Derivatives triazolobenzodiazepine, methods for their preparation, intermediate compounds for their production, pharmaceutical antihistamine composition and its preparation

 

(57) Abstract:

New derivatives of triazolobenzodiazepine General formula (I) and pharmaceutical antihistamine composition are used as active ingredient a therapeutically effective amount of the compounds of formula (I). The compounds of formula (I) possess anti-allergic activity. The claimed compounds of formula (VII), their additive salt or a stereochemical isomeric form, where each of the dashed lines independently from each other represents an optional bond; the compound of formula (XIII). The methods of obtaining compounds of formula (I) for a total of eight). The methods allow to obtain new and valuable derivatives triazolobenzodiazepine having antiallergic activity that allows you to create pharmaceutical compositions on their basis for the treatment of allergic diseases. 13 C. and 4 h.p. f-crystals.

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Similarly get:

()-8-fluoro-6,11-dihydro-5H-[1,2,4] -triazole[5,1-b] [3] benzazepin-11-ol; so pl. 179,8oC (intermediate compound 7), and

()-9-chloro-6,11-dihydro-5H-[1,2,4] -triazole[5,1-b] [3] benzazepin-11-ol; so pl. 138,8oC (intermediate compound 8).

C) a Mixture of intermediate compound (6) (0,0235 peremeshivayte at room temperature over night. The mixture is filtered on celite and washed with methanol. The filtrate is evaporated to dryness. The remainder (of 10.58 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 98/2) (35-70 μm). Pure fractions are collected and evaporated. The remainder (of 8.95 g) is crystallized from 2,2'-oxybisethane get 7,16 g (77%) of 5,6-dihydro-11H-1,2,4 - triazolo-[5,1-b] [3] benzazepin-11-she (intermediate compound 9).

Similarly get:

8-fluoro-5,6-dihydro-11H-[1,2,4] triazole[5,1-b] [3] benzazepin-11-he; (intermediate compound 10); and

9-chloro-5,6-dihydro-11H-[1,2,4]triazole[5,1-b] [3] benzazepin-11-he; so pl. 160,6oC (intermediate compound 11).

Example 2

a) a Mixture of 1H-4,5-dihydro-benzazepin-2-amine (0,068 mol) and formic acid hydrazide (12,25 g) in methanol (980 ml) is stirred and heated under reflux for 72 hours. The mixture is evaporated in vacuum. The residue is placed in a 5% potassium carbonate (150 ml) and extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and evaporated. The residue (9,9 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 95/5). Pure fractions are collected and evaporated, to obtain 8.8 g (70%) of product. Sample (1,9 g) is recrystallized from 2,2'-oknie 12).

Similarly get:

6,11-dihydro-3-phenyl-5H-1,2,4-triazole[3,4-b] [3]benzazepin (intermediate compound 13);

6,11-dihydro-3-methyl-5H-1,2,4-triazole[3,4-b] [3]benzazepin (intermediate compound 14); and

6,11-dihydro-3-(4-pyridinyl)-5H-1,2,4-triazole[3,4-b] [3]benzazepin so pl. 214,4oC (intermediate compound 15).

b) a Mixture of intermediate (12) (0,035 mol) and manganese dioxide (64.4 g) in N, N-dimethylformamide (220 ml) was vigorously stirred for 24 hours at 40oC. the Hot mixture is filtered on celite, washed with hot N, N-dimethylformamide and evaporated in vacuum at 80oC. the Residue is dissolved in 2,2'-oxybisethane and filtered. The precipitate was washed with 2,2'-oxybisethane and dried, to obtain 5.8 g (83%) of product. Sample (2.1 g) is recrystallized from methanol, get to 0.92 g of 5,6-dihydro-11H-1,2,4-triazole[3,4-b] [3]benzazepin-11-it; so pl. 187,2oC (intermediate compound 16).

Similarly get:

11H-1,2,4-triazole[3,4-b] [3] benzazepin-11-he (intermediate compound 17);

5,6-dihydro-3-phenyl-11H-1,2,4-triazole[3,4-b] [3]benzazepin-11-he; so pl. of 188.3oC (intermediate compound 18);

5,6-dihydro-3-methyl-11H-1,2,4-triazole[3,4-b] [3] benzazepin-11-he (intermediate compound 19); and

5,6-dihydro-3-(4-feast is Troicki (1,91 g) and 1,2-dibromethane (3 drops) is stirred in tetrahydrofuran (several ml). Add 4-chloro-1-methylpiperidine (a few ml) and after start of the reaction is added dropwise 4-chloro-1-methylpiperidine (9,52 g) in tetrahydrofuran (40 ml) and the mixture brought to a boil. The mixture is boiled for 2 hours, then add the intermediate compound (9) (being 0.036 mol) in tetrahydrofuran (90 ml) at 60oC and the mixture is boiled for 3 hours. The mixture is cooled, poured into a mixture of ammonium chloride/ice and extracted. The aqueous layer was extracted with dichloromethane and methanol. The organic layer is dried (MgSO4), filtered and evaporated. The residue (16.5 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 99/5/0,05) (15 μm). Pure fractions are collected and evaporated, get to 4.14 g (39%) ()-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-1,2,4-triazole[5,1-b] [3] benzazepin-11-ol (intermediate compound 21).

