CS229076B1 - Method of preparing 3-alkyl-11-piperazino-10,11-dihydrodibenzo/b,f/thiepines and salts thereof - Google Patents

Abstract

The invention is within the scope of synthetic drugs. The object of this is to prepare 3- -alkyl-11-piperazino-10,11-dihydrodibenzo- (b, f) thiopines of formula (I) i - 2 wherein R is methyl or ethyl methyl or 2-hydroxyethyl, and salts thereof with pharmaceutically acceptable inorganic and organic acids. The compounds of the invention are obtained by substitution by reacting 3-alkyl-11-chloro-10,11-dlhydrodibenzo (b, f-thiopines) with 1-methylpiperazine or 1- (2-hydroxyethyl) piperazine in boiling chloroform. Salts of Formula I are obtained by a conventional neutralization reaction. Compounds of formula I and salts thereof they are antihistamines and non-ketaleptic or weakly cataleptic neuroleptics · They are therefore used in allergic therapy and longer in the treatment of schizophrenic psychosis circuit.

Description

The invention falls within the field of synthetic drugs. The present invention relates to a process for the preparation of 3-alkyl-11-piperazino-10,11-dihydrodibenzo (b, phthiepines of the formula I).

wherein R is methyl or ethyl; or R is methyl or 2-hydroxyethyl, and their salts with pharmaceutically acceptable inorganic and organic acids.

The compounds according to the invention are obtained by the substitution reaction of 3-alkyl-11-chloro-10,11-dlhydrodibenzo (b, β-thiepines with 1-methylpiperazine or 1- (2-hydroxyethyl) piperazine in boiling chloroform. .

The compounds of formula I and, in particular, their salts are antihistamines and non-ketaleptic or weakly cataleptic neuroleptics. Thus, they are used in the treatment of allergic diseases and for longer in the treatment of schizophrenic circuit psychoses.

The invention relates to a process for the preparation of 3-alkyl-11-piperazino-10,11-dihydrobenzo (b, f) thiepines of the general formula I

(AND)

2

Wherein R is methyl or ethyl and R is methyl or 2-hydroxyethyl, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The compounds of the invention of formula X, and in particular their salts, are characterized by pharmacodynamic activity which makes them useful in therapy. They have remarkable efficacy with antihistamines for which they are useful in the treatment of allergic diseases, and for a longer time they are low-cataleptic or non-ketaleptic neuroleptics, so they may find use in the treatment of schizophrenic circuit psychosis as a low incidence of adverse side effects.

The following properties have been found in animal tests for individual substances according to the invention:

3-Methyl-11- (4-methylpiperazino) -, 0,11-dihydrocibenzo (b, f) thiepih was tested as monomethanesulfonate. The reported doses are in all cases recalculated on a base basis. Acute toxicity was determined in white mice by i.v. administration, LD ^ q = 37.5 mg / kg. Antihistamine efficacy in guinea pig histarnine detoxification test, ED ^ q = 0.1 to 0.5 mg / kg sc In the rotating rod test ηβ myeh, the median effective dose (ED ^ q), which induces ataxia between 2.5 and 7 0 mg / kg iv An intravenous dose of 7 mg / kg does not induce a cathaleptic effect in rats.

At doses above 7 mg / kg v. 1, mice induce activity and reactivity inhibition.

3-Ethyl-11- (4-methylpiperezino) -10,11-dihydrodibenzo (b, f) thiepine was tested as monomethanesulfonate hemihydrate. Acute oral toxicity in mice, LD ^ q = 265 mg / kg. X-axis reversing effect on the rotating rod in mice when administered orally, ED50 = 54 mg / kg. An oral dose of 50 mg / kg induces catalepsy in 40% of rats. Anti-histamine effect in the guinea pig detoxification test; oral dose of 10 mg / kg my protective effect against the lethal effect of histarnine In 62.5% of animals. Antihistamine effect in guinea pig histamine aerosol test: PD _cn ³ 0.8 mg / kg p.O. (the substance is therefore more effective than the standard preparation mebrofenhydra50 'min, known under the trade mark Bromadryl, whose PU ≥ q = 1.3 mg / kg po).

3-Ethyl-11- [4- (2-hydroxyethyl) piperazino] -, 0,11-dihydrodibenzo (b, f) thlepin was tested in the form of bis (hydrogen maleate). Acute oral toxicity in mice, LU50 - 360 mg / kg. Incoordinating effect on rotating rod in mice by oral administration, = 100 mg / kg. An oral dose of 50 mg / kg induces a cataleptic condition in 80% of mice. Anti-histamine effect in the guinea pig histoxine detoxification test: oral dose, 0 mg / kg given 1 h before hlstamip, has a protective effect against the lethal effect of histarnine in 50% of the animals. Antihistamine effect in histamine aerosol test In guinea pigs: oral dose of 10 mg / kg my protective effect against hlstamin bronchospasm 11 60% of the animals.

