SU1528319A3 - Method of obtaining imidazole derivatives or their physiologically acceptable salts - Google Patents

Abstract

The invention relates to imidazole derivatives, in particular the preparation of 1, 2, 3, 9-tetrahydro-9-methyl-3 - [(2-methyl-1H-imidazol-1-yl) methyl] -4H-carbazol-4-one or physiologically acceptable salts that are used in medicine. The goal is to create new substances with activity not characteristic of this class. Their synthesis is carried out by the reaction of substances total f l I and II: CH = CH-CH = CH-C = C-N (CH ₃ ) -CH-CH-C (O) -CHY- (CH ₂ ) ₂ (I) and CH = CH- N = C (CH ₃ ) -NH (II), where Y is methylene or CH ₂ Z with Z is chlorine, dimethylamino or methanimino iodide group. The process is conducted by heating from 80 ° C to boiling. The resulting mixture of enantiomers is split, if necessary, and / or the base is converted to salt. New substances are antagonists of the "neuronal" receptors of 5-hydroxytryptamine (5HT) located on the main centripetal nerves. An effective dose of AU ₅₀ = 2.5-11.6 mg / kg, a toxic dose 1000 times higher than AU ₅₀ . 2 tab.

Description

CH CH-CH CH-G C-N (CH7VCH-CH-C (0) -CHY- (CHi) -, W

and () -MH (ll),

where Y is methylene or CH., Z with Z is chlorine, a dimethylamino or methanimino iodide group. The process is carried out with heating, from boiling point. The resulting mixture of enantiomers is split, if necessary, and / or the base is converted to salt. New substances are

The invention relates to a process for the preparation of new heterocyclic compounds, namely, imidazole derivatives or their salts, which are used in medicine.

The purpose of the invention is the synthesis of new compounds exhibiting activity: as antagonists, caused by 5-hydroxytryptamine (5-HT) reactions,

antagonists of neuronal receptors of 5-hydroxytryptamine (3-NT), localized on the main centripetal nerves. The effective dose of EDjo is 2.5-11.6 mg / kg, the toxic dose is 1000 times higher than ED. 2 table.

ate yu

00

oo with

isolated vagus nerve of rat.

These compounds act as strong and selective antagonists of neuronal 5-HT receptors located on the main centripetal nerves, which is not characteristic of this series of compounds.

04

The solutions are dried over Na2.S04. the solids are dried under vacuum over PjOj at 50 ° C overnight. Chromatography is carried out using a known technique.

Example 1. 2,3,4,9-Tetrahydro-N, N, N-trimethyl-4-oxo-1H-carbazole-3-methanimino iodide.

A solution of 3- (4-dimethylamino) methyp-1,2, 3,9-tetrahydro-AN-carbazol-4-one (0.53 g) in methane iodide (15 ml) is heated under reflux for 5 hours and evaporated dry up The result is a compound in the form of a white solid (0.8A g), with so pl. 202-205 ° C.

EXAMPLE 2. 2J3, D, 9-Tetrahydro-N, W, H-9-tetramethyl-4-oxo-1H-carbazole-3-methaniminoiodide.

A suspension of 3- {| (dimethylamino) methyl -1,2,3,9-tetrahydro-9-methyl-4H-carbasol-4-one (3.80 g) in iodomethane (100 ml) is stirred under heating with reverse refrigerating for 57 hours. The resulting suspension was evaporated in vacuo to give the desired compound methaniminoidide as a solid (5.72 g) with mp. 192-195 ° C.

PRI me R 3. 1,2,3,9-tetrahydro-9-methyl-3-methylene-an-carbazol-4-one.

A solution of the product from example 2 (5.0 g) in water (20 ml) is treated with 2N. sodium carbonate (6.55 ml) and heated at 35 ° C for 45 minutes. The resulting suspension is cooled to 0 ° C, the solid is filtered, washed with water and dried, resulting in the desired compound (2.8 g) with m.p. 127-129 ° C.

EXAMPLE 4. 1, 2,3, 9-Tetrahydro-3- (2-methyl-1P-imidazole- - pmethyl) - 4I-narbazol-4-one.

