N-2-(1 - r1-5-r2-6-r3- benzimidazolyl)succinamide acid exhibiting neurotic, antihypoxic and antiarrhythmic activity
(57) Abstract:Usage: as a drug possessing neuroleptic, antihypoxic and antiarrhythmic activity. The inventive product of the General formula where (a) R1=CH3; R2=R3=Br (b) R1= H-C4H9; R2=R3=H (a) so pl. 142-143°C BF C15H19N3O3yield 70% b/ T. pl. 309 310°C, CF C12H11N3O3exit 65% Reagent 1: 2-amino - 1-R1-5-R2-6-R3-benzimidazole Reagent 2: succinic anhydride. Environment: dry dioxane. 6 table. The invention relates to the synthesis of new biologically active chemical compounds, specifically to N-2-(I-R1-5-R2-6-R3-benzimidazolyl)-Succinimidyl acids of General formula I
where (a) R1=n-C4H9, R2=R3=H;
b) R1= CH3, R2= R3=Br, which have neuroleptic, antihypoxic and antiarrhythmic activity, and can find application in medicine.Analogues for action are chlorpromazine, sodium oxybutyrate, procainamide drugs, widely used in medical practice.The aim of the invention is the creation of more effective and minipreparation.This goal is achieved by a new chemical structure of N-2-(1-R1-5-R2-6-R3-benzimidazolyl)-succinamide acids of the formula I obtained by the reaction of 2-amino-1-R1-5-R2-6-R3-benzimidazole with succinic anhydride in an environment of dry dioxane scheme
The yield of target products was 65-70% of the Compounds Ia,b colorless crystalline substance, soluble in DMF, DMSO, insoluble in acetone and water.The structure of the synthesized compounds are confirmed by the data of elemental analysis and IR spectroscopy, and individuality was monitored by thin layer chromatography (see tab.1).P R I m m e R. N-2-(1-butylbenzothiazole)-succineidae acid Ia (see tab.1). To a solution of 1.89 g (0.01 mol) 2-amino-1-butylbenzothiazole in 100 ml of dry dioxane was added a solution of 1.2 g (0.012 mol) of succinic anhydride in dioxane. The reaction mixture is boiled for 2 hours, the excess solvent drove in a vacuum. The precipitation was filtered, washed with water and dried. Yield 2.0 g (70%).Similarly, the received connection 1B.Acute toxicity of the compounds under study and comparative drugs were determined in experiments on white mice mA>0compounds 1A and 1B is 380 and 567 mg/kg, respectively.We studied the effect of compounds 1A,b and chlorpromazine on the latent period Atamanova sleep (see tab.2) and the duration of eleminal-sodium sleep (see tab.3).Studies have shown that the effect of chlorpromazine on the latent period of sleep at the doses of 10 mg/kg (1/10 LD50) to 0.7 mg/kg (srednestatisticheskaya dose) remained virtually unchanged (1672,6 and 165 of 4.6). The same can be said about the influence of compounds 1A and 1B in doses equal to 1/10 LD50and equimolecular 0.7 mg/kg of chlorpromazine (differences not statistically reliable, see table.2. Therefore, further studies on the claimed compounds in dose, equimolecular 0.7 mg/kg of chlorpromazine.The influence of compounds on the duration of the latent period eleminal-sodium dream was conducted by the method of  in Wistar rats. The investigated compounds were administered at a dose equimolecular 0.7 mg/kg of chlorpromazine, eleminal-sodium at a dose of 40 mg/kg comparison Drug chlorpromazine dose of 0.7 mg/kg On the effect to be judged by the decrease in the latent period before falling asleep.From table. 2 shows that compounds 1A and 1B in their effects similar to chlorpromazine (180 5, 1901,7 and 1654,6 s, respectively). While the acute 1A and 1B on the duration of eleminal-sodium sleep was studied by the method of  Wistar rats (see table.3).Rats of the first and second groups were injected compounds 1A and 1B, respectively, at doses equimolecular 0.7 mg/kg of chlorpromazine, and after 30 min eleminal-sodium at a dose of 30 mg/kg to Rats of the third group was administered chlorpromazine dose of 0.7 mg/kg and 30 min eleminal-sodium (30 mg/kg). A control group of rats received only eleminal-sodium at a dose of 30 mg/kg