Derivatives of indole or pharmaceutically acceptable salt or solvate

 

(57) Abstract:

Usage: as substances with 5HT1such receptor antagonistic activity. The inventive product: indole derivatives of General formula I; where R1and R2hydrogen or C1-4alkyl; R3hydrogen or C1-3alkyl, or their pharmaceutically acceptable salt, or solvate. 10 C. p. F.-ly.

The invention relates to new indole derivative of General formula

I where R1hydrogen or C1-4-alkyl;

R2hydrogen or C1-4-alkyl;

R3hydrogen or C1-3-alkyl,

or their pharmaceutically acceptable salt, or solvate having NC1-like receptor antagonistic activity.

Selective NC1-like receptor antagonistic activity and a selective narrowing of the vascular activity of the compounds I has been demonstrated in vitro. In addition, these compounds selectively constrict the carotid arterial bed at shot dog, with virtually no impact on blood pressure.

After apparentering, including intraduodenal, the introduction of the compounds of the first, they demonstrate increased rates bioso the50(the molar concentration of compound required to achieve 50% of its maximal effect) and equipotential concentration ratio with 5-hydroxytryptamine (NT) were defined for the compounds of this invention with T1-like receptor, associated with isolated Saphenous vein of the dog by a known method.

Connection I do not have a significant effect on blood pressure or heart rate shot hound dogs at doses of 0.3 mg/kg of body weight intravenously.

The compound of example 1 at a dose of 10 mg/kg of body weight intravenously does not have an adverse effect in rats.

For comparison were taken from the connection of well-known example (see patent GB N 2124210, example 26). The bioactivity of this compound during intraduodenal administration (I. D.) anestesiology the dog was measured and compared with the compounds of the present invention. The results are shown in table. 2.

Test data clearly show that the rate of bioactivity above for compounds of the present invention relative to known compounds.

The intermediate connection 1.

N-methyl-3-(1,2,3,6-tetrahydro-1-methyl - 4-pyridinyl)-1H-indol - 5-acanaloniidae.

A solution of N-methyl-1H-indol-5-ethanal the Institute under reflux for 24 h, cooled and the resulting solid product is filtered (1.0 g). A solid sample (0.2 g) dissolved in hot methanol solution of oxalic acid (0.06 g), the solution is cooled and the resulting salt is precipitated by adding ethyl acetate (20 ml) and dry ether (50 ml). This salt is filtered off and dried in vacuo to obtain the title compound in the form of a solid product (0.12 g), so pl. 87-90about(With shrinkage).

Elemental analysis for C17H23N3O2S C2H2O40,6 H2O:

Found, C 52,2; H 5,6; N 9,5

Calculated C 52,5; H 6,0; N 9,7.

Intermediate compound 2.

5-bromo-3-(1-methyl-4-piperidinyl)-1H-indole.

A mixture of 5-bromoindole (39,2 g), N-methyl-4-piperidone (25,0 g) and pellets of potassium hydroxide (12.0 g) in methanol (9250 ml) is stirred and heated to boiling under reflux for 17 h, and then cooled to 5aboutWith under stirring. The resulting mixture was filtered. The residue is washed successively with methanol, water and again with methanol and ether and dried in vacuo to obtain the intermediate tetrahydropyridine (43,3 g) in powder form (i.e pl. 256-261aboutC), which is used without further characterization in the next stage. A solution of ethanol chloride is megalocnus the tetrahydropyridine (43,2 g) is dissolved in part of (0.95 l) of this solution. Hydrochloride intermediate compound precipitates. In order to re-dissolve this salt, the suspension is heated on a steam bath and add portion 2 N. hydrochloric acid (10 ml), water (15 ml) and concentrated (11n) hydrochloric acid (10 ml). The resulting solution was added to pre-gidrirovannoe suspension of 5% platinum oxide on coal (7.0 g) in ethanolic HCl solution (0.35 l of the above solution) and the resulting mixture hydronaut at room temperature and atmospheric pressure until cessation of hydrogen absorption. The resulting mixture was filtered and the solvent is evaporated. The residue re-suspended in ethyl acetate (600 ml). Add sodium carbonate (2n, 350 ml) with stirring and the resulting mixture filtered. The residue is washed with water and ethyl acetate and dried in vacuo to obtain the title compound (33,4 g) in powder form, so pl. 160-165aboutC.

Intermediate compound 3.

5-bromo-3-(1,2,3,6-tetrahydro-1-(phenyl - methyl)-4-pyridinyl)-1H-indole.

