FR2504524A1 - N- (1-PHENYLTHYL) -N- (3,3-DIPHENYLPROPYL) -HYDROXYLAMINE AND PROCESS FOR THEIR PREPARATION - Google Patents

Abstract

A. NEW COMPOUNDS FOR USE IN THE TREATMENT OF CERTAIN HEART ORDERS. B. CHARACTERIZED IN THAT THEY CONSTITUTE N- (1-PHENYLETHYL) -N (3,3-DIPHENYLPROPYL) HYDROXYLAMINES RESPONDING TO THE GENERAL FORMULA: (CF DRAWING IN BOPI) OR XH OR F, AND THEIR SALTS D 'ADDITIONS WITH PHARMACEUTICALLY ACCEPTABLE MINERAL AND ORGANIC ACIDS. C. APPLICABLE COMPOUNDS WITHOUT TOXIC SIDE EFFECTS TO THE TREATMENT, ESPECIALLY OF CORONARY FAILURES.

Description

l.-

  The invention relates to N- (1-phenylethyl) -N-

  (3,3-diphenylpropyl) -hydroxylamines corresponding to the general formula

I: CH 3

> CHCH 2 CH 2-N-CH X

  OH -H in which X = H or F, their addition salts with acids

  pharmaceutically acceptable inorganic or organic substances.

  This process extends to processes for the preparation of these compounds.

  The compound of formula I (X = H) is the N-hydroxy derivative of 2,6,6-triphenyl-3-azahexane, known under the generic name of fendiline, and which is used because of its vasodilating effects. and its antagonistic effects on calcium, for medial treatment of ischemic heart disease, angina pectoris and certain

other circulatory disorders.

  N-derivatives have now been found to be

  hydroxy, new compounds, exceed the fendiline in its pharmacological properties In the test described below, their activity is at least equal to that of fendiline, the duration

  their effect being appreciably longer In addition, their toxicity

  cited, when applied orally to the mouse, is clearly

  lower than that of fendiline.

  This surprising activity of compound 1 was proven in a load test performed on hamsters at

  which cardiomyopathy had been caused by isoprene

  line The selected hamster group was treated with iso-

  prenal 15 mg / kg subcutaneously on the first day and 12 mg / kg on the second day The third day the test compound was administered to these animals ten minutes to two hours before the load test. proper, in which we have

2. 2504524

  measured the time during which the animals treated by the

  Dicament are able to swim in comparison with the group of control animals Compound I, at the dose of 70 mg / kg per os, prolongs the swimming duration, if we compare with the group that did not receive the drug beforehand up to the level of value measured on the control animals, and if the application was made four hours before the load test It is the same, while the fendiline at the equimolar dose (60 mg / kg) per os is inactive, if the application is done one hour before

the test.

  Compound I has a remarkable influence on the blood supply to the heart muscle and the activity of this cardiac muscle, which assures favorable presumptions for its use in the treatment of ischemic disorders.

  The results of the following pharmacological tests were

riffer these presumptions.

  This compound of Form I is also active

  in the test where one examines the influence on the changes

  to the 8 T segment of the electrocardiogram (EKG) by the

  administration of vasopressin with ergometrine to rats

  whose myocardium had been previously affected by the

  Isoprenaline administration In oral administration, (the maximum dose

  mum administered was 70 mg / kg), the changes in EKG mentioned above are markedly impaired if administration is four hours before vasopressin administration.

with ergometrine.

  A similar favorable protective effect against ergometrine-associated vasopressin was observed with identical doses in the rat with coronary occlusions caused by the administration of a fine suspension of powdered quartz or a collagen solution by means of from a thin vessel driven by a carotid artery to the curved aorta

  to the coronary arteries that leave.

  At the oral dose of 50 mg / kg, compound I increases

  in dogs under pentobarbital anesthesia

  amount of blood flowing through the coronary sinus and pressure

  partial release of oxygen in this blood.

  In vitro, compound I blocks the contraction effects of calcium ions on isolated vestibules of rabbits

  and on strips of rabbit aortas.

