CS227530B1 - Esters of 8-substituted 10-(4-(hydroxyalkyl)-piperazino)10,11-dihydrodibenzo (b,f)thiepines and salts thereof - Google Patents

Description

The present invention relates to esters of 8-substituted 10- [4- (hydroxyalkyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepines of formula I,

K ¹ in which R represents a chlorine atom or a methylthio group, R represents a hydrogen atom or a phenyl and n denotes 2 or 3, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts are low-cataleptic neuroleptics and a central anticholinergic component of action, which is expressed by antagonism to the action of oxotremorine. The particular pharmacological profile of the compounds of the invention makes them antipsychotics with strongly reduced extrapyramidal side effects. These effects were found in tests on experimental animals, as indicated below for each substance.

2-Chloro-11- [4- (2-mandeloyloxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (I, R ', Cl, R' = Η, n = 2) was tested as monomethanesulfonate. Acute toxicity in mice, LD ^ q »

420 mg / kg p * o. The discoordination effect in the rotating rod test in mice (mean effective dose inducing ataxia in 50% of animals at the time of maximum effect) is 10.5 mg / kg p.o. The cataleptic effect in rats, Εβ ^ θ (mean effective dose inducing catalepsy in 50% of animals) is 23 mg / kg p.o. At an oral dose of 40 mg / kg substance

- 2,227,530 significantly antagonizes tremor in oxotremorine-induced mice, suggesting a central antiparkineonic effect.

2-Methylthio-11- [4- (3-mandeloyloxypropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (I, R · SCH p R ¹ = Η, n = 3) was dough like maleate. Acute toxicity in mice, LD ^ q »530 mg / kg po Discoordinating effect in rotating rod test in mice, ED ^ q« mg / kg po Catalytic effect in rats, ED ^ ₀ »6.7 mg / kg po

At doses higher than 40 mg / kg p.o. an intense anti-xotremorin effect in mice was scored. After administration of the substance to rats, there is a significant increase in the level of homovanilic acid in the brain, demonstrating an increased metabolism of brain dopamine and typical of neuroleptics.

2-Chloro-11- [4- (2-benziloyloxyethyl) piperazino] -10,11-dihydro dibenzo (b, f) thiepine (I, R1-Cl, R1-C1-H3, u2) was tested such as methanesulfonate. It is very toxic since it does not cause mice to die in an acute toxicity test up to an oral dose of 400 mg / kg. It has a low incoordinating effect in the rotating rod test in mice; dose 100 mg / kg p.o. induces ataxia in 10% of the animals. Also the cataleptic effect is very low; dose 200 mg / kg p.o. induces catalepsy in 10% of rats. At a dose of 40 mg / kg p.o. has an intense antioxotremorin effect in mice. In this substance, the central anticholinergic action outweighs the neuroleptic effects.

2-Methylthio-11- [4- (3-benziloyloxypropyl) piperazino] -1,11,11-dihydrodibenzo (b, f) thiepine (I, R «CH ^, R ¹ »C ^H ^, n * 3) was tested as methanesulfonate. Acute toxicity in mice, LD ^ q = 530 mg / kg po Discoordinating effect in the rotating rod test in mice, ED ^ q 78 78 mg / kg po Cataleptic effect in rats; ED ₅₀ mg / kg po

The compounds of the formula I according to the invention can be prepared by the reaction of 8-substituted 10- [4- (chloroalkyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepines of the formula II,

 (II) of

3,227,530 in which Ran denotes the same as in formula I, with the potassium salts of mandelic acid and benzilic acid, preferably in boiling 2-propanol. The starting materials of formula II are novel and their preparation is described in the examples. The preparation of potassium salts of mandelic acid and benzilic acid is also described in the examples. The (s) -mandelic acid used introduces a second center of chirality into the end product molecules, so that the resulting esters are mixtures of stereoisomers (two racemates). However, these bases tend to partially crystallize and can be obtained relatively easily as homogeneous substances. By neutralizing the bases of formula I with pharmaceutically acceptable acids, preferably methanesulfonic acid or maleic acid, crystalline salts are prepared which are more advantageous than bases for pharmacological testing and for the manufacture of dosage forms. All of the novel compounds described in this invention were assured by identity and spectra in identity.

Example 1

2-Chloro-11- [4- (2-mandeloyloxyethyl) piperazino] -10,11-dihydro dibenzo (b, f) thiepine. A mixture of 3.14 g of (-) - mandelic acid potassium salt, 6.50 g of 2-chloro-11- [4- (2-chloroethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine and 90 ml of 2 -propanol was refluxed for 7 h. After cooling, the mixture is diluted with 90 ml of benzene. After standing overnight, the precipitated potassium chloride is filtered off with suction and the filtrate is evaporated in vacuo. 8.40 g (100%) of an oily base-mixture of stereoisomers is obtained. Neutralization of this base with maleic acid in acetone yields crystalline bis (hydrogen maleate). which may be recrystallized from a mixture of acetone and ether; m.p. Mp 121-123 ° C. Neutra pressing of the oily base with methanesulfonic acid in acetone yields crystalline monomethanesulfonate, which is purified by crystallization from a mixture of 90% ethanol and ether, m.p. Mp 186-189 ° C.

The (-) - mandelic acid potassium salt used is prepared by neutralizing a solution of 30 g of this acid in 80 ml of methanol with a solution of 13 g of 85% potassium hydroxide in 20 ml of water. The solution is evaporated to dryness in vacuo, the residue is dried and triturated to a powder. 39 g of potassium salt are obtained.