On the duration of eleminal-sodium sleep judged on the time during which the animals were housed in an upright position.The experiments showed that compound Ia increases the duration of sleep compared to the control 2.4 times, and the connection 1B 2.6 times (chlorpromazine 4.7 times). However, the toxicity of these compounds 3.8 and 5.7 times, respectively, lower than that of chlorpromazine.Adjunct effect of the studied compounds were also assessed by determining the threshold of excitability of the motor centers of the forebrain. frogs. In the acute experience on neobuzdannoe the frog exposed front lobe of the brain, and caused irritation with pacemaker WES-1 bipolar rectangular current pulses, with a duration of 0.5 MS and a repetition rate of 50 pulses per second. Electric irritation of the motor centers of the anterior lobe of the brain, caused by the movement of tunjur brain motor reaction, was estimated as the threshold of irritation 
In the experience were compared average values of thresholds of excitability in the initial state and after 15 min during the application of a 2% suspension of the studied compounds. As the comparison drug was used chlorpromazine 
The results of the experiments are presented in table. 4. From the data table. 4 shows that the introduction of compounds 1A leads to an increase of the threshold sensitivity of 60% and a connection 1B 35% comparator Drug chlorpromazine significant increase in the threshold of irritation during the application does not.Defined values of excitability in the initial state and after 30 min after the introduction of the investigated substances in the lymph bag frog (see tab. 4). Compounds 1A and 1B were injected at a dose of 1/10 LD50, chlorpromazine 0.7 mg/kg of Compounds 1A and 1B increase the excitability of 31% and 37%, respectively, and chlorpromazine 18%
In the control groups of animals either during application or during the introduction of saline into the lymphatic bag authentic change of excitability were observed.Thus, compounds 1A and 1B have a marked dampening effect on the excitability of the motor centers of the forebrain. frogs.Most compounds is the ability to increase the body's resistance to hypoxia, and also have antiarrhythmic action, affecting the nervous regulation of heart rate [6,7]
So was also studied antihypoxic and antiarrhythmic activity of the claimed N-2-(1-R1-5-R2-6-R3-benzimidazolyl)-succinamide acids. Antihypoxic activity of the studied compounds and the comparison drug sodium oxybutyrate studied in models of normobaric and hypobaric hypoxia  at a dose of 1/10 LD50. Normobaric hypoxia was produced by placing the animals in thermocamera volume of 500 ml, with standard values of temperature (18-22aboutC). In the experiments recorded the lifetime of the animal. In thermocamera simultaneously placed the test and control animals. Hypobaric hypoxia was produced by the rarefaction of the atmosphere in the chamber. The partial pressure of oxygen was 37.5 mm RT.article Speed "recovery" of animals to a height of 1500 m was equal to 30 m/s In the chamber at the same time put the test and control animals. The exposure time of animals in the chamber 30 min. the results of the experiments are presented in table.5.Compounds 1A and 1B on the model normobaric hypoxia showed approximately equal activity. They increased the duration of x hypobaric hypoxia with the introduction of compounds 1A and 1B, the animals were killed within 30 min (the time of exposure in the chamber, i.e., their life expectancy has increased more than 5 times. Sodium oxybutyrate in these conditions increases the life expectancy of animals 3 times.Antiarrhythmic activity of the claimed compounds was studied on the model chloralkali adults in outbred rats. Arrhythmia was modeled according to the method of  simultaneous introduction of a 10% aqueous solution Cl2(200 mg/kg) into the femoral vein. The analyte and the reference