Potassium salt of 2-[5(6)-nitro-1-(titanyl-3)-benzimidazolyl-2 - thio]acetic acid, showing cardiotonic activity

 

(57) Abstract:

The invention relates to organic chemistry and pharmacology, namely a mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic acid in a molar ratio of 1:3, manifesting cardiotonic activity. The mixture has a high cardiotonic activity. 1 C.p. f-crystals, 2 tab.

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

The technical result - expanding Arsenal of biologically active substances, including having cardiotonic activity.

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

showing cardiotonic activity.

As comparative drugs taken drugs cardiac glycosides - strophanthin K ((3 beta, 5 beta)-[(2,6-dideoxy-3-O-methyl-beta-D-abovecaptionskip)oxy]-5,14-dihydroxy-19-oxcart-20(22)-enolide) and digoxin ((3 beta, 5 beta, 12 beta)-3-(O-2,6-dideoxy-beta-D-RIBO-hexopyranosyl-(1-4)-O-2,6-dideoxy-beta-D-RIBO-hexopyranosyl-(1-4)-2,min((+/-)-4-2-3-(4-hydroxyphenyl)-1-methylpropylamine-1,2-bentolila hydrochloride) and dopamine (4-(2-amino-ethyl)-1,2-bentolila hydrochloride), cardiotonic activity of which is described in numerous original and review papers (muharlyamov N. M., Mareev C. Y. Treatment of chronic heart failure. - M.: Medicine, 1985. - S.; Bill S. D., Mastepanov L. I., Mashkovsky M. D., L. Yakhontov N.//The relationship between structure and action of cardiotonic neglecting and neocatechumenal structure.//Chem. Pharm. Journal, 1992, No. 3, S. 4-17).

The inventive compound is synthesized as follows.

Interaction 5(6)-nitro-2-chlorobenzimidazole with epimyocardium in the presence of potassium hydroxide receive 5(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole, which when boiled with thioglycolic acid in ethanol in alkaline medium becomes 5(6)-nitro-[1-(titanyl-3)benzimidazolyl-2-thio]acetic acid, followed by interaction with sodium hydroxide in ethanol in the target salt.

Example 1.

The synthesis of the claimed compounds.

5(6)-Nitro-2-chlorobenzimidazole of 9.9 g (50 mmol) dissolved in 22 ml of 10% sodium hydroxide solution. To the solution at a temperature of 30-35C add 6.0 g (55 mmol) of aetiocholanolone and stirred for 1 h Crystalline precipitate is filtered off, washed with diethyl ether, water, dried at 60C. TPL=181-S. Poluchat mixture of ethanol-water (1:1).

The IR spectrummaxcm-1: 750 and 845 (C-NO2), 1350 and 1522 (NO2), 1470 (C=N).

An NMR spectrum1H (CDCl3), , M. D.: a 3.6-3.7 m (2N, S(CH)2); 4,12-to 4.23 m (2H, S(CH)2); at 5.9-6.1 m (1H, HCH), and 7.7-8.7 m (3H, H-arene.).

An NMR spectrum13With (CDCl3), , M. D.:

5-nitro-1-(titanyl-3)-2-chlorobenzimidazole: 32,57 (11WITH12); 51,73 (10); 110,40 (7); 116,40 (4); 119,30 (6); 132,83 (8); 141,30 (2); 144, 0MM (WITH9); 144,20 (5).

6-nitro-1-(titanyl-3)-2-chlorobenzimidazole: 32,77 (11WITH12); 51,81 (10); 107,10 (7); 119,0 (5); 120,2 (4); 137,65 (9); 141,30 (2); 143,90 (8); 146,10 (6).

The quantitative composition of both isomers is determined by comparing the integral intensities of the signals of the respective carbon atoms of 5-nitro-1-(titanyl-3)-2-chlorobenzimidazole and 6-nitro-1-(titanyl-3)-2-chlorobenzimidazole confirming the molar ratio of 1:3.

Elemental analysis.

Found, %: C 44,15; N 3,3; N 13,85; S 12,04 - C10H8lO2S.

Calculated, %: C 44,52; N 2,96; N 15,58; S 11,80.

To a solution of 1.84 g (20 mmol) of thioglycolic in ethanol added 1.68 g (30 mmol) of crystalline potassium hydroxide and after dissolution of the app is Italia, cooled to 5-10 ° C, the precipitation is filtered off, dried, dissolved in water. Insoluble impurities are filtered off, the filtrate is added a solution of acetic acid to slightly acid reaction. The precipitation is filtered off, washed with water. Get 1,14 g (35%) of a mixture of 5(6)-nitro-[1-(titanyl-3)benzimidazolyl-2-thio]acetic acid in a molar ratio of 1:3. Dried at t=40-50C. TPL=156-S. Purify by crystallization from ethanol.

