RU2491277C2 - N-isopropylamide 2-(6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1)-ethanoic acid hydrochloride, which possesses hypertensive activity - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: novel invention relates to field of organic chemistry, namely, to N-isopropylamide 2-(6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1)-ethanoic acid hydrochloride

(I).

EFFECT: novel derivative of dihydroisoquinolyl, which has hypertensive activity, is obtained.

1 cl, 1 tbl

Description

The claimed compound relates to the field of organic chemistry, derivatives of isoquinoline, namely, the new biologically active N-isopropylamide N-isopropylamide 2- (6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid hydrochloride I formulas:

which can be used in medicine as a medicine that increases blood pressure.

The closest structural analogue to the claimed compound are compounds of the general formula II exhibiting an anticoagulant effect, in which the effect on systemic blood pressure has not been studied. [Mikhailovsky A.G., Polygalova N.N., Ismaylova N.G., Syropyatov B.Ya., Vakhrin M.I. Synthesis of derivatives of 2- (3-spiro-cyclohexyl-3,4-dihydroisoquinolyl-1) acetic acid and their effect on blood coagulation II Chem. Journal. - 2008.V. 42. - No. 8. - S.21-23]

Among the drugs that increase blood pressure, midodrine hydrochloride is known [Mashkovsky M.D. Medicines: In 2 vols. - 14th ed., Revised., Rev. and add. - M.: Publishing House New Wave LLC, 2000].

The aim of the invention is to obtain a new, previously not described N-isopropylamide 2- (6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid hydrochloride (I), which has a hypertensive effect. This goal is achieved by obtaining N-isopropylamide 2- (6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid hydrochloride (I) by the interaction of 1- (3,4-dimethoxybenzyl) cyclopentanol -cyano-N-isopropylacetamide (Fig. 1):

The method of obtaining N-isopropylamide 2- (6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid hydrochloride. To a mixture of 3.5 g (0.015 mol) of 1- (3,4-dimethoxybenzyl) cyclopentanol and 1.9 g (0.015 mol) of 2-cyano-N-isopropylacetamide in 50 ml of benzene, 2 ml of acetic acid is added dropwise with stirring 6 ml of concentrated sulfuric acid, then the reaction mixture is stirred until complete cooling and poured into 200 ml of ice water. The aqueous layer was separated, washed with benzene and neutralized with 25% ammonia solution. After neutralization, a precipitate precipitates, which is filtered off, dried, dissolved in 100 ml of ethyl acetate and hydrochloride I is obtained by passing dry HCl, which is filtered off, dried and recrystallized from isopropanol. The yield of hydrochloride I is 4.6 g (82%). The inventive compound is a light yellow crystalline substance, soluble in water, chloroform, DMSO, DMF. Mp 168 ° C.

The ¹ H NMR spectrum (Bruker 300, 300 MHz, in DMSO-d ₆ , internal standard - HMDS) of hydrochloride I contains signals: two doublets of protons of two methyl groups (CH ₃ ) ₂ CH (1.01 and 1.08 m. d.); multiplet of 8 protons (CH ₂ ) ₄ spiro-cyclopentyl radical at position 3 (1.55-2.05 ppm); singlet of methylene group in position 4 (3.06 ppm); two singlets of two CH ₃ O (3.81 and 3.86 ppm); degenerate septet of the group CH (CH ₃ ) ₂ (3.40 ppm); singlet of methylene group in position 1 (4.18 ppm); singlets of aromatic protons in the region of 7.03 ppm (5-H) and 7.43 ppm (8-H); doublet of the proton of the amide group of NH (8.91 ppm); the proton singlet of the NH ⁺ group (13.17 ppm).

