(CH2)s-, -(CH2)s-A-, -A-(CH2)v-B- or -CH2-A-(CH2)3-B-; A and B represent-O- U -phenyl, possibly 1-3 substituted with halogen, alkyl, alkoxy, CF3, CF3O - or alkylcarbonyl, or pyridyl, monosubstituted with cyanogroup. T represents -CONR1-, -(CH2)pOCO- or -(CH2)pN(R1)CO- Q-alkylene; M - hydrogen, phenyl, possibly substituted, benzo[1,3]dioxol, possibly substituted, or pyridyl; L represents -R3, -COR3, -COOR3, -CONR2R3 or -SO2R3; R1 - hydrogen, alkyl, C3-7 cycloalkyl, pyrrolidinyl, benzo[b]thienyl, chinoxalinyl, phenylalkyl, thienylalkyl or tetrazolylalkyl, possibly substituted. m=1, n=0 or m=0, n=1, p - integer 1-4, s - integer 2-5, v - integer 2-4, optically pure enantiomers, mixtures of enantiomers, pharmaceutically acceptable salts and complexes with solvents, possessing activity of phenin inhibitors.

EFFECT: efficient application in medicine for treatment of cardio-vascular diseases and renal failure.

8 cl, 743 ex

FIELD: chemistry.

SUBSTANCE: description is given of new diazabicyclic aryl derivatives, with general formula I: its enantiomers, or mixture of enantiomers, or its adjoining pharmaceutical salt, where X and Y independently represent CR2, CR3 or N, where R2 is hydrogen, C1-6alkyl or halogen; and R3 is hydrogen or halogen; and R1 is hydrogen or halogen, CF3, NO2 or phenyl, possibly substituted, group with formula phenyl-Z-(C1-6alkyl)m-, phenyl -C≡C- or pyridyl -Z-(C1-6alkyl)m-, where m equals 0 or 1; Z - O or S, where phenyl and pyridyl are possibly substituted, or R1 and R3 , together with carbon atoms to which they are bonded, form a benzocondensed aromatic carbocyclic ring, which can be substituted. The new compounds are cholinergic ligands of nicotinic acetylcholine receptors.

EFFECT: compounds can be useful for treating such diseases or disorders related to the cholinergic system of the central nervous system, peripheral nervous system etc.

11 cl, 3 ex, 1 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: invention relates to new crystalline form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, including 2 moles water to 1 mole (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, the form II content being equal 75% and more; the above form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3,3,1]non-4-yl)benzamide hydrochloride has one or more optional properties, as follows: a) form II infrared spectrum include characteristic peak at 835±1.5 cm-1; b) X-ray pattern obtained on the above form powder is essentially corresponds to image Fig. 21; and c) water content rates 8.3% to 9.8%. The invention relates also to the form II ofhydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride production methods, to the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride, and the form II of hydrated (±)-4-amino-5-chloro-2-methoxy-N-(1-aza-bicyclo[3.3.1]non-4-yl)benzamide hydrochloride identification method, as well as to pharmaceutical composition and treatment method for gastrointestinal motility impairment related disorders.

EFFECT: composition has improved properties for medical applications.

22 cl, 1 ex, 11 tbl, 22 dwg

FIELD: chemistry.

SUBSTANCE: invention concerns new derivatives of 1- and 7-[ω-(benzhydryl-4-piperazinyl-1)alkyl]-3-alkyloxantines of the general formulae I and II, including their pharmaceutically acceptable salts and/or salt hydrates, the derivatives showing antihistaminic and antiallergenic effect. In the general formulae I and II : R = H, Me, CH2Ph; R1 = Me, "н" - C4H9; n = 0-3; X = H, OH, OCOCH2CH2COOH; Y = Y1 = H, Cl, F; on the condition that R and R1 are not both methyl. Compounds of the invention feature high antihistaminic and antiallergenic activity. E.g., 7-[4-(benzhydryl-4-piperazinyl-1)butyl]-3-methyloxantine dihydrochloride surpasses most efficient antihistaminic and antiallergenic medications, such as cetirizine, loratadine and azelastine, in activity and lasting effect.

EFFECT: obtaining a compound with high antihistaminic and antiallergenic activity.

2 cl, 3 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new N,N'-substituted 3,7-diazabicyclo[3.3.1]nonanes of the general formula 1: (HY), where HY is hereinafter a pharmacologically acceptable acid; E is , R1 is H, low-grade alkyl, C1-C10alkoxy; R2 is generally represented by the general formulae (1.1a) , (1.2a) , (1.3a) , (1.4a) , where L is CHR11, ; R11 is H, NH2; R15 is H, low-grade alkyl, C1-C10alkoxy; R19, R19', R20 and R20' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R24 and R25 can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R3 and R3' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; R4 and R4' can be equal or different, and each is independently H, low-grade alkyl, C1- C10alkoxy; X is a group of the general formula: (CH2)m-Z, where m=0, while Z is acetyl, or X is a valence link. Compounds I are capable of AMPA receptor activity modulation and hence can be applied in pharmaceutical compositions.

EFFECT: obtaining compound capable of AMPA receptor activity modulation.

12 cl, 2 dgw, 2 tbl, 11 ex

FIELD: chemistry.

SUBSTANCE: invention concerns malonamide derivatives of the formulae (IA) or (IB) , and pharmaceutically acceptable acid additive salts of them, where R1, R1',(R2)1,2,3, R3, R4, R14, L, and are such as described in this invention. Also the invention concerns a medicine with inhibition effect on γ-secretase, which can be applied in treatment of Alzheimer's disease.

EFFECT: obtaining new malonamide derivatives with beneficial biological properties.

