Maleic acid 4-methyl-2-pyridylamide eliciting hypertensive activity

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new biologically active compound representing maleic acid 4-methyl-2-pyridylamide of the formula: . Compound is synthesized by interaction of 4-methyl-2-aminopyridine with maleic anhydride. Compound represents white crystalline substance soluble in water, dimethylformamide (DMFA) and dimethylsulfoxide (DMSO) with value Tm = 146oC. Compound elicits the hypertensive activity elevating arterial pressure value in narcotized cats after intravenous administration in the dose 5 mg/kg (about 0.1 LD50) by 60.4 ± 8.23 mm mercury column reliably and acts for 90 min. Value LD50 in intravenous administration to white mice is 44.7 (39-50) mg/kg.

EFFECT: valuable medicinal properties of compound.

1 cl, 1 tbl, 1 ex

 

The claimed connection relates to the field of organic chemistry, class heterylamides dicarboxylic acids, namely new biologically active 4-methyl-2-pyridylamino maleic acid (I) of the formula

which can find application as a medicinal hypertensive drug. The closest structural analogue of the claimed compound is 2-pyridylamino maleic acid formula

obtained and described previously [II IV, Kozminykh V.O., Dolzhenko AV, Kozminykh E.N., Koterov VP, Godin A.T., syropjatov BJ, Novoselova G.N., Chem.-Pharm. magazine, T.35, No. 3, P.26-30 (2001); Dolzhenko AV, Kolotov, NV, Kozminykh V.O., syropjatov BJ, Chem.-Pharm. magazine, T.36., No. 3, P.17-19 (2001)].

Compound II shows hypertensive effect, which, however, shorter and are much weaker than those of the compounds I.

Known and used in medical practice hypertensive drug midodrina hydrochloride [Mashkovsky PPM Medicines (manual for doctors), M: Publishing house New Wave”, T.1, S, (2000)], which is taken by us as the standard of comparison hypertensive action.

The aim of the invention is to obtain a new previously undescribed 4-methyl-2-pyridylamino maleic acid (I)with hypertensive the first action. This goal is achieved by obtaining 4-methyl-2-pyridylamino maleic (I) acid by acylation of 4-methyl-2-aminopyridine is maleic anhydride.

Method for producing 4-methyl-2-pyridylamino maleic acid. A solution of 0.98 g (0.01 mol) of maleic anhydride in 30 ml of dioxane and a solution of 1.08 g (0.01 mol) of 4-methyl-2-aminopyridine in 30 ml of dioxane is poured while stirring, at a temperature of 20°C. After 1 h the precipitated precipitate is filtered off, dried and crystallized from ethanol. Yield 1.50 g (71%). Tpl.=146°C.

The inventive compound is a white crystalline substance, soluble in water, ethanol, DMSO, DMF. The NMR spectrum1N ("OC-2310" (60 MHz) in DMSO-d6internal standard - GMDS) connection I have: a singlet of three protons of methyl groups in 2,28 ppm, a singlet of two protons group CH=CH when 6,18 ppm, multiplet three protons of the pyridine ring system in the area of 6.68-of 7.95 ppm, broadened signal of the proton of the amide group CONH when 7,12 ppm and broadened signal of one proton of the carboxyl group in the field 12,88 ppm

Acute toxicity when administered intravenously were determined by nonlinear white mice weighing 20-25 g test substance and the reference product were injected into the tail vein in aqueous solution at a rate of 0.1 ml / 10 g weight of the animal in increasing doses. Results the ATA worked on Prozorovsky calculation of the median lethal dose (LD 50) at P=0.05 [Prozorovsky CENTURIES, Prozorovsky BTW, Demchenko V.M. Pharmacol. toxicol. T.41, No. 4, C.497-502 (1978)].