Similarly get:

()-8-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinyl)- 5H-1,2,4-triazole-[5,1-b] [3]benzazepin-11-ol (intermediate compound 22);

()-11-(1-methyl-4-piperidinyl)-11H-1,2,4-triazole-[3,4-b] [3] benzazepin-11-ol (intermediate compound 23);

()-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-1,2,4 - triazole-[3,4-b] [3]benzazepin-11-ol (intermediate compound 24);

()-6,11-dihydro-11-(1-methyl-4-piperidinyl)-3-phenyl-5H - 1, is)- 5H-1,2,4-triazole-[3,4-b] [3]benzazepin-11-ol (intermediate compound 26);

()-6,11-dihydro-11-(1-methyl-4-piperidinyl)-3-(4-pyridinyl) -5H-1,2,4-triazole-[3,4-b] [3]benzazepin-11-ol (intermediate compound 27);

()-9-chloro-6,11-dihydro-11-(1-methyl-4-piperidinyl) -5H-[1,2,4] triazole[5,1-b] [3]benzazepin-11-ol (intermediate compound 28).

Example 4

A mixture of intermediate compound (5) (0,098 mole) and aluminum chloride (65,35 g) in 1,2-dichloroethane (400 ml) was stirred at room temperature overnight. The mixture was poured into ice-cold water and alkalinized with ammonia. The inorganic portion of the filter on celite and extracted with methylene chloride. The organic layer is dried (MgSO4), filtered and evaporated. The residue (25 g) purified column chromatography on silica gel (eluent: CH2Cl2/ CH3OH/NH4OH 96/4/0,2) (15-40 μm). Fraction (1) is collected and evaporated. The residue is crystallized from 2,2'-oxybisethane get 1,33 g (4%) ()-6,11-dihydro-7-methyl-11-(1-methyl-4 - piperidinyl)-5H-[1,2,4] -triazole-[5,1-b] [3]benzazepin-11-ol; so pl. 190,8oC (intermediate compound 29).

B. Preparation of the final compounds

Example 5

A mixture of intermediate compound (4) (to 0.127 mol) and methanesulfonate (220 ml) is stirred and heated under reflux overnight. The mixture is cooled, poured into ice, alkalinized the (44,8 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH from 90/10/0,5 to 80/20/0,5) (14-40 mm). Pure fractions are collected and evaporated. Fraction (1) (8.8 g) is recrystallized from a mixture of 2-butanone/2,2'-oxybisethane, obtain 3.8 g (20%) of 6,11-dihydro-8-methoxy-11-(1-methyl-4-piperidinylidene)-5H-[1,2,4]- triazole[5,1-b] [3]benzazepine; so pl. 165,5oC (compound 1). Fraction (2) (6 g) is recrystallized from methanol/2,2'-oxybisethane, get a 5.1 g (16%) of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-[1,2,4] triazole-[5,1-b] - [3]benzazepin-8-ol; so pl. 285,3oC (compound 2).

Example 6

A mixture of intermediate compound (5) (0,098 mole) and aluminum chloride (65,35 g) in 1,2-dichloroethane (400 ml) was stirred at room temperature overnight. The mixture was poured into ice-cold water and alkalinized with ammonia. The inorganic portion of the filter on celite and extracted with methylene chloride. The organic layer is dried (MgSO4), filtered and evaporated. The residue (25 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0,2) (15-40 μm). Fraction (1) is collected and evaporated. The residue is crystallized from 2,2'-oxybisethane get 1,33 g (4%) ()-6,11-dihydro-7-methyl-11-(1-methyl-4-piperidinyl)- 5H-[1,2,4] -triazole-[5,1-b] [3]benzazepin-11-ol. Fraction (2) is collected and evaporated. OST the ilidene)-5H-[1,2,4] - triazole-[5,1-b] [3]benzazepine; so pl. 150,2oC (compound 3).

Example 7

A mixture of intermediate compound (28) (0,006 mole) phosphorylchloride (80 ml) is stirred at boiling for 24 hours. The mixture is evaporated, the residue is placed in ice water with ethyl acetate, alkalinized with sodium hydroxide and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 99/5/0,5). Pure fractions are collected and evaporated, to obtain 1.5 g (80%). The product is crystallized from 2,2'-oxybisethane, obtain 1.04 g (55%) ()-9-chloro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)- 5H-[1,2,4] -triazole[5,1-b] [3] benzazepine; so pl. 176,2oC (compound 4).

Example 8

a) a Mixture of intermediate (21) (0,0139 mol) sulfuric acid (40 ml) is heated at 80oC for 1 hour. The mixture is cooled, poured into ice water, alkalinized with ammonia and extracted with methylene chloride. The organic layer is dried (MgSO4), filtered and evaporated. The residue (2.28 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, from 95/5/0,1 to 90/10/0,1) (15 μm). Pure fractions of subperitoneal)-5H-[1,2,4] - triazole-[5,1-b] [3] benzazepine; so pl. to 126.8oC (compound 5).