The 2-chloro-11- [4- (2-chloroethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine used is new and is obtained, for example, by the following procedure: To a solution of 30.0 g of 2-chloro hemihydrate -11- [4- (2-hydroxy227,530 ethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (Jílek JO et al., Collect.Czech.Chem.Commun. 36, 2226, 1971) in a mixture 250 ml of benzene and 12.5 g of pyridine are slowly added dropwise with stirring at 10 DEG C. to 16.4 g of thionyl chloride. The mixture was stirred for another 2 h at room temperature, quenched with 250 mL of water and basified with 5% sodium hydroxide. The product was extracted with benzene, the extract was washed with water and then shaken with an excess of 3M-HCl. The precipitated hydrochloride is filtered off with suction, suspended in the aqueous phase of the filtrate, the suspension is made alkaline with 10% sodium hydroxide solution and the product is again extracted with benzene. Evaporation of the extract yielded 29.5 g of crude product, which was dissolved in 50 ml of benzene and chromatographed on a 120 g neutral alumina column (activity II). Elution with benzene gave 24.4 g of a homogeneous product which crystallized on standing, m.p. 105-106 ° C (cyclohexane). For characterization, crystalline salts (maleate, mp, 151-153 ° C, monomethanesulfonate, mp 168-169 ° C) can be prepared by neutralization reactions.

Example 2

2-Methylthio-11- [4- (3-mandeloyloxypropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine. Mixture of 3.0 g of (i) -mandelic acid potassium salt (see Example 1), 6.6 g of 2-methylthio-11- [4- (3-chloropropyl) piperazino] -10,11-dihydrodibenzo (b, f) of thiepine and 90 ml of 2-propanol is refluxed for 7 h, allowed to stand overnight, the precipitated potassium chloride is filtered off and the filtrate is evaporated in vacuo. 7.7 g of crystalline base (91%) melting at 116-119 ° C are obtained. Two crystallizations of 85% ethanol achieve a constant melting point of 120-121 ° C and the substance is apparently one homogeneous racemate. Neutralization with maleic acid in aqueous acetone gives the maleate which crystallizes from ethanol and melts at 137-139 ° C.

The starting 2-methylthio-11- [4- (3-chloropropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine used is a novel substance which can be obtained as follows: To a solution of 20 g of 2-methylthio-11 (4- (3-Hydroxypropyl) piperazino) -10,11-dihydro dibenzo (b, f) thiepine (Jílek JO et al., Cited) in 200 ml of chloroform is added 8 ml of pyridine and then slowly stirred with stirring 24 g of thionyl chloride are added dropwise so that the temperature does not exceed 40-45 ° C. The mixture is left at room temperature overnight, quenched with 200 ml of 10% solution of 5,227,530 to sodium hydroxide and strongly alkalinized with 35% sodium hydroxide solution while cooling with ice water. The chloroform phase was separated and evaporated under reduced pressure. The residue is dissolved in 250 ml of benzene, shaken with 200 ml of 3M-HCl, the precipitated hydrochloride is filtered off with suction and suspended in water. The suspension was basified with 15% sodium hydroxide and the base was extracted with benzene. The extract was evaporated and the residue was chromatographed on a column of 500 g of neutral alumina (activity II). Elution with benzene yields

13.5 g (65%) of a homogeneous oily product suitable for further processing. For characterization, crystalline salts can be prepared by neutralization with the appropriate acids (raaleinate, mp 162-164 ° C) dimethanesulfonate, mp 160-163 ° C).

Example 3

2-Chloro-11- [4- (2-benziloyloxyethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine. A mixture of 5.10 g of 2-chloro-11- [4- (2-chloroethyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine (see Example 1), 3.45 g of benzilic acid potassium salt and 90 ml 2-Propanol was refluxed for 7 h. The mixture is diluted with 90 ml of benzene, the potassium chloride is filtered off and the filtrate is evaporated in vacuo. 7.7 g (100%) of a crude glassy base are obtained which does not tend to crystallize. However, it is homogeneous, and neutralization of maleic acid in a mixture of acetone and ether gives a crystalline maleate, m.p. 180 DEG-182 DEG C. (aqueous ethanol). Similarly, neutralization with methanesulfonic acid in acetone gives a crystalline monomethanesulfonate melting at 139-141 ° C (acetone).

The benzilic acid potassium salt used is prepared by neutralizing a solution of 30 g of this acid in 90 ml of methanol with a solution of 25 g of 85% potassium hydroxide in 25 ml of water. The precipitated crystalline salt is filtered, washed with methanol and dried; 28,5 g.

Example 4

2-Methylthio-1- [4- (3-benziloyloxypropyl) piperazino] -10,11-dihydrodibenzo (b, f) thiepine. Prepared in analogy to the preceding compound from 6.4 g of 2-ethylthio-11- [4- (3-chloropropyl) piperazino] 10,11-dihydrodibenzo (b, f) thiepine (see Example 2) and 4.0 g of potassium salt benzylic acid (see Example 3) in 90 ml boiling 2-propanol. 9.2 g (98%) of a crude glassy base are obtained which does not tend to crystallize. Yet it is again apparently homogeneous,

227,530, because by neutralization with the appropriate acids, it yields a smoothly crystalline maleate which crystallizes from acetone and melts at 94-97 ° C, and further a crystalline monomethanesulfonate which also crystallizes from acetone and melts at 185-186 ° C.

Claims (1)

8-Substituted 10- [4- (hydroxyalkyl) piperazino) 10,11-dihydrodibenzo (b, f) thiepine esters of formula I wherein R is chlorine or methylthio, R is hydrogen or phenyl and n is 2 or 3, and salts thereof with pharmaceutically acceptable inorganic or organic acids.