Enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1h-pyrido[4,3- b]indol

FIELD: chemistry.

SUBSTANCE: invention concerns new enantiomers of (+)-and(-)-trans-2,3,4,4a,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol and method of its obtaining. Being optical antipodes for each other, enantiomers exhibit different biological activity and can be applied as an active component in pharmaceutical compositions of nootropic and sedative action for treatment of different individual status of patients.

EFFECT: obtaining of the claimed compound.

1 ex, 5 tbl, 5 cl

 

The technical field

The present invention relates to new substances, namely, to optical isomers (+)- and (-)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, methods for their preparation and use based on the identified therapeutic activity nootropic and sedative action.

Prior art

Known derivatives of hexahydro-gamma-carboline 8-alkyl-2-[gamma-(p-perbenzoic)-propyl]-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indoles and their pharmaceutically acceptable salts (US 3983239, B1), showing the properties of a depressant of the Central nervous system, which may weaken the stereotype caused by amphetamine, which is the brain.

Known 3,6-dimethyl-1,2,3,4,4A,9a-hexahydro-γ-carboline the dihydrochloride having pharmacological activity, and the drug based on it, has received international nonproprietary name "decarbon" (US 3657254, B2). Described psychotropic drug action "decarbon" and expressed his antipsychotic, antidepressant and activating effects that appear only in dependence syndromes, disorders and conditions of the patient, and therapeutic effect depends on the dose and duration of drug administration.

A known method of producing dicarbide (US 3657254, B1), including the restoration of 3,6-dimethyl-1,2,3,4,4A,9a-hexahydro-γ-carboline hydroch oride in aqueous acidic medium at a temperature of up to 100° With subsequent alkalinization of the reaction mixture and isolation of the resulting base 3,6-dimethyl-1,2,3,4,4A,9a-hexahydro-γ-carboline, the processing of hydrochloric acid and isolation of the target product, in which the reducing agent is preferably used amalgamating zinc or tin. According to this method are the CIS-isomer of dicarbide, in which the hydrogen atoms 4A and 9b are attached to carbon atoms in the CIS-position.

It is known that 2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, obtained the drugs name "decarbon", shows activity depressant of the Central nervous system and at the same time the two-phase activity in relation to the effects of amphetamine and antagonism towards stereotypie caused by amphetamine (Psychopharmacologia, Vol.21, 1971, pages 82-88).

Known pharmacological properties, in particular anti-arrhythmic activity and antioxidant properties, peridontal "Stojadin", which is an optical isomer of CIS-dicarbide (L.Horakova and S.Stole. Antioxidant Pharmacodynamic Effects of Pyridoindole Stobadine. General Pharm., V.30, Issue 5, pages 627-638).

The known method of selective synthesis of racemic CIS-dicarbon by catalytic hydrogenation of the corresponding γ-carboline (L.Benes, S.Stole. Drugs of the Future. 1989, Vol.14, No.2, p.135-137). This racemic CIS-dicarbon was divided into optical isomers of crystalliza what their salts with (+)- and (-)-dibenzoyltartaric acid.

Known racemic TRANS-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole hydrochloride with hydrogen atoms 4A and 9b in the TRANS-position and used as an analgesic and sedative drug. It is also used as a major tranquilizer, has antipsychotic effect, or small tranquilizer with anxiolytic action, relaxant, antihypertensives (US 3991199, B2).

A method of obtaining 2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole (2,8-dimethyl-γ-carboline) (Yakhontov, L.N., Glushkov RG Synthetic drugs. Medicine. 1983, s-237) restoration of 2,8-dimethyl-γ-carboline zinc dust. Using this method of synthesis was obtained a mixture of racemate CIS - and TRANS-isomers of dicarbon with a predominance of the CIS isomer.

The known method of selective receipt of racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole-gidroborudovaniya 2,8-dimethyl-γ-carboline complex BF3·Et2O (Y.Nagai et al. Journal of Medicinal Chemistry. 1979, Vol.22, No. 6, 677-683).

However, the above active substances are racemic mixtures of optical isomers, therapeutic activity which may be different that the application of racemic mixtures can cause side effects, in particular when using combo receiver is authorized neuroprotective therapy and sedatives, the use of which should be strictly measured.

Known methods for producing these active substances are not able to distinguish an individual optical isomer of the racemate of the TRANS-isomer and full expression of the unique pharmacological properties of optical (+)- and (-)-isomers of TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole, which may consist of various combinations of their therapeutic effect.

Disclosure of inventions

The aim of the invention was to obtain from the known racemic mixture of individual substances with individual therapeutic efficacy.

While the invention has been tasked separation of the isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole used in therapy as an analgesic and sedative drug and having hydrogen atoms 4A and 9b in the TRANS-position, its optical isomers to obtain individual optical isomers (+)- and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

In addition, the task was detection of individual therapeutic efficacy of each of these optical isomers and their use in therapy.

The task was solved by providing a method to obtain individual optical isomers (+)-TRANS-,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole according to the invention, in which the interaction of 2,8-dimethyl-gamma-carboline with sodium borohydride and efratom boron TRIFLUORIDE, treatment with hydrochloric acid, then alkalinized reaction mixture, isolated free base of racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, conduct crystallization of salts with (+)-dibenzoyltartaric acid from ethanol to obtain individual salts (+)-TRANS-isomer is recovered from the received individual salts free individual basis (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, then the remainder is transferred to the free base of racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, conduct crystallization of salts with (-)-dibenzoyltartaric acid from ethanol to obtain individual salt of (-)-TRANS-isomer and allocate individual basis (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

The task was solved by allocating a new substance representing the optical isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole with a positive optical rotation, in which the hydrogen atoms in positions 4A and 9b are in the TRANS position, having the structural formula:

The task was solved by allocating a new the substances, representing the optical isomer (-)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole with a negative optical rotation, in which the hydrogen atoms in positions 4A and 9b are in the TRANS position, having the structural formula:

The task was solved by the creation of a pharmaceutical composition nootropic and sedative action, containing as active ingredient an optical isomer (+)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and/or its pharmacologically acceptable salt in an effective amount.

The task was solved by the creation of a pharmaceutical composition nootropic and sedative action, containing as active ingredient an optical isomer (-)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and/or its pharmacologically acceptable salt in an effective amount.

The invention is further illustrated by the examples of its implementation, which, however, does not limit the possible variations in its implementation.

The best option of carrying out the invention

A. preparation of optical isomers (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

Obtaining carried out by the method according to the invention in two with the adiya's as follows.