  Intravenous administration of compound I to

  unanesthetized rabbits at a dose greater than 15 mg / kg,

  In the form of pills, the result is a drop in pressure proportional to the size of the dose administered without any symptoms of behavioral changes. Comparing the results of the determination of toxicity is very favorable to compound I in comparison with the toxicity of clinically used fendiline preparations. Compound I is structurally similar to this compound.

  the last of which is only the N-hydroxy derivative.

  thalle ID 50 on the mouse and rat is greater than 1200 mg / kg orally (the ID 50 of fendiline is 650 mg / kg orally) There is also an essential difference in the manifestations

  toxins caused by a high dose of fendiline and in the

  high doses of compound I Fendiline causes

  strongly clonic cramps in mice and rats, animals

  dying in cramps after administration of lethal doses # The lower doses, 200 to 300 mg / kg, which are not fatal, cause cramps lasting several hours Fendiline causes similar effects also in monkeys, while compound I does not show any

  symptoms of cramping up to 1200 mg / kg per os.

  oral application to monkeys Macaca mulata of a dose of

  600 mg / kg gives rise to no symptoms of a change in the

  nor to reactions of treated animals, and has no effect

  fet on blood pressure, pulse rate, or breathing.

  A daily dose of 75 mg / kg

  administered to rats and rabbits for six days does not

  no symptoms of toxic effects.

  of the same oral dose to female rats throughout the

  pregnancy does not cause fetal variation.

  The fluorinated derivative of the compound I (X = P) is a new compound which shows, in the pharmacological tests

  presented below, a remarkable action on food

  heart muscle and its activity According to

  effects determined on a typical attack of the heart of

  evils subjected to the experiments, it can be considered that the compound of formula II given in the following, can be presumed to be favorable

  use for the medical treatment of cardiac disorders

3.-

  This point of view is confirmed by the results

  the following pharmacological tests.

  In a test on hamsters suffering from cardiomyopathy caused by administration for two days of isoprenaline, compound II administered at a dose of 20 to 60 mg / kg per os, 1 to 4 hours before the test, increases the

  during which the treated animals are capable of

  Until determined time in healthy control animals. Similarly, changes in the S T segment of the electrocardiogram (EKG) caused by the administration of

  vasopressin associated with ergometrine in rats with myocardial

  card has been affected by the application of isoprenaline are net-

  significantly lower in animals that received a pre-treatment of compound II at a dose of 60 mg / kg per os, when compared with animals that have not been treated.

  II at the dose of 60 mg / kg per os shows a protective effect if

  against the effects of the application of vasopressin

  ergometrine in rats with coronary occlusion caused by the administration of a fine suspension of powdered quartz or a solution of collagen by means of a

  small vessel guided in the carotid artery until the

  you curve to the coronary arteries that leave.

  At the dose of 50 mg / kg per os, compound II increases

  The amount of blood flowing through the coronary sinus and the partial pressure of oxygen in the blood,

  dogs subjected to anesthesia with pentobarbital.

  Compound II is also slightly toxic.

  In mice and rats, a dose of 1000 mg / kg per os does not

  appear no toxic symptoms.

  Intravenous introduction of doses of 4 to

  mg / kg in unanesthetized rabbits does not give rise to any

  significant reduction in blood pressure, and produces no ef-

  the general condition and reactivity of the test animals. A daily dose of 70 mg / kg administered by the

  orally to dogs for six days does not cause the

  no symptoms of intoxication or variation of

  In monkeys a high dose of 600 mg / kg

a slight depressing effect.

  The invention extends to methods for the pre-

  4.- paration of the compounds corresponding to the general formula I. The first process for the preparation of these compounds according to the invention consists in that the N- (1-phenylethyl) -hydroxylamine of the general formula II is alkylated

3H CH 3

  NHOH o X = H or F, with a 3,3-diphenylpropyl halide in a polar organic solvent, in the presence of an agent capable of combining with the halogeno form thus formed, the compound formed being isolated under the basic form and being converted, by

  neutralization with an organic or mineral acid,

  pharmaceutically acceptable dosage.