The IR spectrum of salt I, recorded in liquid paraffin, contains the absorption bands of the amide group: 1670 cm ^-1 (C = O) and 3340 cm ^-1 (NH). Compound I was examined for the presence of hypertensive activity. The experiments were performed on cats of both sexes, anesthetized with sodium barbital (medinal) at a dose of 400 mg / kg, intraperitoneally. The inventive substance was administered to animals at a dose of 5 mg / kg (1/10 LD ₅₀ ). The comparison standard of midodrin hydrochloride was administered at a dose of 1.84 mg / kg (1/10 LD ₅₀ ) [Dolzhenko A.V., Kolotova N.V., Kozminykh O.V. and other Substituted amides and hydrazides of dicarboxylic acids. Synthesis, hypoglycemic and hypertensive activity of pyridylamides and some acylhydrazides of maleic and citraconic acids // Chem.-Pharm. Journal. - 2002. - T.36. - No. 4. - S.11-12]. Blood pressure was measured by direct method in the carotid artery. In each series of experiments, 5 animals were used. The degree of hypertensive activity of the test substance and the reference standard was expressed in mmHg relative to the initial level at certain intervals. The results were statistically processed by the difference method using the student coefficient [Sernov L.N., Gatsura V.V. Elements of experimental pharmacology, M., S.312-313, (2000)].

The test results are presented in the table.

Table The effect of the claimed compounds and reference standards on systemic blood pressure Compound Increase in blood pressure, mmHg The duration of the hypertensive effect, min P N- isopropylamide 2- (6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid hydrochloride 46.0 ± 2.83 300 <0.01 Midodrine hydrochloride 24.8 ± 4.03 45 <0.01

As can be seen from the table, the test compound exhibits high hypertensive activity, significantly superior to the comparison drug in effect and duration of action.

Acute toxicity was determined by intravenous administration on nonlinear white mice weighing 20-25 g. The test substance was injected into the tail vein in the form of an aqueous solution at the rate of 0.1 ml per 10 g of animal weight in increasing doses. The results were processed according to Prozorovsky with calculation of the average lethal dose (LD ₅₀ ) at p≤0.05 [Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. // Pharmacology and toxicology. - 1978. - T.41. - No. 4. - S.497-502].

Acute toxicity (LD ₅₀ ) with intravenous administration of the claimed compound was 59 (41-85) mg / kg, midodrine hydrochloride - 18.4 (13.0-25.0) mg / kg.

Thus, the 2- (6,7-dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid N-isopropylamide hydrochloride (I) exhibits a significantly higher and longer hypertensive effect. Therefore, the claimed compound (I) may find application in medicine as a hypertensive drug with a long-lasting effect.

Information sources

1. Mikhailovsky A.G., Polygalova N.N., Ismaylova N.G., Syropyatov B.Ya., Vakhrin M.I. Synthesis of 2- (3-spiro-cyclohexyl-3,4-dihydroisoquinolyl-1) acetic acid derivatives and their effect on blood coagulability // Chem. Journal. - 2008.V. 42. - No. 8. - S.21-23.

2. Mashkovsky M.D. Medicines: In 2 vols. - 14th ed., Revised., Rev. and add. - M.: Publishing House New Wave LLC, 2000.

3. Dolzhenko A. V., Kolotova N. V., Kozminykh O. V. and other Substituted amides and hydrazides of dicarboxylic acids. Synthesis, hypoglycemic and hypertensive activity of pyridylamides and some acylhydrazides of maleic and citraconic acids // Chem.-Pharm. Journal. - 2002. - T.36. - No. 4. - S.11-12.

4. Sernov L.N., Gatsura V.V. Elements of experimental pharmacology, M., S.312-313, (2000).

5. Prozorovsky V.V., Prozorovskaya M.P., Demchenko V.M. // Pharmacology and toxicology. - 1978. - T.41. - No. 4. - S.497-502.

Claims (1)

2- (6,7-Dimethoxy-3-spiro-cyclopentyl-3,4-dihydroisoquinolyl-1) -ethanoic acid N-isopropylamide hydrochloride having hypertensive activity