1. Obtaining racemic isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

It is known that racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole is a mixture of two optical isomers, in which the hydrogen atoms in positions 4A and 9b are in the TRANS position and the rotation angles opposite: positive rotation for (+)-TRANS-isomer and negative rotation for (-)-TRANS-isomer:

To a cooled with ice to a solution of 2,8-dimethyl-γ-carboline (20 g, 0.1 mol) in THF (300 ml) was added finely ground powder sodium borohydride (7.6 g, 0.2 mol) and then with good stirring and in an atmosphere of inert gas gradually, within hours, was added a solution of epirate boron TRIFLUORIDE (48% BF3) (38 g, 0.27 mol) in tetrahydrofuran (THF). After adding the total number BF3the reaction mass was stirred for 30 minutes at room temperature and then boiled for 4 hours.

After cooling, to the reaction mass was added 6N-HCl solution (150 ml) and THF was evaporated under vacuum. To the resulting solution was added dioxane (150 ml), boiled for 1 h, then evaporated. The residue was podslushivaet an alkaline solution of NaOH and was extracted with CHCl3.

According to TLC, the resulting substance is a free basis of TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexage is about-1H-pyrido[4,3-b]indole, containing small, less than 10%, the mixture of the CIS isomer, which was separated by crystallization. To separate the CIS-isomer of the mixture was converted into a mixture of dihydrochloride CIS - and TRANS-isomers by the action of alcoholic HCl solution and subsequent crystallization dihydrochloride, TRANS-isomer of ethanol allowed to be free from impurities dihydrochloride of the CIS isomer. Alkalization dihydrochloride racemic TRANS-isomer and the subsequent extraction has led to the individual bases of racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

The resulting product was investigated by TLC and NMR. Analytical TLC was performed on plates Kieselgel 60 F254(Merck).

Based on the research results obtained substances:

for racemic TRANS-isomer Rf=0,33 (system petroleum ether-ethyl acetate-triethylamine, 3:1:0.1);

for the CIS isomer (decarbon) Rf=0,39 (in the same system).

According to TLC and NMR of the obtained CIS-isomer was identical to the known sample of the CIS isomer obtained as described in the literature method (Yakhontov, L.N., Glushkov RG Synthetic drugs. Medicine, 1983, str-237).

The total yield of the Foundation of the TRANS-isomer was about 70%, and it was used to obtain individual optical isomers.

For the obtained products:

a) the melting temperature, measured on the device Buchi SMP-20 and not fixed:

the melting temperature TPLdihydrochloride racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole is 258-260°C;

the melting temperature TPLfree base TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole is 83-87°C.

(b) chromatographic mobility (Analytical TLC was performed on plates Kieselgel 60 F254 (Merck)):

- TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole Rf=0.43 (system chloroform-methanol-triethylamine, 10:1:0.1);

for CIS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole (decarbon) in the same system Rf=0.35.

2. The separation of the racemic isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole optical isomers (+)- and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

To a solution of 10 g of racemic TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole bases in 150 ml of ethanol was added an equimolar amount of (+)-dibenzoyltartaric acid (18.61 g). After some time fell crystalline precipitate of salt, enriched (+)-TRANS-isomer.

Next, the residue is recrystallized several times from ethanol, until he achieved the final rotation angle measured by polarimeter Perkin-Elmer 241: for liberty is th reason [α ]D20+58° (Cl, CHCl3)dihydrochloride [α]20D+7° (Cl, N2About). The free base (+)-TRANS-isomer was obtained by alkalinization of the salt solution with a solution of NaOH followed by extraction with ether and evaporation.

Then the mother liquor after separation of the salt of (+)-isomer was podslushivaet the addition of the alkali solution, the free base was extracted with ether, and after evaporation in vacuum received a substance composed of a mixture of bases, enriched (-)-isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole. To this mixture, 150 ml of ethanol was added an equimolar amount of (-)-dibenzoyltartaric acid. After some time fell crystalline precipitate of salt, enriched (-)-TRANS-isomer.

Next, the residue is recrystallized several times from ethanol, until he achieved the final rotation angle measured by polarimeter Perkin-Elmer 241: for the free base [α]D20-58° (Cl, CHCl3)dihydrochloride [α]20D-10° (Cl, N2O).

The NMR spectra of the optical isomers were recorded on a Varian instrument-VXR 400, with an operating frequency of 400 MHz (1H NMR) and 100,6 MHz (13WITH NMR). Chemical shifts were measured using the residual solvent as internal standards.

Received (+)- TRANS-isomer and its dihydrochloride salt is characterized by:

- free basis: gross formula C13H17N2; angle of rotation [α]20D+58° (Cl, CHCl3);

- dihydrochloride: gross formula C13H18N2·2HCl; angle of rotation [α]20D+7° (Cl, N2O).

Molecular weight 276,1.

Obtained (-)-TRANS-isomer and its dihydrochloride salt is characterized by:

- free basis: gross formula C13H17N2; angle of rotation [α]20D-58° (Cl, CHCl3);

- dihydrochloride: gross formula C13H18N2·2HCl; angle of rotation [α]20D-10°(Cl, N2O).

Moleculary weight 276,1.

For the studied compounds (+)- and (-)-TRANS-isomers NMR spectra are the same:

1H NMR spectrum (CDCl3): 1,92 (multiplet, 2H); 2.08 (multiplet, 2H); 2.19 (singlet, 3H); 2,34 (singlet, 3H); 2.80 (doublet of triplets, 1H); 2.94 (multiplet, 2H); 3.37 (doublet of doublets, 1H); 3.89 (broad singlet, 1H); 6.58 (doublet of doublets, 1H); 6.78 (singlet, 1H); 6.79 (doublet, 1H) ppm;

13With the NMR-spectrum: 20.76; 30.98; 45.83; 47.35; 54.27; 57.02; 67.98; 110.25; at 122.77; 127.36; 128.63; 131.07; 149.10 ppm

Century, the Study of the biological activity of the individual optical isomers (+)- and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

Were investigated involves the alleged pharmacological properties of the substances, which is the optical (+)- and (-)-isomers of TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, in their individual application.

Preclinical evaluation of nootropic and sedative activity of these substances was carried out on mice by test spontaneous orientation (behavior patrol) in the cross maze, which allows you to simultaneously identify nootropic, anxiolytic, sedative and stimulating effect substances.

