CS236148B1 - Methylpiperazine derivatives derived from 4-chlordiphenylsulphide and its salts - Google Patents

Abstract

The invention is within the scope of drug synthesis. Its subject is methylpiperazine derivatives derived from 4-cis-diphenyl sulfide formula I, (51) Int Cl. ’ OJ C 07 D 295/06, OJ C 07 D 295/08 carbonic acid ester; the product is substance ka I, X = Y = CO. This material was reduced with sodium borohydride giving compound I, X = CHOH, Y = CO. Same starting material by reduction with lithium aluminum hydride gives substance I, X = ChOh, X - CHg · The bases I obtained are converted neutralizing to the corresponding salts, of which examples include hydrochlorides and maleates. wherein X is CO or CHOH and Y represents CO or CH2 and salts thereof with pharmacodynamically harmless inorganic acids. Substances of Formula I and their salts exhibit a variety of pharmacodynamic and biological effects that make them useful as drugs (hypotensive, spasmolytic, anti-inflammatory, centrally suppressive, antimicrobial effect). Fabrics formula I are accessible from 2- (2-acetyl-4-chlorophenylthio) benzoic acid, which is is reacted with 1-methylpiperazine either with Ν, Ν -carbonyldiimldazole or mixed anhydride with monoethyl

Description

The present invention relates to the 4-chlorodiphenyl sulfide derivatives of the general formula I, i '

in which X stands for CO or CHOH and Y stands for CO or CHg, and their salts with pharmacodynamically harmless inorganic or organic acids »

The compounds of Formula I of the present invention exhibit a number of remarkable pharmacodynamic effects which are a prerequisite for their practical use in therapy. Thus, in particular, they have a hypotensive, spasmolytic, anti-inflammatory, centrally depressant and antimicrobial in vitro tests. Thus, they can be used as a means of adjusting elevated blood pressure, against spastic smooth muscle conditions, especially the gastrointestinal tract, sedatives and optionally as chemotherapeutics. The properties of individual substances according to the invention are described in more detail below »

1- [2- (2-A-1-4-chlorophenylthio) benzoyl] -4-methylpiperazine (I, X-Y-CO) was tested as the hydrochloride. Its acute toxicity in mice was determined by intravenous administration, LD ₅₀ »40 mg / kg. At a dose of 8 mg / kg iv, it causes short and deep reductions in blood pressure in normotensive rats. At a concentration of 10 µg / ml, it inhibits the contraction of the isolated rat by 50%

- 2 238 148 duo induced by the standard concentration of barium chloride.

At an oral dose of 40 mg / kg, it exhibits a significant anti-inflammatory effect in the rat kaolin arthritis test of approximately 3 h duration. In this test, it is approximately twice as effective as the known phenylbutazone.

1- (2- / 4-Chloro-2- (1-hydroxyethyl) phenylthio / benzoyl) -4'-methylpiperazine (I, X = CHOH, Y'CO) was tested as hydrogen maleate. Its acute toxicity, in mice, LD _{50 -} 90 mg / kg -1 iv

At a dose of 19 mg / kg i.v. lowers the blood pressure of normotensive rats significantly.

1- (2- [4-Chloro-2- (1-hydroxyethyl) phenylthio / benzyl) -4-methylpiperazine (I, X * CHOH, Y = CHg) was tested as the dihydrochloride. Acute toxicity in mice, LD ^ q = 311 mg / kg p.o.

34.8 mg / kg i.v. At an oral dose of 100 mg / kg or an intravenous dose of 10 mg / kg, the mild dis-coordination effect in the mice in the rotating rod test was shown. This effect is probably an expression of a centrally damping effect. Following an oral dose of 100 mg / kg, the spontaneous motility of the mice was reduced to 73% of the control value using the Dews beam method. This is also an expression of the centrally dampening effect. At a concentration of 100 µg / ml, the compound inhibits in vitro tests against these microorganisms Streptococcus haeanol ticus, Staphylococcus pyogenes aureus and Bscherichia coli. íbcetM.tu ”

The compounds of formula I according to the invention can be prepared by processes starting from the novel 2- (2-acetyl-4-chlorophenylthio) benzoic acid, the preparation of which is described in the example. By reacting this acid with 1-methylpiperazine, I, X and Y2CO can be prepared. Two methods can be used for this reaction. In the first case, N, N ' -carbonyldiimidazole is used as an auxiliary agent for coupling the acid with the amine. The reaction is carried out in dichloromethane at room temperature and the desired product is obtained in 75% yield. Neutralization with hydrogen chloride in ethanol / ether gives crystalline hydrochloride. In a second method, the starting acid is first converted by reaction with ethyl chloroformate to a mixed anhydride with monoethyl carbonate, which then acylates 1-methylpiperazine. The mixed anhydride is generated in dimethylformamide in the presence of 1-ethylpiperidine at 0-10 ° C,

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- 3 whereupon the acylation of 1-methylpiperazine takes place at room temperature · Part of the starting acid is regenerated and the desired product is obtained in a yield of 55% on the conversion »

Another compound of the invention, i.e., I *, X * CHOH and Y * CO, is obtained from a substance previously reduced by sodium borohydride in a boiling mixture of benzene and ethanol in the presence of water. The resulting oily base is converted to crystalline hydrogen maleate by neutralization with maleic acid in a mixture of ethanol and ether.

Finally, another compound of the invention, i.e. I, X? CHOH, Y? CH?, Is prepared from I, X? Y = CO by reduction with lithium aluminum hydride in boiling tetrahydrofuran. Both carbonyl groups are reduced and the oily base obtained is converted into crystalline dihydrochloride by neutralization with hydrogen chloride in a mixture of ethanol and ether.

