Salts of 2-[2-(diethylamino)ethylthio] -5,6-dimethylbenzimidazole with anti-ischemic, hypoxic and anti-arrhythmic activity and 2-[2-(diethylamino)ethylthio] - 5,6-dimethylbenzimidazole as an intermediate product for the synthesis of salts of 2-[2-(diethylamino)ethylthio] -5,6 - dimethylbenzimidazole
(57) Abstract:Usage: salt is used as a drug that has anti-ischemic, anti-toxic and anti-arrhythmic activity; 2-[2 - (diethylamino) ethylthio] -5,6-dimethylbenzimidazole - as an intermediate product for the synthesis dihydrochloride and succinate. The inventive product of General formula (I) , where I X = 2 HCl ; II X = 0,5(CH2COOH)2the product of General formula (II) Reagent I: 5,6 - dimethyl - 2 mercaptobenzimidazole. Reagent II: 2 - (diethylamino) ethylchloride in the environment introductory ethanol or dimethylformamide in the presence of a base. Reagent III: ethereal solution of hydrogen chloride or an alcoholic solution of succinic acid. 2 C. p. F.-ly, 3 ill., 9 table. The invention relates to new chemical compounds of benzimidazole series, namely salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole General formula
where I X = 2HCl;
II X = 0,5 (CH2COOH)2that have anti-ischemic, hypoxic and anti-arrhythmic activity and can find application in medicine for the treatment of ischemic heart disease, as well as to the intermediate product to obtain them.The proposed compounds, their properties and the biological is II).The literature describes a number of S-alkyl(dialkyl)aminoalkyl derivatives of 2-mercaptobenzimidazole with cardiotropic , antihistaminic [2-4] , antiallergic [2, 3], analgesic [4-6], anti-inflammatory [4, 7, 8], as well as antidepressant [7, 8], antimicrobial [9, 10] and radioprotective activity .The proposed compounds exhibit anti-ischemic activity characteristic of a bradycardia selective drugs, and, in addition, antihypoxic and antiarrhythmic activity of broad-spectrum. In accordance with this as a prototype for anti-ischemic action selected verapamil, antihypoxic - piracetam, antiarrhythmic - quinidine, procainamide, lidocaine, propranolol, verapamil.The aim of the invention is the creation of new connections in a series of derivatives of 2-mercaptobenzimidazole with anti-ischemic activity in combination with antihypoxic and antiarrhythmic activity.The claimed compounds are synthesized according to standard techniques by alkylation of 5,6-dimethyl-2-mercaptobenzimidazole by 2-(diethylamino)ethylchloride in aqueous ethanol or dimethylcarbamate in Pris is thio]-5,6-dimethylbenzimidazole in ethanol ether solution of hydrogen chloride or alcoholic solution of succinic acid.The invention is illustrated in the following examples.P R I m e R 1. The dihydrochloride of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzamide-ash (I).To a solution of 1.4 g (0.035 mol) of sodium hydroxide in 2 ml of water and 20 ml of alcohol was added 2.67 g (0.015 mol) of 2-mercapto-5,6-dimethylbenzimidazole and 2.75 g (to 0.016 mol) of the hydrochloride of 2-(diethylamino)ethylchloride and boiled for 5 hours After cooling, the reaction mixture is diluted with water and extracted with chloroform. The extract was washed with 10% sodium hydroxide solution and water, dried with calcium chloride and evaporated. Obtain 3.7 g (84%) of the monohydrate of 2-[2-(diethylamino)ethylthio] -5,6-dimethylbenzamide-ash; so pl. 82-83about(From aq. SP.).Found, %:60,76; N 8,20; N 14,22; S 10,97.WITH15H23N3S.H2O.Calculated, %:C 60,98; N 8,53; N, 14.22; S 10,85.UV-spectrum (ethanol),maxnm (lg): 293 (4,32); 301 (4,38).PMR-spectrum (deuterochloroform), , M. D.: 1,19 (6N, t, 2 N-C-CH3); 2,34 (6N, s, 2 CH3-Ar); 2,72 (4H, q, 2 N--CH3); to 2.99 (2H, m, S-CH2); the 3.11 (2H, m, N-CH2); from 7.24 (2H, s, Harene.).The solution 4,43 g (0.015 mol) of monohydrate base in 10 ml of