Fresh 1-benzyl-4-piperidone (11,7 g) is added to a stirred solution of 5-bromoindole (11,0 g) and 2M potassium hydroxide in methanol (81 ml). The resulting mixture is stirred at the boil under reflux for 8 h, and then OS(2:1, 2 x 15 ml) and dried in vacuum at 50aboutC for 18 h to obtain the title compound as a crystalline solid product (18.6 g). So pl. 173-175aboutC (with decomposition).

Intermediate compound 4

5-bromo-3-[1-(phenylmethyl)-4-piperidin-Neil]-1H-indole

A solution of intermediate compound 3 (of 4.00 g) in ethanolic hydrogen chloride (330 ml), obtained by adding acetylchloride (1.65 ml) to ethanol (250 ml) with stirring, hydronaut over 5% platinum on coal (3.0 g) at room temperature and atmospheric pressure until completion of the hydrogenation. The catalyst is removed by filtration. The solid part was washed with ethanol (15 ml) and the combined filtrates evaporated to obtain an oily residue. The remainder is divided between 2M aqueous sodium carbonate (75 ml) and ethyl acetate (175 ml), the phases are separated and the aqueous layer was again extracted with ethyl acetate (100 ml). The combined organic layers are then washed with water (50 ml), extracted with saturated saline solution (50 ml), dried over anhydrous magnesium sulfate and the solvent is evaporated to obtain the title compound as an oil (3.3 grams). TLC on SiO2CH2Cl2:EtOH:0,88 NH3(100:8:1) Rg 0,44.

P R I m e R 1. N-methyl-3-(1-methyl-4-Piperi is 001 mol) in absolute alcohol (70 ml) and anhydrous dimethylformamide (5 ml) hydronaut in the presence of 5% palladium on charcoal (0.36 g) at room temperature and atmospheric pressure. After 20 hours the absorption of hydrogen (25 cm3theoretically 24 cm3) stops. The catalyst is filtered off and the solvent is removed in vacuo to obtain an opaque resin which cures in the form of a soft solid white (0.3 g). After purification on chromatograph with instant evaporation (Sorbsil C60 silica gel, CH2Cl2(Eton)0.88 ammonia 50:80:1) to obtain colorless oil (0.21 g), which was triturated with ether to obtain the title compound (0.17 g), so the melting point 156-158aboutC. TLC SiO2(CH2Cl2:EtOH:0.88 ammonia 50:8:1)

Rf of 0.4; detection by UV, RA.

Determination of water found 0,12% wt./wt.0,02 mol.EQ.

Elemental analysis for C17H25N3O2S O O2H2O

Calculated C of 60.8; H 7,5; N 12,5

Found, C, 60,5; H 7,3; N 12,1

P R I m m e R 2. N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant (i) (E(N-methyl-2-] 3-(1-methyl-4-piperidinyl)-1H-indol-5-yl] -tinsulanond.

A mixture of intermediate compound 2 (1,00 g) N-methylethanolamine (530 mg), tri-ortho-tolylphosphino (300 mg), palladium acetate (50 ml) and triethylamine (730 ml) in dry acetonitrile (added to bring the full volume to 10 ml) is stirred and heated in saaame 10 times. In each case, the sealed ampoule is heated at 100-110aboutWith over 3.5 hours Sealed ampoule is cooled, the contents are combined and the solvent is evaporated. The remainder chromatographic on silica gel (450 g) using a mixture of dichloromethane, ethanol and ammonia (in the early 80:80:1, gradually increasing the polarity to 65: 8: 1). Fractions containing the product are combined and evaporated to obtain a semi-solid substance. It quickly rubbed in a mixture of cyclohexane and ethyl acetate (1:1, 100 ml) to obtain a solid product, which is filtered and dried to obtain the title compound (6.85 g) in powder form, so pl. 190-192aboutC.

(ii) N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant.

A solution of the product from stage (i) (5,78 g) in a mixture of ethanolic hydrogen chloride obtained adding acetylchloride (1,71 g and 21.8 mmol) to 1MS ethanol (400 ml) with stirring, and dimethylformamide (300 ml), was added to the above for dissolving the source material, hydronaut at room temperature and atmospheric pressure, using 10% palladium on coal (5,00 g, 50% wt/wt of water) as a catalyst to the cessation of hydrogen absorption. The resulting mixture was filtered and the resulting filtrate is evaporated to policerelated the mixture is heated until until you dissolve the hard part. The phases are separated, the aqueous phase is extracted with ethyl acetate (200 ml) and the combined organic phases are washed with saturated brine (100 ml), dried over anhydrous sodium sulfate and evaporated to obtain a resin. This resin is crystallized from ethyl acetate (60 ml) to obtain the title compound (4.30 m) in the form of crystals with so pl. 170-171aboutC.

