CS219530B1 - N-Hydroxy-2,6,6-triphenyl-3-azahexane; - Google Patents

Abstract

The subject of the invention is a new N-hydroxy-2,6,6-triphenyl-3-azahexane, its salts and a method for its preparation. This substance shows high coronary vasodilating activity in pharmacological tests with low oral toxicity and is therefore useful as a drug in ischemic heart disease and prevention of angina pectoris attacks.

Description

The present invention provides a novel N-hydroxy-2,6,6-triphenyl-3-azahexane salt thereof and a process for its preparation. This substance exhibits high coronary vasodilatory activity in low oral toxicity in pharmacological tests and is therefore useful as a medicament for ischemic heart disease and the prevention of angina attacks.

The invention relates to N-hydroxy-2,6,6-triphenyl-3-azahexane of formula I

its addition salts with pharmaceutically acceptable inorganic or organic acids and processes for its preparation.

The compound of formula I, which is novel, is the N-hydroxy derivative of 2,6,6-triphenyl-3-azahexane, known under the generic name fendilin, which has found use in the treatment of coronary heart disease, angina pectoris and some of its coronary vasodilatory and calciumantagonistic effects. other diseases of blood circulation. It has now surprisingly been found that the novel N-hydroxy derivative of the formula I outperforms fendilin by its pharmacological properties. Compared to fendilin, it is at least as effective in the test described below, and the duration of action is considerably longer. Moreover, its oral toxicity in mice is significantly lower compared to fendilin. Its LD 50 is 1000 mg / kg (the LD 50 of fendilin is 650 mg / kg).

This surprising activity of the novel N-hydroxy derivative of formula I has been demonstrated in a stress test on hamsters with isoprenaline-damaged myocardium. A selected group of hamsters is administered on the first day isoprenaline at a dose of 15 mg / kg s.c. and on the second day at a dose of 12 mg / kg. On day 3, the animals are dosed with test substance for 10 min. up to 2 hours prior to the actual stress test, in which the time taken for the pre-treated animals to swim compared to the control group of animals is measured. Compound I at 70 mg / kg po prolongs the duration of swimming to the levels measured in control animals compared to the unpremedicated group, even when administered 2 hours prior to the stress test, while fendilin at the equimolar dose (60 mg / kg po) is ineffective 1 hour before test.

These results indicate the utility of the compound of formula I for the treatment of ischemic heart disease and the prevention of angina attacks.

The invention also relates to a process for the preparation of N-hydroxy-2,6,6-triphenyl-3-azahexane of formula I; The essence of this method is that the N- (1-phenylethyl) hydroxylamine alkyl is

3.3-diphenylpropyl halide, preferably

3.3-diphenylpropyl bromide, in a polar solvent, for example a C 1 -C 2 alkanol, for example methanol or ethanol, in the presence of a reagent capable of binding hydrogen bromide, for example pyridine or alkali metal carbonates, at temperatures from 20 ° C to boiling point of the reaction mixture. The optimum conditions are methanol, pyridine as a hydrogen bromide-binding agent and a temperature of 20 ° C.

The product is isolated after evaporation of the solvent by shaking between a water-immiscible organic solvent such as benzene and water. Evaporation of the separated benzene solution gives the crude product base which is purified by chromatography on an alumina column, whereby unreacted is separated before eluting with benzene.

3,3-Diphenylpropyl halide and N- (1-phenylethyl) hydroxylamine The base of the compound of formula (I) is obtained by elution with ether and evaporation, and can be converted to crystalline salts by neutralizing its solution in ether, methanol, ethanol or acetone with inorganic or organic acids, preferably hydrogen chloride .

The 3,3-diphenylpropyl bromide required for the reaction is known (O. Exner et al., Coll. Czechoslov. Chem. Commun. 18, 270, 1953). N- (1-phenylethyl) hydroxylamine can be prepared by either a known method, either by oxidation of 1-phenylethylamine with dibenzyl peroxide and hydrolysis of the obtained O-benzoyl-N- (1-phenylethyl) hydroxylamine (G. Zinner, Arch. Pharm. 296, 420, 1963) or by a new procedure, by reaction of 1-phenylethyl bromide (JF Norris et al. J. Am. Chem. Soc. 38, 1071, 1916) with anti-benzaldoxime (Zvilichovsky, L. Heller, Synthesis 1972, 563) in absolute ethanol in the presence of sodium ethanolate and hydrolysis of the obtained new N-phenyl-N- (1). -phenylethylnitrone with hydrochloric acid.