To assess exploratory behavior of animals used indoor maze (Salimov P.M. estimation of the order of the paths in the process of exploratory behavior in mice. Journal of higher nervous activity, 1988. V.38. No. 3, s-571).

The mouse was placed in the Central compartment of the maze and in semi-automatic mode register the sequence of transitions from one arm to another.

The test was ended when they were 12 such transitions (Salimov P.M. estimation of the order of the paths in the process of exploratory behavior in mice. Journal of higher nervous activity, 1988, T. 38, No. 3, s-571; Salimov R., McBride WJ, J.D. Sinclair, Lumeng L., Li, T.-K. Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior. Addict. Biol. 1996a, 1:273-280; Salimov R., McBride WJ, D.L. McKenzie, L. Lumeng and Li, T.-K. Ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol. 1996b, 13: s-300).

<> Subsequent computer analysis of the records were allowed to identify a number of indicators of behavior. The most informative of them were the following:

1) the total time spent by the mouse in the Central compartment of the maze - the score T_ChTm, and the total time spent by the mouse in the side compartments of the maze - index T_GlTm.

These indicators reflect the level of motor activity of the animal, as well as characterize the intensity of the survey their new environment and can be used to estimate stimulating/timolepticheskoe or, on the contrary, sedative effect substances (Salimov R., McBride WJ, D.L. McKenzie, L. Lumeng and Li, T.-K. Ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol. 1996b, 13:297-300); Salimov R.; Salimova N.B.; Shvets L.N.; Maisky, A.I. Haloperidol administered subchronically reduces the alcohol-deprivation effect in mice. Alcohol. 20:61-68; 2000; Markina N.V., Salimov P.M., Poletaeva I.I. Exploratory behaviour of F2 crosses of mouse lines selected for having different brain weight: A multivariate analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 2004, 28(3):583-589);

2) the latent period is the indicator F_ChTm, and the duration of the first visit in the lateral compartment, the indicator F_GlTm.

These indicators reflect the level of anxiety of the animal in a new environment and can be used to assess anxiolytic (anxiolytic) effects of substances (Salimov R. Different behavioral patterns related to alcohol use in rodents: A factor analysis. Alcohol. 1999, 17:157-162).

These indicators are negatively correlated with long is part of the animal stay in the open arms in the well-known test open elevated cross maze, that allows the use of selective change of these indicators as an indicator of anxiety and, consequently, to apply them to assess anxiolytic effects of substances (Salimov P.M., Markina, NV, Perepelkina O.V., may M., Poletayev I.I. Rapid tolerance to ethanol and voluntary consumption of large doses of alcohol in mice, electrovanne by weight of the brain. Journe. higher nervous activity. 2003, CH, No. 1, p.100-106; Salimov R.; Salimova N.; Shvets L.; Shvets N. Effect of chronic piracetam on age-related changes of cross-maze exploration in mice. Pharmacol. Biochem. Behav. 1995, 52:637-640; Salimov R., McBride WJ, J.D. Sinclair, Lumeng L., Li, T.-K. Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior. Addict. Biol. 1996a, 1:273-280; Salimov R., McBride WJ, D.L. McKenzie, L. Lumeng and Li, T.-K. Ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol. 1996b, 13:297-300; Salimov R. Different behavioral patterns related to alcohol use in rodents: A factor analysis. Alcohol. 1999, 17:157-162; Markina N.V., Popov N.V., Salimov P.M., Salimova NB, Savchuk NB, Poletaeva I.I. compare the level of anxiety and stress reactivity in mice, electrovanne on the big and small weight of the brain // the Journal of higher nervous activity. 1999. V.49. No. 5. S-798);

3) the length of the first cycle patrols indicator F_PtrN, and the length of the second cycle patrols indicator S_PtrN.

These indicators are calculated by the number of visits of the animal in the compartments of the maze, committed for examination of the situation is about the moment, when the animal will visit all four compartments of the maze at least once (Salimov P.M. estimation of the order of the paths in the process of exploratory behavior in mice. Journe. the Supreme. nerve. activities. 1988. V.38. No. 3. S-571; Salimov R., McBride WJ, J.D. Sinclair, Lumeng L., Li, T.-K. Performance in the cross-maze and slip funnel tests of four pairs of rat lines selectively bred for divergent alcohol drinking behavior. Addict. Biol. 1996a, 1:273-280; Salimov P.M., W.J. McBride, D.L. McKenzie, L. Lumeng and Li, T.-K. Ethanol consumption by adolescent alcohol-preferring P rats on subsequent behavioral performance in the cross-maze and slip funnel tests. Alcohol. 1996b, 13:297-300; Markina N.V., Salimov R., Poletaeva I.I. Exploratory behavior of F2 crosses of mouse lines selected for having different brain weight: A multivariate analysis. Prog. Neuro-Psychopharmacol. Biol. Psychiat. 2004, 28(3):583-589). Thus, the greater the number of visits required the mouse to visit all 4 side of the sleeve, that is to make one cycle patrol, the less "systematic" and less effective investigation of the maze;

4) the number of cycles patrol - index PatrlN committed during the experiment, as another indicator of the effectiveness of exploratory behavior. The more cycles patrol, the more systematically and more effectively the labyrinth research animals.

Indicators of groups 3 and 4 can be used to evaluate neuroprotective effects of substances.

The behavior of the patrol assessed for indicators of groups 3 and 4, selectively broken under the action of such damaging the brain of factors, such as ionizing radiation (Grigoriev, A., Salimov P.M. Behavioral criteria for prediction of the outcome of the cerebral forms of radiation injury in rats. Radiobiology. 1988, V.28, No. 2, s-272), alcohol intoxication (Salimov P.M., Markina, NV, Perepelkina O.V., may A.I., Poletaeva I.I. Rapid tolerance to ethanol and voluntary consumption of large doses of alcohol in mice, electrovanne by weight of the brain. Journe. the Supreme. nerve. activities. 2003, CH, No. 1, p.100-106), experimental neurotoxic brain damage (Salimov R., Salimova N.B. L-glutamate abolishes differential responses to alcohol deprivation in mice. Alcohol. 1993, 10:251-257) and aging (Salimov R.; Salimova N., Shvets L.; Shvets N. Effect of chronic piracetam on age-related changes of cross-maze exploration in mice. Pharmacol. Biochem. Behav. 1995, 52:637-640), and improved by the action of nootropic agents, e.g. after administration of piracetam and meklofenoxat (Salimov P.M. estimation of the order of the paths in the process of exploratory behavior in mice. Journe. the Supreme. nerve. activities. 1988. V.38. No. 3. S-571; Salimov R.; Salimova N.; Shvets L.; Shvets N. Effect of chronic piracetam on age-related changes of cross-maze exploration in mice. Pharmacol. Biochem. Behav. 1995, 52:637-640; Salimov R., Kovalev G.I. Effects of N-cholinergic drugs on behavior in the explorative cross-maze in mice: comparison with cognitive enhancers. Eur. Neuropsychopharmacology., 2005, v.15, Suppl. 2, S.230);

