CS239095B1 - Process for preparing phenolic derivatives of 8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine and their salts - Google Patents

Abstract

A method for preparing phenolic derivatives of 8-methylthio-10-piperazino-10, 11-dihydrodibenzo(b, f)thiepine of the general formula I, X5 R X 2 X 60^ i in which R denotes a hydroxyl group in position 2 or } and Ir denotes a hydrogen atom or methyl, as well as their salts with pharmaceutically acceptable inorganic or organic acids. Some of the substances according to the invention are characterized by intense neuroleptic activity and are useful as antipsychotic drugs. The method of preparation consists in demethylation of the corresponding methoxy analogues by reaction with boron tribromide in dichloromethane or chlorobenzene at room temperature. After alkaline hydrolysis, the bases of formula I obtained are optionally converted by neutralization with acids into the corresponding salts.

Description

Process for the preparation of phenolic derivatives of 8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine and their salts

A process for preparing phenolic derivatives of 8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine of formula (I),

X ⁵

wherein R represents a hydroxyl group at the 2-position or} and Ir represents a hydrogen or methyl atom, as well as a salt thereof with pharmaceutically acceptable inorganic or organic acids. Some of the compounds of the present invention exhibit intense neuroleptic activity and are useful as antipsychotic drugs.

The process consists in demethylating the corresponding methoxy analogs by reaction with boron tribromide in dichloromethane or chlorobenzene at room temperature. After alkaline hydrolysis of the base of the formula I obtained, they are optionally converted into the corresponding salts by acid neutralization.

239 095

239 095

The invention relates to a process for the preparation of phenolic derivatives of 8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, E) thiepine of the general formula I,

wherein R represents a hydroxyl group at the 2-position or at the 3-position and R ¹ represents a hydrogen atom or a methyl group, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

2- and 3-Hydroxy derivatives of neuroleptics 10-piperazino-10,11-dihydrodibenzo (b, phthiepine series) are important metabolites of these neuroleptic preparations. .Czech.Chem.

Commun. 39, 3548, 1974), at other times they are virtually ineffective (Sindelar K. et al., Collect.Czech.Chem.Commun. 40, 3530, 1975).

In the study of the metabolism of the neuroleptic methiothepin (I, R = H,

R ¹ = CH 2 (Eschenhof E. et al., Arzneim.-Forsch. 26, 262, 1976), its 3-hydroxy derivative (I, R = 3-0H, R * = CHg) has been identified as a metabolite of this neuroleptic. This substance is cited in the cited work in a list of compounds that have been reported to be synthetically prepared as standards for metabolic studies. However, there are no data at the disposal of how this compound has been prepared, or what has physical or pharmacological properties Hydroxy formula I in which R ¹ = H, are new substances in the literature yet unrecorded.

A process for the preparation of compounds of formula I has now been developed which:

239 095 is an object of the present invention. It consists in the demethylation of the corresponding methyl ethers of the formula I in which R represents a methoxy group in the 2-position or in the 3-position and R 6 represents a hydrogen atom or methyl. This demethylation is preferably carried out with boron tribromide at room temperature in dichloromethane or chlorobenzene. The obtained primary product is subjected to hydrolysis with an aqueous-ethanolic alkali hydroxide solution and the products of the formula I according to the invention obtained are isolated either as crystalline bases or as salts with pharmaceutically acceptable inorganic or organic acids. Further details of the preparation of the compounds of formula I are given in the examples, which are merely illustrative of the possibilities of the invention, but are not intended to fully describe all these possibilities. If the starting methyl ethers are known, reference is made to their preparation. If they are not known, a description of their preparation is included in the examples. The identity of all substances described in the invention was assured by means of analyzes and conventional spectral methods.

Some of the compounds of the present invention are neuroleptically highly active and can be used as antipsychotic drugs against schizophrenia. Such a substance is, in particular, 3-hydroxy-8-methylthio-10- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine, which has been tested in animals as a maleate by oral administration. Acute toxicity in mice, LD ^ q = 136 mg / kg. In the rotating rod test in mice it shows a very intense discoordinating effect, ED = 1.7 mg / kg; this effect subsides within 24 hours after administration. Using the ray method in mice, it can be shown to have a very potent central depressant effect, which is manifested by inhibition of spontaneous motor activity of animals; = 2.1 mg / kg. At 24 h after dosing, a 4 mg / kg dose is statistically significant in this test and ϋ, -θ is 3.1 mg / kg. The substance has a relatively strong cataleptic effect in rats; ED g _Q = 7.4 mg / kg.

A dose of 25 mg / kg induces catalepsy in 40% of the animals 24 hours after administration; within 48 hours the effect disappears.

Examples

1. 10- (4-Methylpiperazino) -8-methylthio-10,11-dihydrodibenzo (b, f) thiepin-2-ol

To a stirred solution of 5.7 g of 2-methoxy-10- (4-methylpiperazino) -8-methylthio-10,11-dihydrodibenzo (b, f) thiepine (U.S. Pat. No. 2,412,521; U.S. Pat. No. 3,954,769) in 70 ml of chlorobenzene is added

A solution of 11.1 g of boron tribromide in 30 ml of chlorobenzene is added dropwise over 15 minutes at 239-205 at 15-20 ° C. The mixture was stirred at room temperature for 6 hours, allowed to stand overnight, and a solution of 3.0 g of methanesulfonic acid in 60 ml of water was added dropwise with stirring. The precipitate formed is filtered off with suction after 15 minutes of stirring, washed with 20 ml of water and added to a mixture of 180 ml of ethanol and 80 ml of 3% sodium hydroxide solution. The mixture was refluxed for 8 h, evaporated in vacuo, diluted with 60 mL water and neutralized with acetic acid. The precipitated product was extracted with chloroform, dried over magnesium sulfate and evaporated. 1.75 g (32%) of the desired base is obtained, which crystallizes from a mixture of ether and petroleum ether. Neutralization with malic acid in ethanol / ether gives bis (hydrogenraaleinate), which melts in pure state at 158-159 ° C (ethanol-ether).