An NMR spectrum1H (CDCl3), , M. D.: 3,30-3.45 m (2N, S(CH)2); 4,15-4,25 m (2H,S(CH)2); of 4.05-4.10 m (2H, CH2); 5,75-6,90 m (1H, HCH); 7,70 cent to 8.85 m (3H, H-arene.).

An NMR spectrum13With (CDCl3), , M. D.:

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

32,86 (11WITH12); 34,90 (13); 52,43 (10); 116,50 (7); 118,52 (4); 119,59 (6); 138,50 (8); 141,0 (5); 143,83 (9); 157,20 (2); 168,99 (14).

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

32,86 (11WITH12); 34,90 (13); 52,43 (10); 107,17 (7); 118,10 (5); 123,80 (4); 134,10 (8); 140,30 (9); 145,60 (6); 157,20 (2); 168,99 (14).

Comparing the integral intensities of the signals corresponding atio]acetic acid confirmed the molar ratio of the isomers 1:3.

Elemental analysis.

Found, %: From 44.4; H 3,3; N 12,8; S 19,4 - C12H11ClO4S2.

Calculated, %: From 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 was added 3.25 g (10 mmol) 5(6)-nitro-[1-(titanyl-3)benzimidazolyl-2-thio]acetic acid and boiled for 1 hour the Solution is filtered hot, the filtrate is cooled to 5-10C. The precipitation is filtered off, washed with ethanol. Get 1,82 g (50%) of the potassium salt of 5(6)-nitro-[1-(titanyl-3)benzimidazolyl-2-thio]acetic acid in a molar ratio of 1:3. Dried at t=40-50C. TPL=172-S. Purify by crystallization from ethanol.

Elemental analysis.

Found, %: From 39.5; H 2,7; 11,4 N; S 17,7 - C12H10N3O4S2K.

Calculated, %: From 39.7; H 2,75; 11,6 N; S 17,6.

Example 2. Cardiotonic activity.

Cardiotonic activity of the claimed compounds was investigated by spectrophotometric method proposed by I. C. Chemmanam and co-workers [A. S. 1668921 (USSR), MKI 5 G 01 N 21/17. The method of determining the biological activity of biologically active compounds./Chekman I. S., M. Gorchakov, A., Samara, C. A., Stepanova, So, Grinevich A. And.. - Appl. 27.03.89. No. 46890022/14.]. Research about

1. Removing the UV spectrum and determination of absorption maxima of the claimed compounds.

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

Determined the optical density of 0.001% aqueous solution of the inventive compounds in the range of wavelengths from 200 to 350 nm.

2. Getting complex with calcium ions and determination of stability constants.

To obtain the complex used an aqueous solution of the inventive compounds (I)(x)=110-3mol/l, calcium chloride(l2)=110-1mol/l, and potassium chloride(KCl)=1 mol/L. For this 5 volumetric flasks with a capacity of 25 ml was injected volumes of reagents in the following proportions (table.1).

Bulb solutions are thoroughly mixed and left for 5 min to process complex formation. Then removed the electronic absorption spectra of the solutions in flasks 1-5. Readings were taken at the maximum absorption of the claimed compounds, where the total optical density is the most stable. As control was used purified water.

Based on the data, the deviation of the values of optical density of the reagent solutions from additive testifies he polzovali to determine the stability constants. The calculation of stability constants was carried out according to the method Nakakura using equation

where C4the concentration of calcium chloride in the flask 4;

WITH5the concentration of calcium chloride in the flask 5;

D1the optical density of the solution in the flask 1;

D4the optical density of the solution in the flask 4;

D5the optical density of the solution in the flask 5.

According to these authors [A. S. 1668921 (USSR), MKI 5 G 01 N 21/17. The method of determining the biological activity of biologically active compounds. / Chekman I. S., M. Gorchakov, A., Samara, C. A., Stepanova, So, Grinevich A. And.. - Appl. 27.03.89. No. 46890022/14.] the magnitude of the stability constants of the formed complexes chemical compounds with calcium ions in excess of 100 l/mol indicates the presence of cardiotonic activity (table.2).

Presents chemical compound possesses cardiotonic activity at the level of the drug strophanthin K, yielding several dobutamine and significantly superior to digoxin and dopamine.

1. The mixture of isomers of the potassium salt of 2-[5(6)-nitro-1-(titanyl-3)benzimidazolyl-2-thio] acetic Cicely activity.