All of the novel compounds mentioned in this invention have been identified in terms of identity both analytically and by spectral methods. The following examples serve to illustrate the possibilities of the invention, but are not intended to fully describe these possibilities »

Example 1

1- [2- (2-Acetyl-4-chlorophenylthio) benzoyl] -4-> methylpiperazine

To a stirred solution of 2.5 g of N, N'-carbonyldiimidazole in 20 ml of dichloromethane under a nitrogen atmosphere was added 4.6 g of 2- (2-acetyl-4-chlorophenylthio) benzoic acid, followed by a solution of 1.5 g. 1-methylpiperazine in 10 ml of dichloromethane, stirred for 3 h at room temperature and allowed to stand for 48 h. Then diluted with dichloromethane, washed with water, 8% sodium bicarbonate solution, 15% sodium carbonate solution and water, dried over sulfate Sodium and evaporate to give 4.4 g (75%) of a viscous oily base. By neutralization with hydrogen chloride in a mixture of ethanol and ether, 5.0 g of hydrochloride is obtained which is pure after crystallization from ethanol and melts at 217-220 ° C. This pure salt is basified with aqueous ammonia and extracted with ether to give a pure oily base which is used further »

- 4 ~

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The starting 2- (2-acetyl-4-chlorophenylthio) benzoic acid is a novel compound which can be prepared as follows:

A mixture of 17.3 g of thiosalicylic acid (Allen C.P.H.,

MacKay D.D., Org. Syn., Coll. Vol. 2, 580 (1943). 18.9 g of 2,5-dd-chloroacetophenone (Rajsner M. et al., Collect.Czech.Chem.Commun. 43, 1276, 1978). 20 ml of dimethylformamide, 41.5 g of potassium carbonate and 0.3 g of copper were stirred and heated at 120 ° C for 2 h and then at 150 ° C under reflux for 2 h. After cooling, it is diluted with water and washed with benzene, the aqueous solution is filtered and the filtrate is acidified with hydrochloric acid. After standing overnight, the precipitated product is filtered off with suction, washed with water and crystallized from 400 ml of methanol. 22.4 g (73%) of 2- (2-acetyl-4-chlorophenylthio) benzoic acid melting at 194-200 ° C are obtained. The analytical product was obtained by recrystallization from methanol, m.p. 200 DEG-202 DEG. Example 2

1- [2- (2-Acetyl-4-chlorophenylthio) benzoyl] -4-methylpiperazine

A mixture of 1.53 g of 2- (2-acetyl-4-chlorophenylthio) benzoic acid (see Example 1), 4 ml of dimethylformamide and 0.6 g of 1-ethylpiperidine was stirred and 0.54 g was added at 0-10 ° C. ethyl chloroformate. The mixture was stirred for 5 h, then 0.6 g of 1-methylpiperidine was added. Stir 20 min at room temperature, leave overnight, evaporate in vacuo and partition the residue between benzene and water. The benzene layer was washed with sodium bicarbonate solution (0.6 g of starting acid was regenerated by acidifying the wash solution) and water, and the product was extracted into dilute hydrochloric acid. The acidic aqueous layer was basified with aqueous ammonia and the base was isolated by extraction with ether. Treatment of the extract yielded 0.65 g (55% per conversion) of a homogeneous oily desired base which was identical to the product obtained according to Example 1. By neutralization with maleic acid in ethanol, a hydrogen maleate was prepared which crystallized from ethanol-ether and melted at 160 to 160 ° C. Mp 162 ° C.

Example 3

1- [2- (4-Chloro-2- (1-hydroxyethyl) phenylthio) benzoyl] -4-methylpiperazine

To a solution of 7.1 g of 1- (2- (2-acetyl-4-chlorophenylthio) benzoyl)

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4-methylpiperazine (Examples 1 and 2) in 20 ml of benzene and 75 ml of ethanol is slowly added with stirring a solution of 0.6 g of sodium borohydride in 5 ml of water containing 0.1 ml of 20% sodium hydroxide solution. The benzene layer was washed with 5% sodium hydroxide solution and water, dried over sodium sulfate and evaporated under reduced pressure.

6.9 g of a crude oily base which is neutralized with 2.04 g of maleic acid in a mixture of ethanol and ether * After a short period of standing, 6.8 g (74%) of crystalline hydrogen maleate melting at 154-160 ° C are aspirated. the salt is obtained by crystallization from a mixture of ethanol and ether, m.p. 158-162 ° C;

Example 4

1- / 2- (4-Chloro-2- (1-hydroxyethyl) phenylthio) benzyl] -4-methylpiperazine

A solution of 8.8 g of 1- [2- (2-acetyl-4-chlorophenylthio) benzoyl] -4-methylpiperazine (Examples 1 and 2) in 130 ml of tetrahydrofuran was added dropwise over 8 minutes to a stirred suspension of 2.2 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. * After cooling, quenched by the dropwise addition of a solution of 8 ml of water in 10 ml of tetrahydrofuran and finally by adding 2.2 ml of 10% sodium hydroxide. The mixture is stirred for 45 min, the precipitated solid is filtered off with suction and washed with a little tetrahydrofuran. The filtrate was dried over sodium sulfate and evaporated to give 8.2 g of a homogeneous oily base. Neutralization with hydrogen chloride in ethanol / ether gave 8.5 g (84%) of the crystalline dihydrochloride, which was purified by re-crystallization from ethanol. up to 202 ° C «

Claims (1)

Methylpiperazine derivatives derived from the 4-chlorodiphenyl sulfide of formula (I), X-OL CL (X) \ y ³ in which X denotes a CO or CHOH group and Ϊ denotes a CO or CH ₂ group and their salts with pharmacodynamically sound inorganic or organic acids.