CS218402B1 - N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine and methods for its preparation - Google Patents

Abstract

The subject of the invention is the coronary vasodilating N-[1-(4-fluorophenyl)ethyl]- -N-(3,3-diphenylpropyl)hydroxylamine of formula I, its pharmaceutically acceptable salts, and two methods of its preparation. According to the first method, N-[1-(4-fluorophenyl)ethyl]hydroxylamine is alkylated with 3,3-diphenylpropyl bromide. The second, more preferred method consists in alkylating N-(3,3-diphenylpropyl)hydroxylamine with 1-(4-fluorophenyl)ethylogenide.

Description

The present invention relates to N- [1- (4-fluorophenyl) ethyl] -

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

The hydroxylamine derivative of formula (I) is a novel compound which exhibits a remarkable effect on the supply and activity of cardiovascular heart muscle in the following pharmacological tests. From the effects found on model heart damage in experimental animals, it can be concluded that the compound of formula I is prerequisite for use in the treatment of ischemic heart disease. This is confirmed by the results of the following pharmacological tests.

In a hamster test with cardiomyopathy induced by a two-day s. C. Application of isoprenaline at 20 to 60 mg / kg p. O.

Also, changes in ST segment to ECG induced by administration of vasopressin with ergometrine to isoprenaline-impaired myocardial rats are significantly less in animals pre-treated with Formula I at 60 mg / kg p.o. compared to untreated animals. A similar protective effect against the effects of vasopressin administration with ergometrine is shown by the compound of Formula I at a dose of 60 mg / kg p.o.

At an oral dose of 50 mg / kg, the compound of Formula I slightly increases the amount of blood leaking from coronary sinus and the partial pressure of oxygen in that blood under pentobarbital anesthesia.

The compound of formula I is of low toxicity. In mice and rats, an oral dose of 1000 mg / kg produces no toxic symptoms. Intravenous infusion of doses of 4 to 10 mg / kg to non-anesthetized rabbits did not cause any significant changes in blood pressure and did not affect the general condition and reactivity of the test animals. A daily dose of 70 mg / kg for 6 days orally administered to dogs also does not induce any signs of intoxication or behavioral changes. In monkeys, a high dose of 600 mg / kg has only a mild depressant effect.

The invention also relates to processes for the preparation of a compound of formula I.

A first process for the preparation of a compound of formula I according to the invention consists in alkylating N- [1- (4-fluorophenyl) ethyl] hydroxylamine with 3,3-diphenylpropyl bromide in a polar organic solvent, for example dimethylformamide, in the presence of a reagent capable of binding hydrogen halide alkali metals or sodium acetate, at temperatures of 15 to 60 ° C, preferably at room temperature. The relatively low reactivity of 3,3-diphenylpropyl bromide under these conditions necessitates a prolongation of the reaction time to 5-7 days and appears to be the main cause of relatively low (about 36% of theory) product yields, which is isolated after dilution of the reaction mixture with excess water. water-immiscible solvents such as ether.

Evaporation of the solvent gave the crude product base which was purified by column chromatography on alumina, eluting with benzene to remove unreacted 3,3-diphenylpropyl bromide and other impurities. The base of the hydroxylamine derivative of formula I is obtained by elution with ether and evaporation.

It can be converted to crystalline salts by neutralizing a solution thereof in ether, methanol or acetone with inorganic or organic acids, preferably filmic acid.

The 3,3-diphenylpropyl bromide required for the reaction is known (O. Exner et al., Coll. Czechoslov. Chem. Commun. 18, 270, 1953). N- [1- (4-fluorophenyl) ethyl] hydroxylamine is a novel substance. It can be prepared by reacting 1- (4-fluorophenyl) ethyl bromide (FL Roe and WH Saunders, Tetrahedron 33, 1581, 1977) with anti-benzaldoxime (G. Zvilichovsky and L. Heller, Synthesis 1972, 563) in absolute ethanol in the presence of sodium ethylate and hydrolysis of the obtained xphenyl-N- [1- (4-fluorophenyl) ethyl] nitrone with conc. hydrochloric acid.

A second, more preferred process for the preparation of the hydroxylamine derivative of the formula I according to the invention utilizes the high reactivity of 1- (4-fluorophenyl) ethyl halides, preferably 1- (4-fluorophenyl) ethyl bromide, which alkylates N- (3,3-diphenylpropyl) hydroxylamine The reaction is carried out in a polar organic solvent, for example methanol, ethanol or dimethylformamide, in the presence of a reagent capable of binding the hydrogen halide formed in the reaction, for example an alkali metal carbonate or bicarbonate, sodium acetate or pyridine.