2. 10- (4-Methylpiperazino) -8-methylthio-10,11-dihydrodibenzo (b, f) thiepin-3-ol

To a solution of 6.0 g of 3-methoxy-10- (4-methylpiperazino) -8-methyl-thio-10,11-dihydrodibenzo (b, f) thiepine (U.S. Pat. No. 2,412,521; U.S. Pat. 3,954,769) in A solution of 11.7 g of boron tribromide in an additional 50 ml of dichloromethane is added dropwise with stirring over 15 minutes over 100 ml of dichloromethane. The mixture was stirred at room temperature for 6 h, allowed to stand overnight and evaporated in vacuo. The residue was dissolved in a mixture of 100 ml of ethanol and 75 ml of 5% aqueous sodium hydroxide solution and stirred at room temperature for 8 h. After standing overnight, evaporate again in vacuo, slightly acidify with acetic acid, add 100 mL of 5% sodium carbonate solution and extract with chloroform. The extract was washed with water, dried over potassium carbonate and evaporated. The residue was crystallized from ethanol. 2.4 g (42%) of the desired crystalline base melting at 199-200 ° C are obtained.

3. 8-Methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepin-3-ol

To a stirred solution of 3.0 g of 3-methoxy-8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine in 50 mL of chlorobenzene was added dropwise a solution of 6.02 g of boron tribromide in 30 mL of chlorobenzene over 15 min. at 15 ° C and stirred at room temperature for 6 h. Leave to stand overnight and shake with a solution of 1.5 g of methanesulphonic acid in 30 ml of water. The precipitate formed is filtered, combined with an aqueous filtrate layer, and the suspension is made alkaline with 30%.

239 095 with sodium hydroxide solution to pH 8, 60 ml of ethanol are added and refluxed for 5 hours. The ethanol was evaporated in vacuo, the residue was dissolved in water and neutralized with acetic acid. The precipitated oil is isolated by decantation and induced to crystallize by dissolving in 10 ml of ethanol and adding ether. 0.7 g (20%) of the hydrobromide of the desired compound precipitates, which crystallizes from ethanol and melts at 146-148 ° C. Reaction of a solution of this salt in ethanol with methanesulfonic acid affords a crystalline dimethanesulfonate which crystallizes from aqueous ethanol as a hemihydrate and melts at 173.5 ° C.

The starting 3-methoxy-8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepin used is a novel compound which can be prepared as follows:

A mixture of 21 g of 10-chloro-3-methoxy-8-methylthio-10,11-dihydrodibenzo (b, f) thiepine (Shindelar K, et al., Collect.

40, 3530, 1975) and 40 g of 1-ethoxycarbonylpiperazine are stirred and heated at 110 ° C for 4.5 h. Leave to stand overnight, then dilute with 200 ml of water and extract with benzene. The benzene layer was washed with water, dried over potassium carbonate and evaporated under reduced pressure. The residue was dissolved in 200 ml of ether and a slight excess of a solution of hydrogen chloride in ether was added. The hydrochloride formed is filtered, washed with ether, suspended in 200 ml of water and 25 ml of conc. aqueous ammonia. The liberated base was isolated by extraction with benzene. Treatment of the extract yielded 20.9 g (72%) of the oily base of 10- (4-ethoxycarbonylpiperazino) -3-methoxy-8-methylthio-10,11-dihydrodibenzo (b, f) thiepine. For characterization, the sample can be converted by neutralization with maleic acid in ethanol to a maleate, which crystallizes from acetone and melts in the pure state at 134-135 ° C.

A mixture of 19.9 g of the previous base, 10 g of potassium hydroxide and 20 ml of ethanol was stirred and boiled in a bath heated to 120 ° C for 3 h. Leave to stand overnight and shake between 200 ml of water and 200 ml of benzene. Wash the benzene layer with water and shake with excess 3M-HCl. The precipitated hydrochloride was filtered, washed with benzene and quenched with dilute aqueous ammonia. The liberated base is isolated by extraction with benzene. Treatment of the extract yielded 14.2 g (86%).

3-methoxy-8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, f) thiepine melting at 118-121 ° C (ether-petroleum ether). Neutra5

Maleic acid lysis yields a crystalline maleate which crystallizes from acetone and melts at 166-167 ° C.

Claims (1)

OBJECT OF THE INVENTION 239 093 A process for the preparation of phenolic derivatives of 8-methylthio-10-piperazino-10,11-dihydrodibenzo (b, phthiepine of the general formula I) wherein R represents a hydroxyl group in the 2-position or the 3-position and R ¹ denotes a hydrogen atom or methyl. with pharmaceutically acceptable inorganic or organic acids, characterized in that the methyl ethers corresponding to formula I, in which R is a methoxy group in the 2 or 3 position, are demethylated by treatment with boron tribromide in a chlorinated hydrocarbon at room temperature, the primary products are hydrolyzed. aqueous-alcoholic solutions of alkali hydroxides and the products are isolated either as bases or directly as salts obtained by neutralization of the crude bases.