Further details of the preparation of the novel compound of formula (I) and N- (1-phenylethyl) hydroxylamine are given in the examples, which, however, are merely illustrative of the possibilities of the invention, but are not intended to fully describe them.

Example 1 α-Phenyl-N- (1-phenylethyl) nitron

To a solution of sodium ethylate, prepared by dissolving 1.2 g of sodium in 100 ml of absolute ethanol, add 6.1 g of anti-benzaldoxime with stirring, and after dissolution, 9.8 g of 1-phenylethyl bromide is added in one portion. The reaction mixture was stirred at 20-25 ° C for 6 h. After standing at room temperature for 20 hours, the precipitated sodium bromide is filtered off, the filtrate is evaporated under reduced pressure and the residue is dissolved in 50 ml of anhydrous chloroform. The residue of precipitated sodium bromide is filtered off from the solution and the filtrate is evaporated. The residue is recrystallized from 30 ml of cyclohexane. 6.4 g (57% of theory) of .alpha.-phenyl-N- (1-phenylethyl) nitrone are obtained, m.p.

Analysis:

for CisHisNO (225.3)

21SS30 calculated;

% C, 79.79;% H, 6.71;% 6.22;

found *

% C, 80.20;% H, 6.92;% N, 6.26.

Example 2

N- (1-phenylethyl) hydroxylamine

A mixture of 13.7 g of α-phenyl-N- (1-phenylethyl) nitrone and 27 ml of conc. hydrochloric acid is heated to about 110 ° C and water is introduced into the mixture at this temperature until the condensate contains no benzaldehyde. After cooling, the reaction mixture was evaporated under reduced pressure. The residue is mixed with water to a volume of about 30 ml and the pH of the solution is adjusted to 1-2 by the addition of 1 M sodium hydroxide solution. The crystalline base is filtered off with suction and washed with water. 6 g (72% of theory) of N- (1-phenylethyl) hydroxylamine are obtained, m.p. 69-70 ° C.

Example 3

N-Hydroxy-2,6,6-triphenyl-3-azahexane

To a solution of 5.5 g of N- (1-phenylethyl) hydroxylamine and 3.4 ml of pyridine in 30 ml of methanol is added a solution of 12.1 g of 3,3-diphenylpropyl bromide in 5 ml of methanol and the reaction mixture is allowed to stand at room temperature. days. It is then evaporated under reduced pressure and the residue is stirred between 50 ml of benzene and 30 ml of water. The benzene solution is washed with 30 ml of water and the benzene is distilled off. The residue is chromatographed on a column of 450 g of alumina. Elution with benzene separates unreacted 3,3-diphenylpropyl bromide and N- (1-phenylethyl) hydroxylamine. Elution with ether gave a viscous N-hydroxy-2,6,6-triphenyl-3-azahexane base. Acidification of the isopropyl alcohol solution with hydrochloric acid gives the hydrochloride which melts at 158-168 ° C (with decomposition) after crystallization from isopropyl alcohol.

Analysis:

Calcd for C26H26ClNO (367.9):

% C, 75.08;% H, 7.12;% N, 3.81;

found:

% C, 75.17;% H, 7.19;% N, 3.64.

Claims (3)

PREDMfiT N-Hydroxy-2,6,6-triphenyl-3-azahexane of formula I The invention and its addition salts with pharmaceutically acceptable inorganic or organic acids. 2. A process for the preparation of N-hydroxy-2,6,6-triphenyl-3-azahexane of the formula I as claimed in claim 1, wherein the N- (1-phenylethyl) hydroxylamine is alkylated with 3,3-diphenylpropyl bromide in an alkanol having from 1 to 2. carbon atoms, in the presence of a reagent capable of binding hydrogen bromide formed in the reaction, at temperatures from 20 ° C to the boiling point of the reaction mixture. 3. The process of claim 2 wherein the reaction is carried out in methanol, in the presence of pyridine, at 20 ° C.