Racemic or optically active derivatives of pyrido[1,2 - a]pyrazine

 

(57) Abstract:

Usage: in medicine, in particular as antidepressants and anxiolytics. The inventive products is racemic or optically active derivatives of pyrido [1,2-a]pyrazine f-ly I, where X Is N or CH; Y and ; b) ; c) ; d) ; Z); (b) SH2, OCH2, Y1(CH2)n; n = 1 or 2; Y1-CH2, NH, or NCH3; output 30 - 40%. Products - racemic derivatives of pyrido[1,2-a] pyrazine f-crystals II, where A - H, B = C1-C3-alkoxycarbonyl, X1- carbonyl; A is H or the group X Is N or CH; X1-CH2B - CH2OH; if A group X Is N or CH; X1-CH2, B - Y2CH2-, Y2- OH; RSO2O, NH2-, N3or ; R - C1-C3-alkyl, phenyl, tolyl. Products - optically active derivatives of pyrido[1,2-a] pyrazine f-ly III, where X Is N or CH; Y3- OH; RSO2O, R1C(O)O or NH2R - C-C-alkyl, phenyl, tolyl; R1- C1-C3-alkyl. Reagent 1: compound f-crystals IV. Reagent 2: Sol MU, where X and Y are the specified values for compounds F.-ly (I) M is alkali metal. Reaction conditions: environment aprotic polar solvent at 90 - 120°C. 3 C. p. f-crystals. The structure of the compounds f-l I - IV.

The invention relates to a number of rat is tov and anxiolytics, as well as intermediates of these derivatives.

Pathological fear and depression are common ailments that afflict a significant portion of the population. Often one and the same species found both of these ailment. For many years it is known that symptoms of the pathological fear of people can often be mitigated by the introduction of certain chemical compounds, which in the context of this particular application called anxiolytics. In modern medical practice, a widely used class of anxiolytic drugs are benzodiazepines, such as diazepam, however, these compounds have a number of negative qualities (e.g., unwanted sedative effect). Known for a number of derivatives of 1-(2-pyrimidinyl)-4-[4-(cycloimide(butyl]piperidine derivatives, which are represented by an anxiolytic drugs, as a rule, devoid of this sedative action. They include such compounds as buspiron, in which cyclic kidna group represents 4,4-tetramethylene - peridin-2,6-Dion-1-ilen group, gepirone, in which this group is a 4,4-dimethylpiperidine-2,6-Dion-1-Ile - ing group, and ipsapirone in which this group represents a 1,1-dioxobenzo[d]isothiazol-3(2H)">

Some derivatives of 2-pyrimidinylpiperazine have combined anxiolytic and antidepres - santim action.

Bis-Aza-bicyclic compounds of the present invention, generally show minimal in vivo stimulations of dopaminergic systems, which indicates a reduced or minimal adverse neurological effects in their clinical application.

The invention relates to a series of bis-Aza-bicyclic compounds, namely the racemic or optically active compounds of the formula I

and their pharmaceutically acceptable salts accession acids, where X Is N or CH;

Y represents a

Z represents a,SCH2, OCH2, -YI(CH2)nor YI(CH2)nsubstituted on the carbon atom by one or two methyl groups;

n takes the values 1 or 2;

YIrepresents CH2, NH or NCH3.

In the compounds of formula I, from the standpoint of ease of preparation and high activity Y preferably represents

Within this subgroup, regardless of what is takes X, Z most preferably represents CH
Z is a Y1(CH2)n, Y1represents CH2and n is 1.

Used in the invention of item corresponds to the item 1. I. R. A. S. Alternative names of kernel meets the present invention bis-azabicycles connections are perhydro-1H-pyrido-[1,2 a] pyrazin, [2,4-a]disabilitating and 1,4-diazabicyclo[5.5.0]Dean.

These pharmaceutically acceptable salt accession acids include salts formed with HCl, HNO3H2SO4H3PO4pair-CH3WITH6H4SO3H or NOESN2CH2COOH, but are not limited to.

The present invention also includes pharmaceutical compositions containing anxioliticeski or antidepres - Santo effective amount of the compounds of formula I as active ingredient pathological fear or depression in people, such methods include the introduction of a specified person anxioliticeski effective antidepressant amount of a compound of formula I.

The invention also relates to intermediate compounds (intermediates), which represent a racemic compounds of formula II

where in the first case

A - hydrogen atom;

IN - (C1-C3) - alkoxycarbonyl group;

X1- C = O; in the second case

A - hydrogen atom, or

X is N or CH;

X1- CH2;

IN NON2; and in the third variant

But a

;

X is N or CH2;

X1- CH2;

IN - Y2CH2;

Y2"BUT-, RSO2O, H2N, N3- or

and R - (C1-C3) - alkyl, phenyl or Tomilina group; or optically active compounds of the formula III

where X Is N or CH;

Y3"BUT-, RSO2O-, R1COO - or H2N-,

R - (C1-C3) - alkyl, Penina or Tomilina group;

R1- (C1-C3) - alkyl group; or their optically active salts with acids when Y3represents H2N. is Preferred salt with (-)-almond acid.< which is preferred for all racemic compounds and preferred for those optically active compounds in which Y is not kidney group, consists in the substitution of the ester sulphonate group in racemic or optically active compound of the formula IV

the anion Y-; where X and Y are as defined above, values, and Y-is the salt anion MY, where M in the most simple variant is an alkali metal, such as, for example, sodium. If desired salt is not commercially available, what happens most often, it is convenient to obtain the desired salt in situ in the form of sodium salt, for example, irreversibly by the action of sodium hydride on the compound of the formula Y-H; or reversible by reaction with a base such as Na2CO3that in itself is not nucleophilic. This method in General is the representative of such substitution reactions. They, as a rule, is carried out in an inert solvent, preferably aprotic, and, of course, having a lower acidity than the compound Y-H. Especially preferred solvents are acetonitrile and dimethylformamide. Typically, the temperature is not essential for the method, but to achieve full conversion within a relatively short time preferred, as a rule, are elevated temperature, directly time as a rule, use a molar excess of one of the reactants, usually more readily available MY salt. In this way R preferably represents a methyl group from the viewpoint of the ease of obtaining of ester nelfinavir and ease of replacement mutilation. The product distinguish such known methods as concentration, evaporation, extraction, chromatography and crystallization, in combination with the addition of the appropriate acid in the required quantity, if it is desirable to direct obtaining salt accession acid, for example, with addition of one molar equivalent of Hcl, if gelatelno getting monoosnock salt.

Used in the invention, the expression "inert solvent" refers to a solvent which does not enter into interaction with the reagents, intermediates or final products, which may adversely affect the yield of the target product.

The second General method of preparing compounds corresponding to the formula I, is a direct doubling of alcohol, having the formula V

with the heterocyclic compound or an imide of the formula YH, where X and Y are as defined above values. Preferred daivim reagent with equimolar amounts of SCIENCES and alcohol formula I use about 2-2,1 molar equivalent of these reagents. Preferred solvents are relatively polar ethers, such as tetrahydrofuran, dioxane or 1,2-dimethoxyethane, especially preferred is the first of the above solvents. Temperature is not significant. However, to achieve full transformation over a relatively short time, it is preferable to use elevated temperatures (for example, the boiling point of tetrahydrofuran).

The compounds of formula I in which the group Y is kidney group, can also be obtained from the corresponding amine having the formula VI

effect on him anhydride having the formula VII

where X and Z have the above values. This is the preferred way to obtain optically active compounds corresponding to the formula I in which Y represents kidney group (excluding those compounds in which the group Z contains an NH group, in this case, the anhydride has the potential to cure). According to an alternative method, the amide (VI) and the anhydride (VII), as a rule, approximately equimolar quantities heated to about 100-160aboutWith in an inert solvent. In this case, particularly preferred rastvoroprovoda when boiled with a reflux at the boiling point of this mixture of xylenes.

The required racemic and optically active source materials that meet the formulae IV, V and VI, are synthetic methods, which are schematically represented in reaction scheme:

< / BR>
While the method in General and the various intermediate compounds are new, distinct chemical steps in generally similar to known chemical transformations. Appropriate conditions for reactions in General are well known in the art. Especially preferred conditions are illustrated in the following examples.

