Isopropylated 2-(4-chloroanilino)cinchoninic acid, exhibiting anti-inflammatory and analgesic activity
(57) Abstract:Isopropylated 2-(4-chloroanilino)cinchoninic acid of the formula I can be used in medicine as anti-inflammatory and analgesic funds. 1 PL.The invention relates to new biologically active compounds, namely isopropylamino 2-(4-chloroanilino)cinchoninic acid of the formula:
< / BR>possessing anti-inflammatory and analgesic activity, suggesting the possibility of its use in medicine as a drug for the treatment of inflammatory processes.The closest analogue to the structure of the claimed compounds is 2- (2,4-dimethylaniline)Tikhonova acid, which exhibits anti-inflammatory activity  (Yanborisova O. A., Konshina T. M., Employees, Y. M., Zaks, A. S., Konshin M. E., Synthesis and antiinflammatory activity of 2-allamericanheroes acids and amides of 1,2-dihydro-2-oxazinone acid, Chem.-Pharm. zhurn., 1995, T. 29, N 6, S. 32-33).< / BR>In medical practice widely used anti-inflammatory medication may also fuse  (Mashkovsky, M. D., Medicines, M, Medicine, 1985, T. 1, S. 198), which has taken us the plants is search in a series of amides of 2-substituted cinchoninic acid compounds, having a high anti-inflammatory and analgesic activity with low toxicity.This goal is achieved by the synthesis of Isopropylamine 2-(4-chloroanilino)cinchoninic acid interaction Isopropylamine 2-horseshoebay acid  (Mikhalev A. I., M. Zueva Century, Sachs A. S. Synthesis and anti-inflammatory activity of substituted amides 2-horseshoebay acid, Dept. in VINITI, 1996, N 2433-B96) with 4-Chloroaniline according to the following scheme:
< / BR>An example of obtaining the claimed compounds.The solution 2,48 g (0.01 mol) of Isopropylamine 2-horseshoebay acid and 1.28 g (0.01 mol) of 4-Chloroaniline in 10 ml of DMF is boiled for 4 h, cooled, poured into 50 ml of water, neutralized with 10 % sodium carbonate solution. The precipitate is filtered off and recrystallized from dioxane. Yield 3.0 g (88%).So pl., 250 - 252oC. C19H18CIN3O.Found, % : C 67,20; H 5,42; N 12,31.Calculated, % : C 67,15; N. Of 5.34; N 12,37.IR-spectrum (UR - 20) vaseline oil, cm-1: 1640 (CO), 3400 (NH). PMR-spectrum (Fourier spectrometer NMR firm Tesla BS-587A, DMSO-d6, GMDS, , M. D. ): 9,63 s (1H, NH), 8.58 in d (1H, NH-amide), 7,0-8,06 m (9H, ArH) 4.1 m (1H, CH) and 1.15 (6H, 2CH3).The compound obtained is when Suche connection stable.The claimed compound was examined for the presence of anti-inflammatory and analgesic actions.Acute toxicity of the compounds and ortofena studied on white mice by the method of  (Prozorovsky Century B., a Practical guide for rapid determination of the average effective doses and concentrations of biologically active substances, S.-Petersburg, SPE-Science, 1992, S. 42) intraperitoneal injection, and found that LD50for the claimed compound is 631 mg/kg, and ortofena - 132 mg/kgAnti-inflammatory activity (PVA) has been studied in outbred rats weighing 160-190 g test substance was administered intraperitoneally in the form of a suspension in water with tween-80) for 1 h prior to the introduction of carragenine. Increase inflamed foot was evaluated ecometrics after 3 and 5 h after injection of 0.1 ml of 1% solution carragenine and calculated the percentage inhibition of edema compared to the control  (Trinus F. P., B. Klebanov M., Kondratyuk C. I. Methodological guidance on experimental (preclinical) study of non-steroidal anti-inflammatory pharmacological substances. M., the Ministry of health of the USSR, 1983, p. 16).It is established that isopropylated 2-(4-chloroanilino)cinchoninic acid intraperitoneal call for the development carragenine edema during all periods of observation. The difference between the PKA of the claimed compounds at a dose of 10 mg/kg and activity ortofena in the same dose statistically insignificant. ED50compounds, calculated graphically equal to 8 mg/kg and corresponds to the ED50ortofena calculated for the same route of administration  (Subev R. F., Mashkovsky M. D., Schwartz, J., Pokryshkin Century. And. Comparative pharmacological activity of modern non-steroidal anti-inflammatory drugs, Chem. Pharm. zhurn., 1986, T. 20, No. 1, S. 33-39). The analyzed connection manifests PVA at a dose of 25 mg/kg and the oral route of administration and causes inhibition of edema after 3 h of 38.2% and 5 h by 42.6%.The positive difference between the claimed compounds from used in medicine anti - inflammatory drugs-ortofena is a large amount of therapeutic index of PVA, which are respectively 79,0 and 16.5, i.e., therapeutic index of the claimed compounds is 4.8 times higher than ortofena.To characterize the analgesic activity of the used test acetic cramps" in mice caused by intraperitoneal introduction of 0.25 ml of a 0.75% solution of acetic acid by counting the number of "cramps" within 10 minutes  C. A. Winter, E. A. Risley and G. W. Nuss // Proc. Soc. Exp. Biol. (New York), -1962. -Vol.111. -P. 544-547).And the Oia irritating agent.The experimental results were processed statistically with the calculation of the criterion of validation  (Belenky, M. L., Elements of quantitative evaluation of the pharmacological effect, 2nd ed., Leningrad, Medgiz, 1963, S. 81 - 106).On the analgetic action of the studied compound at a dose of 25 mg/kg (table). several inferior activity ortofena in the same dose.Sources of information
