CS240384B1 - 4-/2-chlorine-10,10-dihydrodibenzo/b,f-thiepin-10-yl/ piperazinealkyl-ethers and-sulphides as well as their salts - Google Patents

Description

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

Sy

..

Whose

wherein 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 or organic acids. The compounds of the invention are non-cataleptic neuroleptics and have the potential for practical use in the treatment of schizophrenic psychoses without the risk of extrapyramidal side reactions.

A non-cataleptic neuroleptic is described in the literature as a structurally close dojloxythepin, i.e. 2-chloro-10- [4- (2-hydroxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (succinate) (Jílek J. 0. et al., Collect., Czech, Commun., 49, 28887 (1975);

et al., Cesk. Fysiol. 28, 250 (1979), which has the disadvantage of comparatively high acute toxicity (LDOO = 84 mg / kg when administered orally to mice), which then adversely affects chronic administration. Compounds of the present invention of formula I have somewhat reduced hydroxylity compared to pristloxythepine by covering free hydroxyl by etherification by replacing the hydroxyl group with an alkyl- or arylsulfide function, are substantially less toxic, up to high doses of 50-100 mg / kg orally and antipomorphine efficacy, but at the same time significantly increase the turnover and metabolism of dopamine in rat brain, manifested by an increase in the level of homovanilic acid (the main dopamine metabolite) in the rat brain striatum corpus. This property is a clear indicator of the fact that the neuropeltic character of the substances has been retained, although such typical properties as cataleptic and antipomorphine have been suppressed. The compounds of the invention also have discoordination activity in a rotating rod test in mice and centrally depressant activity in an assay for the spontaneous locomotor activity assayed by the Dews beam method. The properties of the individual substances according to the invention now selected:>

2-chloro-10- [4- (2-methoxyethyl) piperazino] -10,11-dihydro-dibenzo [b, f] thiepine (I, X = O, R = CH 3, n = · 2), tested as dihydrogen maleate. All reported values are mg / kg oral doses Acute toxicity, LD 50 = 148. Discoordination efficacy in the rotating rod test in mice, ED 50 = 3.9 Inhibition of spontaneous locomotor activity in mice, dose reducing motor to 50% of control value D 50 - = 3.4 At doses of 100 mg / kg the substance is devoid of cataleptic and antiapomorphine activity in rats.

2-chloro-10- [4- (3-methoxypropyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X = O, R = CH 3, n = 3), tested as the maleate. At doses of 50 mg / kg, the substance is devoid of cataleptic and antiapomorphine activity in rats. In contrast, at a dose of 80 mg / / kg, it increases the level of homovanilic acid in the rat striatum to 148% of the control value.

2-chloro-10- [4- (2-ethoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X equals O, R = C2 H5, n = 2) was tested as the maleate. At doses of 50 mg / kg, the compound is devoid of cataleptic and antipomorphine activity in rats.

2-chloro-10- [4- (2-phenoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (X = 0, R = CsHs, n = 2) was tested as a maleate (all Jsbu values are recalculated to base). Acute toxicity in mice, LD 50 = 780. Discoordinating effect on rotating rod in mice, ED 50 = 33. Inhibition of locomotor activity in mice, D 50 = 27.3. At doses of 100 mg / kg, the compound is devoid of both cataleptic and antiapomorphine activity in rats.

2-Chloro-10- [4- (2-methylthioethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X-S, R = CH 3, n = 2) was tested as the maleate. At doses of 50 mg / kg the substance is devoid of both cataleptic and antipomorphine activity in rats. However, at a dose of 80 mg / kg, it intensively increases the level of homovanilic acid in the rat striatum: to 219% of the control value.

2-chloro-10- [4- (2-phenylthioethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine (I, X equals S, R = CoH 5, n = 2) was tested as the dihydrochloride. Acute toxicity in mice, LD 50 = 2,429; Discoordination effect in mice, ED 50 = 53.3. Inhibition of locomotor activity in mice, D 50 = 161. At doses of 100 mg / kg, the substance is devoid of both cataleptic and antipomorphine activity in rats.