Compounds of formula (I) may be prepared according to the invention by the substitution reaction of 3-alkyl-11-chloro-10,11-dihydrodibenzo [b, f] thienes of formula (IX)

Cl in which R ¹ is as defined in formula I, with 1-or 2-metylpiperezinem hydroxyetylplperazinem in boiling chloroform. The starting materials of formula (II) are novel and their preparation is described in the Examples. The preparation of the salts of formula (I) consists of the neutrelizeol base of formula (I) with pharmacologically harmless (non-toxic) inorganic or organic acids. Methylsulfonic acid salts are very preferred because they are well soluble in water, allowing their parenteral administration. Maleic acid salts crystallize well, are less soluble in water, and are suitable for the manufacture of dosage forms for oral use.

The bases of formula (I) and their salts are crystalline with characteristic melting points. All of the novel compounds disclosed in the invention were characterized in terms of their identity by analyzes, and by all common spectra (ultraviolet, infrared, < 1 > H NMR spectra).

Example 1

3-methyl-11- (4-methylpiperezino) -10,1, -dihydrodibenzyl b, f) thiepine

A solution of 5.0 g of 11-chloro-3-methyl-10,11-dihydrodibenzo (b, f) thepine and 5.7 g of 1-methylpiperazine in 12 µl of chloroform was refluxed for 7 h. The chloroform is evaporated, the residue is dissolved in 200 ml of benzene and the solution is washed with 3% sodium hydroxide solution and water. The base is then extracted to an excess of 1.25 M-H 2 SO 4. The benzene solution was separated and the acidic aqueous sulfate solution of the product was basified with ammonium hydroxide. The excreted base is extracted with beneen. The extract was dried over magnesium sulfate, filtered with charcoal, and the filtrate was evaporated. 4.5 g (72%) of crude base melting at 130-131 ° C are obtained. Recrystallization from benzene gave the pure product, m.p. 132-133 ° C. Neutralization with methanesulfonic acid in ethanol and addition of ether gives a crystalline monomethanesulfonate, which crystallizes from a mixture of ethanol and ether and melts in the pure state at 205-206 ° C.

The starting 11-chloro-3-methyl-10,11-dihydrodibenzo (b, f) thiepine is a novel substance and can be prepared as follows:

In a solution of 26 g of 85% potassium hydroxide in 270 ml of water, 30 g of 3-methylthiophenol (D. S. Tarbell and D. K. Fukushima, Org. Syn., Coll. Vol.

809 (1955) and 60 g of (2-iodophenyl) acetic acid (K. Sindelář,

J. Methye and M. Protiva, Collect. Czech. Chem. Commun. 37, 1,734,172). and 1 g of copper catalyst and the mixture was refluxed for 16 h. The hot solution is filtered with charcoal, the filtrate is cooled and acidified with hydrochloric acid. The resulting crude oily product was extracted with chloroform, dried over magnesium sulfate and evaporated. The residue (51 g) slowly crystallized from a mixture of benzene and petroleum ether.

23.2 g (40%) of crude [2- (3-methylphenylthio) phenyl] acetic acid are obtained, m.p. 94-98 ° C. Recrystallization from the same solvent mixture gave the pure material, melting at 108-110 ° C

A mixture of 7.2 g of the previous acid, 72 g of polyphosphoric acid and 40 ml of toluene is stirred and refluxed for 6 hours. After overnight, the mixture was poured into 250 ml of ice-water and the product was extracted with benzene. The extract was washed with 5X sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. 6.4 g (95%) of crude 7-methyldibenzo (b, f) thiepin-10 (11H) -one melting at 78-82 ° C are obtained. Crystallization from ethanol gave the pure product, mp 86-87 ° C.

A warm solution of 5.8 g of the previous ketone in 95 ml of ethanol is stirred and a solution of 0.35 g of sodium borohydride in 3.5 ml of water containing 0.1 ml of 20X sodium hydroxide solution is added dropwise over 5 min. The mixture was refluxed for 5 h, filtered and the filtrate evaporated under reduced pressure. The residue was dissolved in benzene, the solution was washed with water, dried over magnesium sulfate, filtered with charcoal and evaporated. 5.4 g (92%) of crude 7-methyl-10,11-dihydrodibenzo (b, f) thiepin-10-ol, melting at 115-1.7 ° C, are obtained. Crystallization from benzene gave the pure product, m.p. 18-20 ° C.

To a solution of 5.0 g of the preceding alcohol in 50 ml of benzene was added 6.0 g of powdered anhydrous calcium chloride, and the stirred suspension was saturated with anhydrous hydrogen chloride for 4 h. The mixture is left overnight, diluted with 50 ml of benzene and filtered with charcoal. The filtrate was evaporated under reduced pressure. 5.4 g (100%) of crude 11-chloro-3-methyl-10,11-dihydrodibenzo (b, f) thiepine melting at 88-91 ° C are obtained. Crystallization from benzene gave a pure material, melting at 93-95 ° C.