  According to the invention, the compound I (X = H) is prepared by N-alkylation of N- (1-phenylethyl) -hydroxylamine

  with a 3,3-diphenylpropyl halide, preferably the broach

  3,3-diphenylpropyl, in a polar solvent, for example

  in methanol or ethanol, in the presence of an agent capable of combining with the halogen hydride created in the reaction,

  for example pyridine or alkaline carbonates at a temperature of

  between 20 C and the boiling point of the solvent used

  The product is isolated, after evaporation of the solvent, by distribution between an organic solvent immiscible with water (for example benzene) and water. The crude base of the product is obtained by evaporation of the separated solution, this base being

  purified by chromatography on a column of alumina, the halogenated

  3,3-diphenylpropyl, unreacted, first, and N- (1-phenylethyl) hydroxylamine being eluted with benzene. Base II is obtained by elution with ether and evaporation. to be converted to crystalline salts

  by neutralizing its solution in ether, methanol,

  thanol or acetone, with mineral or organic acids,

preferably with HO Cl.

  It is also possible to ensure the alkylation

  N- (1-phenylethyl) -hydroxylamine or N- (1- (4-fluorinated

  phenyl) ethyl 3-hydroxylamine with a 3,3-diphenyl talcogenide

  5.- Nylpropyl, especially with 3,3-diphenylpropyl bromide in

  another polar organic solvent, for example in dimethyl

  formamide in the presence of an agent capable of combining with the hydrogen halide formed during the reaction, for example alkali carbonates or sodium acetate, at

  temperatures from 15 to 60 00, preferably at room temperature

  The relatively low reactivity of the 3,3-halogenides

  diphenylethyl under the conditions indicated, makes it necessary to prolong the reaction time for 5 to 7 days, and is obviously the main cause of the yield of the product.

  relatively low (about 36% of the theory).

  The product is isolated, after dilution of the reaction mixture with an excess of water, by extraction with an organic solvent immiscible with water of the ether, for example. The crude product base is suspended by evaporation of the solvent, this base is purified by chromatography on a column of alumina,

  the halogenide of 3? 3-diphenylpropyl which has not reacted and the

  very impurities being separated by elution with benzene La

  The base of the compound is obtained by elution with ether and

  It can be converted into crystalline salts by

  of its solution in ether, methanol or acetonitrile

  ne with mineral or organic acids, preferably with

  fumaric acid 3,3-Diphenylpropyl bromide requires

  the reaction is a known compound (O Exner and coll,

  Coll Czeschoslov Chem Common 18, 270, 1953).

  N- (1-phenylethyl) -hydroxylamine can be prepared either by a known method, i.e., by oxidation of 1-phenylethylamine with dibenzoyl peroxide and hydrolyzing O-benzoyl-N- ( 1-phenylethyl) hydroxylamine thus obtained, (Zinner G Arch Pharm 296, 420, 1963), or according to the invention,

  by reaction of 1-phenylethyl bromide (Norris J F et al.

  J Am Chem Soc 38, 1071, 1916) with antibenzaldoxime

  (Zvilichovski G and Heller L, Synthesis 1972, 563), in the

  absolute, in the presence of sodium ethoxide, and by hydrolysis of the newly obtained alpha-phenyl-N- (1-phenylethyl) -nitrone

with hydrochloric acid.

  N1 1- (4-fluorophenyl) ethylhydroxylamine

  is a new compound It can be prepared by making

  1- (4-fluorophenyl) ethyl bromide (Roe F L and Saunders W H, Tetrahedron 33, 1581, 1977) with the antibenzaldoxime, 6.-

701 2504524

  (Zvilichovsky G and Heller L Synthesis, 1972, 563) in ethanol.

  absolute, in the presence of sodium ethoxide and by hydrolysis of the phenyl-N t 1 (4-fluorophenyl) ethyl nitrone with

concentrated hydrochloric acid.

  The other, more advantageous, method for the preparation of compounds of the general formula 1 uses, following

  the invention, the important reactivity of the halides of 1-

  phenylethyl and it is that the N- (3,3-

  diphenylpropyl) -hydroxylamine with a 1-phenylethyl halide of the general formula III

X H CH 3

Hal

  oh x = H or l, and Hal = Cl or Br, again in a solvent or-

  in the presence of agents capable of combining with the halogen hydride which is formed, followed by an isolation of the compound obtained in base form, and its conversion, at

  acid, to the pharmaceutically acceptable acid addition salts

  is lying. According to the invention, the compound I (X = H) is

  preferably prepared under conditions where N- (3,3-diphenyl-

  propyl) -hydroxylamine is alkylated with the halide of

  phenylethyl in a polar organic solvent, in the presence of an agent capable of combining with the halogen hydride formed during the reaction at temperatures of 15 to 600 C.