5) the number of right turns is an indicator R_TrnN, and the number of rotations to the left is an indicator L_TrnN committed by animals when moving from one dead end to another dead end of the maze, and the asymmetry index is an indicator rl_Ind - these rotations:

rl_Ind=R_TrnN·(R_TrnN+L_rnN) -1;

6) spontaneous stereotypic behavior is an indicator S_VisN, describing a visit to the animals in turn two compartments of the maze more than two times in a row.

Reduction of spontaneous stereotypie characteristic of certain sedative drugs, such as haloperidol, and for some sedatives, for example, haloperidol, and for some nootropic tools such as piracetam.

In this work, we used adult male C57BL/6. Mice were kept in a vivarium with natural light and on a standard diet standard cells for 3-5 individuals each. At the beginning of the experiments, their age was 3-4 months.

Animals of the control group were injected with saline.

Animal study groups in the number of animals in the group were injected analyte isomers (+)- or (-)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole in physiological solution or, for comparison, only known drugs piracetam or meclofenoxate in physiological solution, and after 1 hour, evaluated the behavior of animals. The analyte was injected into the starch solution into the stomach using netraverse probe.

The experiments were conducted in the first half of the day in the period from 10:00 to 15:00 in isolated laboratory room using white Shu is the" intensity of 70 dB above the hearing threshold of a person.

The results were processed using the software package STATISTICA. Used analysis of variance with a built-in comparison function medium-criterion of student.

Example 1. The study of the sedative action of haloperidol.

The studied animals were injected once the neuroleptic haloperidol at a dose of 0.5 mg/kg, the results of the test animals test exploratory behavior of mice in the cross maze are shown in table 1.

Table 1
Sedative effect of haloperidol
IndexControl, N=15Haloperidol, N=15
AverageAverage errorAverageAverage error
F_PtrN6,200,616,090,55
S_PtrN4,860,345,200,36
PatrlN1,900,231,910,09
F_ChTm11,351,9019,30*of 3.07
F_GlTm12,421,2531,85*8,54
T_ChTm 54,516,59100,65*of 12.26
T_GlTm115,7210,24284,67*28,09
R_TrnN3,400,793,910,53
L_TrnN4,300,843,360,56
rl_Ind0,460,100,540,06
S_VisNof 5.290,902,35*0,99
* - statistically significant difference from control (p<0,05)

Single injection of mice inside the stomach of neuroleptic haloperidol at a dose of 0.5 mg/kg had a sedative effect, which was expressed in a statistically significant slowing the movement of animals in the maze, that is to increase the time spent in the center and the lateral arms of the maze - indicators T_ChTm, T_GlTm, as well as in reducing spontaneous stereotypie (figure S_VisN). This corresponds to previously published results using this test [Salimov, 1988; Salimov et al., 2000].

Example 2. The study of the neuroprotective action of piracetam and meklofenoxat.

The studied animals were injected once known nootropic drugs piracetam dose of 300 mg/kg or meklofenoxat at a dose of 100 mg/kg, the result of the test animals test exploratory behavior of mice in the cross maze are shown in tables 2A and 2B.

0,0
Table 2A
Nootropic effect of piracetam
IndexControl, N=15Piracetam, N=15
AverageAverage errorAverageAverage error
F_PtrN5,90,44,5*0,2
S_PtrN4,80,4of 5.40,4
PatrIN1,90,12,10,1
F_ChTm17,73,0the 11.62,7
F_ChTmto 19.91,925,02,9
F_GlTm45,22,746,13,6
T_ChTmof 148.49,4135,16,1
T_GlTm5,20,53,4*0,5
R_TrnN2,90,44,5*0,5
L_TrnN3,70,44,10,2
rl_Ind0,60,4*0,1
S_VisN6,90,84,3*0,8
* - statistically significant difference from control by student's criterion (p<0,05)

Table 2B
Nootropic effect of meklofenoxat
Control, N=15The meclofenoxate provided N=15
AverageAverage errorAverageAverage error
F_PtrN5,90,54,8*0,4
S_PtrN5,50,24,6*0,2
PatrlN2,00,22,5*0,1
F_ChTm15,42,715,43,6
F_GlTm22,7a 3.929,15,5
T_ChTm41,92,040,53,6
T_GlTm131,210,3145,48,0
R_TrnN3,5 0,3the 3.80,8
L_TrnNa 4.90,44,50,7
F_PasN3,50,33,60,5
rl_Ind0,40,00,40,1
S_VisN5,50,83,70,7
* - statistically significant difference from control by student's criterion (p<0,05).

A single injection the mice inside of the stomach known nootropic drugs piracetam dose of 300 mg/kg and meklofenoxat at a dose of 100 mg/kg exerted a neuroprotective effect, which was expressed in a statistically significant shortening of the first and second patrolling the maze - reduction values F_PtrN and S_PtrN, and the increase in the total number of patrols - increase PatrlN. These results are consistent with previously published data using this test [Salimov, 1988; Salimov et al., 1995; Salimov, Kovalev, 2005].

Example 3. The study sedative and neuroprotective actions of an optical isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole according to the invention.

For studies have used individual optical isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, gender is produced by the method according to the invention.

The studied animals once introduced into the stomach (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg, the results of the test animals test exploratory behavior of mice in the cross maze are shown in table 3.

Table 3
The effect of isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole on the behavior of mice in the cross maze
Control, N=12TRANS(+) isomer, the dose of 2.5 mg/kg, N=12TRANS(+) isomer, the dose of 5.0 mg/kg, N=12
AverageAverage errorAverageAverage errorAverageAverage error
F_PtrNof 5.920,48of 5.750,546,300,91
S_PtrN6,110,484,55*+0,255,43+0,37
PatrlN1,750,132,000,121,640,24
F_ChTm7,492,32 9,182,8624,60*6,44
F_GlTmof 19.032,8122,913,5943,48*12,61
T_ChTm30,131,4053,27*5,1958,27*9,89
T_GlTm127,0311,03271,98*+42,72391,25*+to 66.30
R_TrnN2,830,42to 2.670,733,090,69
L_TrnN3,250,634,170,754,820,57
rl_Ind0,480,080,390,090,380,08
S_VisNto 6.670,63of 5.750,955,550,88
* - statistically significant difference from control by student's criterion (p<0,05)

+ - statistically significant difference from control by Fisher's exact test, analysis of variance (p<0,05).