1. Yanborisova O. A., Konshina T. M., Employees, Y. M., Zaks, A. S., Konshin M. E., Synthesis and antiinflammatory activity of 2-allamericanheroes acids and amides of 1,2-dihydro-2-oxazinone acid, Chem.-Pharm. zhurn., 1995, T. 29, N 6, S. 32-33.2. Mashkovsky, M. D., Medicines. Medicine, Moscow, 1985, T. 1, S. 198.3. Mikhalev A. I., M. Zueva Century, Sachs A. S., Synthesis and anti-inflammatory activity of substituted amides 2 - horseshoebay acid, Dept. in VINITI, 1996, N 2433-B96.4. Prozorovskiy Century B., a Practical guide for rapid determination of the average effective doses and concentrations of biologically active substances, SPE-Science, S. - Petersburg, 1992, S. 42.5. Trinus F. P., B. Klebanov M., Kondratyuk Century. And., guidance on experimental (preclinical) study of the non-steroidal protivovospalitelnye Century. And., Comparative pharmacological activity of modern non-steroidal anti-inflammatory drugs, Chem.-Pharm.zhurn., 1986, T. 20, No. 1, S. 33-39.7. C. A. Winter, E. A. Risley And G. W. Nuss // Proc.Soc.Exp.Biol. (New York), -1962. -Vol.111.-P. 544-547.8. Belenky, M. L. , Elements of quantitative evaluation of the pharmacological effect, 2nd ed., Leningrad, Medgiz, 1963, S. 81-106.0 Isopropylated 2-(4-chloroanilino)cinchoninic acid formula
< / BR>exhibiting anti-inflammatory and analgesic activity.
< / BR>in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;
R2is halogen, halo(lower)alkyl, cyano, carboxy, (lower alkoxy)carbonyl group, carbamoyl, optionally substituted by alkyl;
R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,
or their pharmaceutically acceptable salts
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: medicine, cardiology.
SUBSTANCE: the suggested method should be performed at the background of medicinal therapy with preparations out of statins group, tevetene, polyoxidonium and conducting seances of plasmapheresis by removing 800 ml plasma twice weekly with N 5 due to additional intramuscular injection of immunophan 0.005%-1.0 with N 10 and fluimucyl 300 mg intravenously daily with N 5-10, total course of therapy lasts for 2 mo. The method provides modulation of leukocytic functional activity, moreover, due to altered cytokine profile and, thus, through disintegration of protein-lipid complexes participating in the development of atherosclerotic platelets.
EFFECT: higher efficiency of therapy.
FIELD: medicine, endocrinology, pharmacology, pharmacy.
SUBSTANCE: invention relates to a pharmaceutical combined composition used for treatment or prophylaxis of hypertension in patients suffering with diabetes mellitus. The composition comprises AT1-antagonist valsartan or its pharmaceutically acceptable salt and calcium channel blocking agent or its pharmaceutically acceptable salt, and pharmaceutically acceptable carrier. The composition elicits synergistic effect and expanded spectrum effect.
EFFECT: improved and valuable medicinal properties of composition.
10 cl, 3 tbl
FIELD: organic chemistry, pharmacy.
SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:
wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.
EFFECT: valuable medicinal properties of compounds and compositions.
16 cl, 1 tbl, 86 ex
FIELD: medicine, pharmacology, pharmacy.
SUBSTANCE: invention proposes the composition comprising xenon as NMDA-antagonist and alpha-2-adrenergic agonist used for treatment of tetanus or narcotics (alcohol) withdrawal syndrome, states with chronic pain syndrome. Also, invention relates to the anesthetic composition comprising xenon and alpha-2-adrenergic agonist and to a method for anesthesia. The synergistic interaction of xenon as NMDA-antagonist and alpha-2-adrenergic agonist provides reducing the dose and to maintain the prolonged effectiveness by prevention for arising the drug habitation to the claimed preparation.
EFFECT: valuable medicinal properties of composition.
9 cl, 6 dwg, 6 ex
SUBSTANCE: the present innovation deals with mixing water for injections, conservation agent, metronidasol till complete dissolving at 50-60 C, adding a buffer (NaOH solution) pH 4.5-6.5 at pre-estimated quantity of water, then one should sterilize the obtained medicinal form due to membranous filtration followed by sterile packaging. As a conservation agent one should apply sodium chloride at the quantity of 1.5-2.0 against metronidasol weight, then metronidasol solution should be supplemented with a half-volume of sodium chloride solution, after complete dissolving the obtained solution should be supplemented with the rest quantity of sodium chloride solution. As for membranous filtration it should be carried out by applying a capsule out of polypropylene with hydrophilic membrane of 1.2 mcm. The method provides no crystallization of an active substance during prolonged period of time.
EFFECT: higher therapeutic efficiency.
1 ex, 1 tbl
FIELD: medicine, cardiology.
SUBSTANCE: it is suggested to apply cortisol antagonists in addition to clonidine while manufacturing preparation to treat heart failure. Moreover, one should introduce cortisol antagonist or a product that includes cortisol antagonist along with the second medicinal preparation being a combined preparation to be applied either simultaneously, separately or successively. The present innovation provides decreased symptoms of heart failure at decreasing cardiac muscle's fibrosis and heart sizes due to preferable impact upon glucocorticoid receptors in patient's heart and/or kidneys.
EFFECT: higher efficiency of application.
12 cl, 2 ex
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