2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid n-41-methyl-21-pyridylamide eliciting hypertensive activity

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a new compound - 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid N-41-methyl-21-pyridylamide of the formula:

. This compound is prepared by interaction of 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid with 4-methyl-2-pyridylamine. Proposed compound can be used in medicine as a hypertensive agent. The hypertensive activity of this compound exceeds activity of standard compound - midodrine hydrochloride by 2-fold increase of arterial pressure value and by 3-fold by duration effect in combination with 2-fold reduced toxicity.

EFFECT: improved and valuable medicinal properties of compound.

1 cl, 2 tbl, 1 ex

 

The invention relates to new biologically active compound from the series of amides of 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid, namely, N-4'-methyl-2'-pyridylamino 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid of the formula:

with hypertensive activity, suggesting the possibility of its use in medicine as a drug that has expressed specific hypertensive action and manifesting in one way or another anticonvulsant activity.

The closest analogue exhibiting pronounced hypertensive activity, is a 4-pyridylamino of succinic acid of the formula [Dolzhenko AV Hypertensive activity 4-pyridylamino some dicarboxylic acids and their antagonism with NO-donors [Text] / A. V. Dolzhenko, BJ syropjatov, NV II, V.O. Kozminykh, A.V., A. Borodin // Actual problems of pharmaceutical science and education: results and prospects. - Perm, 2001. - S.43]:

The standard of comparison is (±)-2-amino-N-(2,5-dimethoxy-β-hydroxyphenethyl)-ndimethylacetamide (midodrin) [Mashkovsky PPM Medicines [Text]: in 2 hours, P.1. Drugs / Medmaravis. - M.: Medicine, 1993. - S] formula:

used in medical practice and also have the focus of specific hypertensive effect.

The invention is search in a series of amides of 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid compounds exhibiting vasoconstrictor effect.

The inventive compound is obtained by reaction of 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid with 4-methyl-2-aminopyridine according to the scheme:

Synthesis published in [Bukanova E.V. Interaction arilpirolilor acids and their amides with amino compounds in the synthesis of biologically active substances [Text]: author. dis.... Kida. Pharm. Sciences: 15.00.02.: protected 27.04.04.: decl. 02.07.04. / Bukanova Ekaterina Viktorovna. - Perm, 2004. - P.19 (for shared use)].

Example obtain the claimed compound N-4'-methyl-2'-pyridylamino 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid

To a solution of 1.35 g (7.8 mmol) of 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid in 20-30 ml of ethanol is added with stirring 10 ml solution of 4-methyl-2-aminopyridine. Then the mixture is left for 1 day at room temperature. The precipitation is filtered off and recrystallized from ethanol. Yield 0.95 g (70%). So pl.: 219-220°C. C14H18N2O3.

The inventive compound is a colorless crystalline substance, soluble in ethanol, dimethylformamide, dimethyl sulfoxide, water.

IR-spectrum (UR-20, vaseline oil, νcm-1): 1680 (O NH), 1600 (C4=O), 3350 (CONH).

PMR-spectrum (WP-80SY, DMSO-d6, TMS, δ, ppm): 1.08 (S, (CH3)3S), 2.08 (3H, CH3), 6.18 (1H, CH), 6.54-7.79 m(3H),6H3N).

Studies of acute toxicity were performed in the laboratory of BAS Science Institute at Perm state University.

Sharp daily toxicity of the claimed compounds was determined on 8 outbred white mice of both sexes weighing 16-18, the combination was administered intravenously in aqueous solution at a rate of 0.05 ml per 10 g in ascending doses. Found that LD50surveyed the compound is intravenously 52,4 (41,7-62,0) mg/kg (table 1).

Table 1
Acute toxicity
A series of experimentsLD50mg/kg, intravenous
N-4'-methyl-2'-pyridylamino 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid52,4(41,7-62,0)
Midodrin18,4(13,0-25,0)

Earlier studies revealed that this compound weak anticonvulsant activity, but in our experiments was diagnosed hypertensive activity. Hypertensive effect was studied in 5 experiments. Study of the effect of the synthesized compounds on the system the arterial pressure were performed on cats under Medialogy anesthesia in a dose of 400 mg/kg intraperitoneally. The test substance was dissolved in 3 ml of isotonic sodium chloride solution and was administered at a dose of 5 mg/kg in the femoral vein of the animals within 2 minutes Systemic arterial pressure was measured in the carotid artery by direct method using a mercury manometer. Hypertensive action of the compounds was compared with the drug midodrine "Gutron®". Comparator drug was administered at a dose of 2.5 mg/kg, which is half of the used dose of the drug. Experimental data were statistically processed differential square method using the student coefficient. Reliable believed the results with a p<0,05. The results of the study are presented in table 2.

