RU2225866C1 - Acetic acid potassium salt eliciting cardiotonic activity - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacology. SUBSTANCE: invention relates to a mixture of isomers of 2-[5(6)-nitro-1-(thietanyl-3)-benzimidazole-2-thio]- acetic acid potassium salt in the mole ratio = 1:3 eliciting cardiotonic activity. The mixture exerts the enhanced cardiotonic activity. EFFECT: enhanced effectiveness, valuable medicinal properties of mixture. 2 cl, 2 tbl, 2 ex

Description

The invention relates to medicine, namely to pharmacology, and can be used to obtain new cardiotonic agents.

The technical result is the expansion of the arsenal of biologically active substances, including those having cardiotonic activity.

The inventive mixture of potassium salt isomers of 2- [5 (6) -nitro-1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid in a 1: 3 molar ratio of the General formula

showing cardiotonic activity.

The preparations of cardiac glycosides taken were strofantin K ((3 beta, 5 beta) - [(2,6-dideoxy-3-O-methyl-beta-D-ribohexopyranosyl) oxy] -5,14-dihydroxy-19 -oxocard-20 (22) -enolide) and digoxin ((3 beta, 5 beta, 12 beta) -3- (O-2,6-dideoxy-beta-D-ribo-hexapyranosyl- (1-4) -O -2,6-dideoxy-beta-D-ribo-hexapyranosyl- (1-4) -2,6-dideoxy-beta-O-ribo-hexapyranosyl) oxy-12,14-dihydroxycard-20 (22) -enolide) , non-glycoside cardiotonics, dobutamine ((+/-) - 4-2-3- (4-hydroxyphenyl) -1-methylpropylaminoethyl-1,2-benzenediol hydrochloride) and dopamine (4- (2-aminoethyl) -1,2-benzenediol hydroch horid), the cardiotonic activity of which is described in numerous original and review works (Mukharlyamov N.M., Mareev V.Yu. Treatment of chronic heart failure. - M .: Medicine, 1985. - 208 pp .; Yuzhakov SD, Mastafanova L .I., Mashkovsky MD, Yakhontov L.N. // Dependence between the structure and action of cardiotonic non-glycoside and non-catecholamine structures. // Chem. Pharm. Journal, 1992, No. 3, p. 4-17).

The inventive compound is synthesized as follows.

By the interaction of 5 (6) -nitro-2-chlorobenzimidazole with epithiochlorhydrin in the presence of potassium hydroxide, 5 (6) -nitro-1- (thietanyl-3) -2-chlorobenzimidazole is obtained, which, when boiled with thioglycolic acid in ethanol, is converted into an alkaline medium into 5 (6) -nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid, which, when reacted with potassium hydroxide in ethanol, becomes the target salt.

Example 1

Synthesis of the claimed compound.

5 (6) -Nitro-2-chlorobenzimidazole 9.9 g (50 mmol) is dissolved in 22 ml of a 10% sodium hydroxide solution. 6.0 g (55 mmol) of epithiochlorohydrin are added to the solution at a temperature of 30-35 ° C and stirred for 1 hour. The crystalline precipitate is filtered off, washed with diethyl ether, water and dried at 60 ° C. _Mp = 181-183 ° C. 2.29 g (85%) of a mixture of 5 (6) -nitro-1- (thietanyl-3) -2-chlorobenzimidazole are obtained in a 1: 3 molar ratio, and purified by crystallization from ethanol-water (1: 1).

IR spectrum, ν _max , cm ^-1 : 750 and 845 (C-NO ₂ ), 1350 and 1522 (NO ₂ ), 1470 (C = N).

¹ H NMR Spectrum (CDCl ₃ ), δ, ppm: 3.6-3.7 m (2H, S (CH) ₂ ); 4.12-4.23 m (2H, S (CH) ₂ ); 5.9-6.1 m (1H, HCH); 7.7-8.7 m (3H, N arom.).