The connection I investigated for the presence of hypertensive activity. Studies hypertensive activity conducted in healthy cats of both sexes anesthetized with barbitala sodium (medial) at a dose of 400 mg/kg, intraperitoneally. The inventive substance and the reference product was administered to animals at a dose of ≈0,1 LD50intravenously. Blood pressure was measured by direct method in the carotid artery. In each series of experiments was used five animals. The degree hypertensive activity of the investigated compounds were expressed in mm RT. Art. from baseline at different time intervals and were statistically processed by a difference method using the student coefficient [Sarnow L.N., Hazura CENTURIES, Elements of experimental pharmacology, M., S.312-313, (2000)]. The severity and duration of the hypertensive effect was compared at the claimed compounds and reference drug in equitoxic doses.

The test results presented in the table. The dynamics of the hypertensive effect of the claimed compounds in comparison with the action midodrina hydrochloride is shown on the drawing.

As can be seen from the table, studied the connection shows high-hypertensive activity, significantly exceeding dei is a journey of a reference preparation, and superior to the reference product for the duration of hypertensive action. It should be noted that the inventive compound is less toxic compared with midodrine.

The drawing shows that the claimed connection of I exceeds the reference drug is not only in intensity and duration of the effect, but the speed of its development.

Thus, 4-methyl-2-pyridylamino maleic acid (I) shows significantly higher hypertensive activity, a more lasting 2.5 times less toxic than the comparator drug. Therefore, the claimed connection I can find application in medicine as hypertensive drugs with long lasting effect.

Table

Acute toxicity, the severity and duration of the hypertensive effect of the inventive compounds (I), similar in structure (II) and midodrina hydrochloride
ConnectionLD50,

mg/kg
The degree of increase

blood

pressure, mm RT. Art.
The duration

hypertensive

effect min
I44,760,4±8,2390
 (39-50)(p<0,01) 
II-35,6±4,45 (p<0,01)15
Midodrin18,424,8±4,145
 (13-25)(p<0,01) 

4-Methyl-2-pyridylamino maleic acid

with hypertensive activity.



 

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EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

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< / BR>
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9 cl, 2 sch, 2 tbl, 29 ex

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22 cl, 2 tbl, 6 ex

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EFFECT: valuable medicinal properties of compounds and composition.

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FIELD: organic chemistry, medicine, pharmacy.

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20 cl, 6 tbl, 192 ex

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EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 cl, 2 tbl, 568 ex

FIELD: medicine, cardiology, endocrinology.

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EFFECT: valuable medicinal properties of agent, enhanced effectiveness of treatment.

4 cl, 6 ex

FIELD: pharmaceuticals.

SUBSTANCE: invention provides topical blood circulation improving remedy containing simultaneously nitroglycerine and aminophylline. Remedy can be provided in the form of emulsion, gel, or ointment, which are administered 1-2 times a day.

EFFECT: strengthened blood circulation activation effect, which is prolonged to 24 hours.

5 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of imidazole of the formula (I): wherein symbols have the following values: R1 means -CaH2a-phenyl wherein phenyl moiety is not substituted; a = 0; or R2 and R3 mean independently of one another CO-R(6), O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17) wherein R(17) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(6) means hydrogen atom; R4 and R5 mean independently of one another hydrogen atom, F, Cl, Br, J, S(O)p-R(16) or O-(alkylene with 2, 3 or 4 carbon atoms)-OR(33); p = 2; R(16) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms; R(33) means alkyl with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and to their physiologically acceptable salts also under condition that at least one of residues R2 or R3 means O-(alkylene with 2, 3 or 4 carbon atoms)-OR(17). Also, invention relates to pharmaceutical composition used for inhibition of Na+-dependent bicarbonate-chloride exchange based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof for aims therapy and/or prophylaxis of diseases wherein the primary or secondary cause is the cell proliferation.

EFFECT: valuable medicinal properties of compounds.

9 cl, 4 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: pharmaceutical industry.

SUBSTANCE: invention provides antituberculous formulation made in the form of solid dosage form containing as active principle combination of isoniazid, rifampicin, pyrazinamide, ethambutol hydrochloride, and pyridoxine hydrochloride plus pharmaceutically acceptable auxiliaries: starch, lubricant, and optionally microcrystalline cellulose. Composition is characterized by storage stability and high therapeutical efficiency.

EFFECT: increased assortment of antituberculous drugs.

6 cl, 2 tbl, 3 ex

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