Anxiolytic activity of the compounds of formula (I) is demonstrated and measured by using a variation engaged in anti-conflict test Vogel. In this test, groups of rats were not given water for 48 hours and then gave them the opportunity to drink water from under electric current drinkers. For rats, which was introduced by the tested compound (treated rats), were determined number of times within 10 min the rats drank water (and therefore received an electric shock). This is the number of times compared with those obtained for control rats, i.e., those rats that had not been entered test the connection. The increase in the number of times in sluchkoi activity of the tested compounds.

The antidepressant action of the compounds of formula I was determined by examining their ability to reduce induced by clonidine hypolocomotion in rats. In this test, groups of rats orally administered the carrier and test the connection in the media once a day for four days. At 24 h after the last injection half of the control rats (received only medium), and all rats treated with the test compound subcutaneously introduced clonidine (0.1 mg/kg) in the second medium. The rest of the control rats subcutaneously introduced only the second medium. Then for 6 h were measured horizontal locomotor activity. Clonidine greatly reduces exploratory locomotor activity ("cross-motion"). This effect is greatly attenuated in rats that had introduced the proposed test connection. Some studies have shown that clinically effective antidepressant therapeutic effects attenuate behavioral responses caused2-adrenal - ronmental agonist is clonidine.

To alleviate the symptoms of pathological fear and/or depression in humans, the compound of the formula or its pharmaceutically acceptable salt is administered in an amount of about special cases, at the discretion of the attending physician, may be prescribed a dose outside this range. The preferred method of introduction, as a rule, is the oral method, but in some cases, for example when oral absorption is weakened due to illness or when the patient cannot swallow, the main positive is parenteral administration (for example, intramuscularly, intravenously, intradermally).

The proposed compounds usually applied in the form of pharmaceutical compositions containing at least one of the compounds corresponding to the formula or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier or diluent. These compositions are prepared by the known methods using liquid or solid carriers or diluents, in forms that meet the selected method of administration: for oral administration in the form of tablets, hard or soft gelatin capsules, suspensions, granules, powders, etc.; for parenteral injection in the form of solutions or suspensions for injection, etc.

P R I m e R 1, CIS-2-(2-pyrimidinyl)-7-(Succinimidyl)-2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

Method A. In the dried fire capacity, equipped with a magnetic prevented the t sodium hydride (0,49 g of 60% suspension in mineral oil, 12.2 mmol), the mixture was stirred at 70aboutC for 1 h Add CIS-7-(methanesulfonylaminoethyl)-2-(2-pyrimidyl)- 2,3,4,6,7,8,9,9 and octahydro - 1H-pyrido[1,2-a] pyrazin (1.56 g, 4.8 mmol), and the mixture is heated under stirring at 110aboutWith over 18 hours by Concentration in vacuum to obtain a solid substance, which is dissolved in 25 ml of methylene chloride. Add the same volume of water and adjusted pH intensively stir the mixture to 2.0 (6NHCl). The separated organic phase is again extracted with the same volume of water at pH 2.0. Finally, the extraction is carried out of the organic phase in the same volume of water at pH of 10.0 (a saturated solution of sodium carbonate). Then separate with alkaline aqueous phase is twice extracted with her methylene chloride (portion 150 ml). The latter organic layers were combined, treated with activated charcoal, dried over sodium sulfate and concentrated in vacuo, obtaining a colorless amorphous foam, which crystallized from 35 ml of isopropanol, getting to 1.14 g (72% ) of target compound in the form of colorless crystals with a melting point 183-184aboutC. Thin layer chromatography: Rf= 0,43 (methylene chloride : methanol 9:1). Mass spectroscopy high resolution (msvr): 329, 1906, Vychisl.

Method B. To stir magnetic stirrer, the solution grifantini (262 mg, 1.0 mmol) and diethylazodicarboxylate (0,174 ml, 192 mg, 1.05 mmol) in 8 ml of dry tetrahydrofuran is added dropwise within 1 h add a solution consisting of succinimide (99 mg, 1.0 mmol) and CIS-7-(hydroxymethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8, and 9,9 - octahydro-1H-pyrido[1,2-a]pyrazine (248 mg, 1.0 mmol) in 20 ml of dry tetrahydrofuran. The reaction is carried out by boiling under reflux for 18 h; then the mixture was concentrated in vacuo, obtaining oil. This oil is dissolved in a mixture of methylene chloride - water (35 ml each). Then pH intensively stirred mixture was adjusted to 2 by addition of 6NHCl, then divide phase. The organic phase is combined with 10 ml of water, and the pH of this mixture in the same way bring to 2. Two having acidic aqueous extract are combined and mixed with the same volume of methylene chloride, bringing the pH to 10 by adding a saturated solution of sodium carbonate. The phases are separated, and the aqueous phase is twice extracted with methylene chloride (portions of 50 ml). All three organic extracts are combined treated with activated carbon, dried over sodium sulfate and evaporated, receiving oil which crystallized from isopropanol that DS-7-(aminomethyl)-2-(2-pyrimidinyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a] pyrazine (149 mg, 0.6 mmol), succinic anhydride (60 mg, 0.6 mmol) in xylenes (9 ml, constant boiling range 138-142aboutC) is refluxed for 18 hours, the Reaction mixture was concentrated in vacuo to an oil, which was taken in methylene chloride (30 ml). Add the same volume of water and adjusted pH intensively stir the mixture to 2.0 by the addition of 6NHCl. The phases are separated, and the organic phase is extracted with a fresh portion of water with a pH of 2. The combined acidic extracts are stirred with methylene chloride (40 ml, bringing the pH to 10.0 by addition of a saturated solution of sodium carbonate. The phases are separated, and the aqueous phase is twice extracted with methylene chloride (portion 40. ml). Alkaline organic extracts are combined treated with activated charcoal, dried over sodium sulfate and concentrated in vacuo, obtaining a solid product, which crystal litout of 7 ml of isopropanol, getting 164 mg (84%) of target compound in the form of colorless crystals, which is identical with the products obtained by methods a and B.

P R I m m e R 2. CIS-7-(substituted methyl)-2-(2-pyrimidinyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazine.

The following additional target compounds were obtained in accordance with the method And predshestvuyuschih output and properties. Unless otherwise noted, all spectra13C-NMR obtained at 300 MHz in CDCl3. If not mentioned specifically, thin-layer chromatography (TLC) was performed on plates of silica gel 60F254thickness 0.25 mm, using as elution solvent a mixture of methylene chloride : methanol composition of 9:1.

a) 3,3,4-trimethylbutyramide (9,7%); crystallized from a mixture of ethyl acetate : hexane; TLC Rf0,58; msvr 371,2274 calculated 371,2321.

13C-NMR: 182,2; 179,4; 161,3; 157,6; 109,5; 60,9; 57,9; 54,4; 48.8; 45,8; 43,5; 43,0; 40,2; 32,3; 32,1; 24,7; 24,3; 21,2; 10,2.

b) thiazolidin-2,4-Dion-3-ID (19,5%); amorphous; SVR: 347,1478 calculated 347,1426.

13C-NMR: 171,9; 171,6; 161,3. 157.6; 109.6; 60.9; 57.8; 54,7; 48,9; 43,9; 43,6; 33,7; 32,2; 24,9. 24,5.

C) meso-3,4-dimethylacrylamide (50%); crystallized from a mixture of methylene chloride - isopropanol; so PL, 168-172aboutC; TLC Rf0,56.

13C-NMR (250 MHz): 179,7; 161,5; 157,7; 109,5; 61,1; 58.0; 54,8; 49,0; 43,7; 43,0; 40,6; 32,3; 25,0; 24,5; 15,2;

g) 3-methylsuccinimide (46,5%); crystallized from a mixture of methylene chloride-isopropanol; so PL, 168-172aboutC; TLC Rf0,51; msvr 344,2011 calculated 344,2086.

13C-NMR (250 MHz): 180,7; 176,7; 161,5; 157,1; 109,6; 61,1; 58,1; 54,8; 49,0; 43,7; 40,7; 36,5; 34,6; 32,3; 25,0; 24,5; 17,0,

d) 3-methylimidazolidine-2,5-Dion-1-yl (28,9%); crystallized from ether, so A7,9; 54,8; 51,6; 48,9; 43,6; 40,9; 32,5; 29,6; 24,8; 24,4.

e) 3-azabicyclo[3,2,1] octane-2,4-dione-3-yl (21% ); TLC Rf0,44; msvr 369,2205 calculated 369,2167,

13C-NMR: 176,7; 161,2; 157,6; 109,4. 60,9; 58,3; 54,7; 48,8; 44,8; 44,7; 43,5; 40,5; 32,5; 32,4; 27,1(2); 24,8; 24,7.