From the test results it follows that a single injection the mice inside the stomach of the optical isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-what irido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg induced sedation, which was expressed in a statistically significant slowing the movement of animals in the maze - the increase in time spent in the center and the lateral arms of the maze - indicators T_ChTm, T_GlTm. These effects of (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole similar to the sedative effects of haloperidol, given in example 1 (table 1).

In addition, the optical isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg exerted a neuroprotective effect, which was expressed in a statistically significant improvement in conduct patrols of the labyrinth - the decrease in S_PtrN (table 3). This action isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole similar neuroprotective effects of drugs piracetam and meclofenoxate provided in example 2 (table and 2B).

Example 4. The study sedative and neuroprotective actions of an optical isomer (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole according to the invention.

Were used for research of the individual isomers (-)TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b] indole, obtained by the process according to the invention.

The studied animals once introduced into the stomach (+) or (-) isomers of TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg, the results of the test animals to test the exploratory behavior of mice in the cross maze is shown in table 4.

From the test results it follows that a single injection the mice inside the stomach of the optical isomer (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg had a sedative effect, which was expressed in a statistically significant slowing the movement of animals in the maze - the increase in time spent in the center and the lateral arms of the maze - indicators T_ChTm, T_GlTm. In addition, (- )- TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole caused a decrease in spontaneous stereotypie (figure S_VisN). These effects of (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido [4,3-b] indole similar to the sedative effects of haloperidol, given in example 1 (table 1).

0,64
Table 4
The effect of isomer (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole on the behavior of mice in the cross maze
Control N=12TRANS(-) isomer, the dose of 2.5 mg/kg, N=12TRANS(-) isomer, the dose of 5.0 mg/kg, N=12
AverageAverage errorAverageAverage errorAverageAverage error
F_PtrN of 5.920,486,100,625,420,48
S_PtrN6,110,484,43+0,305,00+0,33
PatrlN1,750,131,670,312,080,19
F_ChTm7,492,3210,753,098,332,85
F_GlTmof 19.032,8120,27to 2.0633,62*of 7.48
T_ChTm30,131,4033,102,3142,23*to 4.41
T_GlTm127,0311,03166,78*+18,50238,16*+31,13
R_TrnN2,830,42is 3.080,615,08*0,56
L_TrnN3,250,633,000,543,830,68
rl_Ind0,480,080,500,090,580,06
S_VisNto 6.670,636,334,17*0,69
* - statistically significant difference from control by student's criterion (p<0,05).

+ - statistically significant difference from control by Fisher's exact test, analysis of variance (p<0,05).

In addition, the optical isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg exerted a neuroprotective effect, which was expressed in a statistically significant improvement in conduct patrols of the labyrinth - the decrease in S_PtrN (table 3). This action isomer (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole similar neuroprotective effects of drugs piracetam and meclofenoxate provided in example 2 (table and 2B).

From the test results it follows that a single injection the mice inside of the stomach (+) and (-) isomers of TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg had a sedative effect, which was expressed in a statistically significant slowing the movement of animals in the maze - the increase in time spent in the center and the lateral arms of the maze - indicators T_ChTm, T_GlTm. This effect isomers (+)- and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole similar to the sedative effect of haloperidol, given in example 1 (table 1).

In addition, (+) and (-) isomers of TRANS-2,8-dimethyl-2,,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole in doses of 2.5 and 5.0 mg/kg exerted a neuroprotective effect, which was expressed in a statistically significant improvement in conduct patrols of the labyrinth - the decrease in S_PtrN (table 3). This action (+) and (-) isomers of TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole similar neuroprotective effects of drugs piracetam and meclofenoxate provided in example 2 (table and 2B).

At the same time the difference of the pharmacological properties of optical isomers (+)- and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, which is that (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole isomer has a more pronounced sedative activity compared with (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole. At the same time (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, in contrast to (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, had the ability to reduce spontaneous stereotype.

Thus, when the separation of the racemic isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole method according to the invention were obtained optical isomers (+)- and (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole according to the invention, which optical antipodes to each other and having different biological activity and, therefore, the difference in therapeutic application, which allows b is more to use them effectively for the treatment of individual conditions of patients. The compounds can be successfully used in various pharmaceutical compositions with different content of active ingredient, in combination with various fillers.

Industrial applicability

Optical isomers according to the invention, obtained by the process according to the invention, which used the technologically acceptable techniques can be successfully applied, for example, in the pharmaceutical compositions according to the invention, which may be implemented using known technology.

1. The optical isomer (+)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole-positive rotation, having the structural formula:

in which the hydrogen atoms in positions 4A and 9b are in TRANS-position is obtained.

2. The optical isomer (-)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole-negative rotation, having the structural formula:

in which the hydrogen atoms in positions 4A and 9b are in TRANS-position is obtained.

3. The way to obtain individual optical (+)-TRANS - and (-)-TRANS-isomers of 2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, in which the interaction of 2,8-dimethyl-gamma-carboline with sodium borohydride and efratom boron TRIFLUORIDE, about what abotu hydrochloric acid, then alkalinized reaction mixture, isolated free base of racemic isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, conduct crystallization of salts with (+)-dibenzoyltartaric acid from ethanol to obtain individual salts (+)-TRANS-isomer is recovered from the received individual salts free individual basis (+)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, then the residue is transferred to the free base of racemic isomer TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole, conduct crystallization of salts with (-)-dibenzoyltartaric acid from ethanol to obtain individual salts of (-)-TRANS-isomer and allocate individual basis (-)-TRANS-2,8-dimethyl-2,3,4,4A,5,9b-hexahydro-1H-pyrido[4,3-b]indole.

4. The pharmaceutical composition nootropic and sedative action, containing as active ingredient an optical isomer (+)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and/or its pharmacologically acceptable salt in an effective amount.

