2,4,6-trimethyl-3-oxypyridine nitrosuccinate and method for production thereof
FIELD: new 2,4,6-trimethyl-3-oxypyridine nitrosuccinate and method for production thereof.
SUBSTANCE: claimed compound is useful in medicine as future antiishemic agent with vasodilatation effect and has potent protective action in barotraumatic damages and ballistic wounds due to inhibition of secondary necrosis creation and progress. Compound of present invention is obtained by nitration of malic acid with mixture of sulfuric and nitric acids, separation of nitrohydroxymalic acid and treatment thereof with 2,4,6-trimethyl-3-oxypyridine in alcohol media with subsequent isolation of target product.
EFFECT: new antiishemic agent.
2 cl, 1 ex
The invention relates to a new derivative of 2,4,6-trimethyl-3-oksipiridina, specifically to nitroresorcinol 2,4,6-trimethyl-3-oksipiridina formulas (1)
The compound (1) is a hybrid molecule that combines two antiradical fragment. The function of inhibitors of radical chain reactions of oxidation performs 2,4,6-trimethyl-3-oxypyridine.
The compound (1) can be used in pharmacology as the anti-ischemic agent with vasodilator effect.
Known for high cardiac activity nitroglycerin [Ginevich, A.I., Gorehalova N.A. Cardiac glykosides. The positive and negotive aspectsof applikation nitroglyzerin., J.Chim. Pharmakol, 1989, 31, 247], which, treating of polynuclear alcohols, widely used in practice for unloading of the heart and improve coronary circulation. However, it has a high toxicity in relation to caloric animals, LD50for it is 108 mg/kg of the closest in chemical structure and therapeutic use of the present compound is N-(2-nitroxyethyl)nicotinamide commercial name nicorandil, which is currently considered as the most effective drug for the treatment of angina and congestive heart failure [K. Sakai, Am. J. Cardiology, 1989, 63, 2j-10j]. However, nicorandil has insufficient activity and, in addition,does not provide high efficiency when barotraumatic damage to exclude secondary necrosis.
The present invention is the synthesis of new anti-ischemic tools, specifically a new connection with a hybrid structure - nitroresorcinol 2,4,6-trimethyl-3-oksipiridina-based antioxidant - 2,4,6-trimethyl-3-oksipiridina and mitroxantrone acid, a source of nitrogen monoxide and designing method thereof.
This object is achieved by the method lies in the fact that malic acid nitrous mixture of sulfuric acid and nitric acid, then separated microcentro acid and process it 2,4,6-trimethyl-3-oxypyridine, followed by separation of the target product.
The invention is characterized by the following example.
Example. Nitroresorcinol 2,4,6-trimethyl-3-oksipiridina.
To a mixture of 30 ml of HNO3and 10 ml of N2SO4at 10-12°and With vigorous stirring was added 20 g of malic acid, then the reaction mixture was stirred for 30-60 min at 0-10°and poured into ice-cold water, and then neutralizing the mixture with soda to pH 3-4 and extracted target product by ethyl acetate (5×20 ml), the extract was dried over CaCl2the solvent was removed in vacuum. Output mitroxantrone acid 16 g, TPL 133-135°C (With decomp.).
NMR1H (DMSO-d6): 2.87 (DD, J1=17.0 Hz, J2=7.2 Hz, CH), 3.0 (DD, J1=17.0 Hz, J2=4.6 Hz, CH), 5.62 (DD, J1=7.2 Hz, J2=4.6 Hz, CHONO ), 13,30 (USS, noos).
NMR13(DMSO-d6): 37.8 (CH2), 80.3 (CHONO2), 172.5, 173.9 (C=O). Found (%): 27.21; N, 3.05; N, 7.61. C4H5NO7. Calculated (%): at 26.83; N, 2.81; N, 7.82.
A mixture of 1 g (0.0056 mol) mitroxantrone acid and 0.765 g (0.0056 mol) of 2,4,6-trimethyl-3-hydroxypyridine in 10 ml of methanol is boiled for 10 minutes the Solvent is removed in vacuum, the residue is triturated in 5 ml of dry isopropanol, oil crystallizes, a white crystalline precipitate was separated by filtration and dried. Obtain 1.35 g (76.5%) of salt. T square 132-133°C (With decomp.).
NMR1H (DMSO-d6): 2.21(C), 2.36 (C), 2.39 (s, SN3-PY), 2.74 (DD, J1=17.0 Hz, J2=7.8 Hz, CH), 2.95 (DD, J1=17.0 Hz, J2=4.9 Hz, CH), 5.48 (DD, J1=7.8 Hz, J2=4.9 Hz, CH), 7.05 (s, CH-PY), 11.80 (USS, noos). NMR13(DMSO-d6): 20.3, 20.5, 23.9 (CH3), 38.4 (CH2), 80.3 (CH2ONO2), 128.6 (CH-PY), 143.4, 146.3, 148.3, 153.1 (Ru), 173.0, 174.4 (C=O).
Found (%): 45.92; N, 5.30; N, 8.50. With12H16N2O8. Calculated (%): at 45.53; H 5.06; N, 8.83.