W) piperidine-2,6-dione-1-yl (10% ); crystallized from a mixture of methylene chloride-hexane; so PL, 146-148aboutC; TLC Rf0,37; msvr 343,2011 calculated 343,2011.

13C-NMR: 172,7; 161,4; 157,7; 109,5; 61,1; 58,5. 54,8; 48,9; 43,6; 41,4; 33,0; 32,7; 25,0; 24,8; 17,2.

C) 4,4-dimethylpiperidine-2,6-Dion-1-yl (14,5%); crystallized from ethyl acetate; so PL, 212-213aboutC; TLC Rf0,51; msvr 371,2276 calculated 371,2322.

13C-NMR: 172,2; 161,4; 157,7; 109,5; 61,1; 58,6; 54,9. 48,9; 46,5; 43,6; 41,5; 32,9; 29,0; 27,7; 25,1; 24,8.

and) 8-Aza-Spiro[4,5] decane-7,9-Dion-8-yl (31,9% ); crystallized from isopropano; so pl. 172-173aboutC; TLC Rf0,49; msvr 397,2450 calculated 397,2480.

13C-NMR (250 MHz): 172,4; 161,4; 157,7; 109,5; 61,1; 58,5; 54,9; 48,9; 45,0; 43,5; 41.5; 39,4; 37.6; 32,9; 25,0; 24,7; 24,2.

K) 5,5-dimethyloxazolidine-2,4-Dion-3-yl (20,8% ); crystallized from a mixture of ethyl acetate-hexane; so PL; 162-163aboutC; TLC Rf0,65; msvr 359,1936 calculated 359,1957.

13C-NMR: 176,1; 161,2; 157,5; 154,6; 109.5; 83,2; 60,8; 57,5; 54,6; 48,8; 43,5; 41,5; 32,0; 24,6; 24,3; 23,5; 23,4.

l) imidazolidin-2,5-Dion-1-yl (33,6% ); crystallizer>13C-NMR: 171,8; 161,3; 159,1; 157,6; 109,6; 61,0; 57.7; 54,7; 48,9; 46,4; 43,5; 40,4; 32,4; 24,7; 24,4.

m) 3,3-dimethylacrylamide (55,6% ); crystallized from a mixture of methylene chloride-isopropyl ether; so pl. 145-147aboutC; TLC Rf0,53; msvr 357,2126; calculated 357,2164

13C-NMR: 183,4. 175,9; 161,3; 157,6; 109,5; 61,0; 57,9; 54,7; 48,8; 43,5(2); 40,4; 39,8; 32,2, 25,6; 24,8; 24,4.

n) pyrazolo (23,8% ); crystallized from ether; so square 86-88aboutC; TLC Rf0,46; msvr 298,1895; calculated 298,1906.

13C-NMR: 161,3; 157,8; 139,4. 129,8; 109,7; 104,8; 61,0; 56,6; 54,7; 53,0; 49,0; 43,6; 34,6. 25,0; 24,7.

o) 1,2,4-triazole-1-ID (62,3% ); crystallized from a mixture of ethyl acetate-hexane; so pl. 150-152aboutC; TLC Rf0,37; MSIT 299,1853 calculated 299,1858.

13C-NMR: 161,3; 157,6. 152,0; 145,7; 109,8; 60,9; 56,2; 54,6; 50,4; 48,9; 43,6; 33,9; 24,9; 24,6.

p) 4,4-dimethylimidazolidin-2,5-Dion-1-yl (25%); crystallized from a mixture of methylene chloride-ether; so PL, 189-o; TLC Rf0,35; msvr 358,2074 calculated 358,2000.

13C-NMR: 177,8. 161,2; 157,6; 156,9; 109,5; 60.9; 58,4; 57,6; 54,6; 48,8; 43,5; 40,0; 32,3; 25,0; 24,6; 24,3.

R) tetrazol-2-yl (30,5%); amorphous; TLC Rf0,64; msvr 300,1792 calculated 300,1809.

13C-NMR: 161,2; 157,5; 152,8; 109,6; 60,8; 56,6; 54,5; 54,1; 48,8; 43,5; 34,3; 24,9; 24,4.

(C) 4,5-dihydro-1H, 3H-pyrimidine-2,6-Dion-1-yl (46%); crystallized from a mixture of isoprop is 5,5; 109,5; 61,1; 58,4; 54,9; 48.9; 43,6; 42,0. 35,3; 33,0; 31,8; 25,4; 24,8.

t) 5-methyl-4,5-dihydro-1H, 3H-pyrimidine-2,6-Dion-1-yl (23%); crystallized from ethanol; so pl. 201-202aboutC; TLC Rf0,35; msvr 358,2118 calculated 358,2117.

13C-NMR: 172,9; 161,4; 157,7. 155,4; 109.5; 61.1; 58,4; 54,9; 48,9; 43,6; 42,4; 42,3; 42,1; 35,8; 33,2; 33,0; 24,9; 13,4 (the presence of extra peaks due to the presence of diastereomers).

u) 4-methyl-4,5-dihydro-1H, 3H-pyrimidine-2,6-Dion-1-Jn (55%); crystallized from a mixture of methylene chloride-ether; so pl. 202-208aboutC; TLC Rf0,38; msvr 358,2128 calculated 358,2117.

13C-NMR: 169,6; 161,4; 157,7; 155,2; 109,5; 61,1; 58,4; 54,9; 48,9; 43,5; 42,4; 42,0; 39,3; 33,2; 32,9; 24,9; 24,8; 20,8 (the presence of extra peaks due to the presence of diastereomers).

P R I m e R 3. CIS-7-(substituted methyl)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazine.

The following additional target compounds were obtained according to the method a of example 1 by replacing 2-(2-pyrimidinyl) nelfinavir on a similar 2-(2-pyridyl)mesilate.

a) 3-methylimidazolidine-2,5-Dion-1-yl (8,9% ); crystallized from a mixture of methylene chloride-isopropyl ether so pl. 142-143aboutC; TLC Rf0,43; msvr 343,1978 calculated 343,2018.

13C-NMR: 170,0; 159,2; 157,0; 147,8; 137,3; 112,8; 106,8; 60,7; 57,7; 54,6; 51,5; 50,5; 45,0; 40,7; 32,5; 29,5; 24,7; Chislennoe 370,2386.

13C-NMR: 172,2; 159,3; 147,9; 137,4; 112,9; 106,9; 60,9; 58,5; 54,8; 50,6; 46,5; 45,0; 41,5; 32,9; 29,1; 27,7; 25,1; 24,9.

in) succinimide (36,3%); crystallized from a mixture of methylene chloride-ether so pl. 164-165aboutC; TLC Rf0,41; msvr 328,1880 calculated 328,1899.

13C-NMR: 177,4; 159,2; 147,8; 137,3; 112,9; 106,8; 60,7; 57,9; 54,6; 50,5; 45,0; 40,6; 32,1; 28,1; 24,8; 24,5.

g) 8 azaspiro[4,5]decane-7,9-Dion-8-yl (25,3%); TLC Rf0,42 (ethyl acetate); msvr 396,2562; calculated 396,2525.

13C-NMR: 172,4; 159,3; 147,9; 137,3. 112,9; 106,9; 60,9; 58,5; 54,8; 50,6; 45,0(2) 41,5; 39,3; 37,6; 32,9; 25,0; 24,9; 24,2.

d) 5,5-dimethyloxazolidine-2,4-Dion-3-yl (27,3%); crystallized from a mixture of methylene chloride-ether; so pl.; 171-173aboutC; msvr 358,2040 calculated 358,2005; TLC Rf0,56.

13C-NMR: 176,3; 159,2; 154,8; 147,9; 137,4; 113,0; 113,0; 106,9; 83,4; 60,7; 97,5; 54,6; 50,6; 45,1; 41,6; 32,1; 24,7; 24,5; 23,6(2).

e) 4-methylsuccinimide (28%); crystallized from isopropyl alcohol; so pl. 145-150aboutC; TLC Rf0,47; msvr 342,2036 calculated 342,2056.

13C-NMR: 180,8; 176,6; 159,3; 147,9; 137,4; 113,0; 106,9; 60,9; 58,0; 54,7; 50,7; 45,1; 40,6; 36,4; 34,6; 32,3; 24,9; 24,6; 16,9.

W) tetrazolo (36%); amorphous; TLC Rfof 0.48 (ethyl acetate); msvr 299,1778 calculated 299,1859.