As indicated in table 2, N-4'-methyl-2'-pyridylamino 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid showed hypertensive effect during all periods of observation, as evidenced by a significant increase in blood pressure through 1, 2, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 240, 270 minutes From table 2 it is seen that the inventive connection hypertensive effect exceeds the effect of midodrine for the duration of almost 2 times and 3 times for the duration.

Thus, N-4'-methyl-2'-pyridylamino 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid has a pronounced biological activity, which is low toxi is of high hypertensive action. For security and hypertensive activity exceeds a drug reference (midodrin). The foregoing demonstrates the potential use of the claimed compounds to create medicines, which have a hypertensive effect.

N-4'-Methyl-2'-pyridylamino 2-hydroxy-5,5-dimethyl-4-oxo-2-hexenoic acid

showing hypertensive activity.



 

Same patents:

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

FIELD: organic chemistry, biochemistry, medicine, endocrinology.

SUBSTANCE: invention relates to a trans-olefinic activator of glucokinase representing compound taken among the group consisting of olefinic amide of the formula (I): wherein R1 and R2 mean independently of one another hydrogen, halogen atom, nitro-group, perfluoro-(lower)-alkyl, (lower)-alkylsulfonyl or (lower)-alkylsulfonylmethyl; R means -(CH2)m-R3 or lower alkyl comprising from 2 to 4 carbon atoms; R3 means cycloalkyl comprising from 3 to 8 carbon atoms; R4 means the group: or unsubstituted, or monosubstituted five- or six-membered heteroaromatic ring linked by ring carbon atom with indicated amino-group wherein this five- or six-membered heteroaromatic ring comprises from 1 to 2 heteroatoms taken among the group consisting of sulfur or nitrogen atom wherein one heteroatom being as nitrogen atom is arranged near with binding ring carbon atom, and wherein indicated monosubstituted heteroaromatic ring is substituted at ring carbon atom not adjacent with mentioned binding carbon atom with a substitute taken among the group consisting of halogen atom and group of the formula: m = 0 or 1; n = 0, 1, 2, 3 or 4; R7 means hydrogen atom or lower alkyl; Δ means trans-configuration relatively to a double bond; or its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition, method for prophylactic or therapeutic treatment of diabetes mellitus of type II and to methods for preparing compounds of the formula (I). Invention provides preparing activators of glucokinase that enhance insulin secretion in treatment of diabetes mellitus of type II.

EFFECT: valuable medicinal properties of compounds.

25 cl, 29 ex

The invention relates to organic chemistry, in particular to the compounds representing amide of the formula I:

in which * denotes an asymmetric carbon atom; R1and R2independently from each other represent a hydrogen atom or halogen, amino, hydroxyamino-, nitro-, cyano-, sulfamidihappo, (ness.)alkyl, -OR5, -C(O)OR5, PERFLUORO(ness.)alkyl, (ness.)alkylthio, PERFLUORO(ness.)alkylthio, (ness.)alkylsulfonyl, PERFLUORO(ness.)alkylsulfonyl or (ness.)alkylsulfonyl; R3denotes cycloalkyl containing from 3 to 7 carbon atoms, or (ness.)alkyl containing from 2 to 4 carbon atoms; R4means (O)other40or unsubstituted or monosubstituted five - or six-membered heteroaromatic ring bound ring carbon atom of the amino group, and a five - or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur atoms, oxygen, and nitrogen, with one heteroatom is a nitrogen atom, which is adjacent to the connecting ring carbon atom; this is monosubstituted heteroaromatic ring monogamist on the ring angle is found (ness.)alkyl, halo-, nitro-, cyano, -(CH2)n-OR6, -(CH2)n-C(O)OR7, -(CH2)n-C(O)OTHER6, -C(O)-C(O)OR8and -(CH2)n-OTHER6or its pharmaceutically acceptable salts