Elemental analysis for C17H25N3O2S:

Calculated C 60,9; H 7,5; N 12,5

Found, C 60,9; H 7,6; N 12,4

P R I m e R 3. N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant.

A solution of 4-hydrazino-N-methyl-benzenedisulfonamide (0.5 g) and 1-methyl-4-piperidinylidene (0.35 g) in a mixture of water (10 ml) and 2n. hydrochloric acid (1.0 ml, 2.00 mmol) is stirred for 2 days at room temperature. Add the next portion of the aldehyde (0.35 g) and stirring is continued for a further 30 minutes the resulting solution is then alkalinized with 8% sodium bicarbonate to pH 8 and extracted with chloroform (3 x 50 ml). The combined organic extracts dried (Na2SO4) and evaporated in vacuo to obtain the crude hydrazone in the form of an oil (1.0 g). The solution of the hydrazone (1.0 g) in chloroform (20 ml) containing complex on the Ute on the ice (200 g), stirred for 2 h, treated with 2M sodium carbonate (20 ml) and extracted with chloroform (3 x 50 ml).

The combined organic extracts dried (Na2SO4), evaporated in vacuo and the residue purified on a chromatographic column with an instant evaporation (9385 silica, 100 g), elwira CH2Cl2:EtOH:NH3(75:8:1) to obtain the impure material in the form of a yellow oil. Re-chromatography was carried out with an instant evaporation (9385 silica, 100 g) and elution CH2Cl2: EtOH: NH3(100:8:1) gives the product as an oil (0.05 g). It is crystallized from ethyl acetate to obtain the title compound in the form of a solid substance, so the melting point 156-157aboutC.

TLC SiO2CH2Cl2:EtOH:NH3(50:8:1)

Rf0,6

P R I m e R 4. N,N-dimethyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-atonality - MFA.

Sodium hydride (60% wt/wt with paraffin) is carefully added to the stirred solution of the product of example 1 in dry dimethylformamide (20 ml). The resulting mixture was stirred at room temperature under nitrogen atmosphere for 0.25 h, then in the thread add a solution under the conditions (440 mg) in dry dimethylformamide (1 ml). The mixture of paramasivan chromatographic on silica (150 g), elute with dichloromethane, ethanol and ammonia (80:10:1) to obtain a resin. The resin quickly rubbed in diethyl ether and specified in the title compound crystallized in the form of a powder (238 mg), so pl. 170-172aboutC.

TLC SiO2(CH2Cl2:EtOH:NH350:8:1)

Rf0,57.

P R I m e R 5.

(i) (E)-N,N-dimethyl-2- [3-(1-methyl-4 - piperidinyl)-1H - indol-5-yl]ethen - sulfonamide

A mixture of 5-bromo-3-(1-methyl-4-piperidinyl)-1H-indole (2.0 g), N,N-dimethylbenzenesulfonamide (1,184 g), tri-ortho-tolylphosphino (0.6 g), palladium acetate (0.1 g), triethylamine (1.0 ml) and anhydrous acetonitrile (12 ml) is heated in two 10-millimeter sealed ampoule under stirring at 107aboutC (oil bath temperature) in a period of 2.25 hours, the Reaction mixture is combined, the solvent is removed in a rotary evaporator and the residue in the form of foam chromatographic clean, elwira a mixture of dichloromethane, ethanol, 0.88 ammonia (100: 80: 1). In the rotary evaporation of the appropriate fractions give the product as a foam (1.92 g) TLC SiO2(isopropanol ethanol water 0.88 ammonia, 20:20:8:1).

Rf(primary) + 0,55 (lesser) + 0,4 (traces).

(ii) N,N-dimethyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant.

A solution of the product is obtained mixture hydronaut at 65 psi at room temperature for 17 hours The mixture is filtered and the resulting filtrate is evaporated, leaving a solid product (1.0 g), washed with isopropanol (3 x 20 ml) to obtain a solid product (0.8 g), melting 215-225aboutC.

After crystallization from hot ethanol (60 ml) receive specified in the title compound in the form of micro-needles (0.29 grams), so pl. 228-232aboutC.