13C-NMR: 159,1; 152,7; 147,8; 137,3; 113.0; 106,9; 60,6; 56,6; 54,4; 54,1; 50,5; 45,1; 34,3; 24,9; 24,5.

C) 4,4-dimethylsuccinic is SS="ptx2">

13C-NMR: 183,5; 176,0; 159,3; 147,9; 137,4; 113,0; 106,9; 60,9; 57,9; 54,7; 50,6; 45,1; 43,6; 40,6; 39.9; 32,3; 25,6(2); 24,8; 24,6.

and 4,4-dimethylimidazolidin-2,5-Dion-Il (37%); crystallized from a mixture of methylene chloride-isopropyl ether; so pl. 170-171aboutC; TLC Rfof 0.28 (ethyl acetate) msvr 357,2203 calculated 357,2166.

13C-NMR: 177,8; 159,3; 157,0; 147,9; 137,5; 113,0; 107,0; 60,9; 58,6; 57,7; 54,7; 50,7; 45,1; 40,3; 32,5; 25,1(2); 24,7, 24,6.

to) imidazolidin-2,5-Dion-1-yl (45%); TLC Rf0,22; msvr 329,1903 calculated 329,1854.

13C-NMR: 171,9; 159,3; 159,1; 147,8; 137,5; 113,1; 107,1; 60,8; 57,7; 54,6; 50,7; 46,5; 45,1; 40,5; 32,4; 24,7; 24,6,

l) 1,2,4-triazole-1-yl (18,7% ); recrystallized from isopropyl ether-hexane; so pl. 109-110aboutC; msvr 298,1943 calculated 298,1906; TLC Rf0,37.

m) piperidine-2,6-dione-1-yl (22,8%); crystallized from a mixture of methylene chloride-isopropyl ether; so pl. 114-115aboutC; TLC Rf0,44; msvr 342,2043 calculated 342,2055.

13C-NMR (250 MHz): 172,8; 159,3; 147,9; 137,4; 112,9; 106,9; 60,9; 58,4; 54,8; 50,6; 45,0; 41,5; 33,0; 32,8; 25,0(2); 17,2.

h) 4-methyl-4,5-dihydro-1H, 3H-pyridine-2,6-Dion-1-yl (47%); crystallized from isopropanol; so pl. 184-186aboutC. TLC Rf0,35; msvr 357,2155; calculated 357,2164.

13C-NMR: 169,6; 159,3; 155,0; 147,9; 137,4; 112,9; 106,9; 60,9; 58,3; 54,8; 50,6; 45,0; 42,4; 42,1; 39,4; 33,2; 32,9; 24,9. 20,8 (the presence Dion-1-yl (40%); crystallized from isopropanol; so pl. 182-183aboutC; TLC Rf0,34; msvr 357,2147 calculated 357,2165.

13C-NMR: 172,9; 159,4; 155,5; 147,9; 137,4; 113,0; 107,0; 60,9; 58,4; 54,8; 50,6; 45,1; 42,4; 43,3; 42,0; 35,7; 33,3; 33,0; 25,0; 13,4.

p) dihydro-1H, 3H-pyrimidine-2,6-Dion-1-yl (67% ); crystallized from isopropanol; so pl. 190-191aboutC; TLC Rf0,28; msvr 343,1975 calculated 343,2011.

13C-NMR: 169,8; 159,4; 155,4; 147,9; 137,4; 113,0; 107,0; 60,9; 58,3; 54,8; 50,6; 45,1; 42,0; 35,3; 33,0; 31,8; 25,0; 24,9.

R) thiazolidin-2,4-Dion-3-yl (63%); crystallized from isopropanol; t; PL; 159-160aboutC; TLC Rf0,47 (ethylacetat: methanol, 19:1); msvr 346,1528 calculated 346,1463.

13C-NMR: 171,9; 171,7; 159,3; 148,0; 137,5; 113,1; 107,0; 60,8; 57,8; 54,6; 50,6; 45,1; 44,0; 33,7; 32,2; 24,9; 24,6.

P R I m e R 4. CIS-7-(Succinimidyl)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

According to the method In example 1 CIS-7-(hydroxymethyl)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a] pyrazin (247 mg, 1.0 mmol) and succinimide turned in ; 231 mg (70%) of the desired product as crystals (crystallized from isopropyl alcohol), identical with the substance obtained in the preceding example.

P R I m e R 5. CIS-7-[(8-azaspiro[4,5]decane-7,9-Dion-8-yl methyl]-2-(2 - pyrimidinyl)-2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1.2-a]Piras is in (142 mg, of 0.57 mmol) and 3,3-tetramethyleneglutaric anhydride (96 mg, or 0.57 mmol) was turned into 105 mg (46%) of the specified target product as colourless crystals (crystallized from isopropyl alcohol), identical with the substance obtained in example 2.

P R I m e R 6. (7S,9aS)-2-(2-pyrimidyl)-7-(Succinimidyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

A mixture of (7R, 9aS)-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazine (6,30 g 0,025 mol) and succinic anhydride (2,80 g 0,028 mol) in 280 ml of a mixture of xylenes (so pl. 139-143about(C) heated to 100aboutC and at this temperature, add dimethylformamide (4 ml) to ensure complete dissolution. The resulting mixture is subjected to intense boiling under reflux for 2 h, using a trap Dean-stark. The reaction solution is decanted from the tarry residue and concentrated in vacuo, obtaining amorphous solid product, which is transferred into the intensively stirred mixture of methylene chloride and water (250 ml each component) and the pH of the mixture was adjusted 6NNaOH to 11. The organic phase is separated, dried over sodium sulfate and concentrated in vacuo, obtaining a colorless foam (6.4g); Recrystallization of the entire sample from hot isopropyl with the th methylene). Msvr 329,1809 calculated 329,1854. Range13C-NMR identical to the spectrum of the racemic product of example 1.

On the other hand, 5,0 kg )17%) of the same product crystallized from isopropanol, is obtained from (7S,9aS)-7-(hydroxymethyl)-2-(2-pyrimidinyl)- 2,3,4,6,7,8,9, 9a-octahydro[1,2-a] pyrazine (17,1 mg, 0,069 mmol) according to method a of example 1.

P R I m e R 7. CIS-7-(pyrazolones)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1.2-a]pyrazin.

A mixture of CIS-7-(methanesulfonylaminoethyl)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a] pyrazine (350 mg, 1.0 mmol), pyrazole (439 mg, 6.5 mmol), sodium carbonate (228 mg, 2.2 mmol) and 15 ml of acetonitrile is refluxed for 18 hours, the Reaction mixture was cooled, the solvent is distilled off and the residue is divided between 20 ml of methylene chloride and 20 ml of water; pH intensively stirred biphasic mixture was adjusted to 10 by addition of a saturated solution of sodium carbonate. The aqueous layer was extracted with 20 ml of methylene chloride. The organic layers were combined, dried over sodium sulfate and the solvent is distilled off, getting a solid product, which is subjected to pulse chromatographicaliy on 6 g of silica gel, using as eluent ethyl acetate; obtain 134 mg (42%) of the target product .

13C-NMR (300 MHz, CDCl3) Delta: 159,3; 147,9; 139,3; 137,4; 129,8; 113,1; 107,0; 104,9; 60,9; 56,6; 54,6; 53,1; 50,7; 45,2; 34,7; 25,0; 24,9.

The synthesis of 1. Dimethylpyridin to 2.5, in primary forms,

To a stirred suspension of 2,5-pyridinedicarboxylic acid (2407 g, 14.4 mol) in methanol (8.0 l) at a temperature of from -5 to -10aboutWith added dropwise chloride thionyl (3430 g, 2,1, l, 28.8 mol), keeping the temperature in the interval (-5)-(-10)aboutC. After the addition was completed, the reaction mixture was allowed to warm to ambient temperature and stirred for 18 h the resulting solution was concentrated in vacuo to a volume of 4 l and add the same volume of water. Then pH intensively stirred mixture was adjusted to 10 by addition of saturated solution (aqueous sodium carbonate). Solids are removed by filtration. Separate the organic layer filter, washed with water (8 l) and dried in vacuum, obtaining the target compound (2250 g, yield 80%) as amorphous solid.

Synthesis of 2. Acetate dimethyl-CIS - and TRANS-piperidine-2,5-in primary forms.

The product obtained in the previous synthesis (2250 g, 11,53 mol), in the environment of glacial acetic acid (25 l) hydronaut in the presence of a catalyst - 57 g of platinum oxide at a pressure 3,52 kg/the spruce acetates in the form of a viscous syrupy product amber (2300 g, yield 100% ). the purity of which is sufficient to directly (without purification) use it at the next stage.

