CS230245B1

CS230245B1 - 7-Chloro-4-piperazino-4,5-dihydrothieno (2,3-b) -1-benzothiepine derivative

Info

Publication number: CS230245B1
Application number: CS243383A
Authority: CS
Inventors: Miroslav Protiva; Zdenek Polivka; Antonin Dlabac
Original assignee: Miroslav Protiva; Zdenek Polivka; Antonin Dlabac
Priority date: 1983-04-06
Filing date: 1983-04-06
Publication date: 1984-08-13

Abstract

Vynález se týká derivátu 7-chlor-4-pipera- zino-4,5-dihydrothieno (2,3-b)-1-benzothiepinu vzorce I a jeho solí s farmaceuticky nezávadnými anorganickými nebo organickými kyselinami. Látka vzorce I podle vynálezu a její soli jsou velmi účinnými trankvilizéry s minimální kataleptickou komponentou účinnosti. Jsou tedy použitelné v terapii neklidných neurotiků a psychotiků a jejich podávání nevyvolává extrapyramidové vedlejší příznaky, které jsou obvyklé při používání kata- lepticky účinných neuroleptik. V testech na zvířatech byla látka I používána ve formě svého bis(ihydrogenmalei- nátu) a byla podávána orálně. Uváděné dávky jsou přepočty na bázi. V testu na myšíchThe invention relates to the 7-chloro-4-piperazine-4,5-dihydrothieno (2,3-b)-1-benzothiepine derivative of formula I and its salts with pharmaceutically acceptable inorganic or organic acids. The substance of formula I according to the invention and its salts are very effective tranquilizers with a minimal cataleptic component of effectiveness. They are therefore useful in the therapy of restless neurotics and psychotics, and their administration does not cause extrapyramidal side symptoms, which are common when using cataleptically effective neuroleptics. In tests on animals, substance I was used in the form of its bis(hydrogen maleate) and was administered orally. The indicated doses are conversions on the basis. In a test on mice

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CZECHOSLOVAK SOCIALISTIC

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(22) Registered 06 04 83 (21) (PV 2433-83) 230245 (11) (Bl) (51) Int. Cl.3C 07 D 495/04 (40) Published 25 11 83

THE OFFICE OFFICE AND DISCOVERY (45) Published 15 08 86 (75) ', _

The invention of PROTIVA MIROSLAV dr. DrSc., POLÍVKA ZDENEK Ing. CSc., DLABACANTONÍN MUDr. CSc., PRAGUE (54) 7-Chloro-4-piperazino-4,5-dihydrothieno (2,3-b) -1-benzothiepine 1 derivative

The present invention relates to a 7-chloro-4-piperazino-4,5-dihydrothieno (2,3-b) -1-benzothiazine derivative of the formula I

and its salts with pharmaceutically acceptable organic or organic acids. The compounds of the formula I according to the invention and their salts are very effective tranquilizers with a minimal cataleptic component of activity. They are therefore useful in the treatment of restless neurotics and psychotics, and their administration does not induce extrapyramidal side effects which are common in the use of catepteptically active neuroleptics. In animal tests, substance I was used in the form of its bisphosphoric maleate and the oral was administered orally. The quoted doses are based on the base. In the test in mice 2 it is poorly toxic; its mean lethal dose of LDfO is approximately 500 mg / kg. It has an intense disordering effect in mice in a rotating rod test; the mean effective dose at the time of effect of LDfeo is 3.7 mg / kg. It is highly effective at centrally depressing as it inhibits spontaneous locomotor-activity of mice (Dew-se beam method) at 3.6% of control value at 10 mg / kg. At a dose of 50 mg / kg, it induces catalepsy in 20% of rats in an experiment, which can be described as very mild. Anti-apomorphine in rats is ineffective at the same dose. In the literature, the synthesis of these 4-piperazino-4,5-dihydrothieno (2,3-b) -1-benzothiepine derivatives: 4- (4-methylpiperazino) -4,5-dihydrothiene (2, 3-b) -1-benzothiepine (Substance A) (Rajshner, M. et al., Farmaco, Ed. Sc. 23, 140, 1968), 2-chloro-4- (4-methylpiperazino) -4,5-dihydro- thieno (2,3-b) 1-benzothiepline (substance B) (Rajshner M. et al., Collect. Czech. Chem. Comun. 35, 378, 1970), 8-fluoro-4- (4 -methylpiperazino) -4,5-dihydrothieno (2,3-b) -1-benzothiepine (Substance C) (Rajshner M. et al., Col. Czech. Chem. Commun. 44, 2 997 , 1979) and 2-chloro-8-fluoro-10- (4-methylpiperazino) -4,5-dihydrothieno (2,3-b) -1-benzothiepine (Substance D) (Polivka et al., Collect. Chem., 46, 2222, 1981). All of these four 230245 230245 substances are primarily clearly more toxic than substance I of the invention (LD 50 values range from 80 to 170mg / kg). Furthermore, they are too effective in the test rod test, so their discoordination effect is too high (for substance A for intra-intravenous administration, ED 50 = 0.064 mg / kg, and B, C and D is ED 50 for oral administration of 0.36 to 0.25 to 0.55 mg / kg). All previously described compounds have a higher cataleptic effect than the compound I according to the invention (substance C is even highly cataleptically effective, ED 50 = 1.4 mg / kg). According to the present invention, the previously known compounds of this series are at least toxic, are highly centrally buffered at the same time, are at least cataleptically effective, so that by its overall profile the tranquilizer of this series is the most known.