TLC SiO2(isopropanol ether water 0.88 ammonia, 20:20:8:1)

Rf0,5.

P R I m e R 6. 3-(1-methyl-4-piperidinyl)1H-indole-5-econsultant

(i) (E)-2-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]-tinsulanond.

A mixture of intermediate compound 2 (2.0 g), vinylsulfonate (0.88 g), palladium acetate (100 mg), three(ortho-tolyl)phosphine (0,60 g), triethylamine (1.0 g) and acetonitrile (14 ml) divided into two equal portions and placed into two sealed ampoules (10 ml) and heated at 100aboutC for 4 h In each vial add more vinylsulfonate (0,22 g) and the resulting mixture was heated at 100aboutWith another 16 hours the mixture is evaporated to dryness in vacuo and the residue purified chromatographically (silica 9385, 400 g) elwira CH2Cl:EtOH:NH3(100:8:1) to obtain the title compound in the form of a solid product (0.8 g) so pl. 208-209aboutWith ethanolic hydrogen chloride (80 ml) hydronaut over previously restored palladium on coal (50% paste with water, 0.8 g) to stop the flow of hydrogen. The catalyst is filtered off, washed with hot ethanol (50 ml) and the filtrate evaporated in vacuo to obtain the crude material (0.15 g). Then the crystalline residue is heated to 70aboutWith 2 N. hydrochloric acid (200 ml), filtered and the resulting filtrate is evaporated to dryness in vacuum, azeotropic distillation with toluene). The residue is combined with the crude product obtained previously, and purified chromatographically with instant evaporation (9385 silica, 100 g), elwira CH2Cl2: EtOH: NH3(50:8:1) to obtain the title compound in the form of a solid product (0.3 g) so pl. more than 95about(Foams).

TLC SiO2(CH2Cl2:EtOH:NH3, 25:8:1)

Rf of 0.5.

P R I m e R 7. N-methyl-3-(4-piperidinyl)-1H-indol-5-acanaloniidae - chloride.

(i) (E)-N-methyl-2[3-(1-(phenylmethyl)-4-piperidinyl]-1H-indol-5-yl]atenshon - MFA.

In each of the three sealed ampoules mixture of intermediate compound 4 (1.10 g), N-methyl-Tinsulanonda (422 mg), triethylamine (843 μl), tri-ortho-tolylphosphino (242 mg) and palladium acetate (39 mg) in dry acetonitrile (volume adjusted to 10 ml) is stirred and heated at 100aboutC for 4 h After ohlord the Oia oily residue.

The residue is purified through column chromatography on silica gel (Merok 7229, 300 g), elwira a mixture of dichloromethane, ethanol, 0.88 ammonia (300:8:1 to 200:8:1 to 100:8:1). The appropriate fractions are combined and the solvent is evaporated in vacuo to obtain the title compound as a foam (2.14 g).

TLC SiO2(CH2Cl2:EtOH:0,88 NH3, 200:8:1)

Rf0,41

(ii) N-methyl-3-(4-piperidinyl)-1H-indol-5-econsultant, hydrochloride.

A solution of the product from stage (i) (2.14 g) in ethanolic hydrogen chloride (350 ml, obtained adding acetylchloride (860 g) to ethanol (350 ml) with stirring hydronaut on a pre-restored 10% palladium on charcoal (6.4 g) at 25aboutC and a pressure of 1 ATM for 18 h, the Reaction mixture is blown with nitrogen and add a solution of monitorate (8,2 g) in methanol (100 ml). The resulting mixture is stirred and brought to a boil under reflux in nitrogen atmosphere for 10 min, cooled to 25aboutWith, and then the catalyst is removed by filtration. After evaporation of the filtrate in vacuo get a solid residue (8.5 g), which is again dissolved in water (75 ml) and saturated with solid sodium chloride. The formed precipitate is filtered off, washed-Lavie connection in the form of a crystalline solid product (640 mg), so pl. 253-255aboutC.

TLC SiO2(CH2Cl2:EtOH:0,88 NH325:8:1)

Rf0,14.

P R I m e R 8. N-ethyl-3-(4-piperidinyl)-1H-indol-5-econsultant.

(i)(E)-N-ethyl-2-[3-(1-(phenylmethyl)- 4-piperidinyl]-1H-indol-5-yl]tinsulanond.