absolute alcohol and 50 ml of absolute ether is treated with ethereal solution of hydrogen chloride. Fallen UP>about(From a mix of see-EA).Found, %: C 51,48; N 7,30; Cl 20,47; N 12,08; S 9,18.WITH15H23N3S.2HCl.Calculated, %: 51,42; N 7,19; CL 20,24; 12,00 N; S 9,15.UV-spectrum (ethanol),maxnm (lg): 292 (4,30); 299 (4,30).PMR-spectrum (deuterium oxide), , M. D.: 1,33 (6N, t, 2 N-C-CH3); 2.40 a (6N, s, 2 CH3-Ar) to 3.35 (4H, q, 2 N--CH3); of 3.57 (2H, m, S-CH2); 3,74 (2H, m, N-CH2); the 7.43 (2H, s, Harene.).P R I m m e R 2. Succinate 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole (II).To a solution of 1.78 g (0.01 mol) 2-mercapto-5,6-dimethylbenzimidazole and of 2.06 g (0.012 mol) of the hydrochloride of 2-(diethylamino)ethylchloride in 25 ml of dimethylformamide is added to 4.14 g (0.03 mol) of potash and stirred for 1 h at 80-90aboutC. After cooling, the reaction mixture is diluted with 250 ml of water. Separated oily product crystallized upon standing. The precipitate is filtered off, washed with water and dried in air. Obtain 2.24 g (76%) of the monohydrate of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole; so pl. 82-83about(From aq. SP.).The substance does not depression so plasma sample obtained above and is identical to him in the UV and IR spectrum.To a solution 4,43 g (0.015 mol) of the monohydrate of the base in 30 ml of absolute alcohol portiamo the beginning of sedimentation, then add 50 ml of absolute ether. The precipitate is filtered off, washed with water and dried in air. Get to 4.33 g (87%) of compound (II); so pl. 180-181about(From the abs. SP.).Found, %: C 60,94; N. Of 7.68; N 12,17; S 9,46.WITH15H23N3S.0.5 C4H6O4.Calculated, %: C 60,68; N 7,79; N 12,49; S At 9.53.UV-spectrum (ethanol),maxnm (lg): 293 (4,44); 301 (4,44).PMR-spectrum (deuterium oxide + 2 drops triperoxonane acid), M. D.: 1,45 (N, t, 4 N-C-CH3); 2,47 (N, s, 4 CH3Ar); 2,73 (4H, s, PRAS2CH2CO); 3,43 (8H, kV, 4 N--CH3); to 3.64 (8H, s, SCH2CH2N); 742 (4H, c, Harene.).Pharmacological study of the claimed compounds was carried out on various models of ischemia, hypoxia and arrhythmia, in comparison with reference drugs.1. Anti-ischemic activity.For the evaluation of anti-ischemic properties of the claimed compounds were investigated for their influence on hemodynamics and activity of the intact heart cats. We also used two models of myocardial ischemia: a model of acute failure of coronary circulation and the model 20-minute occlusion and subsequent 30-min reperfusion of the coronary artery in cats. It was found that with the e 30 min after injection. However, other hemodynamic parameters and cardiac activity (mean arterial pressure, heart rate, average acceleration of blood flow in the aorta) was almost unchanged (see table. 1 and 2 of the act biological testing). Comparison drug verapamil also cause significant bradycardia. However, under his influence more significantly reduced systemic arterial pressure and decrease the average acceleration of blood flow in the aorta, which indicates the inhibition of the contractile function of cardiac muscle (see tab. 3).As shown by experiments on a model of acute failure of coronary circulation have shot cats, compounds I and II (1.0 mg/kg bolus + 50 µg/kg/min during the intravenous experience) significantly reduce the average ST segment elevation in multiple leads epicardial electrogram during the 5-minute occlusion of the coronary artery. This is reflected in Fig. 1 and 2. On the y - axis the average rise in segment SI mV; the abscissa shows the time of occlusion and reperfusion of the coronary artery, min. Curve 1 - control occlusion; curve 2 - occlusion immediately after the introduction of the connection; curve 3 - 20 minutes and the comparator Drug verapamil on this model operates in a similar manner.