A solution of the product of example 1 (6.60 g) and 2-methylimidazole (17.00 g in dimethylformamide (75 ml) is heated at 100 ° C for 17.24 h, cooled, introduced into water and extracted six times with ethyl acetate. the extract is washed, dried and infused. As a result, a solid is obtained which is purified in a column of silica (Merck 7734) by elution with a mixture of ethyl acetate and methanol in a ratio of 4: 1.

the compound is obtained in the form of a solid, which is suspended in hot ethanol and is subjected to maineic acid treatment. The solution is cooled and the crystalline solid is filtered and dried, resulting in the desired compound, which is a salt of maleic acid (0.4 g with t. mp 155-156 ° C.

EXAMPLE 5 1,2,3, 9-tetrahydro-9-methyl-3 (2-methyl-1H-imidazol-1 -yl) methyl-4H-carba-aol-4-one hydrochloride.

A solution of methanimino iodide (2.0 g) and 2-methylimidazole (5.0 g) in dried dimethylformamide (30 ml) is stirred under a nitrogen atmosphere at -95 ° C for 16.75 hours and then cooled. The solid product, which crystallizes from solution, is filtered, washed cold. ice dry dimethylformamide (3 x X 2 ml) and dried with simple ether (2 x 10 ml) and then dried. The resulting solid (0.60 g) is suspended in a mixture of absolute ethanol (30 ml) and ethanolic hydrogen chloride solution (1 ml) and heated gently until a solution is obtained which is filtered in a warm condition. The filtrate is then diluted with dried space of ether, resulting in a precipitated solid (0.6 g), which is recrystallized from absolute ethanol. The result is the title compound as a solid (0.27 g) with mp. 186-187 C.

Found,%: C 61.9; H 6.4; N 11.8.

C, 8H, N, 0 HC1

Calculated,%: C, 62.3; H 6.1; N 12.16.

EXAMPLE 6 Maleate 1, 2,3,9-tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1 -yl) methyl-4H-carbagol-4-one.

1,2,3,9-Tetrahydro-9-metsh1-3- (2-methylimidazol-1-yl) metip | -4H-carba-ZOL-4-OH (ZOO mg) is suspended in hot ethanol (5 ml) and treated with maleic acid (116 mg). The solution is cooled, and the resulting white solid crystalline product is filtered and dried, yielding the target compound (MLA), m.p. 132, W. C.

515

Example. 1, 2,3, 9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) methyl} -AN-carbazol-4-one.

A solution of 1, 2,3, 9-tetrahydro-3- (2-methyl-1H-imidaeol-1-yl) methyl-4H-carbazol-4-one (1.0 g) in dried dimethylformamide (Yu ml) is added dropwise under nitrogen to a stirred, ice-cooled suspension of sodium hydride (80% in oil, 0.11 g) in dried dimethylformamide (5 ml). After 0.5 hours, dimethyl sulfate (0.34 ml) is removed and the solution is stirred at room temperature for 4 hours. The resulting solid is filtered, washed with ice-cooled dry dimethylformamide (2 x 5 ml) and dried with ether (D x 15 ml) and dried, resulting in the desired compound as a solid (0.25 g), m.p. 223-224 C (with decomposition).

Thin layer chromatography on silica, eluting with chloroform / methanol 93: 7, R 0.27, analyzed using the ultraviolet spectrum and iodoplatinic acid, the data are identical to the results obtained for the product using Example 1.

Example 8. Maleate 9-cyclopentyl-1, 2,3, 9-tetrahydro-3- (2-methyl-1H-imidazol-1 -yl) methyl 4H-carbazol-4-one.

A solution of 1, 2, 3,9-tetrahydro-Z- (2-methyl-1H-imidazol-1-yl metsh-1H-carzol-4-one (1.20 g) in dry dimethylformamide (9 ml) is introduced mixed with ice-cooled suspension of sodium hydride (80% in oil, O, 14 g) in dimethylformamide (2 ml) under nitrogen, stirring continued for 0.25 h. Bromocyclo-pentane (0.51 ml) is added and the stirred solution is heated at 100 ° C for 18.5 hours. This solution is cooled and then partitioned between water (100 ml) and ethyl acetate (3.times x 70 ml). The combined organic extracts are washed with 2N sodium carbonate (2 x 50 m ), water (2 x 50 ml) and brine (50 ml) are dried, evaporated to dryness and purified in a chromatographic column by eltoting with a mixture of dichloromethane, ethanol, 0.88 ammonia (150: 10: 1), in the result