In each of two 10 ml sealed vials placed acetate plates (50 ml), tri-ortho-tolylphosphino (300 ml), triethylamine (650 mg), N-acylethanolamine (275 mg) and intermediate compound 4 (710 mg). Each mixture was adjusted to 110 l of dry acetonitrile. The ampoule is heated at 100aboutC for 16 h, then leave at room temperature for 4 days. The contents of the sealed vials are combined and the solvent and triethylamine is removed in vacuum. The residue is treated chromatography on silica (205 mg, merck 9385), elwira dichloromethane, ethanol and ammonia (100:8:1) to obtain a foamy substance (759 mg). This foam is crystallized from a hot mixture of ethyl acetate and cyclohexane to obtain the title compound (582 mg) in the form of microcrystals, so pl. 178-180aboutC.

(ii) N-ethyl-3-(4-piperidinyl)-1H-indol-5-econsultant.

A solution of the product from stage (i) (370 mg) in ethanolic hydrogen chloride obtained adding acetylchloride (105 gallade coal (50% wt/wt H2O; 1.13 g), at room temperature and atmospheric pressure until, until you stop the flow of hydrogen. The resulting mixture was filtered and the resulting filtrate is evaporated to obtain a foam (280 mg) which was dissolved in methanol (4 ml). Add sodium carbonate (2n. 1 ml) and the solvent is evaporated. The residue is divided between water (10 ml) and ethyl acetate (50 ml). The aqueous phase is extracted with ethyl acetate (50 ml) and the combined organic fractions are dried (Na2SO4) and evaporated to obtain a resin (235 mg) which crystallized from a mixture of ethyl acetate and ether (10 ml, mainly ethyl acetate) to obtain the title compound (104 mg) in powder form, so pl. 95-100aboutC.

TLC SiO2(CH2Cl2:EtOH:NH3, 25:5:1)

Rf0,3.

P R I m e R 9. N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant, hydrochloride.

A solution of the product of example 1 (50 mg) in hot ethanol (0.5 ml) are added to ethanol chloride in the hydrogen obtained by adding acetylchloride (33 mg, 0,420 mmol) to ethanol (1 ml) at room temperature in a stream under stirring, at room temperature. The solid product crystallizes from the initially clear solution. Poluchennym amount of ethanol, then dried at 60aboutC in vacuum for 1 h to obtain the title compound (44 mg) in the form of microcrystals, so pl. 237-239aboutC.

TLC SiO2(CH2Cl2:EtOH:NH3, 50:8:1)

Rf0,45.

Derivatives of indole of General formula

< / BR>
where R1and R2hydrogen or C1WITH4-alkyl;

R3hydrogen or C1WITH3-alkyl,

or their pharmaceutically acceptable salt or solvate.

2. Derivatives of indole under item 1, where R1hydrogen or C1WITH3-alkyl.

3. Derivatives of indole under item 1 or 2, where R2hydrogen or C1- C3-alkyl.

4. Derivatives of indole on PP.1 3, where R2WITH1WITH3-alkyl.

5. Derivatives of indole on PP.1 to 4, where R3means1WITH3-alkyl.

6. Derivatives of indole under item 1, which represents the N-methyl-3- (1-methyl-4 - piperidinyl)-1H-indol-5-econsultant or its pharmaceutically acceptable salt or solvate.

7. A derivative of indole under item 1, which represents a N, N-dimethyl-3- (1-methyl-4-piperidinyl) -1H-indol-5 - econsultant or its pharmaceutically acceptable salt or solvate.

8. A derivative of indole under item 1, represent Almaty.

9. A derivative of indole under item 1, which represents the N-methyl-3-(4-piperidinyl) -1H-indol-5-econsultant or its pharmaceutically acceptable salt or solvate.

10. A derivative of indole under item 1, which represents a 3-(1-methyl-4-piperidinyl) 1H-indole-5-econsultant or its pharmaceutically acceptable salt or solvate.

11. A derivative of indole under item 1 active agonists 5-HT1similar recipes.

Priority signs:

14.06.88 all values of the radicals R1R3.