5. The pharmaceutical composition nootropic and sedative action, containing as active ingredient an optical isomer (-)-TRANS-2,3,4,4A,5,9b-hexahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole and/or its pharmacologically acceptable salt in an effective amount.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention concerns pyrido[2,3-b]pyrazine derivatives of the general formula I where R1 and R2 are hydrogen, unsubstituted C1-C8 alkyl or substituted with hydroxy-, alkoxy-, nitro- or CO2-alkyl, aryl, heteroaryl selected out of the group of pyrinidile or benzodioxalyl, independently from each other; R4 is hydrogen, R3 is a NR9R10 group where R9 is hydrogen and R10 is a -C(Y)NR11R12 group where Y is O or S and R11 is hydrogen, R12 is an alkyl, alkenyl, alkinyl, cycloalkyl, aryl, possibly substituted by a haloid nitro-, trifluormethyl, alkyl, substituted aryl or heterocyclyl selected out of the group of furanyl or morpholinyl, alkyl or their salts endurable physiologically, their solvates, hydrates and polymorphous forms, where the mentioned compounds can be in the forms of theirs racemates, pure enantiomers and/or diastereomers, or anatiomer and/or diastereomer mixes, or tautomers. The invention also describes a medicine based on the compounds, a method of the medicine obtaining, and application of the medicine in treatment of diseases or abnormalities caused by misdirected cellular signal transduction processes.

EFFECT: possible application in cancer treatment.

12 cl, 2 tbl, 38 ex

FIELD: chemistry.

SUBSTANCE: invention concerns a new 1-(3,4-diethoxyphenyl)-2,3,5,6-tetrahydro-(3,4-diethoxybenzo)[g]quinoxalino[2,3-b]indolisine hudrochloride of the formula: which exhibits direct anticoagulation effect and credibly prolongs coagulation time for nitrate blood and coagulability change rate in the concentration of 1 mg/ml at 36.5%. LD50 for intraperitoneal introduction to white mice comprised 355.0 (310.0÷410.0) mg/kg. T"пл" 160-161°C (isopropanol).

EFFECT: obtaining of the claimed compound.

1 tbl

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: chemistry.

SUBSTANCE: invention pertains to compounds with general formulae (I) and (II) and their pharmaceutical salts, their use as inhibitors of HIV-integrase and to pharmaceutical salts based on them. In formula (I) , R1 represents H or NR2R5; R2 represents CH3; R5 represents 1) C(O)CH2SO2CH3, 2) C(O)C(O)N(CH3)2, 3) SO2N(CH3)2 or 4) SO2R20 where R20 represents , , or ; or alternatively, R2 and R5 together with a nitrogen atom, to which they are bonded, form or , R3 represents hydrogen; R4 represents 1) n-fluorobenzyl, 2) 4-fluro-3-methylbenzyl, 3) 3-chlorobenzyl or 4) 3-chloro-4-methylbenzyl; R12 and R14 both represent H, except that, when R5 represents C(O)C(O)N(CH3)2 and R4 represents n-fluorobenzyl, and n equals 1, then R12 and R14 both represent H, or both represent CH3; and n is an integer, equal to 0, 1 or 2.

EFFECT: compounds can be used for treating HIV-infection.

12 cl, 5 dwg, 1 tbl, 8 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to producing the novel compounds with dipeptidyl peptidase IV (DPP-IV) inhibiting activity and particularly, it relates to the compounds with the condensed 1,3-dihydroimidazole cycle. The invention relates to the compounds represented by the common formula (II), or their pharmaceutically acceptable salts, where, Z3a means nitrogen atom or the group with formula -CR2a=; X3a means oxygen atom or sulfur atom; T1a means piperazine-1-yl group, 3-amino-piperidine-1-yl group, 3-methylamino-piperidine-1-yl group; X1a means oxygen atom hydrogen, C2-6-alkenyl group, C2-6-alkynyl group or benzyl group; each of R1a and R2a independently means hydrogen atom, halogenatom, C1-6-alkyl group, cyanogroup or group, represented with formula-A0a-A1a; A0a means oxygen atom, sulfur atom or group, represented with formula-NA2a-; Ala means hydrogen atom, C1-6-alkyl group, C1-6-alkenyl group, C2-6-alkynyl group, phenyl group, cyanophenyl group, carbamoylphenyl group, benzyl group; A2a means hydrogen atom or C1-6-alkyl group; X2a means hydrogen atom, C2-6-alkenyl group, C2-6-alkynyl group, 1H-piridine-2-onyl group, 1-methyl-1H-piridine-2-onyl group, C1-6-alkyl group, which can have a group, selected from the substitutes group specified below B, phenyl group, which can have a group, selected from the substitutes group specified below B, 5- or 6-membered heteroarylgroup, containing one or two nitrogen atoms, oxygen or sulfur, which can have a group, selected from the substitutes group specified below B, phenylC1-6-alkyl group, which can have a group, selected from the substitutes group specified below B: <Substitutes group B> substitutes group B is group, including chlorine atom, bromine atom; cyanogroup, C1-b-alkyl group, C2-b-alkenyl group, C2-6-alkynyl group, C3-8-cycloalkyl group, C1-6alcoxigroup, carbamoyl groupcarboxyl group and C1-6-alcoxicarbonyl group.

EFFECT: research and revealing compounds with DPP-IV inhibiting activity, useful as pharmaceutical agents which can be used as therapeutic and preventing medicines in such diseases as diabetes, obesity and hyperlipidemia.

12 cl, 84 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel compounds with the formula (I) or their pharmaceutically or veterinary-acceptable salts: where: R1 and R3 independently represent H; F; Cl; Br; C1-C6alkyl; R2 represents H or C3-C7cycloalkyl; Y represents -S- or -N(R5)-, where R5 represents H; X represents the bind; R4 represents -C(=O)NR6R7, where R6 represents H or radical of formula -(Alk)b-Q, where b is equal to 0 or 1, and Alk is not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, F, Cl, Br, oxo, COOH, bivalent C1-C12alkylen, C2-C12alkenylen with direct or ramified chain, which can be disconnected with one ore several non-adjacent -O-, -S- or -N(R8)-, where R8 represents H or C1-C4alkyl, C3-C4alkenyl or C3-C6cycloalkyl, and Q represents H; -SH; -NR8R8, where each R8 can be similar or different; the complex ether group; or not necessarily substituted with C1-C6alkyl, C1-C6alkoxi, phenyl, benzyl, phenoxy, C3-C8cycloalkyl, amino, fluor, bromine, oxo, -COOH, -CORA, -COORA, NHRA, -NRARB, where RA and RB are independent (C1-C6)alkyl group, phenyl, C3-C7cycloalkyl, C5-C7cycloalkenyl or heterocyclilc ring containing 5 to 8 ring atoms; and R7 represents H or C1-C6alkyl; or, taken together with atom or atoms, they are bound with, R6 and R7 form not necessarily substituted with (C1-C6)alkyl, COORA, where RA is the (C1-C6)alkyl group, phenyl, not necessarily substituted with F, Cl, Br, heterocyclilc ring containing 5 to 8 ring atoms. The invention also relates to N-(3-dimethylaminopropyl)-4-(4-cyclopropyl-3-oxo-3,5-dihydropirazol[4,3-c]quinoline-2-il]benzamide; to application of the compounds; to the immunomodulation method and to the pharmaceutical and veterinary composition.