The reaction is carried out at temperatures of 15 to 60 degrees Celsius, preferably at room temperature. The product is isolated by diluting the reaction mixture with excess water and shaking it into a water immiscible solvent such as methylene chloride or ether. Evaporation of the solvent affords the crude base of the compound of formula (I) which is converted to crystalline salts by neutralizing its solution in methanol, ethanol or acetone with inorganic or organic acids. For example, adding 218402 fumaric acid to a solution of the base in ether, heating to boiling in dissolved fumaric acid, and cooling to give a crystalline fumarate that can be purified by crystallization from polar organic solvents such as isopropanol.

N- (3,3-Diphenylpropyl) hydroxylamine is a novel substance. It can be prepared by alkylating the anti-benzaldoxime with 3,3-diphenylpropyl bromide in boiling absolute ethanol in the presence of sodium ethylate and hydrolyzing the obtained α-phenyl-N- (3,3-diphenylpropylnitrone) with concentrated hydrochloric acid.

The details of the methods of preparation according to the invention and of the preparation of the novel intermediates are given in the examples, which, however, are merely illustrative of the possibilities of the invention, but not all of these possibilities. Example 1 α-Phenyl-N- [1- (4-fluorophenyl) ethyl] nitrone

To a solution of sodium ethylate prepared by dissolving 2.9 g of sodium in 250 ml of absolute ethanol, 15.1 g of anti-benzaldoxime are added with stirring, and after dissolution, 26.9 g of 1- (4-fluorophenyl) ethyl bromide are added in one portion. The reaction mixture was stirred at 20-25 ° C for 5 hours. After standing at room temperature for 15 hours, the precipitated sodium bromide is filtered off, the filtrate is evaporated under reduced pressure and the residue is dissolved in 75 ml of anhydrous chloroform. The residual sodium bromide precipitated is filtered off and the filtrate is evaporated under reduced pressure. The residue is recrystallized from 70 ml of cyclohexane. There was obtained 18.9 g (62.2% of theory) of .alpha.-phenyl-N- [1- (4-fluorophenyl) ethyl] nitron, m.p. 60-78 ° C. The analytically pure material melts at 79-80 ° C (cycloxane).

Example 2

N- [1- (4-Fluorophenyl) ethyl] hydroxylamine

A mixture of 17.7 g of .alpha.-phenyl-N- [1- (4-fluorophenyl) ethyl] nitron and 33 ml of concentrated hydrochloric acid is heated to about 110 DEG C. and water vapor is introduced into the mixture at this temperature until the condensate contains no benzaldehyde.

After cooling, the pH of the reaction mixture was adjusted to 1-2 by the addition of 1M sodium hydroxide solution. The solution was filtered with charcoal, the clear filtrate was evaporated under reduced pressure to a volume of about 25 ml and basified with sodium hydroxide solution. The precipitated oily base is crystallized by cooling. Aspirate and wash with water. 8.5 g (76.3% of theory) of N- (1- (4-fluorophenyl) ethyl) hydroxylamine, m.p. 75-77 [deg.] C. The analytically pure material recrystallized from cyclohexane has m.p. 77-78 [deg.] C.

Example 3 α-Phenyl-N- (3,3-diphenylpropyl) nitron

To a solution of sodium ethylate prepared by dissolving 18.4 g of sodium in 1600 ml of absolute ethanol is added 96.8 g of anti-benzaldoxime, and after dissolution with stirring 232.5 g of 3,3-diphenylpropyl bromide.

The mixture was heated to boiling under stirring for 5 hours. After standing at room temperature for 15 hours, it was cooled to about 4 ° C with ice and water. The precipitated solid is filtered off with suction and washed with 250 ml of cold ethanol and 750 ml of ice water. After drying, 204 g (80.8% of theory) of .alpha.-phenyl-N- (3,3-diphenylpropyl) nitrone are obtained, m.p. 169-173 ° C. The analytically pure material melts at 171-173 ° C after recrystallization from ethanol.

Example 1 a d 4

N- (3,3-Diphenylpropyl) hydroxylamine

A mixture of 204 g of .alpha.-phenyl-N- (3,3-diphenylpropyl) nitrone and 300 ml of concentrated hydrochloric acid is heated to about 110 DEG C. and water vapor is added at this temperature until the condensate contains no benzaldehyde.