  Bromide of 1 is preferably used.

  phenylethyl as alkylating agent and the reaction is carried out

  killed in dimethylformamide, in the presence of hy-

  sodium dicarbonate at a temperature of 15 to 25 ° C.

  Due to the high reactivity of bromide

  of 1-phenylethyl, the alkylation takes place even at temperatures of

  relatively low levels of 15 to 6000, with sufficient speed

  particularly if it is carried out in a polar solvent, for example

  example in methanol, ethanol or preferably dimethyl-

  formamide. Pyridine or 8- or alkaline hydrocarbonates can be used as agents capable of combining

  with the hydrogen bromide that forms during this

  coylation. The optimum conditions are represented by the use of dimethylformamide as reaction medium

  sodium hydrogencarbonate as an agent for fixing the broach

  hydrogen is formed and at temperatures from 15 to 2500. The product is isolated by dilution of the mixture

  reaction with excess water, and by extraction into a

  The crude base of the product is obtained by evaporation of the solvent, and this baue is purified by conversion into a salt with a mineral acid or organic,

  pharmaceutically acceptable for the purpose of eliminating

  the purities present in the crude base, it is advantageous for the hydrochloride to be converted into it. The crude base is dissolved in the ether and the solution is intimately mixed with an excess of hydrochloric acid. When it crystallizes, the hydrochloride is very pure By-products and starting compounds which have not reacted remain, in this process of preparation, in the mother liquors Further details of how to proceed

  are indicated in the description of exemplary embodiments that

we will find further.

  The process is analogous if we use the

  1- (4-fluorophenyl) ethyl rings, highly reactive, and

  preferably 1- (4-fluorophenyl) ethyl bromide with

  Which alkyl is N- (3,3-diphenylpropyl) hydroxylamine?

  The reaction is carried out again in a polar organic solvent, for example methanol, ethanol or in dimethylformamide, in the presence of an agent capable of combining with the halogen hydride which forms during the course of the reaction. , for example alkali metal carbonates or hydrocarbons, acetate

  sodium or pyridine The reaction is carried out at temperatures

  The product is isolated by diluting the reaction mixture with an excess of water, and by extraction with a water-immiscible solvent, for example methylene chloride or The crude base of the compound I is obtained by evaporation of the solvent and then converted into crystallized salts by neutralization of its solution 9 in methanol, ethanol or acetone with mineral or organic acids and crystallized fumarate. is obtained for example by addition of fumaric acid to the solution of the base in ether, by heating to the boiling temperature of the dissolved fumaric acid and cooling, this fumarate being able to be purified by crystallization from organic solvents

  polar, for example from isopropanol.

  N- (3,3-diphenylpropyl) -hydroxylamine is a novel compound. It can be prepared by a synthesis in

  two phases from 3,3-diphenylpropyl bromide already

  (Exner O et al., Coll. Czechoslov Chem Chem 18, 270, 1953) and antibenzaldoxime, (Zvilichovsky G and Heller L, Synthesis 1972, 563) The new, -ph 6 nyl-N- (3,3- diphenylpropyl) nitrone corresponding to formula IV

> CHCH 2 CH 2 -N = CH O

  is obtained by alkylation of the antibenzaldoxime with 3,3-diphenylpropyl bromide in the presence of sodium ethoxide in boiling ethanol, this nitrone being hydrolysed with acid

  concentrated hydrochloric acid to give N- (3,3-

  diphenylpropyl) -hydroxylamine of the formula II from which

  we release the base in the usual way.

  The compounds of general formula I according to

  they are properly fed in the form of additive salts

  with mineral or organic acids that should not be excluded from the point of view of health, can be adjusted to

  a final drug form in a pharmaceutical composition

  particularly for the purposes of oral administration, by using

  the usual processes and the auxiliary pharma-

  known carriers such as carriers and / or diluents.