¹³ C NMR spectrum (CDCl ₃ ), δ, ppm:

5-nitro-1- (thietanyl-3) -2-chlorobenzimidazole: 32.57 (C ¹¹ , C ¹² ); 51.73 (C ¹⁰ ); 110.40 (C ⁷ ); 116.40 (C ⁴ ); 119.30 (C ⁶ ); 132.83 (C ⁸ ); 141.30 (C ² ); 144.0 (C ⁹ ); 144.20 (C ⁵ ).

6-nitro-1- (thietanyl-3) -2-chlorobenzimidazole: 32.77 (C ¹¹ , C ¹² ); 51.81 (C ¹⁰ ); 107.10 (C ⁷ ); 119.0 (C ⁵ ); 120.2 (C ⁴ ); 137.65 (C ⁹ ); 141.30 (C ² ); 143.90 (C ⁸ ); 146.10 (C ⁶ ).

The quantitative composition of both isomers was determined by comparing the integrated signal intensities of the corresponding carbon atoms of 5-nitro-1- (thietanyl-3) -2-chlorobenzimidazole and 6-nitro-1- (thietanyl-3) -2-chlorobenzimidazole, confirming a molar ratio of 1: 3.

Elemental analysis.

Found,%: C 44.15; H 3.3; N 13.85; S 12.04 - C ₁₀ H ₈ ClO ₂ S.

Calculated,%: C 44.52; H 2.96; N, 15.58; S 11.80.

To a solution of 1.84 g (20 mmol) of thioglycolic acid in ethanol, 1.68 g (30 mmol) of crystalline potassium hydroxide was added and, after dissolution, 2.69 g (10 mmol) of 5 (6) nitro-1- (thietanyl- 3) -2-chlorobenzimidazole. The mixture is boiled for 3 hours, filtered, 2/3 of the solvent is distilled off, cooled to 5-10 ° С, the precipitate formed is filtered off, dried, and dissolved in water. Insoluble impurities are filtered off, a solution of acetic acid is added to the filtrate until a slightly acidic reaction. The precipitate formed is filtered off and washed with water. 1.14 g (35%) of a mixture of 5 (6) nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid are obtained in a 1: 3 molar ratio. Dried at t = 40-50 ° C. _Mp = 156-158 ° C. Purified by crystallization from ethanol.

¹ H NMR Spectrum (CDCl ₃ ), δ, ppm: 3.30-3.45 m (2H, S (CH) ₂ ); 4.15-4.25 m (2H, S (CH) ₂ ); 4.05-4.10 m (2H, CH ₂ ); 5.75-6.90 m (1H, HCH); 7.70-8.85 m (3H, N arom.).

¹³ C NMR spectrum (CDCl ₃ ), δ, ppm:

5-nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid:

32.86 (C ¹¹ , C ¹² ); 34.90 (C ¹³ ); 52.43 (C ¹⁰ ); 116.50 (C ⁷ ); 118.52 (C ⁴ ); 119.59 (C ⁶ ); 138.50 (C ⁸ ); 141.0 (C ⁵ ); 143.83 (C ⁹ ); 157.20 (C ² ); 168.99 (C ¹⁴ ).

6-nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid:

32.86 (C ¹¹ , C ¹² ); 34.90 (C ¹³ ); 52.43 (C ¹⁰ ); 107.17 (C ⁷ ); 118.10 (C ⁵ ); 123.80 (C ⁴ ); 134.10 (C ⁸ ); 140.30 (C ⁹ ); 145.60 (C ⁶ ); 157.20 (C ² ); 168.99 (C ¹⁴ ).

Comparison of the integrated signal intensities of the corresponding carbon atoms of 5-nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid and 6-nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid confirmed the molar the ratio of isomers 1: 3.

Elemental analysis.

Found,%: C 44.4; H 3.3; N, 12.8; S 19.4 - C ₁₂ H ₁₁ ClO ₄ S ₂ .

