CS211335B1 - 2-l 4-phenoxyacetylpiperazin-1-yl p-4-amino-6,7-dimethoxychinazolin,the salts and method of preparation of the same - Google Patents

Abstract

The invention relates to a novel, antihypertensive effective 2- (4-phenoxyacetylpiperazine- -1-yl-4-amino-6,7-dimethoxyquinazoline, its editing salts and its two ways preparation, consisting in the reaction 2-chloro-4-amino-6,7-dimethoxyquinazoline with 1-phenoxyacetylpiperazine, both in N- -acylation-2- (piperazin-1-yl) -4-amino-6, 7- -dimethoxyquinazoline by phenoxyacetyl chloride.

Description

The present invention relates to a novel 2- (4-phenoxyacetylpiperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline of the formula X, _NH

CH ₃ O.

CH3O-

(I) its pharmacologically acceptable salts with inorganic or organic acids and processes for its preparation.

The compound of formula I of the invention reduces blood pressure by about 30% for 24 hours in rats with experimental hypertension induced by subcutaneous implantation of a DOCA palette after unilateral nephrectomy at oral doses of less than 1 mg / kg. Its toxicity in mice is very low. An oral dose of 2 g / kg does not cause any toxic symptoms. These results indicate the potential for use of this compound in the treatment of various forms of hypertension in humans.

The compound of formula (I) may be prepared according to the invention in two ways. According to a first method, the known 2-chloro-4-amino-6,7-dimethoxyquinazoline (US Pat. 3,518,836; Chem. Abstr. 71 91519 (1969)) is reacted with 1-phenoxyacetylpiperazine. The reaction is carried out by heating their mixture in n-butanol or isoamyl alcohol to boiling. Upon cooling, the hydrochloride of the product of formula I crystallizes, which is either recrystallized from a lower aliphatic alcohol, e.g. ethanol or aqueous ethanol, or can be converted by alkalising an aqueous suspension, e.g. aqueous sodium hydroxide, on a base obtained by shaking it into a suitable water of a miscible solvent such as chloroform and evaporation. The crude base can be recrystallized from e.g. ethanol. Addition salts can be obtained by neutralizing the pharmacologically acceptable inorganic or organic acids in an anhydrous or aqueous aliphatic alcohol such as ethanol.

Phenoxyacetylpiperazine is a new substance. It can be prepared by acylating piperazine hexahydrate with phenoxyacetyl chloride in aqueous solution at pH 2-3. Details of its preparation are given in the Examples.

A second method for the preparation of the compound of formula (I) consists in reacting the known 2-piperazino-4-amino-6,7-dimethoxyquinazoline (Althuis, H. and Hess HJ, J. Med. Chem. 20 148 (1977)) with phenoxyacetic acid or a functional derivative thereof acting as an acylating agent, preferably phenoxyacetyl chloride. Heakoe is carried out in a suitable inert solvent, e.g. methylene chloride or chloroform at a temperature of 20 ° C to the boiling point of the solvent used. The product is isolated either by aspiration from the reaction mixture of the precipitated crystalline hydrochloride, or is introduced on a crystalline basis as described above.

The details of the processes for the preparation of the compound of the formula I according to the invention are given in the following examples, which, however, are merely illustrative of the possibilities of the invention and are not intended to fully describe these possibilities.

He did

1-Phenoxyacetylpiperazine

18.2 g of piperazine hexahydrate are dissolved in 180 ml of water and the solution is acidified with about 10% hydrochloric acid to pH 1.9. The pH of the mixture was adjusted to 2.8 by addition of 50% aqueous sodium acetate solution. After the addition of 90 ml of acetone, a solution of 16.5 g of phenoxyacetyl chloride in 130 ml of acetone was added portionwise to the stirred solution heated at 50 ° C, maintaining the pH of the mixture at 2.8 by the addition of aqueous sodium acetate solution. After the last portion of phenoxyacetyl chloride was added and the pH adjusted, the mixture was stirred for an additional hour and evaporated to dryness under reduced pressure. The residue was extracted with boiling ethanol, from which 1-phenoxyacetylpiperazine hydrochloride crystallized in 10.8 g (43%) by cooling. The product was ansitically pure after crystallization from ethanol, m.p. 202-203 ° C.