Example 2

3-ethyl-11- (4-methylpiperezino) -10,11-dihydrodibenzo (b, f) thiepine

Similar to Example 1, 11 g of 3-ethyl-11-chloro-10,11-dihydrodibenzo (b, f) thiepine and 12 g of 1-methylpiperazine are reacted in 25 ml of boiling chloroform. 10.7 g (79%) of an oily base are obtained, which crystallizes on standing, m.p. 83-85 ° C. Crystallization from acetone gave a pure material, melting at 85-86 ° C. It yields monomethanesulfonate which crystallizes from a mixture of 95% ethanol and ether as the hemhydrate and melts in the pure state at 179-180 ° C.

The starting 3-ethyl-11-chloro-10,11-dihydrodibenzo (b, f) thiepine is an avian novel prepared by the following procedure: except for the first step, this procedure is analogous to the p03 procedure described in Example 1.

Reaction of 169 g of 3-ethylbromobenzene (Z. Horli, S. Yamamura, H. Hakusui, T. ldshikado and T. Momose, Chem. Pharm. Bull. £ 6, 2,456, 1968) with 22.8 g of magnesium in 470 ml of ether preparing a Grignard reagent solution in a conventional manner; the reaction is completed by boiling the mixture for 2 h.

After cooling to 5-7 ° C, a total of 22 g of sulfur flower was added in small portions to the stirred solution under nitrogen atmosphere over 1 h. Stirring is continued for 2 h at room temperature, allowed to stand overnight and is quenched by stirring slowly by adding 320 ml of 1: 1 dilute hydrochloric acid.

The organic layer was separated and the product was extracted into excess 10% sodium hydroxide solution. The aqueous alkaline phase was cooled to 5-8 ° C, overlaid with ether and slowly acidified with 1: 1 dilute hydrochloric acid with stirring. The product was extracted with ether, dried over magnesium sulfate and worked up by distillation. 81 g (64%) of 3-ethylthiophenol boiling at 103-107 ° C / 50 mbar are obtained.

Similar to Example 1, 53 g of 3-ethylthiophenol is reacted with 98 g of (2-iodophenylacetic acid) in a boiling solution of 77 g of 85% potassium hydroxide in 420 ml of water in the presence of 1 g of copper. of crude [2- (3-ethyl-phenylthio) -phenyl] -acetic acid, melting at 65-67 [deg.] C. Crystallization from aqueous acetic acid afforded the pure product, mp 68-69 [deg.] C.

The previous acid (63 g) was cyclized by boiling with 6.0 g of polyphosphoric acid and 600 ml of toluene with vigorous stirring. 55 g (94%) of crude 7-ethyldibenzo (b, f) thiepin-10 (11H) -one melting at 57-59 ° C are obtained. Crystallization from ethanol gave a pure material, melting at 60.5-61.5 ° C.

Reduction of 25.4 g of the previous ketone in 400 ml of ethanol with 4.0 g of sodium borohydride in 27 ml of water afforded 23.7 g (93%) of the oily 7-ethyl-10,11-dihydrodi-benzo (b, f) thic oil. -pin-10-ol, which crystallizes from petroleum ether, mp 91-92 ° C.

To a solution of 28 g of the preceding alcohol in 500 ml of benzene was added 33 g of powdered anhydrous calcium chloride, and 3U3pense was saturated with anhydrous hydrogen chloride for 6 hours with stirring. Work-up gave 30.1 g (100%) of oily 3-ethyl-11-chloro-10,11-dihydrodibenzo (b, f) thiepine, which crystallized on standing, m.p. 84-86 ° C. Crystallization from benzene gave the pure product, mp 86-87 ° C.

22907 p.

Example 1 β d 3

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

Similarly to Example 1, 13.5 g of 3-ethyl-11-chloro-10,11-dihydrodibenzo (b, f) thiepine (see Example 2) is reacted with 19 g of 1- (2-hydroxyethyl) piperazine in 20 ml. boiling chloroform.

There were obtained 15.9 g (87 A) of crude base which was purified by crystallization from ethanol, m.p. 121-122 ° C. Neutralization with maleic acid in ethanol and addition of ether yields bisthydrogen maleate (ether) which is pure after crystallization from aqueous ethanol and melts at 167-168 ° C.

Claims (2)

Process for preparing Formula I 3-alkyl-11-piperazino-10,11-dihydrodi benzol b, f) thiepines of general (I) Wherein R is methyl or ethyl and E is methyl or 2-hydroxyethyl, and their salts with pharmaceutically acceptable, inorganic or organic acids, characterized in that 3-alkyl-1-chloro-10,11-dihydrodibenzo ( b, f) thiepines of formula II Cl in which R ⁴ is the same as in formula I, is subjected to a substitution reaction with 1-methylpiperezine or 2-hydroxyethylpiperezine, in a chlorinated C 1 -C 2 alkane medium, for example chloroform, at the boiling point of the reaction mixture, in the form of a base, do not neutralize the pharmaceutically acceptable inorganic or organic acids