Similarly get:

8-fluoro-6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H- [1,2,4] -triazole-[5,1-b] [3]benzazepin; so pl. 146,2oC (compound 6);

11-(1-methyl-4-piperidinylidene)-11H-1,2,4-triazole[3,4-b] [3] benzazepin; so pl. 252,2oC (compound 7);

6,11-dihydro-11-(1-methyl-4-piperidinylidene)-3-phenyl-5H-1,2,4-triazole-[3,4-b] [3]benzazepin; so pl. 221,2oC (compound 9);

6,11-dihydro-3-methyl-11-(1-methyl-4-piperidinylidene)- 5H-1,2,4-triazole-[3,4-b] [3]benzazepin; so pl. of 226.7oC (compound 10); and

6,11-dihydro-11-(1-methyl-4-piperidinylidene)-3-(4-pyridinyl)-5H - 1,2,4-triazole-[3,4-b] [3]benzazepin; so pl. 239,6oC (compound 11).

Example 9

a) Ethylchloride (34,1 ml) is added dropwise at 80oTo a solution of compound (5) (0,0446 mol) in N,N-diethylethanamine (12,4 ml) and toluene (800 ml) and the mixture is stirred and boiled for 2 hours. The mixture is cooled, poured into water, decanted and extracted with ethyl acetate. The organic layer was washed with water, dried (MgSO4) filtered and evaporated. The residue is used without further purification, to obtain 19.3 g (100%) of product. The sample (2 g) is purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4 is open, receive 1 g of ethyl-4-(5,6-dihydro-11H-[1,2,4] triazole-[5,1-b] [3] benzazepin-11-ilidene)-1-piperidinecarboxylate; so pl. 105,9oC (compound 12).

Similarly get:

ethyl-4-(8-fluoro-5,6-dihydro-11H-[1,2,4] triazole-[5,1-b] -[3]benzazepin-11-ilidene)-1-piperidinecarboxylate; so pl. 118,2oC (compound 13);

ethyl-4- (5,6-dihydro-7-methyl-11H-[1,2,4]triazole-[5,1-b] [3]benzazepin-11-ilidene)-1-piperidinecarboxylate; so pl. 163,0oC (compound 14); and

ethyl-4-(9-chloro-5,6-dihydro-11H-[1,2,4] triazole-[5,1-b] [3]benzazepin-11H-ilidene)-1-piperidinecarboxylate (compound 15).

b) a Mixture of compound (12) (0,051 mol) of 48% aqueous solution of Hydrobromic acid (315 ml) is stirred and heated to 100oC for 6 hours. The mixture is cooled, poured into ice, alkalinized with ammonia and extracted with dichloromethane. The organic layer is dried (MgSO4), filtered and evaporated. The residue (10.2 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 93/7/0,2) (15-40 μm). Pure fractions are collected and evaporated, gain of 9.2 g (68%) of product. The sample (2 g) is crystallized from a mixture of 2-butanone/2,2'-oxybisethane, gain of 1.88 g of 6,11-dihydro-11-(4-piperidinylidene)-5H-[1,2,4] triazole-[5,1-b] benzazepine, hemihydrate; so pl. to 116.2oC (the who-[5,1-b] [3]benzazepin, hemihydrate; so pl. 125,3oC (compound 17);

9-chloro-6,11-dihydro-11-(4-piperidinylidene)-5H-[1,2,4] - triazole-[5,1-b] [3]benzazepine oxalate (1:1); so pl. 217,5oC (compound 18); and

6,11-dihydro-7-methyl-11-(4-piperidinylidene-5H- [1,2,4] triazole-[5,1-b] [3]benzazepin, hemihydrate; so pl. 144, 0mmoC (compound 19).

Example 10

A mixture of compound (16) (0,00751 mol), 1-(2-bromacil)- 4-methoxybenzene (0,0113 mol), potassium iodide (0.125 g) and potassium carbonate (2.1 g) in 4-methyl-2-pentanone (50 ml) stirred at the boiling point during the night. The mixture is cooled and evaporated. The residue is dissolved in methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and evaporated. The residue (4.5 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, from 99.5/1,5/0,2 to 98/2/0,2) (15 μm). Pure fractions are collected and evaporated. The residue (2.5 g) is recrystallized from a mixture of 2-propanone/2,2'-oxybisethane, gain of 1.94 g (88%) of 6,11-dihydro-11- [1-[2-(4-methoxyphenyl)ethyl)-4-piperidinylidene] - 5H-[1,2,4] -triazole[5,1-b] [3] benzazepine; so pl. is 129.3oC (compound 20).

A similar method get:

8-fluoro-6,11-dihydro-11-[1-[2-(4-methoxyphenyl)ethyl] -4 - piperidinylidene] -5H-[1,2,4]triazole-[5,1-b] [3]benzazepin; so pl. 128,2oC (sedesol- [3,2-a]pyrimidine-5-he; so pl. 196,2oC (compound 22);

8-fluoro-6,11-dihydro-11-[1-[2-(2-pyridinyl)ethyl] -4-piperidinylidene] -5H-[1,2,4] -triazole[5,1-b] [3] benzazepine oxalate (1:2), hemihydrate; so pl. of 161.7oC (compound 23);