Example 2

2- (4-Phenoxyacatylpiperazin-1-yl) -4-amino-6,7-diethoxyquinazoline

A mixture of 4.2 g of 1-phenoxyacetylpiperazine (obtained by alkalizing 5 g of hydrochloride with aqueous ammonia, shaking the base into chloroform and evaporating) and 4.2 g of 2-chloro-4-amino-6,7-dimethoxyquinazoline in 100 ml of isoamyl alcohol is heated to boiling. 4 o'clock. After standing overnight at room temperature, the precipitated product hydrochloride is filtered off with suction, 6 g (68%), m.p.

252 ° C. An analytically pure product crystallizing in the form of ethanol hemihydrate melts at

253 DEG -256 DEG.

The base obtained by alkalizing the aqueous hydrochloride suspension with aqueous sodium hydroxide solution, shaking it into chloroform and evaporating it after crystallization from ethanol, melting at 213-215 ° C.

Example 3

2- (4-Phenoxyacetylpiperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline

To a solution of 2.7 g of 2- (piperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline in 50 ml of dry chloroform was added dropwise a solution of 1.8 g of phenoxyacetyl chloride in 20 ml of chloroform dropwise with stirring over about 20 minutes. The reaction mixture is then heated to boiling and cooled briefly with stirring. The resulting product hydrochloride suspension in chloroform was stirred with 10% sodium hydroxide solution and the chloroform solution of the product base was separated, dried over anhydrous sodium sulfate. After addition of 50 ml of isoamyl alcohol, 3.1 g (63.6%) of the hydrochloride of the title compound of m.p. Heating the crystal modification of the product with 50 ml of ethanol for 3 hours to boiling gave the hydrochloride, m.p. 255-257 ° C, its identity to the product obtained according to Example 2 was verified by thin layer silica gel chromatography and spectra.

Claims (5)

2- (4-Phenoxyaoethylpiperazin-1-yl) -4-amino-6,7-diaethoxyquinazoline of the formula I and its pharmacologically acceptable salts with inorganic or organic acids. 2. A process for the preparation of 2- (4-phenoxyacetylpiperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline according to claim 1, characterized in that 2-chloro-4-amino-6,7-dimethoxyquinazoline is reacted. with 1-phenoxyacetylpiperazine in a 4 to 5 carbon boiling aliphatic alcohol, and the product hydrochloride precipitated by cooling the reaction mixture is either purified by crystallization from an anhydrous or aqueous aliphatic alcohol, preferably ethanol, or is rendered alkaline by crystallization of the aqueous suspension. 3 _211335,: 3. The process of claim 2 wherein the reaction of 2-chloro-4-amino-6,7-dimethoxyquinazoline with 1-phenoxyacetylpiperazine is carried out in boiling isoamyl alcohol for 4 hours. 4. A process for the preparation of 2- (4-phenoxyacetylpiperazin-1-yl) -4-amino-6,7-dimethoxyquinazoline according to claim 1, which comprises reacting 2-piperazino-4-arsino-6,7-dimethoxyquinazoline. with a functional phenoxyootic acid derivative acting as an acylating agent in an inert organic solvent at a temperature of 20 ° C to the boiling point of the solvent. 5. The process of claim 4, wherein the phyloxyacetyl chloride is used as the ecylating agent and the reaction is carried out in chloroform. O. Process for the preparation of the salts of 2- (4-phenoxyacetylpiperazin-1-yl) -4-emino-6,7-dimethoxyquinazoline according to item 1, characterized in that the base of the formula I obtained according to item 2 is neutralized with pharmacologically harmless inorganic or organic acids in an anhydrous or aqueous aliphatic alcohol.