The compound of formula I is accessible by reacting 4,7-di-chloro-4,5-dihydrothieno (2,3-b) -1-benzothiazine of formula II

with 1- (2-hydroxyethylpiperazine preferably in boiling chloroform. The base thus obtained crystallizes from benzene as a benzene solvate and by neutralization of acids provides salts, of which bis (hydrogen maleate) has been found to be suitable for both pharmacological testing and forempro drug preparation Oral use The substance of formula II is a substance which has not been described in the literature so far, and a method for its preparation from the compounds known in the art, the identity of all novel substances, i.e. both the final product and the novel intermediates, has been provided. The following example illustrates, but is not limited to, the following examples.

A mixture of 3.2 g of 4,7-dichloro-4,5-dihydrothieno- (2,3-b) -1-benzothiepine, 2.9 g of 1- (2-hydroxy-ethyl) -piperazine and 3.0 ml of chloroform is stirred and boiling under reflux for 5 hours under nitrogen. After standing overnight, 100 ml of water was added and the mixture was extracted with dichloromethane. The extract was washed with water and shaken with 50 ml of 5% hydrochloric acid. The precipitated hydrochloride was added to the solution by adding 100 ml of water, the aqueous solution was separated, basified with aqueous ammonia and the base was isolated by extraction with dichloromethane. Drying and evaporation of the extract yielded 3.6 g (85%) of crude 7-chloro-1,4- [4- (2-hydroxyethyl] piperazino] -4,5-dihydrothieno [2,3-b] - 1-benzothiepine (I). Crystallization from ethanol affords an (116-126 ° C) ethanol solvate. Therefore, it is recrystallized from a benzene / hexane mixture to give a base melting at 130-136 ° C, which is a 6: 1 solvate with benzene. Neutralization of maleic acid in a mixture of ethanol and ether gives the bis (hydrogen maleate) which crystallizes from a mixture of ethanol and ether and melts at 129-130 ° C.

The desired 4,7-dichloro-4,5-dihydro-thieno (2,3-b) -1-benzothiepine (II) starting material can be prepared from the known raw materials, i.e. 2, by the following procedure. 5-dichloroacetophenone (Rajshner M. et al., Collect. Czech. Chem. Commun. 43, 1176.1978) and 2-thiofenthiol (Houff. WH, Schuetz RD, J. Amer. Chem. Soc. 75, 6,316 , 1953): 24 g of potassium carbonate are slowly added to a stirred mixture of 18.3 g of 2,5-dichloroaceto-phenone, 12.5 g of 2-thiofenthiol and 0.4 g of copper, and the mixture is then heated to 130-140 ° C for 1 hour without stirring. C (bath temperature) in the nitrogen atmosphere. After cooling, the mixture is diluted with 300 ml of benzene, filtered through a 1 cm layer of silica gel, the filtrate is evaporated under reduced pressure and the residue is chromatographed over a column of 600 g of neutral alumina (activity II). 3.2 g of starting 2,5-dichloroacetophenone are eluted with a mixture of 80% benzene and 20 ° / chloroform and then 8.7 g (41%) are eluted with a mixture of equal parts (ie 1: 1) of the solvents mentioned of crude 5-chloro-2- (2-thienylthioacetophenone, mp 70-74 ° C. Crystallization from benzene / hexane gave a pure material melting at 74-76 ° C).