17.06.88 N-methyl-3-(1-methyl-4-piperidinyl)-1H-indol-5-econsultant.

 

Same patents:

The invention relates to new derivatives of azetidine General formula:

O-R7 (I) where a nitrogen atom or the group-CH-, or C-HaI, where HaI, a chlorine atom or fluorine;

R1lower alkyl or cycloalkyl, lower halogenated or phenyl substituted mono - or Diptera;

R2, R3and R5the same or different and signify hydrogen or lower alkyl;

R4hydroxyl, amino, aminoalkyl, alkylamino, dialkylamino, pyrrolyl-1 or pyrrolidinyl-1, acylaminoalkyl, trifurcated;

R6hydrogen or amino group,

or

A and R1together form a group-O-CH2-and in this case have a chiral center configuration R or S,

R7hydrogen or lower alkyl,

or their pharmaceutically acceptable salts

The invention relates to new derivatives of intellipedia General formula

where R1phenyl substituted by substituents selected from the group consisting of lower alkyl, hydroxyl, protected hydroxyl, halogen or lower alkoxy,

And lower alkylen,

In the lower albaniles, or their pharmaceutically acceptable salts which exhibit anti-allergic effect

The invention relates to new biologically active pyridyl - or pyrimidinediamine derivative of piperazine or 1,4-disallocation, or their pharmacologically active acid additive salts with psychotropic action

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 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, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new antibacterial agents. Invention describes cycloalkyl-substituted derivatives of aminomethylpyrrolidine represented by the general formula (I): wherein each among R1 and R2 represents hydrogen atom; n represents a whole number from 1 to 4; Q represents structural moiety represented by the following formula (Ia): wherein R3 represents cyclic alkyl group comprising from 3 to 6 carbon atoms that can be substituted; R4 represents hydrogen atom; R5 represents hydrogen atom or amino-group; X1 represents halogen or hydrogen atom; A1 represents nitrogen atom or structural moiety represented by the formula (II): wherein X2 represents hydrogen, halogen atom or alkyl group comprising from 1 to 6 carbon atoms, or alkoxyl group comprising from 1 to 6 carbon atoms; X2 and R3 can form a ring structure in common with part of the parent skeleton optionally comprising oxygen, nitrogen or sulfur atom as a ring-forming atoms and optionally comprising alkyl group comprising from 1 to 6 carbon atoms as a substitute; Y represents hydrogen atom. Also, invention describes an antibacterial an agent containing compound by cl. 1. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds and agent.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

Substituted indoles // 2255087

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to new substituted indoles of the formula (I): and/or stereoisometic form of compound of the formula (I) and/or physiologically acceptable salt of compound of the formula (I) wherein R3 means residue of the formula (II): wherein D means -C(O)-; R7 means hydrogen atom (H) or -(C1-C4)-alkyl; R8 means (a) typical residue of amino acid among the group: phenylalanine or homophenylalanine wherein phenyl residue is unsubstituted or substituted with halogen atom; or (b) -(C1-C4)-alkyl wherein alkyl is a linear or branched and (b) 1) mono- or multi-substituted independently of one another with pyrrole residue wherein this residue is unsubstituted or substituted with halogen atom; (b) 2) mono- or bi-substituted independently with residue -S(O)x-R10 wherein x = 0, 1 or 2, or (b) 3) mono- or bi-substituted independently of one another -N(R10)2 wherein R10 means (a) hydrogen atom (H); (b) means -(C1-C6)-alkyl wherein alkyl is unsubstituted or substituted with halogen atom from 1 to 3 times; (c) phenyl wherein phenyl is substituted or substituted with halogen atom from 1 to 3 times; in the case (R10)2 residues R10 have values independently of one another (a), (b), (c); Z means (a) residue of heterocycles group comprising benzothiadizine, pyrrole, pyridine, pyrimidine, pyrazine, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, tetrazole, oxadiazolone, triazole being heterocycles are unsubstituted or substituted with -NH2=, =O, alkoxycarbonyl or aminocarbonyl from 1 to 3 times, or (b) means -C(O)-R11 wherein R11 means 1. -O-R10 or 2. -N(R10)2; R9 means (a) hydrogen atom (H); (b) means (C1-C6)-alkyl wherein alkyl is unbranched or branched and substituted with phenyl or =O independently of one another from 1 to 3 times; (c) phenyl wherein phenyl is unsubstituted or substituted with halogen atom; R1, R2 and R4 mean hydrogen atom (H); R5 means hydrogen atom (H); R6 means (a) phenyl wherein phenyl is unsubstituted or substituted with -NH2; (b) pyridine, or (c) pyrimidine being pyridine or pyrimidine is unsubstituted or substituted with groups -NH2, -NH-CH3. Compounds of the formula (I) are specific inhibitors of IkB kinase.

EFFECT: valuable biochemical properties of compounds.

3 cl, 3 tbl, 29 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

Up!