CS220569B1 - Substituted n-aniline-4-chloro-3-sulphamoylbenzamides and method of preparing same - Google Patents

Abstract

The invention provides substituted N-aniline-4-chloro-3- sulphamoyl benzamides of the general formula I <IMAGE> wherein R represents a hydrogen atom or a methyl group and R<1> is a methyl, ethyl, isopropyl, 2- hydroxyethyl or phenyl group and a process for production thereof which comprises acylation of substituted hydrazines of general formula II <IMAGE> with a 4-chloro-3-sulphamoylbenzoyl halide preferably the chloride. Compounds of general formula I have diuretic and saliuretic activity and significant antihypertension effect.

Description

The present invention relates to substituted N-anilino-4-chloro-3-sulfamoylbenzamides of formula I

SQ ₂ NH 2 wherein ^R represents a hydrogen wire ^to T ^b of not ^et mm yl and ^R1 m ^e l ^h ^ ^0, ethyl, ^{ipropyl-2-hydroxy-ethyl} divots n ^eb of phenol and a process for their preparation.

In the literature, there have been described low substituted E-chloo-4-stllafoylbenzoic acid Hodrinides which exhibit ditoetCckot and salitoetCckc activity. For example, U.S. Pat. U. S. Patent No. 3,119,847 discloses 4-chloro-3-tuaffinoylbenzoic acid Ubnylhyrazinyl with various substituents on the Ubnylhyiraniline benzene core having diuretics and salicyclic acid. The same was found in the case of the 4-chloro-3-sulphinylbenzylic acid aminoalkyls described in U.S. Pat. No. 3,043,874.

It has now been found that the novel hydroxides of the formula I exhibit, in addition to high diuretic and salitobtic activities, also significant intestinal activity. A particularly preferred compound of the invention after le ^d in that direction] .at ^the formula ^I and, ^{in some} m ^{of R} is hydrogen and ^R1 represents MMTTY ⁰ group.

and the talitobtic ЛШИ! of this substance at 0.2 mg administered orally to the rat is equivalent to an oral dose of 0.5 ml of the known and used diuretic clopamide.

Antihypertensive ιΗΜΙ! This substance was found both in rats with experimental hypertensive induced subcutaneous implantation of DOCA pellet after unilateral tefrbttlmia and in Macacus rhesus monkeys. The effect was compared with the known, clinically used indepamide dilution. At a dose of 10 mg / kg p.o. in rats, the compound had a blood pressure of 10-15%, purging at the maximum decrease at 3 h after dosing. In this test, it was at least as effective as the above. In monkeys, the effect of the compound of the invention was compared with indapamide at a dose of 2 x 25 m &lt; 2 &gt; kg p.o.

In addition, the substance is of low toxicity. At a dose of 2.5 g / kg, it did not induce any signs of toxicity in mice. Thus, it has the potential for clinical humiliation in the treatment of hypertensive disease.

The invention relates to a process for the preparation of the compounds of the formula I. They can be prepared by acylating the substituted weeksins of the formula II.

(II) wherein ^R and ^{r 1 are the same} in formula ^h allgbti ^{d ,} preferably tyseline chloride ⁰

4-chllrзЗ-tulffIloybbtnzc) Lion / British Pat. No. 915,259].

Substituted yellow hydrides of the formula II are generally known.

The acylation of the sub-hydrates of formula II can be carried out by adding 4-chloro

-3-sulfamoylbenzoyl chloride or a solution thereof in tetrahydrofuran to a solution of the substituted hydrazine of formula II in a suitable inert solvent, e.g. chloroform or tetrahydrofuran, without or with cooling with ice water. The reaction is then completed by standing the reaction mixture at room temperature for 2 to 16 h. The solvents are evaporated off under reduced pressure and the residue is stirred between water and a water-immiscible solvent such as ethyl acetate. The separated organic solution was dried over anhydrous potassium carbonate or anhydrous sodium sulfate and the solvent was evaporated. The evaporation residue is. It is directly crystallized from an organic solvent or solvent mixture or is first purified by alumina column chromatography, whereby less polar impurities are separated by elution with benzene. The compounds of formula I are then eluted with a mixture of chloroform and methanol.