6-[2-[4-(8-fluoro-5,6-dihydro-11H-[1,2,4] -triazole[5,1-b] [3]benzazepin-11-ilidene)-1-piperidinyl] ethyl] -2,3 - dihydro-7-methyl-5H-triazole[3,2-a]pyrimidine-5-he, monohydrate; so pl. 129,7oC (compound 24);

3-[2-[4-(8-fluoro-5,6-dihydro-11H-[1,2,4] -triazole-[5,1-b] [3] benzazepin-11-ilidene)-1-piperidinyl] ethyl]-2-methyl-4H-pyrido [1,2-a]pyrimidine-4-one; so pl. 176,4oC (compound 25);

1-[3-[4-(8-fluoro-5,6-dihydro-11H-[1,2,4] -triazole- [5,1-b] [3]benzazepin-11-ilidene)-1-piperidinyl]propyl] -1,3-dihydro-2H-benzimidazole-2-it, hemihydrate; so pl. 131,8oC (compound 26);

1-ethyl-4-[2-[4-(8-fluoro-5,6-dihydro-11H-[1,2,4]-triazole- [5,1-b] [3] benzazepin-11-ilidene)-1-piperidinyl]ethyl]-1,4 - dihydro-5H-tetrazol-5-he oxalate (2:5); so pl. 190,0oC (compound 27);

11-[1-[3-(4-pertenece)propyl] -4-piperidinylidene] - 6,11-dihydro-6H [1,2,4]-triazole[5,1-b][3]benzazepin, oxalate (1:1); so pl. 185,5oC (compound 28);

(E)-8-fluoro-6,11-dihydro-11-[1-(3-phenyl-2-propenyl)-4 - pyridinoline] -5H-[1,2,4] -triazole[5,1-b] [3] benzazepine oxalate (1: 1); so pl. 212,9oC (compound 29);

3-[2-[4-(5,6-dihydro-11H-[1,2,4] triazole [5,1-b] [3] benzazepin-11-ilidene)-1-piperidin originalidad]-6,11-dihydro-5H- [1,2,4]triazole[5,1-b] [3]benzazepin; so pl. 99,0oC (compound 31); and

4-(5,6-dihydro-11H-[1,2,4] triazole[5,1-b] [3] benzazepin-11-ilidene)-1-piperidinecarbonitrile; so PL, 161>5oC (compound 32).

Example 11

Tribromide boron (28 ml) is added dropwise at 0oC to a solution of compound (21) (0,00471 mol) in methylene chloride (50 ml) and the resulting mixture was stirred at room temperature for 24 h the Mixture was poured into ice, alkalinized with potassium carbonate and extracted with methylene chloride. The organic layer is dried (MgSO4), filtered and evaporated. The obtained residue (1.8 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 96/4/0,5) (15-40 μm). Pure fractions are collected and evaporated. The residue (0,61 g) is converted into the salt of oxalic acid (1:1) in 2-propanol. Get 0,57 g(32%) 4-[2-[4-[8-fluoro-5,6-dihydro-11H-[1,2,4]triazole[5,1-b] [3]benzazepin-11-ilidene)-1-piperidinyl] ethyl] phenol oxalate (1: 1) hemihydrate; so pl. 181,2oC (compound 33).

Example 12

A mixture of compound (32) (0,0245 mol) in methanol saturated with ammonia (200 ml), hydronaut for 12 h in a Parr apparatus (temperature, pressure 2,96 MPa (3 bar) in the presence of Raney Nickel (7.5 g) as a catalyst. After uptake of hydrogen (2 EQ.) the flask Pro,1-b] [3]-benzazepin-11-ilidene)-1-piperidylamine (used in the next stage without additional purification) (compound 34). The product was then purified column chromatography on silica gel (eluent CH2Cl2/CH3OH/NH4OH 90/10/1) (15-40 μm). Pure fractions are collected and evaporated. The residue (2.7 g) is transformed into g (E)-2-botanically (1:2) and recrystallized from methanol (abs.). Gain of 1.53 g of 4-(5,6-dihydro-11H- -[1,2,4] triazole[5,1-b] [3] benzazepin-11-ilidene)-1-piperidylamine butenedioate (1:2), hydrate (2:5); so pl. 184,3oC (compound 35).

Example 13.

A solution of 1,1'-carbonyl-bis-1H-imidazole (0,028 mol) in tetrahydrofuran is added dropwise at room temperature to a solution of compound (34) (0,00937 mol) in tetrahydrofuran and the mixture is stirred at room temperature for 1 h and Then added dropwise a solution of methanamine (40%) (1.5 g) and the resulting mixture was stirred at room temperature for 12 hours the Mixture is evaporated and the residue extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium chloride, dried (MgSO4), filtered and evaporated. The residue (3.6 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 92/8/0,5) (15-40 μm). Pure fractions are collected and evaporated, to obtain 2.4 g of the product. The product sample (1,95 g) turn in ethanol salt of (E)-2-the Teal] -N-metallocene (E)-2-butenedioate (1:1); so pl. 196,3oC (compound 36).