Synthesis of 3, Dimethyl -, CIS - and TRANS-1-(cyanomethyl)piperidine-2,5, in primary forms.

Intensively stirred mixture of the target product of the previous synthesis (3000 g, 11,53 mol), chloroacetonitrile (1.00 kg, 13,25 mol, 1.1 equivalents), sodium carbonate (8,00 kg, and 75.5 mol, 6.5 equivalent) and potassium iodide (320 g, 1,90 mol, 0.17 equivalent) in isobutyl ketone (36 l) was refluxed for 18 hours, the Reaction mixture was cooled to room temperature and the solids removed by filtration using a water-jet pump. The filtered solid product is subjected to a first extraction with isobutyl ketone (12 l), then methylene chloride (30 l). The original filtrate and both extract the filtered precipitate are combined and concentrated in vacuo, obtaining a mixture of target products (1400 g, 51% yield) in the form of oil of amber.

Synthesis of 4, Methyl-CIS-1-oxo-2,3,4,6,7,8, and 9,9-octahydro-1H - pyrido[1.2-a] pyrazin-7-carboxylate.

The solution of the target product of the previous synthesis )60,0 g, 0.25 mol) in methanol (1 l) and ethyl acetate (0.4 l) is subjected to hydrogenation in the presence of Ni PM The catalyst is filtered off and the filtrate was concentrated in vacuo, obtaining oil. After crystallization during the night from a mixture of methylene chloride/isopropyl ether (90 ml/120 ml, respectively) receive only the target CIS-isomer (target product) in the form of colorless crystals with tons of dps, 166-168aboutC (decomposes during melting) 24,99 g, i.e. a yield of 47%, SVR: 212,1156 calculated 212,1162.

13C-NMR (300 MHz, CDCl3) Delta: 173,9; 171,2; 64,8; 64,7; 56,3, 56,2; 51,7; 50,8; 40,6; 39,5; 25,0; 24,4.

Synthesis of 5. CIS-7-hydroxymethyl-2,3,4, 6,7,8,9,9 and octahydro-1H-pyrido[1.2-a]feast - zine.

In a flame dried capacity, equipped with a magnetic stir bar, refrigerator and input of nitrogen load suspension sociallyengaged (14,88 g, 0.46 mol) in 500 ml of dry tetrahydrofuran. Portions add target product of the preceding synthesis (53,61 g, 0.25 mol) in solid form; the addition is carried out for 1 h, intensively stirring the reaction mixture. The mixture is then refluxed 18 hours After cooling to 15aboutWith reaction "extinguish", carefully (dropwise) adding water (100 ml). The mixture is then filtered, and the filter cake was washed with 150 ml of tetrahydrofuran. The filtrate was concentrated in vacuo, obtaining the solid is lorenia extracts concentrated in vacuo, after receiving the target connection(42,06 g, yield of 97.8%) in the form of a solid amorphous material.

Msvr: 170,1413 calculated 170,1419.

13C-NMR (300 MHz, CDCl3) Delta: 65,6; 62,6; 57,8. 56,0; 51,8; 45,8; 34,7; 26,4; 26,0.

Synthesis of 6. CIS-7-hydroxymethyl-2-(2-pyrimidinyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

The solution of the target product of the previous synthesis (19.7 g, 0.12 mol), sodium carbonate (30,45 g, 0.29 mol) and 2-chloropyrimidine (13,6 g, 0.12 mol) in water (150 ml) is stirred under heating (95aboutC) for 14 hours, the Reaction mixture is cooled, and then extracted with 200 ml methylene chloride. The organic extract is washed with water, then brine (each wash 200 ml), stirred with activated charcoal, filtered, dried over anhydrous sodium sulfate and concentrated, obtaining an oily product amber color. Crystallization of all samples from a mixture of methylene chloride/hexane (45 ml/150 ml, respectively) gives a 21.5 g (yield 76,7% ) target compound as colorless crystals, so pl. 135-136aboutC. msvr 248,1622 calculated 248,1637.

TLC Rf0,3 (methylene chloride : methanol, 9:1)

13C-NMR (300 MHz, CDCl3) Delta: 161,2. 157,6. 109,7; 65,6; 60,9; 57,3; 54,8; 48,9; 43,4; 34,8; 26,1; 25,8.

Synthesis nsive mixed solution of the target product of the previous synthesis (1.5 g, 6.0 mmol) and triethylamine (by 1.68 ml, 12 mmol) in methylene chloride (28 ml), cooled to 5aboutWith dropwise for 15 minutes, add a solution of the acid chloride methansulfonate (0,70 ml, 9.0 mmol) in methylene chloride (7 ml). Within 10 minutes of mixing (at the 5about(C) after adding the acid chloride methansulfonate, analysis of aliquots of the reaction solution by thin layer chromatography (silica gel, eluent is a mixture of methylene chloride methanol composition of 9:1 by volume) shows that the reaction proceeded completely. To the reaction mixture are added water (50 ml), and pH intensively stirred mixture was adjusted to 9.5 by adding a saturated solution of sodium carbonate. The organic phase is separated, washed five times with water (portions 150 ml), dried over anhydrous sodium carbonate and concentrated in vacuo, obtaining the target compound (1,87 g, yield 95.4 percent), which is of sufficient purity to be used in the next stage without additional purification. All the resulting product is dissolved in 3 ml of hot methylene chloride, to which are added dropwise hexane (about 3 ml) as long as the solution is not turbid. By stirring for 1 h obtain 1.10 g of the crystal of the target product (the; 5,7; 54,6; 48,9; 43,5; 36,9. 33,4; 24,7; 24.2.

Synthesis of 8. CIS-7-hydroxymethyl-2-(2-pyridyl)-2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

The mixture consisting of the target product of the synthesis of 5 (9,10 g, with 53.4 mmol), sodium carbonate (14.1 g, 0.13 mol), 2-bromopyridine (25,5 ml of 42.3 g, 0.27 mol) and isoamyl alcohol (25 ml) is refluxed for 72 hours, the Reaction mixture is filtered while hot and the filter cake washed with 50 ml of methylene chloride. The filtrate was concentrated in vacuo, obtaining oil, which is taken in 100 ml of ethyl acetate. Add the same volume of water, and the pH intensively stirred mixture was adjusted to 11.5 by adding a saturated solution of sodium carbonate. Separate the organic phase, process it with activated carbon, dried over anhydrous sodium sulfate and concentrated in vacuo, obtaining an oily product. Pulse chromatographytandem just received sample (125 g of silica gel, the fraction 32-63 mesh, eluent is a mixture of methylene chloride/methanol composition of 97: 3 by volume), with monitoring of the obtained fractions by TLC [Rfproduct = 0,26 (eluent is a mixture of methylene chloride/methanol composition of 9:1 by volume), detection by means of UV-spectroscopy and the method of using the ledno yellow

13C-NMR (300 MHz, CDCl3) Delta: 159,1. 147,8; 137,4; 113,2; 107,0; 65,8; 60,7; 57,3; 54,7; 50,6; 45,0; 34,7; 26,2; 26,0.

Synthesis of 9. CIS-7-(methanesulfonylaminoethyl)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

Using the method of synthesis of 7, the target product of the previous synthesis (240 mg, 0.97 mmol) is converted into the target product of this synthesis (0,30 g, yield 94,7% ), has the form of a colorless oil, TLC Rf0,34 (ethyl acetate). Msvr 325,1474 calculated 325,1460.

13C-NMR (250 MHz, CDCl3) Delta: 159,2. 147,9; 137,5; 113,2; 107,1; 71,2; 60,7; 55,7; 54,6; 50,7; 45,2; 37,0; 33,5; 24,9; 24,2.

Synthesis of 10. CIS-7-(phthalimido)methyl-2-(2-pyrimidinyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

Method a Using method a of example 1 phthalimide (4,13 g of 36.5 mmol) and target product synthesis 7 (of 7.93 g, 2,43 mmol) is converted into the target product of this synthesis in the form of colorless crystals after crystallization from warm isopropyl alcohol, 1.86 g, 20% ), so pl. 161-162aboutWith, msvr 377,1815 calculated 377,1852.

13C-NMR (300 MHz, CDCl3) Delta: 168,4; 161,3; 157,6; 133,8; 132,0; 123,0; 109,5; 61,0; 57,8, 54,7; 48,9; 43,5; 39.8; 32,9; 24,8; 24,4.