Thus, the proposed method for obtaining compounds of formula (1) allows to solve the problem of the invention and to obtain the unknown nitroresorcinol 2,4,6-trimethyl-3-oksipiridina, which, according to VSC BAS, has a high antianginal activity (the ratio of the area of necrosis of the ischemic area is 11±3.4%) and can be used in medicine in cachestatistics active compounds, with anti-ischemic activity.
According to the laboratory of physical chemistry of Biosystems, Institute of chemical physics RAS, prior the introduction of the drug as a medicine before mechanical acoustic effects on rabbits and rats allows you to fully protect the lungs of experimental animals from hemorrhage.
1. Nitroresorcinol 2,4,6-trimethyl-3-oksipiridina formulas (1)
2. The method of producing nitroresorcinol 2,4,6-trimethyl-3-oksipiridina, namely, that malic acid nitrous mixture of sulfuric acid and nitric acid, then separated microcentro acid and process it 2,4,6-trimethyl-3-oxypyridine, followed by separation of the target product.
< / BR>where R1and R2each independently of one another, denote hydrogen, fluorine, chlorine, bromine, iodine
< / BR>Currently, a number of oxypyridine known only two drugs having antihypoxic action (emoxipin and Mexidol)
There is a method to produce succinic acid by ozonation 1,5,9-cyclododecatriene at 30-40aboutWith acetic acid 
The disadvantages of this method of obtaining are high cost and high toxicity of raw materials (1,5,9-cyclododecatriene) 
Also known is a method of obtaining succinic acid by ozonation 3-chlorocyclopentane followed by additional oxidation products of ozone with nitric acid, or hydrogen peroxide, or potassium permanganate 
The disadvantages of this method are the scarcity and high cost of raw materials (3 chlorocyclopentane), the complexity of the separation of succinic acid from by-products, not a high yield of succinic acid (81-85%)
SUBSTANCE: the present innovation deals with phospholipid complexes of proanthocyanidine A2 and pharmaceutical compositions upon their basis as antiatherosclerotic agents, those for preventing and treating myocardial and cerebral infarction. Phospholipids of the above-mentioned complex should be preferably chosen out of lecithins, phosphatidyl choline, phosphatidyl ethanolamine, phosphatidyl serine. The innovation provides the preparation to treat the above-mentioned diseases due to decreasing the quantity and burden of atheromatous plaque, decreased obstruction of carotid arteries and decreased thickness of vascular walls.
EFFECT: higher efficiency of prophylaxis and therapy.
9 cl, 11 dwg, 6 ex, 2 tbl
FIELD: organic chemistry, biochemistry, medicine, pharmacy.
SUBSTANCE: invention relates to new aminobenzophenones of the formula (I):
or their pharmaceutically acceptable salts. These compounds elicit properties of inhibitors of cytokines secretion, in particular, 1β-interleukin (IL-1β) and tumor necrosis α-factor (TNF-α) and to secretion of polymorphonuclear superoxide that are useful for treatment of inflammatory diseases, for example, skin diseases, such as psoriasis, atopic dermatitis. In the formula (I) R1 is taken among the group consisting of halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, cyano-group, carbamoyl, phenyl or nitro-group under condition that when R1 means a single substitute then it at ortho-position, and when R1 means more one substitute then at least one substitute of R1 is at ortho-position; R2 means one substitute at ortho-position being indicated substitute is taken among the group consisting of (C1-C3)-alkyl, (C1-C3)-alkoxy-group; R3 means hydrogen, halogen atom, hydroxy-, mercapto-group, trifluoromethyl, amino-group, (C1-C3)-alkyl, (C2-C3)-olefinic group, (C1-C3)-alkoxy-, (C1-C3)-alkylthio-, (C1-C6)-alkylamino-group, (C1-C3)-alkoxycarbonyl, phenyl, cyano-, carboxy-group or carbamoyl; R4 means hydrogen atom or (C1-C3)-alkyl; Q means a bond or -SO2-; Y means (C1-C15)-alkyl, (C3-C10)-carbocyclic group or phenyl being each of them can be substituted optionally with one or some similar or different substitutes designated by the formula R5; R5 means halogen atom, (C1-C4)-alkyl, amino-, (C1-C3)-alkoxy-group, (C1-C3)-alkoxycarbonyl or -COOH; X means oxygen or sulfur atom. Also, invention relates to a pharmaceutical composition and to a method for treatment and/or prophylaxis of inflammatory diseases.
EFFECT: valuable medicinal properties of compounds and composition.
9 cl, 2 sch, 2 tbl, 29 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: medicine, pharmacology, pharmacy, medicinal biochemistry.
SUBSTANCE: invention proposes a pharmaceutical composition that comprises, in particular, N-(1-octyl-5-carboxymethyl-dimethylindolin-7-yl)-2,2-dimethylpropaneamid or its pharmacologically acceptable salts as inhibitor of enzyme ACAT and inhibitor of HMG-CoA-reductase that represents pravastatin, lovastatin, simvaststin, fluvastatin, rivastatin, atorvastatin, rosuvastatin or pitavastatin used as active component of the composition. The combination of active substances shows the expressed synergistic effect. Invention provides enhancing activity of the composition in clinical applying.
EFFECT: valuable medicinal properties of composition.
71 cl, 2 tbl, 3 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