< / BR>where I X - 2HCl;
II X - 0,5 (CH2COOH)2,
with anti-ischemic, hypoxic and anti-arrhythmic activity.2. 2-[2-(Diethylamino)ethylthio]-5,6-dimethylbenzimidazole
< / BR>as an intermediate product for the synthesis of salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole.
(1) where Неt is a heterocyclic group, possibly substituted by 1-3 substituents selected from lower alkyl, lower alkenyl, lower quinil, group cycloalkyl-lower alkyl, arylalkyl, lower alkoxycarbonyl, halogen atom;
X represents a single bond attached to the carbon atom of the heterocyclic group
enhance the body's resistance to the action of nitrogen dioxide and has cytoprotective and antihypoxant activity (N state of registration 10191991)
where R1-COOH or the group< / BR>R2=H-C3H7or n-C4H9;
R3-Cl, CF3C2F5C6H5or COOH;
R4-COOH, CHO, or CH2HE, provided that
a) when R4-CH2OH, R3-C2F5and R2-n-C3H7,
b) when R3-COOH, R4also is COOH,
b) when R2-n-C3H7, R3-C2F5and R4-COOH, R1is the groupwhich inhibit the action of the hormone angiotensin and can be used in medicine
where R is H, CH3; R1= CH3H
provided that 1A R - H, R1- H (N 65 in the work log); 1B, R = CH3, R1= H (N 66 in the work log); 1B, R = CH3, R1= CH3(N 71 in the work log);
possessing antibacterial action
FIELD: medicine, oncology.
SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.
EFFECT: higher efficiency of therapy.
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, medicine, pharmacy.
SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.
EFFECT: valuable medicinal properties of compounds and composition.
10 cl, 19 ex
FIELD: organic chemistry and pharmaceutical compositions.
SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.
EFFECT: new effective kinase p38 inhibitors.
23 cl, 6 dwg, 1 tbl, 1 ex
FIELD: veterinary science.
SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.
EFFECT: higher efficiency of therapy.
4 cl,262 ex, 12 tbl
FIELD: medicine, gynecology, anesthesiology.
SUBSTANCE: invention concerns to a method for carrying out the anesthesiology assistance for woman in childbirth with accompanying bronchial asthma. Method involves administration of atropine, dimedrol, analgin and clophelin. Method involves additional intravenous administration of transamine for 5-7 min. Transamine is administrated in doses 12-14 and 15-17 mg/kg in woman in childbirth with body mass 75 kg and above and 74 kg and less, respectively. Method provides enhancing quality and safety of anesthesia in this class of woman in childbirth.
EFFECT: improved assistance method.
7 tbl, 4 ex
FIELD: medicine, dermatology, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to an antifungal gel pharmaceutical composition based on ketoconazole and clotrimazole that are derivatives of imidazole. The composition comprises ketoconazole or clotrimazole as an active component, polyethylene glycol-400 (PEG-400) as a solvent, carboxyvinyl polymer as a gel-forming agent, polyethylene glycol as a gel stabilizing agent, organic amine or inorganic bas as a regulator of pH and water taken in the definite ratio of components. The composition is prepared by dissolving active component in PEG-400, dispersing carboxyvinyl polymer in water, successive addition to dispersion propylene glycol as a stabilizing agent and regulator of pH and combination of prepared solution and gel followed by stirring the mixture up to preparing the gel composition with pH 5-7. Invention provides preparing antifungal composition with reduced adverse effect.