196

It is obtained by the hour (0.27 g). This is ma-. It dissolves in absolute ethanol (7 ml) boiling with Llegma and a solution of maleic acid (o, 10 g) in absolute ethanol (0.5 ml) boiling with reflux is introduced. The hot solution is filtered and diluted with dried ether. (20 ml). The resulting yellow gummy product was washed dry with ether (7 x 25 ml) and the combined mother liquors and washes were allowed to settle. The solid product, which crystallizes from this solution, is taken up, washed with dry ether (3 X 5 ml) and dried. The result is a target salt in the form of a white crystalline solid (0.058 g) with mp. 104, -5-106 ° C.

Found,%: C 65.95; H 6.4; N 8.6.

 6.

Calculated,%: C 65.8; H 6.4; N 8.9

PRI me R 9. Maleate 1,2,3,9-tetrahydro-3- (2-methyl-1H-imidazol-1-yl) methyl-9- (2-propenyl) -4H-carbazole- 4th she.

A solution of 1, 2, 3,9-tetrahydro-Z- (2-methyl-1H-imidazol-1-yl) methyl | -4H-carbazol-4-one (1.0 g) in dry dimethylformamide (6 ml) is introduced into a stirred, ice-cooled suspension of sodium hydride (80% in oil, 0.12 g) in dry dimethylformamide (2 ml). After 0.25 hours, allylbromide is introduced, the solution is stirred at 0 ° C for 0.25 at room temperature for 20 hours, after which it is distributed between water (75 ml) and ethyl acetate (3 x 50 ml). The combined organic extracts are washed with water (2 x X 50 ml), brine (50 ml) dried, evaporated in vacuo and purified in a chromatographic column with elution with a mixture of dichloromethane, ethanol and 0.88% aqueous ammonia (200:: 10: 1) The result is a solid (0.43 g), which dissolves in absolute boiling water with reflux, ethanol (2 ml) and a solution of maleic acid (0.18 g) is added in absolute ethanol boiling with reflux (1 ml ). This hot solution is filtered, diluted with dry ether (4 ml), and crystallized from

solid solution is filtered, washed with dry ether (3 X 5 ml) and dried, resulting in a compound in the form of a white solid (0.48 g), st. square 150.5-151 C.

Found,%: C 66.3; H 5.75; N 9.6. CjoH ,,

Calculated,%: C 66.2; H 5.8; N 9.65.

EXAMPLE 10 1,2,3,9-Tetrahydro-9-methyl-3- (2-methyl-4H-imidazol-1-yl) -4H-carbazol-4-one.

A solution of 3- (dimethyl-amino) methyl -1,2,3, 9-tetrahydro-9-methyl-4H-carbazol-4-one hydrochloride (1.7 g) in water (17 ml) is treated with 2-methylimdazole ( 1.4 g), then heated under reflux for 20 hours. The cooled mixture is filtered, the precipitate is washed with water (3 x 15 ml), resulting in a crude product (1.7 g) with mp 212-221 , 5 ° C. This product recrystallized from methanol to give the desired compound (1.4 g) with m.p. 231-232 C. Analysis by thin-layer chromatography showed that this product was identical to the product of Example 3.

Example 11. 1,2,3,9-Tetragide-po-9-methyl-3-L (2-methyl-1H-imidazol-1-yl) methyl 1-4H-carbazol-4-one.

A suspension of the product from example 3 (0.5 g) and 2-methylimidazole (0.4 g) in water (5 ml) is heated under reflux for 20 hours. The cooled reaction mixture is filtered and the precipitate from filtration is washed with water (3). x 10 ml), dried and recrystallized from methanol (18 ml), resulting in a target compound (0.3 g with a melting point of 232-234 ° C (with decomposition). Analysis by thin layer chromatography shows that this product is identical to the product of example 3.

Example 12. 1,2, 3,9-tetrahydro-9- (prop-2-yl) -3- (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-one hydrochloride.