  The nonlimiting examples described hereinafter 10.-

  give details of the application of the processes according to the invention.

tion

EXEMPLE I -

  Y-phenyl-N- (1-phenylethyl) nitrone 6.1 g of anti-benzaloxime are added with stirring to the solution of sodium ethoxide prepared by dissolving

  1.2 g of sodium in 100 ml of absolute ethanol, and after dissolving

  1-phenylethyl bromide (9.8 g) was added in one portion. The reaction mixture was stirred for six hours.

  at 20 to 2500 After twenty hours of rest at room temperature

  The sodium bromide which has separated is filtered off, the filtrate is evaporated under reduced pressure and the residue of the evaporation is dissolved in 50 ml of dry chloroform. The residue of sodium bromide which has separated is filtered off. of the solution, and the liquid which has passed through the filter is evaporated. The evaporation residue is recrystallized from 30 ml of cyclohexane. 6.4 g (57% of the theory) of c-phenyl-N- (1-phenylethyl)

  nitrone with a melting point of 85 to 8600.

EXEMPLB 2 -

  N- (1-phenylethyl) -hydroxylamine A mixture of 13.7 g is heated to about 1100 C

  of co-phenyl-N- (1-phenylethyl) nitrone and 27 ml of hydrochloric acid.

  drique concentrated, and sends steam into the mixture, at this temperature, until the condensate contains no more benzaldehyde After cooling, the mixture is evaporated

  reaction under reduced pressure The residue of the evaluation is mixed

  poration with water to reach a total volume of about

  ml and adjust the pH of the solution to about 1 to 2,

  1M solution of sodium hydroxide The solution is filtered through activated charcoal, the filtrate is evaporated to a volume

  about 25 ml and made alkaline with sodium hydroxide.

  dium The crystallized base is filtered by suction and washed

  with water We obtain 6 g (72% of theory) of N- (1-

  phenylethyl) -hydroxylamine with a melting point of 69 to

70 C 0.

EXAMPLE 3

  N- (1-phenylethyl) -N- (3,3-diphenylpropyl) -hydroxylamine A solution of 12.1 g of 3,3-diphenylpropyl bromide in 5 ml of methanol is added to the solution of 5.5 g of N- (1-phenylgthyl) -hydroxylamine and 3.4 ml of pyridine in 11.-

  ml of methanol, and the mixture is allowed to stand at room temperature.

  room temperature for five days. The reaction mixture is evaporated.

  under reduced pressure The residue of evaporation is

  mixed and distributed 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 evaporation.

  on a column of 450 g of aluminum oxide.

  3,3-diphenylpropyl and N- (1-phenylethyl) -hydroxylamine

  which have not reacted by elution with benzene N- (1-phenyl)

  thyl) -N- (3,3-diphenylpropyl) -hydroxylamine (base form

  viscous) is obtained by elution with ether, chlorhydrin

  drate is prepared by acidification of the solution in the iso-

  propanol of the base with hydrochloric acid, this hydrochloride

  drate having a melting point of 158 to 16800 C (decomposition)

  after crystallization from isopropanol.

BXU 4 PLX 4 -

  o -phenyl-N- (3,3-diphenylpropyl) nitrone To a solution of sodium ethozyde, prepared

  by dissolving 18.4 g of sodium in 1600 ml of absolute ethanol

  96.8 g of anti-benzaldoxime are added, and when it is

  under, 232.5 g of 3,3-bromine were stirred while stirring.

Diphenylpropyl The mixture is heated while stirring at room temperature.

  boiling point, for five hours, after 15 hours

  The precipitated solid compound is cooled, with ice and water, to about 40 ° C. The precipitated solid compound is separated and washed with 250 ml of cooled ethanol and 750 ml of water and ice. after drying 204 g (80.8% of theory) of c -phenyl-N- (3,3-diphenylpropyl) -nitrone having a melting point of 169 to 17300 is obtained. The analytically pure compound

  melting at 171 to 173 O after recrystallization from the étha-

nol.