product was administered at a dose of 1/10 LD50. The data obtained are given in table.6.Studies have shown that the introduction of compounds 1A leads to increased survival rate of animals in 2.5 times, compared with procainamide. This connection is stronger procainamide hydrochloride and antifibrillatory activity. Compound 1B increases the survival rate of animals at the level of the comparison drug.Thus, the claimed compounds 1A,b in neuroleptic effect on indicators of the latent period eleminal-sodium sleep equal to chlorpromazine, but the effect on the magnitude of the threshold of excitability of the forebrain. frogs superior to chlorpromazine 50 and 25%, respectively. While acute toxicity of the inventive compounds 3.8 and 5.7 times, respectively, lower than VA the lives of animals in thermocamera 2.0 and 2.1 times, respectively (sodium oxybutyrate 1.5 times). In the conditions of hypobaric hypoxia their life expectancy has increased more than 5 times (sodium oxybutyrate 3 times).On antiarrhythmic action (indicator surviving animals) compound 1B is procainamide, 1A and the connection exceeds 2.5 times. N-2-(1-R1-5-R2-6-R3-Benzimidazolyl)succinamide acid of General formula
< / BR>where (a) R1CH3, R2R3Br;
b) R1H C4H9, R2R3hydrogen
exhibiting neurotic, antihypoxic and antiarrhythmic activity.
(1) where R1the atom of hydrogen, fluorine, chlorine or bromine, alkyl-, aralkyl-, aryl-, heteroaryl-, R3O-, (R3)2N-, R4CO - NR3-, alkylsulfonyl - NR3-, arylsulfonyl - NR3-, R3S-, R3SO, R3S2O-, or R5group, and R3is a hydrogen atom, an alkyl group containing from 1 to 6 carbon atoms, aryl, heteroaryl, kalkilya, carboxialkilnuyu or alkoxycarbonylmethyl group;
R4a hydrogen atom, alkyl or CNS group containing 1-6 carbon atoms, aryl, heteroaryl or kalkilya group containing 1-6 carbon atoms in the alkyl part;
R5azetidinone, pyrolidine, hexamethyleneimino or heptamethylnonane or piperidino group in which the methylene group in the fourth position may be substituted with oxygen, sulfenyl, sulfinil or sulfonylureas or aminogroups, which can be substituted for R3, R4CO4, alkylsulfonyl - or aryl is
RR6(I) in which groups are represented as follows: R1, R2, R3independently represent a hydrogen atom, hydroxy group, lower alkyl group, which optionally can be substituted by halogen atom, lower alkoxy group, a lower alkylthio group, aralkylated group, aryloxy group, lower alkanoyloxy group, carboxy group, lower alkoxycarbonyl group or nitro group;
R4, R5, R6represent a hydrogen atom or a lower alkyl group;
X represents an oxygen atom or a sulfur atom
(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where
-A1= AND2- A3= AND4- bivalent radical having the formula
-CH=CH-CH=N (a-5) or
n=1 or 2
IN - NR4or CH2< / BR>R4is hydrogen or C1-C6alkyl
L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula
-Alk - R5(b-1),
-Alk - Y - R6(b - 2),
-Alk - Z1- C(=X) - Z2- R7(b-3), or
-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)
Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;
R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;
Y is O or NH;
Z1or Z2each independently NH or a direct link X-O
each Аlk independently - C1-C6alcander
(I)< / BR>(II),whereR is the residue of carboxylic acids, which are used as intermediates in obtaining antibiotics cephalosporin and penicillin ranks as the number of individual substances and mixtures
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, medicine, pharmacology.
SUBSTANCE: invention relates to gyrase inhibitors that reduce amount of microorganisms in biological sample by contacting the indicated sample with compound of the formula (I): , to a method for treatment of bacterial infection by using compounds of the formula (I), compounds of the formula (I) and a pharmaceutical composition comprising compounds of the formula (I). Invention provides the enhanced effectiveness of treatment.
EFFECT: valuable medicinal properties of gyrase.
54 cl, 5 tbl, 13 ex