Example 14

A mixture of 3-frankenboob acid (0,00741 mole) of 2-chloro-1-methylpyridinium (0,00744 mol) and N,N-diethylethanamine (1.5 g) in methylene chloride is stirred at room temperature for 1 h, and then added dropwise a solution of compound (34) (0,00743) in methylene chloride and the resulting mixture was stirred at room temperature for 48 hours the Mixture was poured into 5% potassium carbonate, extracted with methylene chloride and washed with water. The organic layer is dried (MgSO4), filtered and evaporated. The resulting residue is purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 95/5/0,5) (15-40 μm). Pure fractions are collected and evaporated. The residue (1.9 g) is recrystallized from 2-butanone get to 1.15 g (38%) N-[2-[4-(5,6-dihydro-11H-[1,2,4]-triazole[5,1-bl [3]benzazepin-11-ilidene)-1-piperidinyl]ethyl] -3-furancarboxylic hemihydrate; so pl. of 167.2oC (compound 37).

Example 15

A mixture of compound (34) (0,00969 mol), 2-chloropyrimidine (0,0116 mol) and potassium carbonate (0,0194 mol) in N,N-dimethylformamide (100 ml) is stirred at boiling temperature for 12 hours, the Reaction mixture was cooled to room temperature and extracted with methylene chloride. Separated organice chromatography on silica gel (100 g, 15-40 μm; eluent: CH2Cl2/CH3OH/NH4OH, 95/5/0,2). Pure fractions are collected and the solvent evaporated. The residue (1,95 g) is recrystallized from 2-butanone. The residue is filtered off and dried, to obtain 1.1 g (29 %) N-[2-[4-(5,8-dihydro-11H-[1,2,4] - triazole[5,1-b] [3]benzazepin-11-ilidene)-1-piperidinyl] ethyl]- 2-pyrimidinamine; so pl. 161,5oC (compound 38).

Example 16

a) Methyl ester of 2-propanolol acid (0,0176 mole) is added dropwise to a mixture of compound (17) (0,0088 mol) in methanol (30 ml) and the mixture is stirred at the boiling temperature for 12 hours the Mixture is evaporated to dryness. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH 97/3/0,1). Pure fractions are collected in the form of oil. Obtain 2.8 g (61%) of product. The product in ethanol turned into salt (E)-2-botanically (1:1). Obtain 2.7 g (61%) of methyl ester of 4-(8-fluoro-5,6-dihydro-11H-[1,2,4]-triazole[5,1-b] [3]benzazepin-11-ilidene)-1-piperidinemethanol acid in the form of a salt of (E)-2-botanically (1:1) hemihydrate; so pl. 170,6oC (compound 39).

Similarly obtained:

Methyl ester of 4-(5,6-dihydro-11H-[1,2,4]triazole- [5,1-b] [3] benzazepin-11-ilidene)-1-piperidinemethanol acid in the form of oxalate (2:3), hemihydrate; so pl. 144,4oC (connect(80 ml) was stirred at room temperature overnight. The mixture is evaporated and the residue extracted with methylene chloride. The aqueous layer was evaporated, the obtained residue is neutralized 1 N. hydrochloric acid and evaporated to dryness. Product (2,05 g) is recrystallized from water, obtain 1.2 g (38%) of 4-(8-fluoro-5,6-dihydro-11H-[1,2,4]triazole[5,1-b] [3]benzazepin-11-ilidene)-1 - piperidinemethanol acid, dihydrate; so pl. 120,1oC (compound 41).

Example 17

At a temperature of 0oC is passed through the methanol oxiran (2 EQ.). The prepared mixture is added dropwise to a solution of compound (16) (0,0113 mol) in methanol and stirred the reaction mixture at room temperature for 24 hours and Then evaporated the solvent and the resulting residue is extracted with methylene chloride, washed with water, dried (MgSO4), filtered and evaporated the solvent. The residue is purified column chromatography on silica gel (260 g 15-40 μm, eluent: CH2Cl2/CH3OH/NH4OH , 95/5/0,3). Pure fractions are collected and evaporated the solvent. The residue (2.3 g) is recrystallized from 2-butanone, the precipitate is filtered off and dried. Gain of 1.62 g (46%) of 4-(5,6-dihydro-11H-[1,2.4] triazole[5,1-b] -[3] benzazepin-11-ilidene)-1-piperazineethanol; so pl. 153,7oC (compound 42).

Example 18

A mixture of compound (17) (0,01 mol), ()-[(4-fluoro is singing for 20 hours The mixture is filtered and the filtrate evaporated. The remainder in the form of oil dissolved in methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and evaporated to dryness. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 97/3/0,1). Pure fractions are collected and the solvent evaporated. Obtain 2.6 g (57%) of product. The product is crystallized from 1,1'-oxybisethane, produce 1.7 g(33%) ()-4-(8-fluoro-5,6-dihydro-11H-[1,2,4] triazole[5,1-b] [3]benzazepin-11-ilidene)-alpha- [(4-pertenece)methyl] -1-piperazineethanol; so pl. RUR 134.4oC (compound 43).