3 EMPIE 5-

  N- (3,3-Diphenylpropyl) -hydroxylamine A mixture of 204 g of CL -phenyl-N- (3,3-diphenylpropyl) nitrone and 300 ml of concentrated hydrochloric acid is heated to about 110 ° C. and introduced. at this temperature, in the mixture, water vapor until the condensate

  no longer contains benzaldehyde N- hydrochloride (3,3-

  Diphenylpropyl) -hydroxylamine crystallizes on cooling, settling in the clear solution at about 0 °, this hydrochloride being isolated by suction, and being obtained in a practically quantitative yield. The melting point is 156 to 15,800 (isopropyl alcohol) The base can be obtained

  either by release from the hydrochloride as usual

  or directly by alkalinisation of the mixture, after

  have eliminated the benzaldehyde by distillation, with ammonia

  the extraction of the separated base with methyl chloride

  ethylene chloride, drying of the methylene chloride solution with anhydrous sodium sulfate and then evaporation In this case,

  145 g (98.6% of theory) of N- (3,3-diphenylpropyl)

  pyl) -hydroxylamine whose melting point is 79 to 800 ° C. after recrystallization from cyclohexane or a mixture

toluene and cyclohexane.

XOlPIB 6 -

  N- (1-phenylethyl) -N- (3,3-diphenylpropyl) -hydroxylamine A mixture is stirred at room temperature

  102.3 g of N- (3,3-diphenylpropyl) -hydroxylamine, 56.7 g of hy-

  sodium dicarbonate and 91.4 g of 1-phenylethyl bromide in 450 ml of dimethylformamide as long as it escapes

  carbon dioxide from the reaction mixture (about 18 hours).

  The reaction mixture is then diluted with 2.5 l of water, and the product is extracted with ether. The ether solution is washed with water and saturated sodium chloride solution until neutral. The reaction is dried with anhydrous sodium sulphate and the ether is evaporated. The dry solids (164.5 g) representing the crude base of the product are dissolved in 490 ml of ether. The solution is poured into the solution while stirring.

  diluted hydrochloric acid (60 ml of hydrochloric acid

  centered in 150 ml of water) It crystallizes a hydrochloride during

  stirring continues, this hydrochloride is filtered

  The mixture was washed with 500 ml of ice-water and 500 ml of ether after the mixture was cooled to about 50 ° C. After drying, 127 g (76.8% of theory) of N-hydrochloride were obtained. (1-phenyldthyl) -N- (3,3-diphenylpropyl) hydroxylamine, having a melting point of 157 to 170 ° C (with decomposition) after

  recrystallization from 450 ml of isopropyl alcohol.

XEML 7 -

  C -phenyl-N t 1 (4-fluorophenyl) ethyl 3-nitrone To a solution of sodium ethoxide prepared by dissolving 2.9 g of sodium in 250 ml of absolute ethanol, 13- 15.1 is added. of anti-benzaldoxime with stirring, and after dissolution, 26.9 g of bromide of

  1- (4-Fluorophenyl) -ethyl The reaction mixture is stirred for 5 hours at 20 to 2500 ° C. The sodium bromide which separates is

  filtered after standing at room temperature for 15 hours, the liquid which has passed through the filter under reduced pressure is evaporated, and the evaporation residue is dissolved in 75 ml of anhydrous chloroform. The residual sodium bromide is filtered off. of the solution, and the liquid which has passed through the filter under reduced pressure is evaporated. The residue of the evaporation is then recrystallized from 70 ml.

  of cyclohexane 18.9 g (62.2% of theory) of CO

  phenyl-N (1- (4-fluorophenyl) ethyl] nitrone, which has a melting point of 60 to 7800. The analytically pure compound has a

  melting point (p f) from 79 to 8000 (cyclohexane).

EXAMPLE 8 -

  N l 1- (4-fluorophenyl) ethyl 1-hydroxylamine A mixture of 17.7 g of Ol -phenyl-N t 1- (4-fluorophenyl) ethyl nitrone and 33 ml of hydrochloric acid is heated to about 1100 C concentrate, and steam is introduced into the mixture at this temperature until the

  Condensate no longer contains benzaldehyde After cooling

  The pH of the reaction mixture is adjusted to a value of 1 to 2 by the addition of 1 M sodium hydroxide solution.

  filter the activated charcoal solution, evaporate the liquid

  pide which has passed through the filter, under reduced pressure, to a

  volume of about 25 ml and basified with a solution of

  sodium hydroxide The oily base which separates crystallizes upon cooling. It is filtered under suction and washed with water. 8.5 g (76.3% of theory) of 14-fluorophenyl) ethyl are obtained. hydroxylamine, whose point of

  melting is 75 to 7700 The analytically pure compound recreates

  tallied from cyclohexane has a melting point of 77 to

78 00.

