CS240041B1 - 4-/2-c-chlor-1,11-dihydrodibenzo/b,f/thiepin-11-yl/piperazinolalkyl-ethers and sulphides as well as their salts - Google Patents

Abstract

4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-11-yl) piperazinoalkyl ethers; sulfides of the general formula I, with / 1/9 K N-CH 2 R 2 -R-R wherein X represents an oxygen atom or an atom S, R is methyl, ethyl or phenyl; n is 2 or 3, and salts thereof and pharmaceutically acceptable salts thereof harmless inorganic or organic acids. Compounds of the Invention are very little toxic neuroleptics with mild discoordination and cataleptic activity, useful in schizophrenic therapy psychoses. They are accessible by substitution by reactions with 1,11-dichloro-10,11-dihydrodibenzo / b, f / thiepine monosubstituted piperazines of formula II, HN / 11 / in which X, R and n start the same as in formula I

Description

The invention relates to 4- (2-chloro-10,11-dihydrodibenzo [b, f] thiepin-11-yl) piperazinoalkyl ethers and sulfides of formula I,

 in which X represents an oxygen atom or a sulfur atom, R represents methyl, ethyl or phenyl and n is 2 or 3, as well as their salts with pharmaceutically acceptable inorganic or organic acids.

The literature reports a large number of differently Η-substituted 2-chloro-11-piperazino-10,11-dihydrodibenzo [b, f] thiepines, many of which are very potent neuroleptics useful in the therapy of schizophrenic psychoses. When the N-substituent is methyl, lower alkyl or lower hydroxyalkyl (Jílek JO et al., Collect. Czech.Chem. Commun. 36, 2226, 19711 Shindelář K, et al., Ibid. 41, 910, 1976; Jílek JO et al. al., ibid., 41, 443, 1976), although the compounds are very potent and useful neuroleptics, but their strong cataleptic efficacy results in relatively large extrapyramidal side reactions in patients which need to be abolished by concomitant administration of antiparkinsonian drugs. On the other hand, if the N-substituent is a more hydrophobic, bulky or basicity nitrogen atom-canceling group (aryl, pyridyl, aralkyl, acetyl, methanesulfonyl.1), the substances in question are poorly active or ineffective and hence, virtually unusable (Jílek JO et al. Chem.Coramun 32, 3, 186, 1967 Jílek JO et al., Ibid. 40 «

240 041

386, 1975; Bartl V., et al., Ibid. 45, 3 182, 1980; 46, 141, 1981).

It has now been found that the introduction of an oxygen or sulfur atom into an alkyl or aralkyl of 3-9 carbon atoms as an N-substituent results in a slight decrease in the lipophilicity of this residue, which results in retention of the neuroleptic nature of the compounds while reducing their toxicity and cataleptic activity. In this way, the compounds of formula I which are the subject of the present invention have been derived. Their pharmacological properties are a prerequisite for their usefulness in the therapy of schizophrenia with a reduced incidence of extrapyramidal side reactions, generally

The compounds of Formula I have been pharmacologically tested in mice and rats by oral administration in the form of said salts; however, the reported doses in mg / kg are converted to bases. The acute toxicity in mice was determined in terms of the mean lethal dose. Furthermore, their discoordination activity was determined by the rotating rod method in mice (the median effective doses induce ataxia in 50% of the animals). Cataleptic efficacy was determined in rats (mean effective doses of ΕΏΏ θ induce catalepsy in 50% of animals) and finally anti-apomorphine activity was also determined in rats, with the reported D ^ q being a dose reducing the incidence of apomorphine stereotypes to 50%. By comparison, the efficacy of chlorothepine, which is 2-chloro-1 (4-methylpiperazino) -10,11-dihydrodibenzo [b, f] thiepine, used in practice as an oral antipsychotic maleate formulation, is reported; compared to the substances according to the invention, it is a substance which is highly toxic, with a high discoordination, cataleptic and antiapomorphine activity (Metyšová J. et al., Acta Biol.Med.Ger. 39. 723,

1980). Acute toxicity, LD ^ q = 78 mg / kg; rotating rod, ΕΏ, = 2.2 mg / kg; catalepsy, ED? _Q = 4.3 mg / kg; anti-apomorphine activity, D ₅₀ = 1.8 mg / kg.