Method C. Using the method of example 1, phthalimide (147 mg, 1.0 mmol) and target product of the synthesis of 6 (248 mg, 1.0 mmol) turn 331 ml (0.5%) IDO[1,2-a]pyrazin.

Target product synthesis 7 (57,1 g, 0,175 mol) and sodium azide (71,5 g, 1.1 mol) in dry dimethylformamide (500 ml) is stirred for 17 h at 100aboutC (oil bath). Then the stirring and heating is stopped and allowed to settle suspension of an excess of sodium azide . Carefully decanted supernatant, which was concentrated in vacuo, obtaining a light yellow oil. The remaining precipitate twice subjected to extraction with methylene chloride (portions of 500 ml). The oil is dissolved in United methylenechloride extracts. Add the same volume of water, and the pH intensively stirred mixture was adjusted to 11.5 by addition of 6N sodium hydroxide solution. The organic phase is separated, dried over anhydrous sodium sulfate and concentrated in vacuo, receiving, or 48.2 g of target compound as a pale yellow oil. TLC Rfof 0.53 (ethyl acetate).

Msvr 273,1735 calculated 273,1705.

13C-NMR (250 MHz, CDCl3) Delta: 161,3; 157,6; 109,6; 60.9; 56,7; 54,6; 52,8; 48,9; 43,5; 33,7; 25,3; 24,7.

Synthesis of 12. CIS-7-(aminomethyl)-2-(2-pyrimidinyl)-2,3,4,6,7,8,9,9 and octahydro - 1H-pyrido[1,2-a]pyrazin.

Method A. a Suspension of the target product of the synthesis of 10 (1.86 g, 4.9 mmol) in ethanol (15 ml) and anhydrous hydrazine (0,156 ml, 158 mg, 4.9 mmol) is refluxed islote (10 ml), and the resulting mixture is refluxed for 3.5 hours, the Reaction mixture was filtered, and the filtrate was concentrated in vacuo, obtaining a solid substance, which is dissolved in 15 ml of water, and the pH of the resulting solution was adjusted to 10.0 by the addition of 6N sodium hydroxide solution. The alkaline solution is extracted with methylene chloride (5 times 50 ml), organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo, getting 1.07 g (88% ) slotted product in the form of oil of amber. TLC Rfof 0.50 (methylene chloride : methanol : kontsentrirovannyi ammonia = 3:1:0,3). Msvr 247,1784 calculated 247,1787.

13C-NMR (300 MHz, CDCl3) Delta: 161,3; 157,6; 109,5; 61,1; 57,0; 54,9; 48,9; 43,4; 42,9; 36,6; 25,6; 24,9.

Method C. a Solution of the target product, obtained in the previous synthesis (48,0 g, 0,176 mol) in 800 ml of ethanol and 70 ml of ethylacetate hydronaut at a pressure of 3.5 kg/cm2in the presence of 24 g of catalyst (5% palladium on carbon for 2 hours After filtering off the catalyst, concentri simulation of the filtrate in vacuo get to 34.8 g (80.%) target compound as a colorless oil that crystallized upon standing, which was identical to the product obtained by method A.

Synthesis of 13. CIS-7-(phthalimido)methyl-2-(2-mmol) and target product synthesis 8 (1,00 g, 4.1 mmol) in turn 1,02 g (67%) of the target product of this synthesis in the form of colorless crystals (crystallization from isopropanol), so pl. 167-168aboutC. msvr 376,1900 calculated 376,1900.

13C-NMR (300 MHz, CDl3) Delta: 168,6; 159,3; 147,9; 137,4; 133,9; 132,1; 123,2; 113,0; 107,0; 60,9; 57,8; 54,7; 50,7; 45,1; 39,9; 33,0; 24,9; 24,6.

Synthesis of 14. CIS-7-(azidomethyl)-2-(2-pyridyl)-2,3,4,6,7,8,9,9 and octahydro - 1H - pyrido[1,2-a]pyrazin.

Using the method of synthesis 11, the target product obtained in the synthesis of 9 (1.0 g, a 3.06 mmol) in turn 0,70 g (84%) of the target product of this synthesis in the form of a colorless oil. Msvr 272,1739 calculated 272,1750.

13C-NMR(300 MHz, CDCl3) Delta: 159,2; 147,7; 137,2; 112,8; 106,8; 60,9; 56,9; 54,8; 50,5; 44,9; 43,1; 37,0; 25,6; 25,0.

Synthesis of 15. CIS-7-(aminomethyl)2-(2-pyridyl)-2,3,4,6,7,8,9,9 and octahydro-1H-Piri-up[1,2-a] feast

Using the method And the synthesis of 12, the target product of the synthesis of 13 (0,484 g, 1,29 mmol) turn in 0,311 g (98%) of the target product of this synthesis in the form of a colorless viscous oil. TLC Rf0,51 (methylene chloride : methanol : concentrated ammonia = 3:1:0,3). Msvr 246,1861 calculated 246,1844.

Identical product (0,60 g, 95%) obtained from the target product synthesis (0,70 g, 2.6 mmol) using the method In the synthesis of 12.

Synthesis of 16. (7R, 9aS)-7-(Aminata 12 (33,54 g, 0,136 mol) 1.44 l heated nearly to boiling isopropanol added (-)-almond acid (20,63 g, 0,136 mol), stirring the mixture to achieve complete dissolution. Stir the solution is allowed the opportunity to slowly cool to ambient temperature; after 24 h, filtered through water-jet pump is separated nitrogen crystalline mass which is dried in vacuum . All the obtained product is dissolved 1.85 l of hot isopropanol, and the resulting solution was allowed to cool down to ambient temperature, then stirred at this temperature for 72 h; during this time, the formation of nitrogen a colorless crystalline mass. 14.0 g, 51% yield of the salt of the desired product of this synthesis of (-)-almond acid, so pl. 202-203aboutWith that decomposes during melting. All the resulting product is dissolved in water (200 ml), Add the same volume of methylene chloride, and pH intensively stirred mixture was adjusted to 9.5 by addition of 6N NaOH solution. The organic phase is separated, dried and concentrated in vacuo, getting 6,30 g (37.6 per cent) of the target product of this synthesis in the form of a colorless solid. [ ]D25= 36,7aboutin methylene chloride [C = 0,0337 g/ml].

Target product predydushih-1H-pyrido[1,2-a]pyrazin.

Synthesis of 17. (7S,9aS)-7-(acetoxymethyl)-2-(pyrimidinyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

To a solution of the target product of the previous synthesis (180,4 mg, 0.73 mmol) in 2 ml of chloroform, add acetic acid (0,125 ml, 2,19 mmol) and isoenergetic (to 0.108 ml, 0,802 mmol). The resulting mixture was refluxed for 4 h, cooled, diluted with 25 ml of chloroform, then with 10 ml of water, and the pH of the mixture was adjusted to 10 by addition of a saturated solution of sodium carbonate. The aqueous layer was separated and extracted with 20 ml of methylene chloride. The organic layers were combined, treated with activated charcoal, dried over anhydrous sodium sulfate and the solvent is distilled off, getting 188,5 mg of oily product, which is subjected to chromatographicaliy on silica gel, using as eluent 500 ml of a mixture of ethyl acetate : hexane composition 3: 2; monitoring the separation carried out by TLC (ethylacetat). Fractions of the desired product (Rf0,30) gather together and the solvent is distilled off, getting 58.5 mg (28%) of the target product of this synthesis, []D25= -35,9about(methylene chloride). Msvr 290,1752 calculated 290,1742,

13C-NMR (300 MHz, CDCl3) Delta: 171,2; 161,4; 157,7; 109,6; 65,5; 61,0; 56,4; 54,8; 48,9; 43,5; 33,0; 24,9; 24,7; 21,1.

-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]-pyrazin.

Synthesis of 18. (7S,9aS)-7-(hydroxymethyl)-2-(2-pyrimidinyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazin.

The target product of the previous synthesis (51,4 mg, 0,177 mmol) dissolved in 1 ml of a mixture water : methanol composition 1:1 and added 6N NaOH (0.06 ml, 3.6 mmol). After stirring for 3 h of the mixed solvent is distilled methanol, aqueous residue was diluted with 25 ml of methylene chloride and 10 ml of water, and the pH of the obtained two-phase system was adjusted to 10. The aqueous layer was separated, extracted with him methylene chloride (2 times 10 ml), organic layers combined, dried over magnesium sulfate, the solvent is distilled off and the resulting residue is recrystallized from methylene chloride and isopropyl ether, getting 27 mg of the target product, so pl. 160-162aboutC.