 

Same patents:

The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, showing inflammatory and bronchodilatory activity

The invention relates to 4-hydroxy-3-chinainternational and hydrazides of General formula (I), where a represents a-CH2- or-NH-, a R1, R2, R3and R4such as defined in the claims

The invention relates to new compounds of the mixture of isomers of 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole of the formula I

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

The invention relates to sulphonilecarbomide acids of the formula

< / BR>
and/or their stereoisomeric forms and/or physiologically acceptable salts, where R1means phenyl, phenyl, one or twice substituted by a group WITH1-C6-alkyl-Oh, halogen, trifluoromethyl, a group WITH1-C6-alkyl-O-C(O)-, methylenedioxy-, R4-(R5)N-; triazole, thiophene, pyridine; R2means H, C1-C6alkyl; R4and R5are adnikowymi or different and denote H, C1-C6-alkyl; R3means H, C1-C10-alkyl, where alkyl unsubstituted and/or one hydrogen atom of the alkyl residue substituted by hydroxyl,2-C10alkenyl, R2-S(O)n-C1-C6-alkyl, where n means 0, 1, 2; R2-S(O)(=NH)-(C1-C6)-alkyl and the other, or R2and R3together form a cycle with a carboxyl group as a substituent cycle of partial formula II:

< / BR>
where r is 0, 1, 2, 3 and/or one of the carbon atoms in the cycle replaced by-O-, and/or the carbon atom in the cycle part of the formula II substituted once by phenyl; a represents a covalent bond, -O-;

The invention relates to new non-steroidal compounds which are high-affinity modulators of steroid receptors

The invention relates to amide derivative of the General formula I, the symbols in the formula have the following meanings: D is pyrazolidine group which may have 1-3 halogenated derivatives or unsubstituted lower alkyl group as the Deputy(I)her is fenelonov or topendialog group, X represents a group of formula-NH-CO - or-CO-NH -, and a represents a phenyl group which may be substituted by one or more halogen atoms, or a five - or six-membered monocyclic heteroaryl group which may be substituted by one or more of lower alkyl groups
The invention relates to the pharmaceutical industry, namely the creation of pharmaceutical compositions with a wide range of pharmacological actions on derived orotovoy acid

The invention relates to new sulfadimethoxine benzopyranones derivative of the formula I

< / BR>
where R(5) is in one of positions 5, 6, 7 and 8, and R(1) and R(2) independently of one another denote hydrogen or alkyl with 1-6 carbon atoms, R(3) means R(10)-CnH2nR(10) means a hydrogen atom or methyl, n denotes an integer equal to 0-10, R(4) means R(13)- CrH2rand one of CH2group can be replaced by-CO-O - or-O-CO - group, R(13) denotes methyl or trifluoromethyl, r is an integer equal 0-12, R(5) means-Y-CsH2s-R(18), Y represents-O-, s indicates an integer equal to 1-8, R(18) denotes hydrogen, trifluoromethyl or phenyl, R(6) means-OR(10d) or-OCOR(10d) group, R(10d) denotes hydrogen or alkyl with 1-3 carbon atoms, denotes hydrogen or R(6) and together form a bond; and their physiologically acceptable salts

The invention relates to inhibitors tyrosinekinase type bis-indolylmaleimide compounds of the formula I

< / BR>
where Z denotes a group of General formula II

< / BR>
where A, B, X, Z, R1-R10have the meanings indicated in the claims, as well as the way they are received and drug based on these compounds
The invention relates to pharmaceutical, cosmetic and food industry
The invention relates to the field of pharmaceutical industry and relates to a method of obtaining a suppository "Epiproct", featured in complex therapy of inflammatory processes of the rectum, prostatitis, hemorrhoids, treatment for anal fissures

The invention relates to medicine

The invention relates to novel condensed to thienopyrimidine formula I and their physiologically acceptable salts, having the effect of inhibitors of phosphodiesterase V(PDE V), and which can be used for the treatment of diseases of the cardiovascular system and for the treatment and/or therapy of disorders of potency

The invention relates to new compounds of the formula (I) and their pharmaceutically acceptable salts and esters possessing inhibitory ability against endothelioma receptors, the Compounds can be used to treat diseases associated with abnormal vascular tone and endothelial dysfunction

The invention relates to the derivatives of benzosulfimide formula (I):

< / BR>
where X represents a nitro-group, a cyano or halogen; Y1represents a secondary or tertiary amino group; Y2represents nitrogen or NH group; Z represents oxygen, sulfur, -N-CN or CH-NO2; and R1and R2that may be the same or different, are each independently saturated or unsaturated linear or branched alkyl group containing from 2 to 12 carbon atoms, saturated or unsaturated alicyclic group containing from 3 to 12 carbon atoms, phenyl, unsubstituted or substituted by one or more substituents, which represents a1-C4alkyl group, nitro, cyano, trifluoromethyl, carboxy and halogen, benzyl group or phenylethylene group, or Y1means tertiary amino group and R1form a morpholine or homopiperazin and Y2represents nitrogen and R2forms homopiperazin, except for derivatives, for which X is a nitro-group, Y1represents a secondary amino group (-NH-), Y2represent the group, includes m-toluyl, phenyl and cyclooctyl, and with the exception of N-[(2-cyclooctylamino-5-cyanobenzoyl)sulfonyl] N'-Isopropylamine, or its pharmacologically acceptable salt
The invention relates to medicine, namely to orthopedics and neurology
Up!