EXAMPLE 9

  N, 1- (4-fluorophenyl) ethyl N- (3,3-diphenylpropyl) -hydroxyl

  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 sodium acetate (trihydrate) is stirred for 7 days. ) 14 finely ground, in 30 ml of dimethylformamide, remaining at room temperature 300 ml of water are then added with stirring, the mixture is adjusted to a value of 7 to 8 with 1M sodium hydroxide solution, and the product which separated with ether was extracted. The combined ether solutions were washed with water and the ether was evaporated under reduced pressure from from a water bath to 3000

  after drying with anhydrous sodium sulphate The

  Evaporation (11.9 g) is chromatographed on a column of 360 g of aluminum oxide. The unreacted 3,3-diphenylpropyl bromide is separated by elution with benzene. crude viscous base of the product by elution with ether, this base is dissolved in ether and converted

  crystallized fumarate by the addition of 0.75 g fumaric acid

  4.4 g (36.2% of theory) of fumarate are obtained.

  N (1- (4-fluorophenyl) ethyl-N- (3,3-diphenylpropyl) -hydroxy-

  which has a melting point of 133 to 13600 (isopropanol)

propyl).

EMPIEIR 10 -

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

  18.9 g of hydrocarbon are added with stirring.

  finely ground sodium bonate and 33.5 g bromide of 1- (4-

  fluorophenyl) ethyl to the solution of 34.1 g of N- (3,3-diphenyl-

  propyl) -hydroxylamine in 150 ml of dimethylformamide, and

  The mixture is stirred for 30 hours at room temperature.

  After addition of 800 ml of water, the separated product is extracted with ether. The ethereal solution is then washed with water and with a saturated solution of sodium chloride.

  drying with anhydrous sodium sulphate, the

  The residue of evaporation, viscous, oily, (56.6 g) is dissolved in 300 ml of ether, 8.7 g of fumaric acid is added to the solution, and the mixture is heated to room temperature. boiling for 30 minutes The crystallized fumarate separates from the solution already during boiling. Crystallization is

  completed by cooling to 000. 46.2 g of

  N 1- (4-fluorophenyl) ethyl) -N- (3,3-diphenylpropyl) marate

  hydroxylamine, taken up by suction and washing with ether, its melting point is 131 to 135 ° C. After recrystallization from 175 ml of isopropyl alcohol, 45.6 g (74.6% of theory) are obtained. pure fumarate with a melting point

is from 134 to 1360 ° C.

prl A _ 9 /.

15., 'i

Claims (6)

  1. New compounds, likely to be used   for the treatment of certain cardiac disorders,   are constituted by N- (1-phenylethyl) -   N (3,3-diphenylpropyl) hydroxylamines corresponding to the general formula 3 OH   o X = H or P and their addition salts with mineral acids   organic and pharmaceutically acceptable salts.   2 novel compound according to claim 1, characterized in that it consists of N- (1-phenylethyl)   N- (3,3-diphenylpropyl) -hydroxylamine.   3. The novel compound according to claim 1,   characterized in that it is constituted by N 1 1- (4-fluorophemide).   nyl) ethyl-N- (3,3-diphenylpropyl) -hydroxylamine.   Process for the preparation of compounds of the general formula I according to claim 1,   characterized in that the N- (1-phenylethyl) -hydro-   xylamine corresponding to the general formula II H CH 3   ## STR2 ## where X is H or P, with a 3,3-diphenulpropyl halide in a polar organic solvent, in the presence of an agent capable of combining with the halogen hydride which forms, the general formula I obtained in base form, and converted by neutralization with inorganic or organic acids into pharmaceutically acceptable addition salts,   5. Process for the preparation of compound   compound of general formula 1, according to claim 1,   characterized in that N- (3,3-diphenylpropyl) is alkylated -   hydroxylamine with a 1-phenylethyl halide having the general formula III X CH CH 3 Have it   o X = H or F and Hal = Cl or Br, in a po-   in the presence of an agent capable of combining with the   halogen chloride which is formed during the reaction, the compound of general formula I obtained in base form is isolated and converted by neutralization with mineral acids.   or organic salts of pharmaceutically acceptable additions.   Pharmaceutical compositions characterized by containing a compound of the formula   general I, together with auxiliary compounds, pharmaceuticals   known ticks, such as carriers and / or diluents.