A mixture of 26.1 g of the previous ketone, 5.0 g of sulfur flower and 18.6 g of morpholine was stirred and heated under a reflux condenser for 2 hours at 140 ° C (bath temperature). After cooling to 60 ° C, the chloroform was diluted -mem and filter with carborafine. The filtrate was washed with water, 5% hydrochloric acid and again with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was chromatographed on a 300 g silica gel (Silpearl) column. Elution with a mixture of 60% benzene and 40% petroleum ether removes the starting ketone and, simultaneously, the 5-chloro-2- (2-thienylthio) phenylglyoxylic acid thio-morpholide (mp 120-123 ° C). The following elution with benzene alone gives 27.7 g of [5-chloro-2- (2-thienylthio) phenyl] acetic acid, an oily thiomorpholide, which is treated with a solution of 20.8 g of potassium hydroxide in 42 ml of ethanol and boiled with stirring for 2 hours. 5 h under reflux. It was then diluted with 230 ml of water and acidified with 50 ml of hydrochloric acid upon stirring. The precipitated [5-chloro-2- (2-thienylthio) phenyl] acetic acid was extracted with benzene, the extract was washed with water, dried over sodium sulfate and magnesium sulfate, and evaporated under reduced pressure. The residue is crystallized first from a mixture of dichloromethane and hexane and then from a mixture of ethanol and hexane; the product obtained melts at 133 ° C

Claims

The invention relates to a 7-chloro-4-piperazino-4,5-dihydrothieno (2,3-b) -1-benzothiepine derivative of the formula I and its salts with pharmaceutically acceptable inorganic or organic acids.

The compound of the formula I according to the invention and its salts are very effective tranquillizers with a minimal cataleptic component of activity. Thus, they are useful in the treatment of restless neurotics and psychotics and their administration does not induce the extrapyramidal side-effects that are common in the use of cataleptically active neuroleptics.

In animal tests, Compound I was used as its bis (ihydrogen maleate) and was administered orally. The doses are calculated on a basis of basis. It is poorly toxic in the mouse test; its mean lethal dose of LDfeo is approximately 500 img / kg. It has an intense disfcoordina effect in mice in a rotating rod test; the median effective dose at the time of maximal LDfeo effect is 3.7 mg / kg. It is highly effective centrally depressant since at a dose of 10 mg / kg, spontaneous locomotor activity inhibits mouse activity (Dews ray method) to 3.6% of control value. At a dose of 50 mg / kg, it induces catalepsy in 20% of the rats in the experiment, which is a very mild effect. At the same dose, it is ineffective antiapomorphine in rats.

So far, the synthesis and pharmacology of these 4-piperazino-4,5-dlhydrothieno (2,3-b) -1-benzothiepine derivatives: 4- (4-methylpiperazino) -4,5-dihydrothieno (2, 4, 4-methylpiperazino) -4 has been described in the literature. 3-b) 1-benzothiepine (Compound a) ⁽¹ Rajsner al., Farmaco, Ed. Sc., 23, 140, 1988);