Example 19

The compound (5) (0,00767 mol) in ethanol (200 ml) hydronaut in the Parr apparatus at 50oC and the pressure 2,96 MPa (3 bar) in the presence as catalyst of palladium on activated carbon (2.2 g) for 5 hours After uptake of hydrogen (1 EQ.) the catalyst is filtered off through celite and the filtrate evaporated. The obtained residue (2.1 g) purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 94/6/0,5 to 90/10/0,5). Pure fractions are collected and the solvent evaporated. The resulting residue is crystallized from 1,1'-oxybisethane, allocate 1.22 g (83%) ()-6,11-dihydro-11-(1-methyl-4-piperidinyl)-5H-[1,2,4] triazole [5,1-b] [3] benzos is I (a few grams) in formaldehyde (540 ml) and acetic acid (80 ml) was stirred at 130oC during the night. The mixture is cooled and poured into ice, alkalinized with ammonia and extracted with methylene chloride. The organic layer was washed with water, dried (MgSO4), filtered and evaporated to dryness. The resulting residue is dissolved in 3 N. hydrochloric acid and washed with ethyl acetate. The aqueous layer was alkalinized 3 N. sodium hydroxide and extracted with ethyl acetate. The organic layer is dried (MgSO4), filtered and evaporated to dryness. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH/NH4OH, 90/10/1). Pure fractions are collected and the solvent evaporated, get 7,71 g (76 %). The product sample (2 g) is recrystallized from 2-propanol, gain of 1.2 g of 6,11-dihydro-11-(1-methyl-4-piperidinylidene)-5H-[1,2,4] triazole[3,4-b] [3] benzazepin-3-methanol, hemihydrate; so pl. 250,1oC (compound 45).

C. examples of the compositions.

The following formulations are examples of pharmaceutical compositions in unit dosing form acceptable to systemic or local injection of warm-blooded animals in accordance with the present invention.

The term "Active ingredient" (A. I.) used in these examples relates to a compound of formula (I) or formula (VII), to their formats the Oral drops.

500 g of A. I. dissolve at 60-80oC in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol. After cooling to 30-40oC to the solution was added 35 l of polyethylene glycol and the mixture was thoroughly stirred. Then add a solution of 1750 g of sodium saccharide in 2.5 l of purified water and while stirring add 2.5 l of odorants cocoa and the required amount of polyethylene glycol to a volume of 50 l, get solution for oral drops containing 10 mg/ml A. I. the resulting solution fill in suitable packaging.

Example 22 - Oral solutions.

9 g of Methyl ester of 4-hydroxybenzoic and 1 g of propyl ester of 4-hydroxybenzoic acid dissolved in 4 l of boiling purified water. In 3 l of the resulting solution dissolve 10 g of 2,3-dihydroxybutanedioate, and then 20 g of A. I. Last solution is mixed with the remaining part of the previous solution and 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 40 g of sodium Saccharide is dissolved in 0.5 l of water and add 2 ml of raspberry and 2 ml of gooseberry family essences. The last solution is mixed with the previous one, add the required amount of water to volume of 20 l, receive oral solution containing 5 mg A. I. the teaspoon (5 ml). The resulting solution fill the appropriate packaging.

Example 24 Tablets, film-coated

Preparation of core tablets

Here 100 g A. I., 570 g lactose and 200 g starch is thoroughly mixed and then moisturize with a solution of 5 g of dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon - K 90) approximately 200 ml of water. The wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose (Avisel) and 15 g hydrogenated vegetable oil (Sterotex). The entire mixture is thoroughly mixed and pressed into tablets, get 10,000 tablets each containing 10 mg of active ingredient.

Floor.

To a solution of 10 g of methyl cellulose (Methocel 60 HG) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of methylene chloride. Then add 75 ml of methylene chloride and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of methylene chloride. The last solution is added to the first and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opasprey K-1-2109) and the entire mixture is homogenized. The core tablet is for injection

1.8 g of Methyl ester of 4-hydroxybenzoic acid and 0.2 g of propyl ester of 4-hydroxybenzoic acid dissolved in approximately 0.5 l of boiling water for injection. After cooling to approximately the 50oC with stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g of A. I. the Solution is cooled to room temperature and add water for injection to a volume of 1 l, get a solution with a concentration of 4 mg A. I. the ml Solution is subjected to sterilization by filtration (U. S. P. XVII p. 811) and fill sterile packaging.

Example 26 - Candles.

Dissolve 3 g of A. I. in a solution of 3 g of 2,3-dihydroxybutanedioate in 25 ml of polyethylene glycol 400. Melt together 12 g of surfactant (SPAN) and triglycerides (Wetepsol 555) in the quantity necessary to obtain 300 g of a mixture. The latter mixture is thoroughly mixed with the first solution. Thus obtained mixture was poured into moulds at a temperature of 37-38oC and get 100 suppositories each containing 30 mg A. I.