17 cl, 188 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 1,4-diazabicycloalkane of the formula (IV): or its pharmaceutically acceptable addition salt wherein Ar represents carbocyclic aromatic (aryl) group or heterocyclic aromatic (heteroaryl) group that represents 5-6-membered ring comprising one nitrogen, sulfur or oxygen atom as a heteroatom and wherein aromatic group can be substituted with one substitute chosen from group consisting of (C1-C6)-alkoxy, halogen atom, -CF3, phenyl and benzyl. Also, invention relates to a pharmaceutical composition possessing inhibitory effect on nicotine acetylcholine receptors and containing the effective amount of compound of the formula (IV) or its pharmaceutically acceptable addition salt in combination with at least one pharmaceutically acceptable carrier or diluting agent. Invention provides derivatives of 1,4-diazabicycloalkane possessing inhibitory activity with respect to nicotine acetylcholine receptors.

EFFECT: valuable medicinal and pharmacological properties of compounds.

10 cl, 3 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention relates to novel 3-phenyl-3,7-diazabicyclo[3,3,1]nonane compounds of the formula (I): wherein R1 means (C1-C6)-alkyl, (C4-C7)-cycloalkyl; R2 means (lower)-alkyl; R3 means (lower)-alkyl, or R2 and R3 form in common (C3-C6)-alkylene chain; R4 means phenyl monosubstituted at ortho- or para-position with nitro-, cyano-group or (lower)-alkanoyl, or disubstituted at ortho- and para-position with nitro-group, and their physiologically acceptable acid-additive salts. Compounds of the formula (I) possess anti-arrhythmic activity and therefore they can be used in pharmaceutical composition used in treatment and/or prophylaxis of cardiac rhythm disorders. Also, invention describes a method for synthesis of these compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

8 cl, 6 tbl, 2 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to condensed heterocyclic succinamide compounds of the formula (I): , their pharmaceutically acceptable salts, solvates or isomers wherein G represents mono- or polycyclic aryl or heterocyclic group substituted possibly at one or more positions; L represents a bond, -(CR7R7')n (wherein n = 1; R7 and R7' represents independently hydrogen atom (H), alkyl or substituted alkyl) or -CH2-NH-; Z1 represents oxygen atom (O); Z2 represents O; A1 and A2 represent -CR7 or in common with R7 from group W is a heterocyclic ring wherein oxygen represents a heteroatom; Y represents -O-, -SO-, -N(V2)-, -CH2-N(V2)-, -CO-N-(alkyl)-, -CH2-S-, -CH2-SO2-; V2 represents hydrogen atom, alkyl, arylalkyl, -CO-alkyl, -CO-O-aryl, -CO-O-arylalkyl; W represents -CR7R7'-CR7R7'-, -CR7R7'-C=O, -NR9-, -CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'-, cycloalkyl or substituted cycloalkyl, cycloalkenyl or substituted cycloalkenyl, heterocyclo- or substituted heterocyclo-group, aryl or substituted aryl wherein if W doesn't mean -NR9-CR7R7'-, -N=CR8-, -N=N, -NR9-NR9'- or heterocyclo- or substituted heterocyclo-group then Y must mean -O-, -CH2-S-, -SO-, -CH2-SO2-, -N-(V2)- or -CH2-N-(V2)-; Q1 and Q2 represent hydrogen atom (H). Also, invention describes a method for synthesis of intermediate compounds in synthesis of compounds of the formula (I), using the latter for preparing agents modeling function of the nuclear hormone receptors. Compounds of the formula (I) can be used in treatment of prostate cancer.

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

8 cl, 11 tbl, 463 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to a novel chemical compound, namely, to biologically active compound of the formula (I): possessing anti-arrhythmic activity and representing 5'-bromolappaconitine hydrobromide. Toxicity of this compound is by 4.8-fold less toxic as compared with analog used in medicinal practice and representing lappaconitine hydrobromide. Proposed compound possesses the expressed anti-arrhythmic activity in models with calcium chloride and adrenaline arrhythmia and provides the complete blocking both types of arrhythmia after administration of the dose that is 10-fold less of the therapeutic dose of lappaconitine hydrobromide.

EFFECT: improved and valuable medicinal properties of compound.

2 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of formula I or their pharmaceutically acceptable salts: , where R1 is selected out of C3-10cycloalkyl-C1-6alkyl, tetrahydropyranyl-C1-6alkyl and tetrahydropyranyl, where the C3-10cycloalkyl-C1-6alkyl, tetrahydropyranyl -C1-6alkyl and tetrahydropyranyl used in definition of R1 are possibly substituted by one or more group selected out of halogen, methyl and ethyl; R2 is C1-10alkyl, where the C1-10alkyl used in definition of R2 is optionally substituted by one or more group selected out of methyl, ethyl; R3 is selected out of -H, C1-10alkyl, C2-10alkenyl, pyrrolidinyl, morpholinyl, piperidinyl, pyrrolidinyl-ethyl, morpholinyl-ethyl, piperidinyl-ethyl and , possibly substituted by one or more group selected out of C1-6alkyl, amino, C1-6alkoxy; or R3 is 2-aminoethoxy-ethyl or (2-hydroxyethyl)amino-ethyl; each of R8 and R9 is C1-10alkyl; and R4 is selected out of -H and C1-10alkyl. Invention also concerns compounds selected out of the group, application of compounds for any of claim points 1-5, pharmaceutical composition, and method of obtaining compounds of the formula I.

EFFECT: obtaining new bioactive compounds with agonistic effect selective in respect of CB1 receptors.

11 cl, 12 ex

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