Now the acute toxicity and efficacy values in the above tests for the compounds of the invention:

2-chloro-11- [4- (2-methoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X = 0, R = CH3, n = 2), tested as maleate : Acute toxicity, BD ^ q = 207 mg / kg; rotating rod, ^ED 50 - ^{2 m} s / kg; catalepsy, ED? q = 8.5 mg / kg; antiapomorfino3 above effect, D ^ _o = 7.7 mg / kg. 240 041

2-Chloro-11- [4- (3-methoxypropyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X = O, R = CHp n = 3), tested as hydrogen maleate} values in the same ranking as above and mostly in mg / kg: 179, 4.2, 7.3, 7.5.

2-Chloro-11- [4- (2-ethoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X = O, R = CgH4, n = 2), tested as maleate: 355 , 7.8, 7.1, 7.3.

2-Chloro-11- [4- (2-phenoxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (1), X = 0, R = C, H, π = 2), tested as dihydrochloride ^500, 5050, 22.4, 30.6.

2-Chloro-11- [4- (2-methylthioethyl) piperazino] -10,11-dihydro-dibenzo [b, f] thiepine (I, X = S, R = CH3, n = 2), tested as dimethanesulfonate: 311, 6.4, 9.2, 4.0.

2-Chloro-11- [4- (2-phenylthioethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X. = S, R = C ^H H, n = 2), tested as dimethanesulfonate:?> 500,? -100, 34.3, c. 80.

The compounds of Formula I of the present invention are amenable to substitution reactions of the known 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine (Jílek JO et al., Collect.Czech.Chem ₀ Commun. 33, 1831, 1968). with piperazine derivatives of formula II in which X, R and n are the same as in formula I. Compounds of formula II have been described in general (Polívka Z. et al., Collect.Czech.Chem.Commun. 48, 2 395, 1983). These substitution reactions are preferably performed by heating said dichloro derivative with at least 100% excess piperazine derivatives of formula II in a small volume of chloroform to boiling. For more hydrophilic products of formula I (R = CH 2 or O ₂ Η 4), isolation is performed by extracting the basic products into a dilute aqueous solution of sulfuric acid or hydrochloric acid, from which they are then liberated by alkaline aqueous ammonia and converted to the corresponding salts by acid neutralization. The main purification operation is the crystallization of these salts. In the case of the more lipophilic products of formula I (R = C CH H), the hydrochlorides of these products remain

240 041 by shaking the chloroform solution of the reaction mixture with dilute hydrochloric acid - in the chloroform layer, while only the hydrochlorides of the starting piperazines of formula II are transferred to the aqueous layer. The hydrochlorides of the products of formula I are then obtained by crystallization from chloroform solutions. As pharmaceutically acceptable acids suitable for the preparation of salts of the compounds of formula I, maleic acid, methanesulfonic acid and γ-hydrochloric acid are preferred. All substances according to the invention are novel and their identity was ensured both by salt and base analyzes and by common spectra (UF, IR, HMR, MS). Further details of the preparation of the compounds of formula (I) are given in the following examples, which serve only to illustrate the possibilities of the invention, but in no way have any limiting function.

Example 1

2-Chloro-11- [4- (2-methoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine

A mixture of 5.6 g of 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine,

5.8 g of 1- (2-methoxyethyl) piperazine and 6 ml of chloroform were stirred and refluxed for 6 h. Diluted with 50 ml of chloroform, washed with water and the base was extracted by shaking in 100 ml 1N H ₂ S0 ^. The aqueous acidic solution was separated, filtered with carboraffin, and the base was liberated with aqueous ammonia. They are isolated by extraction with chloroform, dried over potassium carbonate and evaporated. The oily residue (5.6 g) was dissolved in 20 ml of ethanol and a solution of 3.35 g of maleic acid in 10 ml of ethanol was added at 50 ° C. After standing to the next day, 7.9 g (72%) of the maleate precipitated, which was purified by recrystallization from ethanol; mp 175-176.5 ° C.