Sodium hydride (80% dispersion in oil, 0.208 g) is introduced into a mixed solution of 1,2,3,9-tetrahydro-3- (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazole -4-one (1.93 g) with dimethylformamide (35 ml), the resulting suspension is stirred at

O C for 0.25 hours. Then 2-bromopropane (o, 78 ml) is added and stirring is continued at room temperature overnight, after which it continues for 4 hours at 40 ° C. The reaction mixture is distributed between sodium carbonate (2 I. solution, 200 ml) and ethyl acetate (2 x X 150 ml). The combined organic extracts are washed with water (3 x x 75 ml), dried and ground in vacuo. The product is purified on a chromatographic column at. eluting with dichloromethane: ethanol: ammonia (100: 8: 1), resulting in an oil that dissolves in ethanol (3 ml), acidified with ethereal hydrogen chloride solution and diluted with dry ether resulting in precipitation of the desired compound as a white solid (0.13 g), mp 232-232 ° C

Found,%: C 65.3; H 6.6; N 11.1.

C2OH23N, 0 HCl - 0.5H20

Calculated,%: C 65.4; H 6.9; N 11.45.

PRI me R 13. Chlorohydrate dihydrate I, 2,3,9-tetrahydro-9-methyl-3- (2-methyl-1 H-imidazol-1-yl) metshu - 4H-carbazol-4- she is.

1,2,3,9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1 -yl) methyl | j-4H-carbazol-4-one (18.3 g) in hot mixtures of isopropanol (90 ml) and water (18.3 ml) are treated with concentrated hydrochloric acid (6.25 ml). The hot mixture is filtered, and the filtrate is diluted with isopropanol ($ 0 ml) and stirred at room temperature for 17 hours, cooled to and the solid is filtered (21.6 g). The resulting product (b g) is recrystallized from a mixture of water (b ml) and isopropanol (10 ml), resulting in a compound which is obtained in the form of a white crystalline solid (b g), m.p. 178.5-179 ,.

Found,%: C 59.45; H 6.45; N 11.5.

C, 2H, qN, O HC 2H20

Calculated,%: C 59.1; H 6.6; N 11.5.

A. Analysis of the content of the water.

Found,%: 10.23.

C, eH ,, Njn. HC1.

Calculated,%: N 9.85.

PRI me R 14. 1, 2,3,9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-one - fsfat (1: 1).

1, 2,3,9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazole-A-one (0.61 g) is dissolved in the hot mixture phosphoric acid (90%, 0.13 bp) and water (10 yl), filtered through Hyflo and crystallized, resulting in the desired compound (O, 5 g), m.p. 225 C.

Found,%: C 55.1; H 5.6; N

10.55 N 10.7

CM, .

10.55 N 10.7

Calculated,%: C 55.2; H 5.7;

Example 15. Citrate 1,2,3,9-tetrahydro-9-methyl-3 (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-one (2: 1) .

1,2,3, 9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-one (0.89 g) is dissolved in the mountains than a solution of citric acid (o, 58 g) in ethanol (20 ml) and the solution crystallizes. The resulting crystalline solid is recrystallized by dissolving in acetone / water (2: 1.2 ml) and diluted with acetone (20 ml), resulting in the desired compound (0.6 g), with a mp of 162 ° s

PRI me R 16. 1, 2,3,9-Tetra-hydro-9-methyl-3 (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-one.

(i) 3- (chloromethyl) -1,2,3,9-tetrahydro-9-methyl-4H-carbazole-D-one.

An ether (ether) solution of hydrogen chloride (H, 0 ml) is introduced into a stirred ice-cooled solution of the product from Example 3 (1.90 in chloroform (15 ml)., The resulting suspension is stirred in a sealed vessel at room temperature for 16, 5 hours; evaporated in vacuo and the residual solid (2.27 g) is purified in:

the chromatographic column was eluted under vacuum in a vacuum, resulting in

chloroform, resulting in a target compound (1.75 g) with m.p. 109-110 ,. An attempt to crystallize a portion of this material from ethyl acetate results in partial decomposition.

(ii) 1,2, 3,9-Tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) metsh1-4H-carbazol-4-one.

55

a clear free base is obtained (0.07 g). The base is dissolved in methanol (5 ml), acidified with i-maleic acid (0.03 g), and the salt is precipitated by adding an excess of dry ether (80 ml), resulting in the desired compound (0.062 g) from m.p. 142-145 s.