The compounds of the formula I according to the invention are accessible by substitution reactions of the known 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiopine (Pelz K. et al., Collect. Czech. Commun. 33, 1852, 1968) with piperazine derivatives of the general formula II, (II) in which X, R and n are the same as in the formula I. Compounds of the 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 the more hydrophilic products of formula I (R = methyl or ethyl), isolation is carried out by extracting the basic products into a dilute aqueous sulfuric acid solution, from which they are then liberated by alkaline aqueous ammonia and converted into the appropriate salts by neutralization with suitable acids; maleic acid is preferred because the maleate crystallizes very well. The main purification operation is the crystallization of these salts. In the case of the more lipophilic products of formula I (R = C 6 H 5), the hydrochloride of these products - after shaking the chloroform solution of the reaction mixture with dilute hydrochloric acid - remains 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, or they can be converted to other salts via bases. Maleic acid and hydrochloric acid are preferred as pharmaceutically acceptable acids suitable for the preparation of salts of the compounds of formula (I). All substances according to the invention are novel and their identity was ensured both by salt and base analyzes and by common spectra (UV, IR, NMR, 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-10- [4- (2-methoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f] thiepine

A mixture of 5.6 g of 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiopine, 5.8 g of 1- (2-methoxyethyl) piperazine and 6 ml of chloroform is stirred and refluxed for 5.5 hours. Dilute the mixture with 50 ml of chloroform, wash with water, and then extract the bases by shaking with 100 ml of 1 H H2SO1. The separated acidic aqueous solution is filtered with carboraffin, the base is liberated with aqueous ammonia and isolated by extraction with chloroform. the extract was evaporated under reduced pressure to give 6.7 g of a crude oily base, the whole of which was dissolved in 25 ml of ethanol and neutralized with 4.0 g of maleic acid in 10 ml of ethanol. hydrogen maleate), which is obtained in a yield of 8.5 g (77%) and which melts at 147-149 ° C after recrystallization from ethanol.

Example 2

2-chloro-10- [4- (3-methoxypropyl) piperazino] -1,10,11-dihydrodibenzo [b, f] thiepine

A mixture of 5.6 g of 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiepine, 6.3 g of 1- (3-methoxypropyl) piperazine and 6 ml of chloroform is stirred and refluxed for 7.5 hours. . Work up as in Example 1 gave 7.0 g (88%) of a crude oily base which, by neutralization with 4.1 g of maleic acid in 25 ml of ethanol, yielded 8.4 g of the maleate, which melted at 155-157 in the pure state. ^C (propanol).

Example 3

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

A mixture of 5.6 g of 2,10-dichloro-10,11-dihydrodibenzo [b, f] thiepine, 6.3 g of 1- (2-ethoxyethyl) piperazine and 6 ml of chloroform is stirred and refluxed for 6 hours. After cooling, it is diluted with 50 ml of chloroform and worked up as in the previous examples. 6.0 g (75%) of a crude oil base are obtained. This was neutralized with 1.74 g of maleic acid in 20 ml of ethanol to give 5.4 g of crystalline maleate which melted at 151-153 ° C (ethanol) in pure form.

Example 1 a d 4

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

A mixture of 4.8 g of 2,10-dichloro-10,11-dihydrodibenzo (b, phthiepine, 4.2 g of 1- (2-methylthioethyl) piperazine and 6 ml of chloroform is refluxed for 6.5 hours and It was then worked up in the same manner as above to give 4.05 g (66%) of a crude oil base which crystallized after melting on an alumina column (activity II) and melted at 67-70 ° C (benzene-petroleum ether). maleic acid in ethanol gives a crystalline maleate which melts at 168-170 ° C (2-propanol) in pure form.

Example 1 a d 5

2-chloro-10- [4- (2-phenoxyethyl) piperazino] -10,11-dihydrodibenzo [b, f thiepin

A mixture of 5.60 g of 2,10-dichloro-10,11-dihydrodibenzo [b, phthiepine, 8.25 g of 1- (2-phenoxyethyl) -piperazine and 6 ml of chloroform was stirred and refluxed for 4 hours, then diluted with 60 ml. ml of chloroform, washed with water and extracted with 100 ml of 2.5 H HG1, the chloroform solution was separated, partially evaporated under reduced pressure and left to stand overnight, and 9.1 g of the crude dihydrochloride were filtered off with suction and decomposed with aqueous ammonia. and the base was isolated by extraction with chloroform: 7.1 g (78% ^w / ^w ) of oil, and neutralization with a slight excess of maleic acid in 2-propanol gave a crystalline maleate which melted at 142-144 ° C (ethanol) in pure state.

Example 6

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

A mixture of 5.6 g of 2,10-dichloro-10,11-dihydrodibenzo [b, phthiepine, 5.6 g of 1- (2-phenylthioethylplperazine) and 6 ml of chloroform was heated and stirred at reflux for 5.5 hours. Similarly to the previous case and crystallization of the partially evaporated chloroform phase, 4.1 g (38% of pure dihydrochloride) melting at 219 DEG-221 DEG C. (ethanol-ether) is obtained.

Claims (1)

SUBJECT 4- (2-Chloro-10,11-dihydrodibenzo [b, f] thiepin-10-yl) piperazinoalkyl ethers and sulfides of formula (I) of the invention wherein X is O or S, R is methyl, ethyl or phenyl and n are 2 or 3 as well as their salts with pharmaceutically acceptable inorganic or organic acids.