EFFECT: production of novel immunobiologic compounds.

14 cl, 173 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the novel substituted indoline phemylsulfamide derivatives with the common formula , where A means C-R11 group or nitrogen, and R11 means hydrogen or alkyl with 1-4 carbon atoms, X means oxygen, R1 means aryl with 6-10 carbon atoms, unsubstituted or once-triple substituted with the similar or different substitutes, selected from the group which includes halogen, zyano, alkyl with 1-6 carbon atoms, alkoxi with 1-6 carbon atoms, phenoxi, benziloxi, trifluoromethyl, trifluorometoxi, alkenil with 2-6 carbon atoms, phenyl, alkylthio with 1-6 carbon atoms, mono- and dialkylamino with 1-6 carbon atoms in each alkyl group, or means the group with formula , R2 and R3 similar or different and independently from each other mean hydrogen or alkyl with 1-6 carbon atoms, or with the carbon atom they are bound to form the 3-7-membered spiro-compound cycloalkylic ring, R4 means hydrogen or alkyl with 1-6 carbon atoms, R5 R4 means hydrogen or alkyl with 1-6 carbon atoms, R6 means hydrogen or alkyl with 1-6 carbon atoms, R7 means hydrogen, alkyl with 1-6 carbon atoms, R8 - R10 mean hydrogen; as well as to their pharmaceutically compatible salts.

EFFECT: compounds are designated for prevention and/or treatment of cardio-vascular diseases, particularly dislipidemia and ischemic heart disease.

4 cl, 1 dwg, 96 ex

FIELD: chemistry; medicine.

SUBSTANCE: invention pertains to derivatives of 7-phenylpyrazolopyridine with formula (I) ,where R1, R5, R6, R40, R41 and R42 represent different hydrocarbon substitutes or functional groups, its salts or hydrates, and especially to salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine. The compound with formula (I), especially salts of N-cyclopropylmethyl-N-7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-ethylpyrazolo[1,5-a]pyradin-3-yl-N-tetrahydro-2H-4-pyranylmethylamine, act as antagonists of the receptor of corticotrophin release factor and can be used in medicine for treating various diseases of the nervous system and the gastrointestinal tract.

EFFECT: obtaining of new biologically active substances.

162 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of indole with general formula 1: where R is unsubstituted or substituted quinolyl, pyridopyrazinyl, indazolyl or pyridyl and which is directly bonded to nitrogen of the amide group; R1 is unsubstituted or substituted alkly-aryl; R2 represents hydrogen; R3-R6 represent hydrogen, R7 represents (C1-C6)-alkylcarbonyl or (C1-C6)- alkoxycarbonyl, and X, Y represent oxygen or sulphur, under the condition that, when R is an unsubstituted or substituted 2-, 3-, 4-, 5- and 6-pyridyl group and R1-R6 have the above mentioned values, R7 is not an acetyl radical or tert-butyloxycarbonyl group. The invention also relates to physiologically tolerant salts of the indole derivatives, as well as to pharmaceutical compositions based on them and their use in obtaining medicinal preparations.

EFFECT: obtaining of medicinal preparations, used as medicines for curing tumorous diseases, especially in case of resistance to other drugs and metastasising carcinomas.

14 cl, 7 tbl, 6 dwg, 25 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: medicine; pharmacology.

SUBSTANCE: invention concerns application of selective agonist of alpha-2B or alpha-2B/2C adrenoreceptors for manufacture of medical product (MP), applied for treatment of neurodegenerative cerebrum conditions. Applicability of selective agonist of alpha-2B or alpha-2B/2C adrenoreceptors as MP is first shown for diseases causing damaged neurons with endings approaching to black substance or moving away.

EFFECT: products have improved efficiency.

9 cl, 1 tbl, 1 ex

FIELD: medicine.

SUBSTANCE: invention concerns application of polypeptide FGF-9 or its biologically active fragment to produce medical product for multiple sclerosis treatment. Polypeptide can be 94-95% identical to sequence from amino acid 1 to amino acid 208 of human FGF-9, presented on fig. 3 (SEQ ID NO: 5).

EFFECT: invention stimulates myelination, proliferation and persistency of oligodendrocyte neurons, improves nervous regeneration.

6 cl, 9 dwg, 3 tbl, 3 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to application as ligands of 5-NT6 receptor azaheterocyclic compositions of general formula 1 or their racemates, or their optical isomers, or their pharmaceutically acceptable salts and/or hydrates , where R2 and R3 independently represent substitute of amides chosen from hydrogen; substituted carbonyl; substituted aminocarbonyl; substituted aminothiocarbonyl; substituted sulphonyl; C1-C5-alkyl, optionally substituted with C6-C10-aryl, optionally substituted with heterocyclil, C6-C10-arylaminocarbonyl, C6-C10- arylaminothiocarbonyl, C5-C10-azaheteroaryl, optionally substituted with carboxyl, nitrile group; optionally substituted with aryl; R1k are 1 to 3 independent substitutes to cyclic system chosen from hydrogen, optionally substituted C1-C5-alkyl, C1-C5-alkyloxy, C1-C5-alkenyl, C1-C5- alkenyl, halogen, trifluoromathyl, nitrile, carboxyl, optionally substituted heterocyclil, substituted sulphonyl, optionally substituted carboxyl; dashed line with accompanying continuous line () corresponds to single or double bond; n=1.2 or 3. Invention also concerns a pharmaceutical formulation, production method and tabletted, capsulated or injection medical product in pharmaceutically acceptable package.

EFFECT: agent has improved efficiency.

17 cl, 8 tbl, 5 ex, 1 dwg

FIELD: chemistry.