EFFECT: improved preparing method, valuable medicinal properties of composition.
2 cl, 1 tbl, 11 ex
FIELD: veterinary science.
SUBSTANCE: the present innovation deals with applying selector as a selenium-containing organic preparation to be introduced for cows and calves monthly intramuscularly at the dosage of 10 mcg/kg body weight. The method provides decreased fodder expenses for the synthesis of the production obtained.
EFFECT: higher productivity in cattle.
2 ex, 7 tbl
FIELD: organic chemistry, medicine, allergology, chemical-pharmaceutical industry, pharmacy.
SUBSTANCE: invention relates to a method for treatment of patient suffering with allergic disease. Method involves administration to patient the therapeutically effective dose of pharmaceutical composition comprising compound of the formula (I)
. The compound elicits high effectiveness in treatment of allergy and shows low toxicity also.
EFFECT: improved method for treatment.
9 cl, 2 tbl, 2 dwg, 40 ex
FIELD: veterinary science.
SUBSTANCE: one should apply a selenium-containing preparation named selecor: it should be introduced on the 80-90th d of swine gestation twice at 10-15-d-long interval parenterally at the dosage of 20 mg/kg animal body weight. Application of low-toxic antioxidant as selecor enables to improve functional properties of cell membranes of placental system and endometrium and increase inspecific immune resistance in sows. It, also, enables to increase fertility in sows, values of uncomplicated deliveries and puerperal period.
EFFECT: higher viability of off-spring.
2 ex, 3 tbl
FIELD: organic chemistry, biochemistry, pharmacy.
SUBSTANCE: invention relates to new heterocyclylsulfonyl alkylcarboxylic acids and their derivatives of the general formula (1): or their pharmaceutically acceptable salts, N-oxides or hydrates possessing the inhibitory effect on kinase activity and to the focused library for search of active leader-compounds comprising at least abovementioned compound. In the general formula 91) W represents optionally substituted heterocyclic radical, among them: pyrrole-3-yl, thiophene-2-yl, isooxazole-4-yl, pyrazole-4-yl, imidazole-4-yl, pyridine-3-yl, 1H-2,4-dioxopyrimidine-5-yl, 2,3-dihydro-1H-indole-5-yl, 2,3-dihydro-1H-indole-7-yl, 1,3-dihydro-2-oxoindole-5-yl, 2,3-dioxo-1H-indole-5-yl, 2-oxo-3H-benzoxazole-6-yl, benzothiazole-6-yl, 1H-benzimidazole-5-yl, benzo[1,2,5]oxadiazole-4-yl, benzo[1,2,5]thiadiazole-4-yl, 1,2,3,4-tetrahydroquinoline-6-yl, 3,4-dihydro-2-oxo-1H-quinoline-6-yl, quinoline-8-yl, 1,4-dihydro-2,3-dioxoquinoxaline-6-yl, 3-oxo-4H-benzo[1,4]oxazine-7-yl, 3-oxo-4H-benzo[1,4]thiazine-7-yl, 2,4-dioxo-1H-quinazoline-6-yl, 2,4-dioxo-1,5-dihydrobenzo[b][1,4]diazepine-7-yl or 2,5-dioxo-3,4-dihydrobenzo[b][1,4]diazepine-7-yl; Y represents optionally substituted methylene group; R1 represents chlorine atom, optionally substituted hydroxyl group, optionally substituted amino-group, optionally substituted azaheterocyclyl; n = 1, 2 or 3; or Yn represents carbon atom of optionally substituted (C3-C7)-cycloalkyl or optionally substituted (C4-C7)-heterocyclyl. Also, invention relates to a pharmaceutical composition in form of tablets, capsules or injections placed into pharmaceutically acceptable package.
EFFECT: valuable properties of compounds.
5 cl, 3 sch, 5 tbl, 6 ex