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in which R denotes hydrogen, C1-C7alkyl, C1-C7alkoxy, halogen or CF3, R1means H or halogen, or R and R1may together form-CH=CH-CH=CH-; R2means H, halogen, CF3, R3means H or C1-C7alkyl, R4means H or piperazine-1-yl; R5means H or C1-C7alkyl, X is-C(O)N(R5)-, -(CH2)mO-, -(CH2)mN(R5)-, -N(R5)C(O)- or N(R5)(CH2)m-; n is an integer from 0 to 4, m is 1 or 2, and their pharmaceutically acceptable acid additive salts

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The compound obtained by the interaction of 4-methyl-2-aminopyridine with anhydride tetrachlorophthalic acid

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< / BR>
where R4represents N or CH3, R5is CHR, benzyl or ortho - or para-substituted benzyl, R represents H, CH3CH2CH3CH2CH2-CH3or CH(CH3)2, R' represents the residue of phosphoric acid, salt of phosphoric acid or-S-S-R" group, R" is CH2CH2OTHER6CH2CH2HE, CH2COOR7, ortho - or para-substituted C1-C3alkylphenyl or ortho - or para-substituted nitrophenyl, R6represents H, C1-C4acyl group, trifluoracetyl, benzoyloxy or substituted benzoyloxy group, R7represents H, C1-C4alkyl, phenyl, substituted phenyl, benzyl or substituted benzyl

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FIELD: organic chemistry, chemical technology, medicine.

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

15 cl, 1 tbl, 250 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of composition.

23 cl, 2 tbl, 1 ex

FIELD: organic chemistry, vitamins, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

13 cl, 3 sch, 3 tbl, 6 ex

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

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

5 cl, 1 tbl, 4 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

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

21 cl, 70 ex

FIELD: medicine.

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EFFECT: stable physiological response within prolonged period of 6-12 months.

3 tbl

FIELD: organic chemistry, medicine, pharmacy.

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or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: medicine, cardiology, gastroenterology.

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EFFECT: improved method for treatment.

5 cl, 6 tbl, 2 ex

FIELD: organic chemistry, madicine.

SUBSTANCE: tricyclic benzodiazepines of formula I as well as their pharmaceutical acceptable salts, pharmaceutical composition containing the same and methods for hypertension treatment are disclosed. In formula A is -C(O)-; Y is CH2 or CH as olefinic site; X is CH2 or CH as olefinic site S, O or NR3 (R3 is C1-C8-alkyl) with the proviso that when Y is CH, X also is CH; Z is N or CH; R1 is hydrogen, C1-C8-alkyl, C1-C8-alkoxy or halogen; R2 is NR4COAr (R4 is hydrogen; Ar is phenyl optionally substituted with 1-3 substitutes independently selected from C1-C8-alkyl, halogen, hydroxyl, fluorinated C1-C8-alkylthio and another phenyl optionally substituted with substitute selected from C1-C4-alkyl, halogen, and hydroxyl); R5 is hydrogen, C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine, hydroxyl or di-(C1-C4)-alkylamino.

EFFECT: improved pharmaceutical composition for hypertension treatment.

12 cl, 5 tbl, 52 ex

FIELD: medicine.

SUBSTANCE: method involves administering Noliprelum in postoperative period for reducing left ventricle hypertrophy.

EFFECT: enhanced effectiveness of treatment in early postoperative period.

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new nitrogen-containing aromatic derivatives of the general formula:

wherein Ag represents (1) group of the formula:

; (2) group represented by the formula:

or ; (3) group represented by the formula:

; Xg represents -O-, -S-, C1-6-alkylene group or -N(Rg3)- (wherein Rg3 represents hydrogen atom); Yg represents optionally substituted C6-14-aryl group, optionally substituted 5-14-membered heterocyclic group including at least one heteroatom, such as nitrogen atom or sulfur atom, optionally substituted C1-8-alkyl group; Tg1 means (1) group represented by the following general formula:

; (2) group represented by the following general formula: . Other radical values are given in cl. 1 of the invention claim. Also, invention relates to a medicinal agent, pharmaceutical composition, angiogenesis inhibitor, method for treatment based on these compounds and to using these compounds. Invention provides preparing new compounds and medicinal agents based on thereof in aims for prophylaxis or treatment of diseases wherein inhibition of angiogenesis is effective.

EFFECT: improved treatment method, valuable medicinal properties of compounds and agents.

40 cl, 51 tbl, 741 ex

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