By cooling the clear solution to about 5 ° C, N- (3,3-diphenylpropyl) -hydroxylamine hydrochloride crystallizes which is isolated by suction and is obtained in practically quantitative yield, m.p. 156-158 ° C (isopropyl alcohol). release from the hydrochloride in the usual manner, or directly alkalinization of the reaction mixture by distilling off the benzaldehyde with aqueous ammonia, shaking the precipitated base into methylene chloride, drying the separated methylene chloride solution with anhydrous sodium sulfate and evaporating to give 145 g (98.6% of theory). 3,3-diphenylpropyl) -hydroxylamine which, after recrystallization from hyclohexane or a mixture of toluene and cyclohexane, melts at 79-80 ° C.

Example 1 a d 5

N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine

A mixture of 4.6 g of N- [1- (4-fluorophenyl) ethyl] hydroxylamine, 9.1 g of 3,3-diphenylpropyl bromide and 4.5 g of finely divided sodium acetate (trihydrate) in 30 ml of dimethylformamide is stirred at room temperature for 7 days. 300 ml of water are then added with stirring, the pH of the mixture is adjusted to 7-8 with 1M sodium hydroxide solution and the precipitated product is taken up in ether.

The combined ether solutions were washed with water and, after drying with anhydrous sodium sulfate, the ether was evaporated under reduced pressure from a warm bath of 30 ° C. The oily residue (11.9 g) was chromatographed on a column of 360 g of alumina. Unreacted 3,3-diphenylpropyl bromide was eluted with benzene. Elution with ether gave 5 g of crude viscous base product, which was dissolved in ether and 0.75 g of acid was added. The fumarate was converted to crystalline fumarate to give 4.4 g (36.2% of theory) of N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine fumarate, m.p. 133-136 ° C (isopropyl alcohol).

Example 6

N- [1- (4-fluorophenyl) ethyl] -N- (3,3-dienylpropyl) hydroxylamine

To a solution of 34.1 g of N- (3,3-diphenylpropyl) hydroxylamine in 150 ml of dimethylformamide, 18.9 g of finely divided sodium bicarbonate and 33.5 g of 1- (4-fluorophenyl) ethyl bromide are added with stirring, and the mixture is stirred at After addition of 800 ml of water, the precipitated product is taken up in ether and the ether solution is washed with water and saturated sodium chloride solution.

After drying over anhydrous sodium sulfate, the ether was evaporated under reduced pressure. The viscous oily residue (56.6 g) was dissolved in 300 ml of ether, 8.7 g of fumaric acid was added, and the mixture was heated to boiling for 30 minutes. Already during boiling, crystalline fumarate precipitates from the solution. The crystallization is completed by cooling to 0 ° C. Aspiration and washing with ether gave 46.2 g of N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine fumarate, mp 131-135 [deg.] C. After recrystallization from 175 ml of isopropyl alcohol, 45.6 g (74.6% of theory) of pure fumarate of m.p.

Claims (4)

N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine of formula I and its addition salts with pharmaceutically acceptable inorganic and organic acids. 2. A process for the preparation of N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine of the formula I according to claim 1, characterized in that N- [1- (4-fluorophenyl)] ethyl] hydroxylamine is alkylated with 3,3-diphenylpropyl bromide in a polar organic solvent, such as dimethylformamide, in the presence of a reagent capable of binding hydrogen bromide, such as sodium acetate, at 15 to 60 ° C, preferably at 15 to 25 degrees Celsius. whereupon the resulting compound of formula I is isolated in the form of a base and converted into the corresponding pharmaceutically acceptable addition salts by neutralization with inorganic or organic acids. 3. A process for the preparation of N- [1- (4-fluorophenyl) ethyl] -N- (3,3-diphenylpropyl) hydroxylamine of formula (I) according to claim 1, characterized in that N- (3,3-diphenylpropyl) The hydroxylamine is alkylated with 1- (4-fluorophenyl) ethyl halide, in a polar organic solvent, in the presence of a reagent capable of binding the hydrogen halide formed in the reaction at temperatures from 15 ° C to 60 ° C, whereupon the resulting compound of formula I neutralization with inorganic or organic acids in the corresponding pharmaceutically acceptable addition salts. 4. The process of claim 3 wherein the alkylation of N- (3,3-diphenylpropyl) hydroxylamine is carried out with 1- (4-fluorophenyl) ethyl bromide, in dimethylformamide, in the presence of sodium bicarbonate, at a temperature of 15-25 ° C.