[]D25= -34,2about(methylene chloride), msvr 248,1647 calculated 248,1638. The same method peredelnyj analogue obtained in the previous synthesis, in turn (7S,9aS)-7-(hydroxymethyl)-2-(2-pyridyl)- 2,3,4,6,7,8, and 9,9-octahydro-1H - pyrido[1,2-a]pyrazin.

Synthesis 19. (7S, 9aS)-7-(Methanesulfonylaminoethyl)-2-(2-pyrimidinyl) -2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a] pyrazin.

Using the synthesis method of 9, the target product of the previous synthesis (20.5 mg) with almost S="ptx2">

Using the same method peredelnyj analogue obtained in the previous synthesis, in turn (7S,9aS)-7-(methanesulfonylaminoethyl)-2-(2-pyridyl)- 2,3,4,6,7,8,9,9 and octahydro-1H-pyrido[1,2-a]pyrazole.

In table. 1 shows comparative data on the antidepressant action of many compounds of this invention and the known antidepressant desipramine (DMI). All the claimed compounds are low - or non-toxic.

Several studies have shown that clinically effective antidepressants attenuate behavioral responses caused2-adrainostimulatoram clonidine . This treatment includes tricyclic antidepressants, monoamine oxidase inhibitors and electroconvulsive therapy. In the following study, we tested the ability of the tricyclic antidepressant desipramine (DMI) and CF-93393 loosen caused by clonidine reduced motility in rats

Method. The male rats were administered oral filler. DMI (to 17.8 mg/kg) or CF-93393 (of 32.0 mg/kg) once a day for 4 days. At 24 h after the last injection, the animals received a filler or clonidine (0.1 mg/kg subcutaneously) and for 6 h was measured horizontal locomotor activity.

Results. Clonidine Sitel, but this effect was significantly weaker in rats pre-treated with DMI and CP-93393.

Anxiolytic action of the claimed compounds (see table.2) was verified by engaged in anti-conflict test, above.

1. RACEMIC OR OPTICALLY ACTIVE DERIVATIVES of PYRIDO[1,2-A]PYRAZINE General formula

< / BR>
where X Is N or CH;

Y

,,, or ,

Z , , , SCH2,,

OCH2, - Y1(CH2)nor - Y1(CH2)nsubstituted on the carbon atom by one or two methyl groups;

n = 1 or 2;

Y1- CH2, NH or N3.

2. Racemic derivatives of pyrido [1,2-a]pyrazine General formula

< / BR>
where A is hydrogen B - C1- C3-alkoxycarbonyl;

X1- C = O;

when A is hydrogen or a group

< / BR>
X is N or CH;

X1- CH2;

B - NON2;

when A group

< / BR>
X is N or CH,

X1- CH2,

B - Y2CH2-,

Y2- HO-, R SO2O, H2N, N3< / BR>
< / BR>
R - C1- C3-alkyl, phenyl or tolyl.

3. Optically active derivatives of pyrido [1,2-a] pyrazine General formula

< / BR>
where X Is N or CH;

Y3- HO , RSO2O-, R1COO - R> or optically active salts formed as a result of the merger acid when Y3- H2N-.

 

Same patents:

FIELD: biology, medicine.

SUBSTANCE: invention relates to chemical compounds and compositions that can be used as modulating agents of phototoxicity of skin cells. Proposed "modulators" relate to material that can either accelerate or decelerate damage of cells, for example, skin cells caused by effect (exposition) of light, for example, UV-rays of type A. Modulators are chosen from group consisting of 3-hydroxyproline pharmacophor or proline, 4-hydroxyproline or its alkyl ester. Invention provides modulating effect of phototoxicity of cells wherein modulators relate to molecule that can be molecule of skin components, in particular, collagen.

EFFECT: improved and enhanced method of modulation.

14 cl, 2 tbl, 13 dwg, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of converting group >C=O (I) in a compound into group >C=S (II) or into a tautomeric form of group (II) in a reaction resulting in a thionated reaction product when using the crystalline P2S5·2C5H5N as a thionizing reagent, as well as to a thionizing agent, that is a crystalline P2S5·2C5H5N and has the melting point of 167-169 °C.

EFFECT: proposed is a novel method of converting group >C=O (I) in a compound into group >C=S (II).

22 cl, 3 tbl, 4 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3,5-dimethylpyridine. Method involves reaction of propanol-1, formaldehyde and ammonia in presence of granulated binder-free zeolite Y-BS in Η-form at 250–450 °C and volume rate of supply of raw material (w), equal to 2-7 h-1, molar ratio of propanol-1: formaldehyde: ammonia is 1.0:0.2–2.0:1.5–5.

EFFECT: use of present method enables to obtain 3,5-lutidine with high volume rate of supply of raw material with high output.

1 cl, 1 tbl, 1 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to (R)-enantiomers of 2-arylpropionamides of the formula (Ia): and their pharmaceutically acceptable salts wherein Aryl represents phenyl group substituted with a group chosen from isopropyl, acetyl, (2'',6''-dichlorophenyl)amino-group, α-hydroxyisopropyl, (R,S)-α-hydroxybenzyl and its individual R-isomers, (R,S)-(α-methylbenzyl) and its individual R-isomer and (R,S)-α-hydroxy-α-methylbenzyl and its individual R-isomer; R represents hydrogen atom (H) or (C1-C4)-alkyl; R' represents the following groups: -amino acid residue consisting of linear or branched (C1-C6)-alkyl substituted with carboxy-group -CO2H; -residue of the formula: -CH2-CH2X-(CH2-CH2O)nR wherein R has abovementioned values; n means a whole number from 0 to 1 while X represents oxygen atom; -heteroaryl chosen from the group consisting of 2-pyrimidinyl or 4-pyrimidinyl. Also, invention proposes a pharmaceutical composition inhibiting of interleukin-8-induced chemotaxis of neutrophiles and comprising as an active components (R)-enantiomers of 2-arylpropionamides of the formula (I) and their pharmaceutically acceptable salts in mixture with a suitable carrier. Also, invention proposes a method for preparing compounds of the formula (Ia). Also, invention proposes (R)-enantiomers of 2-arylpropionic acids of the formula (Va) given in the invention description and their pharmaceutically acceptable salts. Proposed (R)-2-arylpropionamides are useful in prophylaxis and treatment of tissue damage caused by enhanced accumulation of polymorphonuclear neutrophiles in the inflammation sites.

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

13 cl, 6 tbl, 24 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a novel method that can be used in industry for synthesis of substituted aniline compound represented by the following general formula (6):

wherein in the general formula (6) each R1, R2 and R3 means independently alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group, alkylcarboxamide group, nitro-group, aryl group, arylalkyl group, aryloxy-group, halogen atom or hydrogen atom; each X and Y means independently hydrogen atom, alkyl group, alkoxy-group, alkoxyalkyl group, halogenalkyl group, carboxyl group, alkoxycarbonyl group or halogen atom. Method involves oxidation of substituted indole compound represented by the following general formula (3):

(wherein values R1, R2, R, X and Y are given above) resulting to opening indole ring to yield acetanilide compound represented by the following general formula (4):

(wherein values R1, R2, R3, X and Y are given above) and Ac means acetyl group, and treatment of this compound by reduction and deacetylation. Also, invention relates to novel intermediate compounds. Proposed compound (6) can be used as intermediate substance for production of chemicals for agriculture and as medicinal agents.

EFFECT: improved method of synthesis.

20 cl, 1 sch, 3 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention concerns method of obtaining monofluoridated complex pyridinil and pyrimidinil beta-ketoesters of the formula (I) , where R1 is a 4-pyridine or 4-pyrimidine ring; R2 is a hydrogen atom, C1-6 alkyl group or halogen atom; and R3 is a C1-6 alkyl group. The method involves interaction of fluorine gas with a compound of the formula (II) , where R1, R2 and R3 are the same as above. The invention also concerns compounds of the formula (I).

EFFECT: possible application as intermediary products for pharmaceutical compounds.

12 cl, 1 dwg, 3 ex

FIELD: chemistry.

SUBSTANCE: inventive subject matter is compouns and their pharmaceutically acceptable salts which can be applied in prevention and treatment of diseases caused by HCV infection. Structural formulae of the compounds are presented in the claim.