Example 2

2-Chloro-11- [4- (3-methoxypropyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine

As in the previous example, a mixture of 5.6 g of 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine, 6.3 g of 1- (3-methoxypropyl) piperazine with 8 ml of chloroform was boiled for 9 h and similarly treated . 6.1 g (76%) of a crude oily base are obtained which, by neutralization with maleic acid in ethanol, yields 7.6 g of bis (hydrogen maleate) which melts in a pure state at 144-145 ° C (pthanol).

Example 3 ^{240 041}

2-Chloro-11- [4- (2-ethoxyethyl) piperazino] -10,11-dihydrodibenzo/b, f/thiepine

As in the previous examples, 5.6 g of 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine were reacted with 6.3 g of 1- (2-ethoxyethyl) piperazine in 8 ml of chloroform (var. 4 h). work-up gave 6.4 g (80%) of a crude oily base which was neutralized with maleic acid in ethanol to give 7.5 g of maleate. After crystallization from ethanol, the salt is pure and melts at 148-150 ° C.

Example 4

2-Chloro-11- [4- (2-phenoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine

A mixture of 5.6 g of 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine, 8.25 g of 1- (2-phenoxyethyl) piperazine and 10 ml of chloroform is stirred and refluxed for 5.5 hours. . It is then diluted with 60 ml of chloroform, washed with water and shaken twice with 50 ml of 1M HCl. The chloroform solution was separated and evaporated under reduced pressure to give 10.2 g of the crude dihydrochloride monohydrate of the title compound. Crystallization from aqueous ethanol gave a pure material, m.p. 168-168.5 ° C.

Example 5

2-Chloro-11- [4- (2-methylthioethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine

A mixture of 5.0 g of 1- (2-methylthioethyl) piperazine, 5 ml of chloroform and 4.4 g of 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine was stirred and refluxed for 6.5 h. . It is diluted with 60 ml of chloroform, washed with water and the product is extracted into 100 ml of 1MHgSO4. The aqueous layer with a little oily sulfate is basified with aqueous ammonia, the base is extracted with benzene and the extract is evaporated as an oil; 4.2 g (67%) · A portion (2.9 g) was dissolved in 5 ml 2-propanol and the solution was neutralized with a solution of 1.45 g methanesulfonic acid in 4 ml ether. On standing, 3.4 g of crystalline dimethanesulfonate monohydrate, which melts at 155 DEG-158 DEG C. (2-propanol-ether), is pure. Decomposition of pure dimethanesulfonate with aqueous ammonia and extraction with ether yields

240,041 crystalline base melting at 90-95 ° C (benzene-petroleum ether). · Example 6

2-Chloro-11- [4- (2-phenylthioethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine

In analogy to Example 4, 5.6 g of 2,11-dichloro-10,11-dihydrodibenzo [b, f] thiepine is reacted with 5.6 g of 1- (2-phenylthioethyl) piperazine in 16 ml of chloroform in the presence of 1, 2-chloro-2-phenylthioethyl) piperazine. 5 g of triethylamine (10 h boiling). Dilute with 60 ml of chloroform and wash. shake with 50 ml of 1M HCl. The chloroform solution was separated, evaporated under reduced pressure to half volume and acidified by addition of 5 ml of a solution of hydrogen chloride in ether. After addition of 40 ml of ether it is left to crystallize. Yield 6.1 g (58%) of the product, which is pure after recrystallization from ethanol / ether and melts at 191-191.5 ° C. Decomposition of this salt with aqueous ammonia and extraction with ether yields a homogeneous oily base whose neutralization with methanesulfonic acid can produce crystalline dimethane sulfonate, which crystallizes from a mixture of 2-propanol (containing a small amount of water) and ether as a hemihydrate, m.p. 177.5 ° C.

Claims (1)

OBJECT OF THE INVENTION ^{240 041} 4- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-11-yl) piperazinoalkyl ethers and sulfides of formula I, in which X represents an oxygen atom or a sulfur atom, R represents methyl, ethyl or phenyl and n is 2 or 3, as well as their salts with pharmaceutically acceptable inorganic or organic acids