2-chloro-4- (4-methylpiperazino) -4,5-dihydrothieno (2,3-b) 1-benzothiepline (Compound B) (Rajsner M. et al., Collect. Czech. Chem. Commun. 35, 378) , 1970), 8-fluoro-4- (4-methylpiperazino) -4,5-dihydrothieno (2,3-bJ-1-benzothiepine (Compound C) (Rajsner M. et al., Collect. Czech. Chem. Commun 44, 2 997, 1979) and 2-chloro-8-fluoro-10- (4-methylpiperazino) -4,5-dihydrothieno (2,3-b) -1-benzothiepine (Compound D) (Polek Z. a. Chem. Commun., 46, 2222 (1981), all of which are first and foremost distinct to substantially more toxic than substance I according to the invention (LD 50 values ranging from 80 to 170 mg / kg). Furthermore, they are too effective in the rotating rod test, so that their discoordination effect is too high (for Compound A when administered intravenously ED 50 = 0.064 mg / kg and for Compounds B, C and D the ED 50 for oral administration is 0.36 to 0.54 mg / Finally, all the substances described above have a higher cataleptic action than the substance I according to the invention climbing (substance C is even highly effective catalepsy, ED = 1.4 mg / kg p. D.J. It can therefore be concluded that the substance I according to the invention is the least toxic of the known substances of the series so far, is highly centrally depressant and at the same time the least cataleptically active, so that its overall profile is the most specific known tranquilizer of the series.

The compound of formula I is accessible by reacting 4,7-dichloro-4,5-dihydrothieno (2,3-b) -1-benzothiepine of formula II with 1- (2-hydroxyethyl) piperazine, preferably in boiling chloroform. benzene as a benzene solvate and acid neutralization yields salts of which bis (hydrogen maleate) has been shown to be suitable for pharmacological testing and for the preparation of dosage forms for oral use, and the compound of formula II is a novel substance not previously described in the literature. The identity of all novel compounds described in the invention, i.e. both the final product and the novel intermediates, was assured by analytical and conventional spectral methods The following example illustrates the invention, but does not limit it in any way.

A mixture of 3.2 g of 4,7-dichloro-4,5-dihydrothieno (2,3-b) -1-benzothiepine, 2.9 g of 1- (2-hydroxyethyl ethyl) -pyrazrazine and 3.0 ml of chloroform is stirred and boiled for 5 h. After standing overnight, 100 ml of water are added and the mixture is extracted with dichloromethane, the extract is washed with water and shaken with 50 ml of 5% hydrochloric acid, and the precipitated hydrochloride is brought into solution by addition of 100 ml of water. The organic layer was separated, basified with aqueous ammonia, and the base was isolated by extraction with dichloromethane to give 3.6 g (85%) of crude 7-chloro-4- [4- (2-hydroxyethyl) piperazino] -4,5-dihydrothieno. (2,3-bj-1-benzothiepiin (1). Crystallization from ethanol yields a non-faint (116-126 ° C) ethanol solvate. Therefore, it is better to crystallize from a mixture of benzene and hexane to give a base melting at 130-136. ° C, which is a 6: 1 benzene solvate by neutralization with malignic acid in ethanol and ether gives bis (hydrogen maleate), which crystallizes from a mixture of ethanol and ether and melts at 129-130 ° C.

The required starting 4,7-dichloro-4,5-dihydrothieno (2,3-b) -1-benzothiepine (II), which is a novel substance, can be prepared from known raw materials, i.e. 2,5-dichloroacetophenone, by the following procedure (Rajšner M. et al., Collect. Czech. Chem. Commun. 43, 1276, 1978) and 2-thiophenethiol (Houff. WH, Schuetz RD, J. Amer. Chem. Soc. 75, 6 316, 1953) :

To a stirred mixture of 18.3 g of 2,5-dichloroacetophenone, 12.5 g of 2-thiophenethiol and 0.4 g of copper was slowly added 24 g of potassium carbonate, and the mixture was then heated at 130-140 ° C for 1 h without stirring. bath) in a nitrogen atmosphere. After cooling, the mixture is diluted with 300 ml of benzene, filtered through a 1 cm pad of silica gel, the filtrate is evaporated under reduced pressure and the residue is chromatographed over a column of 600 g of neutral alumina (activity II). 3.2 g of the starting 2,5-dichloroacetophenone are eluted with a mixture of 80% benzene and 20% chloroform and then eluted with a mixture of equal parts (i.e. 1: 1) of the solvents mentioned.

8.7 g (41%) of crude 5-chloro-2- (2-thlenylthio) acetophenone, m.p. 70-74 [deg.] C. Crystallization from benzene-hexane gave a pure material melting at 74-76 [deg.] C.