SUBSTANCE: compounds with the formula are described and its pharmaceutically acceptable salts, where Y, Z, R1, R2, R3, R4, R5, R6, R7, R8, R9, m, n, p and q are as specified in the invention. The obtained compounds have the modulating activity regarding the 5-HT receptors. The pharmaceutical composition which contains the compounds with formula (I) and used in treatment of certain central nervous system diseases is also described.

EFFECT: novel compound group with useful biological properties is obtained.

10 cl, 2 dwg, 7 ex

FIELD: chemistry; obtaining of medicinal preparations.

SUBSTANCE: description is given of a compound with general formula where R1 represents a halogen, C1-C6alkyl, CF3, CF2H or cyano, R2 represents C1-C6alkyl, R3 represents 5- or 6 - member hetero-aryl, optionally substituted with one, two or three substitutes, chosen from a group, consisting of a halogen, C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkylhalogen, C1-C6alkoxy, NR'R", or substituted with a 1-morpholinyl group or substituted with thiomorpholinyl groups, 1-oxothiomorpholinyl or 1,1-dioxothiomorpholinyl; R', R" independently represent hydrogen, C1-C6alkyl, (CH2)0,1-(C3-C6)cycloalkyl, R represents hydrogen as well as its pharmaceutical salts and the method of obtaining them. The invention also relates to use of the given amidazole derivatives for obtaining medicinal preparations and to medicinal preparations containing them, meant for prevention or treatment of damages, through the mGluR5 receptor, such as acute and/or chronic neurologic damages, primarily shock pain, or for treatment of chronic and sharp pain.

EFFECT: obtaining of new compounds, with useful biological properties.

40 ex

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to methods of self-specific T-cell vaccine production. Self-specific T-cell vaccine for disseminated sclerosis treatment includes attenuated T-cells which are reactive relative to one or several epitopes, yet SEQ ID NOS: 1-6 contain these epitopes. Invention is intended for treatment of autoimmune diseases, such as disseminated sclerosis or rheumatoid arthritis using self-specific T-cell vaccines. Besides, invention provides diagnostics of diseases associated with T-cells. Advantage of this invention implies that it can be applied for production of T-call vaccines with heterogenous gene VR-Dp-JR to take into consideration clonal shift if self-reactive T-cells.

EFFECT: method has improved efficiency.

10 cl, 7 ex, 2 dwg

FIELD: medicine; pharmacology.

SUBSTANCE: invention refers to production of medicinal agents for dementia treatment, including Alzheimer's disease (AD), method of treatment and pharmaceutical composition effective for dementia treatment, including AD or Alzheimer's dementias, as well as first signs of memory derangement. Offered invention implies application of polyprenols of formula where n=8-20, as active ingredients for medicinal agent and treatment of dement syndrome and for medicinal agent and treatment of Alzheimer's disease. Offered pharmaceutical composition is used for treatment of dement syndrome, including Alzheimer's disease, and pharmaceutically acceptable adjuvants, including carriers, and/or solvents, additives and/or lubricants. Pharmaceutical composition can be made as solution, suspension, tablets, filmed tablets, capsules, rectal suppositories, liposome form. Pharmaceutical composition is oil solution, parenteral suspension or solid form for oral application, so specified polyprenol content is 0.10 to 80 mass.%. Offered method of treatment applied for dement syndrome, including Alzheimer's disease, is distinguished by the fact that patients are introduced with effective amount of polyprenols of formula where n=8-20, as separate agent or within pharmaceutical composition containing assist ingredients. Agent based on specified composition provides aid for patients suffering from first signs of memory derangement.

EFFECT: due to absence of by-effects treatment with polyprenols can be performed within long period of time.

7 cl, 2 tbl, 5 ex

FIELD: medicine; pharmacology.

SUBSTANCE: purpose of given invention lies in development of stable preparative form of injection phenotropyl with high biologicale accessibility, and related method of production. Set purpose is achieved by solution-like injection agent containing phenotropyl and solvent consisting of mixed polyethylene glycol (PEG), ethyl alcohol and injection water. Solution is made phenotropyl dissolved in ethyl alcohol, added with polyethylene glycol and injection water followed with microfiltering sterilisation, preferably through filter with pore sizes 0.1 -1.0 mcm, most preferably through filter with pore sizes 0.45 mcm.

EFFECT: reduced disabling probability and hospitalisation time.

5 ex, 2 tbl, 4 cl

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention refers to medicine and pharmaceutics. Dry granulated pharmaceutical formulation containing atorvastatin or its pharmaceutically acceptable salt, in combination with at least one other active medicinal agent, method of specified formulations production, sets including such formulations, and treatment of hypercholesterolemia and/or hyperlipidemia, osteoporosis, benign prostate hyperplasia (BPG) and Alzheimer's disease by using pharmaceutical formulation in amount providing therapeutic effectiveness. Offered pharmaceutical formulation of atorvastatin is characterised with good solubility, bioavailability, dosage homogeneity, and method of atorvastatin production with low content of impurities and adequate stability.

EFFECT: production of atorvastatin formulation, characterised with good solubility, bioavailability, dosage homogeneity, and method of atorvastatin production with low content of impurities and adequate stability.

6 cl, 6 ex, 5 tbl

FIELD: chemistry.

SUBSTANCE: description is given of a derivative of carboxylic acid with general formula , where R1 represents a hydrogen atom, C1-4alkyl, benzyl, E represents C(=O)-, -SO2- or -CH2-;R2 represents a halogen atom, C1-6 alkyl, C1-6 alkoxy, hydroxyl, C1-4 alkyl, substituted -OR8 , R3 represents a halogen atom, C1-6 alkyl, C1-6 alkoxy; R4 represents a hydrogen atom, C1-6alkyl; R5 represents C1-6 alkyl, C1-10 alkoxy, R8 represents C1-4 alkyl, phenyl; represents a benzol ring; G represents (1) C1-6 alkylene; represents dihydrobenzoxazine; m and n represent 0 or an integer from 1 to 4; I represents 0 or an integer from 1 to 8, where, when m is more or equal to 2, R2 is the same or different; when n is more or equal to 2, R3 is the same of different; when i is more or equal to 2, R5 is the same of different, or its pharmaceutical salt. Since the compound with formula (I), is linked to the DP receptor and has antagonistic effect to the DP receptor.

EFFECT: it is useful for preventing and/or curing such diseases as allergic rhinitis, allergic conjunctivitis, bronchial asthma, malt cell disease, migraine, contact dermatitis, stroke, ulcerative colitis, thrombocyte aggregration or sleep disorder.

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