CS236147B1 - 1- [5-Chloro-2- (2-methylpiperazine methylphenylthio) benzo] - and its maleate - Google Patents

Abstract

The invention falls within the field of drug synthesis. Its subject is a new l-/5-chloro- -2-(2-methylphenylthio)benzyl/-4-methylpiperazine of the formula I (51) Int. Cl.' C 07 D 295/06, C 07 D 295/08 maleate. The invention describes the preparation of a new starting material. and its maleine. The substance of the formula I and its maleate show hypotensive activity in normotensive animals and are considered in therapy as drugs correcting conditions with increased blood pressure. The substance also has a mild centrally stimulating activity and acts inhibitory against some microorganisms. .It can be prepared by the substitution reaction of 5-chloro-2-(2-methylphenylthio)benzyl chloride with excess 1-methylpiperazine in boiling chloroform. The obtained oily base I is converted by neutralization with maleic acid to crystalline hydrogen

Description

The present invention relates to a novel 1- (5-chloro-2- (2-methylphenylthio) benzyl) -4-ethylpiperazine of formula I

(1) and its maleate ·

The compound of formula I and its maleate exhibit a hypotensive effect in normotensive animals and are suitable for practical use in the treatment of hypertensive disease, for short-term lowering of blood pressure and as a medicament for blocking sudden increases in blood pressure (hypertensive crises). They also have a mild central stimulating effect and inhibit the growth of some microorganisms in in vitro assays, suggesting chemotherapeutic properties. · In animals, laUa VWcI was tested in the form of bis (hydrogen maleate), Acute toxicity by intravenous administration was determined in mice, mg / kg. At a dose of 10 mg / kg i _e v, it induces short and deep reductions in blood pressure in normotensive rats. At doses higher than 10 mg / kg iv, it causes a significant increase in mouse activity and reactivity (central stimulation).

At the following concentrations in µg / ml, they inhibit growth of the following microorganisms: Streptococcus β-haemolyticus 25, Streptococcus faecalis 50, Staphylococcus pyogenes aureus 25-, Escherichia coli 25, Proteus vulgaris 100, Mycobacterium tuberculasis H37Rventa 100

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The compound of formula I can be prepared from 5-chloro-2- (2-methylphenylthio) benzyl chloride of formula II

C% or substitution reaction in boiling chloroform. 1-Methylpiperasin is used in excess of at least 200%, since in the reaction it not only has the function of a reactant but also of a condensing agent which binds at. reaction - liberated hydrogen chloride. The resulting oily base vic * dse is then converted by neutralization with maleic acid in ethanol to crystalline bis (hydrogen maleate), which is suitable for pharmacological tests and for preparation of drug preparations and melts in the pure state at 181-184 ° C. The starting material is novel and the process for its preparation is described in the example below. The identity of the novel compounds described in this invention was assured analytically and by spectral methods. The following example describing the preparation of ν2.οτ <β.Τ is only illustrative of the possibilities of the invention, but is not intended to fully describe these possibilities.

A mixture of 46 g of 5-chloro-2- (2-methylphenylthio) -benzyl chloride, g of 1-methylpiperidine and 50 ml of chloroform is refluxed for 10 h. The chloroform was evaporated under reduced pressure, the residue was dissolved in benzene and washed thoroughly with water. From the benzene layer, the basic product is extracted into 5% hydrochloric acid, the acidic aqueous solution (containing the product hydrochloride) is basified with aqueous ammonia, and the base is isolated by extraction with benzene. Evaporation of the extract gave 35 g (62%) of oily base I. Neutralization with 23.5 g of maleic acid in 250 ml of boiling ethanol gave 50 g of crystalline bis (hydrogen maleate) melting at 181-184 ° C (ethanol).

The starting 5-chloro-2- (2-methylphenylthio) benzyl chloride used is a novel substance which can be prepared from substances known as follows:

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To a solution of 121 g of potassium hydroxide in 1300 ml of water, 79 g of 2-methylthiophenol (Leuckart R®, J.Prakt.Cham® / 2 / £ 1, 188, 1890: Bourgeois E., Rec. Chim® Pays Bas t8® 426, 1899; Chem® Zentralbl. 1900. I, 252), 179 g of 5-chloro-2-iodobenzoic acid (Pelz K® et al®, Gollect.Czech® CheeuCoramun® 33. 1θ52, 1968 ) and 4 g of copper catalyst and the mixture is refluxed for 11 h. It is filtered hot and the filtrate is acidified with hydrochloric acid. After standing overnight, the crude product is filtered off with suction, washed with water and dried. Yield 160 g (90%). 5- »chloro-2- (2- (ethylphenylphenylthio)) benzoic acid melting at 157-165 ° C; pure material was obtained by misleading from aqueous ethanol, m.p. 170-172 ° C.

To a stirred suspension of 112 g of the preceding acid in 300 ml of tetrahydrofuran was slowly added 18 g of sodium borohydride and then at 15 ° C under a nitrogen atmosphere dropwise with 60 ml of boron trifluoride etherate. The mixture was stirred for 3 hours at room temperature. night, decomposed by slow addition of 100 ml of 1: 1 dilute hydrochloric acid and after dilution with 500 ml of water, the product was extracted with benzene®. The extract was washed with 5% sodium hydroxide solution and water, dried over sodium sulfate and evaporated under reduced pressure. (96% on conversion) (63 g of the starting acid is recovered by acidifying the alkaline aqueous layer) of the crude

5-chloro-2- (2- »ethylphenylthio) benzyl alcohol, which boils without decomposition at 166 to 168 ° C / 0,1 KPa® The distillate solidifies to a crystalline substance melting at 58 to 60 ° C (hexane) ®

To a stirred mixture of 77 g of the preceding alcohol and 30 ml of pyridine is added dropwise 47 g of thionyl chloride at 20 ° C, the mixture is stirred for 2 hours at 20 ° C, allowed to stand overnight at room temperature and then heated for 35 hours. 40 [deg.] C. After cooling, it is quenched by the slow addition of 250 ml of water and the product is isolated by extraction with benzene. The extract was washed with dilute hydrochloric acid, 5% sodium hydroxide solution and water, dried over calcium chloride and evaporated. 71 g (87%) of crude 5-chloro-2 '- (2-methylphenylthio) benzyl chloride are obtained which can be purified by distillation. The substance boils without decomposition at 186-188 ° C / 0.3 kPa.

Claims (1)

SUBJECT OF THE INVENTION 236 147 1- (5-Chloro-2- (2-methylphenylthio) benzyl) -4-methylpiperazine of formula I (I) and its maleate.