A mixture of 26.1 g of the previous ketone, 5.0 g of sulfur blossom and 18.6 g of morpholine is stirred and refluxed at 140 ° C (bath temperature) under nitrogen for 2 h. After cooling to 60 ° C, it is diluted with chloroform and filtered with carboraffin. The filtrate was washed with water, 5% hydrochloric acid and again with water, dried over potassium carbonate and evaporated under reduced pressure. The residue is chromatographed on a column of 300 g of silica gel (Silpearl). Elution of a mixture of 60% benzene and 40% petroleum ether removes the starting ketone and the 5-chloro-2- (2-thienylthio) phenylglyoxylic acid thiomorpholide (m.p. 120-123 ° C) formed by reaction. Subsequent elution with benzene alone gave

27.7 g of oily [5-chloro-2- (2-thienylthio) phenyl] acetic acid thiomorpholide, to which is added a solution of 20.8 g of potassium hydroxide in 42 ml of ethanol, and the mixture is refluxed for 2.5 hours with stirring. . It is then diluted with 230 ml of water and, after cooling, the solution is acidified with stirring with 50 ml of hydrochloric acid. The precipitated [5-chloro-2- (2-thienylthio) phenyl] acetic acid is extracted with benzene, the extract is washed with water, dried with a mixture of sodium sulfate and magnesium sulfate and evaporated under reduced pressure. The residue was crystallized first from a mixture of dichloromethane and hexane and then from a mixture of ethanol and hexane; the product obtained melts at 133

238245-136 ° C. After treatment of the mother liquors by chromatography on 120 g of silica gel and crystallization of the benzene eluates from the ethanol / hexane mixture, a further crop of product is obtained so that the total yield is 9.4 g (34% based on the starting ketone). Crystallization from ethanol gave the pure product, m.p. 134-138 ° C.

A mixture of 6.4 g of the previous acid, 8.0 g of phosphorous pentoxide and 65 ml of toluene was stirred and refluxed for 3 hours. After cooling, it is washed with 5% potassium hydroxide solution and water. Acidification of the aqueous phase regenerates 2.0 g of the starting acid (m.p. 133-136 ° C). The toluene solution is dried over potassium carbonate and evaporated. The residue was crystallized from a mixture of 20 ml of benzene and 10 ml of hexane to give 2.8 g of 7-chlorothieno (2,3-b) -1-benzothiepin-4 (5H) -one, mp 154-157 degrees C. Evaporation of the mother liquor and chromatography The residue on a column of 30 g of silica gel, eluting with benzene, gave an additional 1.0 g of the title product so that the total yield was 3.8 g (92% by convection). Crystallization from a mixture of hexane and benzene gave a pure solid which melted at 156-157 ° C.

To a stirred solution of 4.1 g of the previous ketone in a mixture of 40 ml of ethanol and 20 ml of tetrahydrofuran was slowly added 0.45 g of sodium borohydride and the mixture was boiled for 10 min. under reflux. It is then evaporated in vacuo, the residue is treated with 60 ml of water and extracted with benzene. The extract was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue is crystallized from a mixture of ethanol and hexane and the mother liquor is worked up in the usual manner. 3.5 g (80%) of 7-chloro-4,5-dihydrothieno (2,3-b) -1-benzothiepin-4-ol are obtained, m.p. 133 DEG-134 DEG C. (ethanol).

To a solution of 3.5 g of the preceding alcohol in 35 ml of benzene was added 1.3 g of anhydrous calcium chloride powder and the suspension was saturated with a slow stream of hydrogen chloride at 10-15 ° C for 2 h. After standing overnight, the mixture was filtered, the filtrate was evaporated and the residue was crystallized from a mixture of benzene and hexane. 3.5 g (94%) of the desired 4,7-dichloro-4,5-dihydrothieno (2,3-b) -1-benzothiepine is obtained, which crystallizes from benzene and melts at 145-147.5 ° C.

SUBJECT

7-Chloro-4-piperazino-4,5-dihydrothieno (2,3-b) -1-benzothiene derivative of formula (I) Alzez and its salts with pharmaceutically acceptable inorganic or organic acids.