7

25

thirty

t- 20

- e

-

-

40

)

45

The solution of H- (chloromethyl) -1,2,3,9-Tet-ragidro-9-methyl-4H-carbazol-D-one (o, 50 g) and 2-methyl-1H-imidazole (1.60 g) in dry dimethylformamide, it is stirred under nitrogen at 90 ° C for 3.75 hours, then poured into water (25 ml). The suspension is stirred for 1 hour and solid.

The Q product is filtered off, washed with water (3 x 20 ml) and dried under vacuum at 50 ° C. After chromatographic separation in a column of this solid product (0.53 g) with eluant), a mixture of dichloromethane, ethanol and 0 88% aqueous ammonia solution (150: 10: 1) gives the title compound (0.45 g), m.p. 228-229 C. As shown by thin-layer chromatography, nuclear magnetic resonance, this material is identical to the product of example 6.

EXAMPLE 17 Maleate 33-1,2,3,9-tetrahydro-3- (2-methylimidazol-1-yl) methyl 1-9-methyl-4H-carbazol-4-one. A solution of the product from Example 6 (0.5 g) is dissolved in hot methanol (30 ml) and treated with a hot solution of (- -) - di-p-toluyl-B-tartaric acid monohydrate (0.7 g) in methanol (Yu ml), the resulting solution crystallizes overnight, resulting in a resultant / 1eva

salt (o, 68 g), which is dissolved in hot dimethylformamide (20 ml),

diluted with hot water (10 ml)

and crystallizes during the night. The resulting product is filtered and dried under vacuum, resulting in approximately 90% pure zantiomeric (as shown by nuclear magnetic resonance analysis) salt of (+) - di-para-toluyl-B-tartaric acid (0.23 g) t. pl.231-233 ° C. This salt (0.15 g) is distributed between 8% sodium bicarbonate (25 ml) and chloroform (2x25 ml). The combined extracts are dried and rotated under vacuum, with the result that

a clear free base is obtained (0.07 g). The base is dissolved in methanol (5 ml), acidified with i-maleic acid (0.03 g), and the salt is precipitated by adding an excess of dry ether (80 ml), resulting in the desired compound (0.062 g) from m.p. 142-145 s.

eleven

As shown by analysis by thin layer chromatography on silica with elution with dichloromethane, ethanol, 0.88 ammonia (100: 8: 1) R 0.3, as well as analysis using the UV spectrum and using iodoplatinic acid, this product is identical to from example 6. The ratio of enantiomers (5: K) as shown. proton nuclear magnetic resonance (NNMR) analysis is 93: 7. A sample of this maleate salt does not detect significant optical rotation in methanol. The free base derived from the maleate salt gives (c 0.19, MeOH).

Approx 18. Maleate 3 B-1,2, 3,9-tetrahydro-9-methyl-3- (2-methyl-1H-imidazol-1-yl) methyl-4H-carbazol-4-one.

A solution of the product from Example 6 (0.5 g) is dissolved in hot methanol (30 ml) and treated with a hot solution of (-) - di-para-toluyl-b-tartaric acid monohydrate (0.7 g) in; methanol (10 ml). The resulting solution crystallizes overnight, resulting in the desired salt (0.8 g). This salt is dissolved in hot dimethylformamide (20 ml), diluted with hot water (10 ml) and crystallized within 3 days. The product is filtered and dried under vacuum, resulting in approximately 95% pure enantiomeric (as shown by NMR analysis) salt of (-) - di-para-toluyl b-tartaric acid (0.26 g) with t .pl. 170-172 ° C. A portion of this salt (0.2 g) is distributed between 8% sodium bicarbonate (25 ml) and chloroform (2x25 ml). The combined extracts are dried and evaporated in vacuo, resulting in a clear free base (0.12 g). This base is dissolved in methanol (5 ml) and acidified with mapecic acid (0.045 g) and salt is precipitated by adding an excess of dry ether (80 ml), yielding the desired compound (0.08 g) with m.p. 142-U5 ° C.

As shown by thin-layer chromatography on silica with elution with a mixture of dichloromethane, ethanol, 0.88 ammonia (in

n Q - 20

25 so - Q, in

52831912

the ratio of 100: 8: 1) R, 0.3, as well as the analysis using the UL spectrum and iodoplatinic acid, this material is identical to the product of Example 6. The ratio of enantiomers, which is determined by the NNMR method, was 95: 5.