Calculated,%: C 44.3; H 3.4; N, 12.9; S 19.7.

To a solution of 0.67 g (12 mmol) of crystalline potassium hydroxide in 30 ml of ethanol is added 3.25 g (10 mmol) of 5 (6) nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid and boil for 1 h. The solution is filtered while hot, the filtrate is cooled to 5-10 ° C. The precipitate formed is filtered off and washed with ethanol. 1.82 g (50%) of the potassium salt of 5 (6) nitro [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid are obtained in a 1: 3 molar ratio. Dried at t = 40-50 ° C. _Mp = 172-174 ° C. Purified by crystallization from ethanol.

Elemental analysis.

Found,%: C 39.5; H 2.7; N, 11.4; S 17.7 - C ₁₂ H ₁₀ N ₃ O ₄ S ₂ K.

Calculated,%: C 39.7; H 2.75; N, 11.6; S 17.6.

Example 2. Cardiotonic activity.

The cardiotonic activity of the claimed compounds was studied by spectrophotometric method proposed by I. S. Chekman and co-authors [A. S. 1668921 (USSR), MKI 5 G 01 N 21/17. A method for determining the cardiotonic activity of biologically active compounds./ Chekman I.S., Gorchakova M.A., Samarsky V.A., Stepeneva T.G., Grimevich A.I. .. - Applic. 03/27/89. No. 46890022/14.]. The studies were carried out in vitro on an SF-46 spectrophotometer. The determination of cardiotonic activity took place in several stages:

1. The removal of the UV spectrum and the determination of the maximum absorption of the claimed compounds.

To record the UV absorption spectra of the claimed compounds used spectrophotometer SF-46.

The optical density of a 0.001% aqueous solution of the claimed compound was determined in the wavelength range from 200 to 350 nm.

2. Obtaining a complex with calcium ions and determination of the stability constant.

To obtain the complex used an aqueous solution of the claimed compound (I) C _(x) = 1 * 10 ^-3 mol / l, calcium chloride C ° (CaCl ₂ ) = 1 * 10 ^-1 mol / l and potassium chloride C ° (KCl) = 1 mol / L. For this, the volumes of reagents in the following proportions were introduced into 5 volumetric flasks with a capacity of 25 ml (Table 1).

The flasks with the solutions were thoroughly mixed and left for 5 min for the complexation process to proceed. Then, the electronic absorption spectra of solutions in flasks 1-5 were recorded. The readings were taken at the maximum absorption of the claimed compounds, where the optical density is most stable. Purified water was used as a control.

Based on the obtained data, the deviation of the optical density of the reagent solutions from the additive indicates the formation of the complex. The average optical density of the resulting complexes with calcium cations was used to determine the stability constant. The calculation of the stability constant was carried out according to the Nakagura method using the equation

where C ₄ is the concentration of calcium chloride in flask 4;

C ₅ is the concentration of calcium chloride in flask 5;

D ₁ - the value of the optical density of the solution in the flask 1;

D ₄ - the value of the optical density of the solution in the flask 4;

D ₅ - the optical density of the solution in the flask 5.

In accordance with the data of the authors [A.S. 1668921 (USSR), MKI 5 G 01 N 21/17. A method for determining the cardiotonic activity of biologically active compounds. / Chekman I.S., Gorchakova M.A., Samarsky V.A., Stepeneva T.G., Grimevich A.I. - Decl. 03/27/89. No. 46890022/14.] The value of the stability constant of the resulting complexes of chemical compounds with calcium ions in excess of 100 l / mol indicates the presence of cardiotonic activity (table 2).

The presented chemical compound has cardiotonic activity at the level of the drug strophanthin K, slightly inferior to dobutamine and significantly superior to digoxin and dopamine.

Claims (2)

1. A mixture of isomers of the potassium salt of 2- [5 (6) -nitro-1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid in a 1: 3 molar ratio of the general formula

2. The mixture of isomers according to claim 1, having cardiotonic activity.