EFFECT: obtaining anti-HCV medicine including the claimed compound or its pharmaceutically acceptable salt as active component.

2 cl, 100 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula (I) , in which A is selected from one or several X and/or Y groups; X represents methylene group; Y represents C2-alkinylene group; n represent integer number from 1 to 5; R1 represents group R2, optionally substituted with one or several R3 and/or R4 groups; R2 represents group selected from pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, pyrazolyl, isoxazolyl, oxadiazolyl, naphtyl, chinolinyl, isochinolinyl, dihydroisochinolinyl, 2-oxo-3,4-dihydrochinolinyl, indolyl, benzimidazolyl, pyrrolopyridinyl; R3 represents group selected from halogen atoms, groups C1-6-alkyl, C3-7-Cycloalkyl, C1-6-alkoxy, NR5R6 and phenyl; R4 represents group selected from groups: phenyl, naphtyl, pyridinyl; R4 group or groups can be substituted with one or several R3 groups, similar or different from each other; R5 and R6 independently on each other represent C1-6-alkyl group; R7 represents hydrogen atom or C1-6-alkyl group; R8 represents hydrogen atom or group C1-6-alkyl, C3-7-cycloalkyl, C3-7-Cycloalkyl- C1-3-alkylene; in form of base, acid-additive salt, hydrate or solvate. Invention also relates to methods of obtaining formula (I) compound by any of ii. 1-3, to compounds, determined by general formula (IV), (VII), to pharmaceutical composition, as well as to application of formula (I) compounds by any of ii. 1-3.

EFFECT: obtaining novel biologically active compounds possessing activity of enzyme FAAH inhibitors.

10 cl, 5 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to compounds of formula I and its pharmaceutically acceptable salts and esters where X1 stands for O or CH2; R1 stands for hydrogen; R2 stands for hydrogen or C1-C7-alkyl, or if X1 stands for CH2, R2 stands for hydrogen, C1-C7-alkyl or C1-C7-alkoxygroup; R3 stands for hydrogen or C1-C7-alkyl; R4 and R5 or R5 and R6 are bound and form a ring together with carbon atoms whereto attached, and R4 and R5 or R5 and R6 simultaneously stand for -CH=CH-CH=CH- or -(CH2)P- where p is equal to 4; and R4 and R6 are included in a ring structure as specified above, or independently stand for hydrogen; R7 and R8 stand for hydrogen; and one of R6 and R7 stands for where X2 stands for O or NR9; R9 stands for C1-C7-alkyl; one or two of Y1, Y2, Y3 and Y4 stand for N, and the others stand for C-R12; R10 stands for hydrogen, C1-C7-alkyl; R11 stands for hydrogen, C1-C7-alkyl; R12 independently in each case are chosen from the group including hydrogen, C1-C7-alkyl, C3-substituted with CF3; and n is equal to 0 or 1.

EFFECT: agonistic activity to PPARδ and PPARα.

20 cl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula and to their pharmaceutically acceptable salts or esters, where X1 is O, S, CH2; R1 is hydrogen; R2 is hydrogen or C1-C7alkyl, R3 is hydrogen or C1-C7alkyl; R4 and R8 are independently hydrogen, C1-C7alkyl, C1-C7alkoxy-C1-C7alkyl, fluoroC1-C7alkyl; R5, R6 and R7 are independently hydrogen, C1-C7alkyl, halogen, fluoroC1-C7alkyl; and one or R5, R6 and R7 represents , where X2 is S, O, NR9, (CH2)PNR9CO or (CH2)PCONR9, R9 is hydrogen, C1-C7alkyl; one or two of Y1, Y 2, Y3 and Y4 is N, and the rest represent C-R12 R10 is C1-C7alkyl, C3-C7 cycloalkyl; R11 is hydrogen; R12 in each case is independently selected from hydrogen, C1-C7alkyl, C3-C7 cycloalkyl, fluoroC1-C7 alkyl, C1-C7alkoxy-C1-C7alkyl, hydroxyC1-C7alkyl, di-C1-C7alkylamino-C1-C7alkyl; R13 is phenyl or heteroaryl, which is a 6-member aromatic ring, containing nitrogen as a heteroatom, which can be substituted with a CF3 group, lower fluroalkoxy group or halogen; m=0 or 1, n=0, 1, 2, and p=0, 1 or 2, and the sum of m, n and p=1, 2, 3 or 4; under the condition that, there are no formula I compounds, where X1 is O, R2 and R3 are hydrogen; R6 is , X2 is O or S, and m=0. The invention also relates to pharmaceutical compositions containing such compounds, with agonistic activity towards PPARδ and/or PPARα.

EFFECT: obtaining compounds for pharmaceutical compositions, with agonistic activity towards PPARδ and/or PPARα.

28 cl, 155 ex

FIELD: medicine.

SUBSTANCE: invention is related to compound of formula (I), (values of radicals are described in formula of invention) or its pharmaceutically acceptable salts, to methods of its production, pharmaceutical composition, which contains it. Application of invention is described for manufacturing of medicinal agent intended for provision of inhibiting action in respect to HDAC in warm-blooded animal, in production of agent used for treatment of malignant tumor. Method is also described for provision of inhibiting action in warm-blooded animal.

EFFECT: compounds have inhibiting activity in respect to HDAC.

15 cl, 17 tbl, 24 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new derivatives of phenylpiperazine of the formula (I): , wherein X represents 1) group of the formula (1): , wherein S1 means hydrogen, halogen atom; S2 and S3 mean independently of one another hydrogen atom, (C1-C6)-alkyl, phenyl or benzyl; S4 means two hydrogen atoms, oxo-group; S5 means hydrogen atom (H), (C1-C4)-alkyl; Y means CH2, oxygen atom (O), sulfur atom (S); or 2) group of the formula (2): , wherein S1 has above given values; R means hydrogen atom (H), (C1-C4)-alkyl, (C2-C6)-alkoxyalkyl, (C2-C4)-alkenyl or (C2-C4)-alkynyl; or 3) group of the formula (3): wherein S1 has above given values; Z means CH2, oxygen atom (O), nitrogen atom (N); or 4) group of the formula (4): , wherein S1 has above given values; or 5) group of the formula (5): , wherein S1 has above given values; A means oxygen atom (O), nitrogen atom (N) linked with piperazine ring at position 5 or 8; or 6) group of the formula (6): , wherein S1 has above given values; S6 and S7 mean hydrogen atom or oxo-group; or 7) group of the formula (7): , wherein one of dotted line can represent a double bond; S1 has above given values; P = T = Q mean nitrogen atom or P = T mean nitrogen atom; Q means CH or CH2; or P = Q mean nitrogen atom; T means CH, CH2, CH-CH3, C-CH3; or P means nitrogen atom; T means CH, CH2; Q represents sulfur atom; m = 2-6; n = 0-2; R5 and R6 mean independently of one another hydrogen atom (H), (C1-C3)-alkyl; or R5 + R6 represent group -(CH2)p- wherein p = 3-5; R7 means (C1-C3)-alkyl, (C1-C3)-alkoxy-, halogen atom, cyano-group; or R6 + R7 (R7 at position 7 of indole ring) mean group -(CH2)q wherein q = 2-4, and their salts. Compound of the formula (I) elicit high affinity both to dopamine D2-receptor and to serotonin reuptake site that allows their applying in treatment of the central nervous system diseases.

EFFECT: valuable medicinal properties of compounds.

5 cl, 3 tbl, 4 sch, 8 ex

FIELD: organic chemistry, heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to nitrogen-containing heterocyclic derivatives of the formula (I): A-B-D-E (I) wherein A means 5- or 6-membered heteroaryl comprising one or two nitrogen atoms in ring; B means ethenylene; D mean phenylene; E means group -N(COR)-SO2-G wherein G means phenyl; R means 5- or 6-membered heteroaryl or heteroarylmethyl comprising one or two nitrogen atoms in ring, or group -(CH2)n-N(R5)R6 wherein n means a whole number from 1 to 5; R5 and R6 are similar or different and mean: hydrogen atom, (C1-C6)-alkyl, hydroxyalkyl, aminoalkyl; or R5 and R6 in common with nitrogen atom can form 5-7-membered cyclic amino-group -N(R5)R6 that can comprise, except for nitrogen atom, also oxygen, sulfur or nitrogen atom as a component forming the ring, or their N-oxides. Compounds of the formula (I) elicit anticancer activity and can be used in medicine.

EFFECT: valuable medicinal properties of compounds.

10 cl, 1 tbl, 24 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

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