The details of the preparation process according to the invention are given in the examples, which, however, are merely illustrative of the possibilities of the invention, but not all of these possibilities. Example 1

N- (N-methylanilino) -4-chloro-3-sulfamoylbenzamide

To a solution of 8.7 g of 1-methyl-1-phenylhydrazine and 7.1 g of triethylamine in 100 ml of chloroform, 18 g of 4-chloro-3-sulfamoylbenzoyl chloride are added in portions with stirring so that the temperature of the reaction mixture does not exceed 20 ° C. The reaction mixture is allowed to stand at room temperature for 16 h. The chloroform is distilled off under reduced pressure and the residue is stirred between 100 ml of ethyl acetate and 50 ml of water. The organic layer was separated and the aqueous layer was shaken with 50 mL of ethyl acetate. The combined organic solutions were dried over anhydrous sodium sulfate, and ethyl acetate was evaporated under reduced pressure. The residue was recrystallized from a small amount of methanol / ether. 12.3 g (52% of theory) of the product with a melting point of 224 DEG-225 DEG C. are obtained. The analytically pure material recrystallized from methanol had mp 225-226 ° C.

Example 2

N- (N-ethyl or 1,1-ino) -4-chloro-3-sulfamoyl benzamide

In analogy to Example 1, 16.3 g of crude non-crystalline residue are obtained from 6.8 g of 1-ethyl-1-phenylhydrazine for 12.7 g of 4-chloro-3-8-flamoyl chloride in 80 ml of chloroform in the presence of 5.1 g of triethylamine. which is purified by chromatography on a column of 500 g of alumina. Elution with benzene removes less polar impurities and the product is obtained by eluting with a 9: 1 mixture of chloroform and methanol. 6.4 g (36% of theory) of the product with a melting point of 155-159 DEG C. are obtained. Mp 160-161 ° C (methanol-ether).

The following compounds were prepared in the same manner as in Example 2:

N- (N-isopropylanilino) -4-chloro-3-sulfamoylbenzamide, mp 117-119 ° C (methanol-ether).

N- (N-methyl-p-toluidino) -4-chloro-3-sulfamoylbenzamide, m.p. 201-203 ° C (ethanol),

N- (diphenylamino) -4-chloro-3-sulfamoylbenzamide, hemihydrate, m.p. 200-202 ° C (methanol).

Example 3

N - [N - (2-hydroxyethyl) anilino] -4-chloro-3-sulfamoylbenzamide

To a solution of 6.1 g of chlor- (2-hydroxyethyl) -1-phenylhydrazine and 4 g of triethylamine in 120 ml of tetrahydrofuran is added dropwise a solution of 10.1 g of 4-chloro-3-sulfamoylbenzoyl chloride in 80 ml of tetrahydrofuran dropwise over 1 hour. cooling to 10 ° C. The reaction mixture is left at room temperature for 16 h, the precipitated triethylamine hydrochloride is filtered off with suction and the filtrate is filtered off with suction.

A was evaporated under reduced pressure. The residue (16 g) is purified by chromatography on a column of 480 g of alumina. Elution with benzene separates the polar impurity. The product is obtained by eluting with a mixture of chloroform and methanol (9: 1). After crystallization from methanol with the addition of ether, 5.8 g (40% of theory) of pure product are obtained, m.p. 140-141 ° C.

Claims (4)

SUBJECT OF THE INVENTION Substituted N-anilino-4-chloro-3-sulfamoylbenzamides of the general formula I in which R is hydrogen or methyl and R ^{1 is} methyl, ethyl, isopropyl, 2-hydroxyethyl or phenyl. 2. N- (N-Methyl-4-nino) -4-chloro-3-sulfamoyl-benzamide. 3. A process for the preparation of substituted N-enilino-4-chloro-3-sulfamoylbenzenes of the formula I according to claim 1, characterized in that the substituted hydrazine of the formula II (II) is acylated in which R and R &lt; ¹ &gt; in Formula I, 4-chloro-3-sulfamoylbenzoic acid halide in an inert organic solvent in the presence of a reagent capable of binding the hydrogen halide formed in the reaction at a temperature of 10 to 30 ° C. 4. The process of claim 3 wherein the acylation is carried out with 4-chloro-3-sulfamoylbenzoyl chloride in chloroform or tetrahydrofuran in the presence of triethylamine.