1. Derivatives triazolobenzodiazepine General formula I

< / BR>
and its pharmaceutically acceptable salt additive and stereochemical isomeric forms,

where each of the dashed lines independently of each item is R2represents a hydrogen atom, a halogen atom, a hydroxy-group or C1-4-alkyloxy;

R3represents a hydrogen atom, a C1-4-alkyl;

fragment-B=D - represents a bivalent radical of formula C(R4)=N- (a-1) or-N=C(R5)- (a-2);

R4represents a hydrogen atom;

R5represents a hydrogen atom, a C1-4- alkyl, hydroxy - C1-4- alkyl, phenyl or pyridinyl;

L represents hydrogen, C1-6- alkyl, C1-6- alkyl, substituted by one of the substituents selected from the group comprising a hydroxy-group, C1-4-alkyloxy, hydroxycarbonyl, C1-4- allyloxycarbonyl, C1-4- alkylaminocarbonyl, phenyl, substituted by hydroxyl or C1-4-alkoxy, and phenoxy, substituted with halogen; C1-6-alkyl, substituted hydroxy and fenoxaprop, substituted with halogen; C3-6alkenyl, substituted phenyl, or a residue L is a radical of the formula

-Alk - Y - Het1(b-1)

- Alk-NH-CO-Het2(b-2)

-Alk-Het3(b-3)

where Alk represents a C1-4- alcander,

Y represents-NH-;

Het1- pyrimidinyl;

Het2- furanyl;

Het3is abominator-1-yl or a radical of the formula

< / BR>
where the fragment-A - Z - represents-S-CH=CH-, -S-CH2-CH2-, -CH=CH - CH=CH-.

2. Connection on p. 1, where the fragment-B=D - represents a bivalent radical of the formula-C(R4)=N- (a-1), where R4has specified in paragraph (1 value.

3. Connection on p. 2, where Deputy L represents a C1-4-alkyl or a radical-Alk-Het3(b-3), where Alk and Het3are specified in paragraph 1.

4. Connection on p. 1, where the specified connection is a 6,11-dihydro-11-(1-methyl-4-piperidinylidene) -5H-1,2,4-triazole (5,1-b) (3) benzazepin, its stereochemical isomeric form or acid additive salt.

5. Pharmaceutical antihistamine composition comprising an active ingredient, a pharmaceutically acceptable carrier and adjuvants, wherein as the active ingredient it contains a therapeutically effective amount of the compounds under item 1.

6. The method of obtaining the antihistamine composition, comprising mixing an effective amount of the active ingredient, a pharmaceutically acceptable carrier and auxiliary additives, characterized in that the active ingredient is used as a compound of formula I under item 1.

7. With the additive salt or a stereochemical isomeric forms, where each of the dashed lines independently from each other represents an optional bond; where the radicals R1- R3, -B = D - are specified in paragraph 1 values, Q represents C1-6-allyloxycarbonyl, C1-4-alkylaryl or C1-6-alkyl substituted by halogen, cyano or amino group, as an intermediate product.

9. The compound of formula XIII

< / BR>
where K is oxygen or two hydrogen atoms, and the radicals R1-R3, -B=D - are specified in paragraph 1 values, provided that excluded 11N-1,2,4-triazole (3,4-b) (3) benzazepine, as an intermediate product.

10. The method of obtaining derivatives triazolobenzodiazepine General formula I on p. 1, characterized in that the alcohol of General formula II or ketone of General formula III

< / BR>
< / BR>
where R1-R3L-B = D - are specified in paragraph 1 values

is subjected to cyclization in the presence of acid.

11. The method of obtaining derivatives triazolobenzodiazepine General formula I and ii. 1

< / BR>
characterized in that the alcohol of General formula V or VI

< / BR>
< / BR>
where R1-R3L-B = D are specified in paragraph 1 values

subjected to dehydration using a dehydrating agent.

12. The way Polui formula I-a, as described in paragraph 11, is subjected to catalytic hydrogenation.

13. The method of obtaining derivatives triazolobenzodiazepine General formula I-c under item 1

< / BR>
where R1-R3and a-B = D - are specified in paragraph 1 values;

L is C1-6is alkyl or substituted C1-6-alkyl,

characterized in that compounds of General formula I-d

< / BR>
subjected to interaction with the corresponding alkene.

14. The method of obtaining derivatives triazolobenzodiazepine General formula I-d

< / BR>
where R1-R3and a-B = D - are specified in paragraph 1 values

characterized in that the compound of General formula I-c, as described in paragraph 13, is subjected to the interaction with the C1-4-alkylchlorosilanes in the presence of base, followed by hydrolysis of the thus obtained compounds of formula VII-a

< / BR>
15. The method of obtaining derivatives triazolobenzodiazepine General formula I-f under item 1

< / BR>
where R1-R3and a-B = D - are specified in paragraph 1 values;

L1has the meanings given for L in paragraph 1, but is different from a hydrogen atom,

characterized in that the compound of General formula I-d, as described in paragraph 13, is subjected to N-alkylation with a reagent of formula L1- W (VIII) in an inert solvent,nd formulas I through p. 1, where R1-R3and a-B = D - are given in paragraph 1 values, L is C1-6-alkyl, substituted by a hydroxy-group, characterized in that the compound of General formula I-d, as described in paragraph 13, is subjected to the interaction with the corresponding epoxide.

17. The method of obtaining derivatives triazolobenzodiazepine General formula I on p. 1, where the radicals L, R1- R3are specified in paragraph 1 values, the radical-B=D - means-N= C(R5)- , where R5- hydroxy - C1-4-alkyl, wherein the compound of General formula I, where R5- hydrogen, is subjected to the interaction with the appropriate aldehyde in the presence of acid, and if necessary the compound of General formula I transform into each other by known methods of transformation of functional groups, or a compound of General formula I is converted into the salt form by treating pharmaceutically acceptable salt or base, or Vice versa, perform the conversion of the salt form into the free base or free acid by treatment with alkali or acid and/or get it stereochemical isomeric form.