A sample of this maleate salt does not detect significant optical rotation in methanol. The free base obtained from this maleate salt, ° -t-16 ° (c 0.34, MeOH).

EXAMPLE 19 1, 2,3,9-Tetrahydro-9-methyl-3- (2-methylimidazol-1-yl) methyl-4H-carbazol-4-one hydrochloride.

A mixture of the substance according to example 2 (37.0 g) and 2-methylimidazole (90.0 g) in dry dimethylformamide (400 ml) was peremergueut 21 hours in a nitrogen atmosphere at 100 ° C, and then cooled with ice. Filter the resulting solid, rinse with ice-cold dimethylformamide (XxZO ml) and dry ether (3x100 ml) and dry in vacuo at 50 ° C for 18 h. The obtained solid (16.20 g) is purified by chromatography ic using a mixture of dichloromethane, ethanol and 0.880 ammonia (120: 10:: 1) as eluent to obtain a solid (7.42 g), which is dissolved in di chloromethane (250 ml). Ethanolic hydrogen chloride (5 ml) was added and the stirred solution was diluted with dry ether (30% ml). The precipitated solid is filtered off, washed with dry ether (4x150 ml) and dried under vacuum for 16 hours at which time the desired substance is obtained (6.51 g) with mp. 166.5-167 ° C, fine chromatography (dichloromethane:: ethanol: 0.88 120: 10: 1) H 0.35, NMR indicated 0.25 mol of ethanol.

Example 20, 2,3,9-Tetrahydro-9-methyl-3 (2-methylimidazol-1-yl) methyl-4H-carbazol-4-one hydrochloride.

A suspension according to example 2 (1, 40 g) and 2-methylimidazole (3.5 g) in dry dimethylformamide (15 ml) is stirred for 6.25 hours at, then cooled with ice. The resulting solid is filtered off, washed with dry dimethylformamide (2x3 ml) and dry ether (3xb ml) ,. dried and get solid (0.5 g). It is suspended in a mixture of absolute ethanol (20 ml) and ethanol chloride.

45

50

Hydrogen (J ml}, slightly warmed and a solution is obtained that is filtered through warm. The filtrate is stirred rapidly and diluted with dry ether (50 ml). The resulting solid is filtered, washed with dry ether (3x15 ml) and dried in vacuo 18 h at 40 ° C, after which the target substance is obtained (0.25 g) with a melting point of 185.5-187 ° C.

Found,%: C 61.06; H 6.4; N 12

 HC1 1,

Calculated,%: C, 61.4; H 6.4; IN 11.9.

Information on acute toxicity was obtained by intravenous administration of various dosages to mice of characteristic representatives of a number of compounds of the formula (O. The dosages at which less than 50% of the animals survived were 5.2 mg / kg IV for the compound of Example 1 and more than 10 mg / kg / v for examples 4, 5, and 8. In vivo to detect antagonism of the reaction caused by 5-HT in neuronal 5-HT receptors, we used the method for determining the effect of the proposed compounds on the reflex; vyzgayemoe 5-NT.

The antagonism of the responses induced by 5-HT at neuronal 5-HT receptors by the compounds of the invention can be determined in vitro in a known manner.

The results of these tests are expressed as pA2 values given in Table 1. These values are determined by the negative logarithm of the molar concentration of the antagonist, which is required to reduce the effect of double CD to from 5-HT to the EDjQB effect; the absence of an antagonist.

Table 1

9

14

can be determined in vivo to determine the effect of compounds on the Be3old-Tarisch reflex caused by 5-HT.

The results are presented in Table 2, as the dose required to inhibit the reflex induced by 5-HT.

by 50%. „, - about

ITABLE2

ten

15

The lethal doses for the proposed compounds are 1000 times greater than the dose that is necessary for the inhibition of the 5-HT-induced Bezold-Jarry reflex by 50%.

Claims (1)

Invention Formula The method of obtaining imidazole derivatives of the formula (ABOUT thirty 11 of their physiologically acceptable salts, characterized in that the compound of formula II O .y (Ii) ks I SNS where or a group of the formula, where Z is a chlorine atom or a dimethylamino group or a methanimino iodide, is reacted with an imidazol Lormula