 

Same patents:

The invention relates to new chemical compounds with valuable properties, in particular to derive hinolan and naphthyridinone acid of General formula

< / BR>
in which

A is CH, CF, CCl, C-OCH3C-CH3N;

X1hydrogen, halogen, NH2CH3;

R1alkyl containing 1 to 3 carbon atoms, FCH2CH2- cyclopropyl, phenyl, which can be from one to three times substituted by halogen, or

A and R1together can mean the bridge structure C-O-CH2-CH(CH)3,

R2hydrogen, not substituted or substituted by a hydroxy-group, halogen or amino alkyl containing 1 to 3 carbon atoms, or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl;

B balance formulas

< / BR>
where

Y is O or CH2;

R3oxaalkyl containing 2 to 5 carbon atoms, CH2-CO-C6H5CH2CH2CO2R', R O2C-CH=-CO2R', -CH=CH-CO2R' or CH2CH2-CN, where R' denotes hydrogen or alkyl containing 1 to 3 carbon atoms;

R4hydrogen, alkyl containing 1 to 3 carbon atoms, окMG SRC="http://www.fips.ru/fullimg2/rupat3/19981/010.dwl/2105770-6t.gif" ALIGN="ABSMIDDLE">CH=CH-CO2-R' or CH2CH2-CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, where R' denotes hydrogen or alkyl containing 1 to 3 carbon atom,

in the form of mixtures of isomers or individual isomers, pharmaceutically applicable hydrates and salts, for example acid additive salts and alkaline, alkaline earth, silver and guanidinium salts of the corresponding carboxylic acids

The invention relates to pharmaceutically active bicyclic heterocyclic amines (XXX) and can be used as pharmaceuticals for the treatment of diseases and injuries

,5,6]-6-amino-3-azabicyclo [3.1.0] gex-3-yl)- 6-fluoro-1-(2,4-differenl)-1,4 - dihydro-4-oxo-1,8 - naphthiridine-3-carboxylic and methanesulfonic acid and its preparation" target="_blank">

The invention relates to a new form of the anhydrous salt methanesulfonic acid and 7-([1,5,6]-6-amino-3-azabicyclo[3.1.0] Gex-3-yl)-6-fluoro-1-(2,4-differenl)- 1,4-dihydro - 4-oxo-1,8-naphthiridine-3-carboxylic acid, to a method of use of the compounds in the treatment of bacterial infections in mammals, especially humans, and to pharmaceutical compositions useful for him

The invention relates to pyrazolopyrimidines General formula I and their pharmaceutically acceptable salts, where A is the group NR1R2or CR'1R'2R11, R1- H or C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, F, CL and others, or C2-C6alkenyl; or C2-C6-quinil; R2-C1-C6-alkyl, unsubstituted or substituted certain substituents, such as HE, C1-C6-alkoxy and others; or C2-C6alkenyl or2-C6-quinil, or furanyl; and (C1-C4-alkylene)phenyl which may be substituted by 1 to 3 substituents: CL, F, C1-C4-alkyl, and one Deputy:1-C6-alkoxy, CF3, NO2, NH2; or (C1-C4-alkylen) hetaryl where hetaryl - thienyl, possibly substituted by CL, benzothiazyl, pyridyl, chinoline, furanyl, benzofuranyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrrolidinyl, 1-benzylpiperidine, tetrahydropyranyl; or (C1-C4-alkylen)cyclopropyl; or NR1R2form hetaryl selected from the group consisting of pyrrolidyl, possibly substituted benzyl, pyrrolidinyl, possibly substituted by benzyl or HE, the IIR>-C6-alkyl; R3is hydrogen, C1-C6-alkyl, O-(C1-C6alkyl), S(C1-C4- alkyl); R4- C1-C6- alkyl, or S(O)n(C1-C6)-alkyl, where n= 0-2, R5- 2,4,6-substituted phenyl CL, C1-C6-alkyl, CF3; R11-N., HE, or COO- (C1-C2alkyl), provided that the group CR'1R'2R11not an alkyl straight chain; and when R3is N, then R4isn't C1-C6the alkyl

The invention relates to pharmaceutical compositions for the treatment of inflammatory diseases, for example asthma, arthritis and allergies; fear; depression; fatigue syndrome; headache; pain; cancer; irritable bowel syndrome, including Crohn's disease, mucous colitis and symptoms of irritation of the colon; deregulation of the immune system; infections caused by human immunodeficiency virus (HIV); neurovirology diseases, such as Alzheimer's disease; gastrointestinal diseases; disorders of appetite, such as anorexia nervous system; stress caused by bleeding; symptoms of drug and alcohol withdrawal symptoms; addiction to the excessive use of drugs; stress-induced psychotic States and problems of fertilization, containing the above compound of formula I is effective for the treatment of these diseases the number and pharmaceutically acceptable carrier

The invention relates to animal husbandry, in particular to methods of breeding cattle with the regulation of the sex of offspring

The invention relates to a new method of treatment of patients, such as people with benign prostatic hyperplasia (BPH), which includes treatment by assigning a therapeutically effective amount of an inhibitor 5- reductase in combination with blocker1- adrenergic receptor

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds
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