CS217879B1 - 2-Substituted 11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepines and a process for their preparation - Google Patents

Abstract

The invention relates to 2-substituted 11-(η-methyl-4-piperidyl)-11H-dibenz(b,f)- -1,4-oxathiepines (the 2-substituent is a chlorine atom or trifluoromethyl), their salts and pharmaceutically acceptable acids and a method for their preparation. The substances mentioned are low-toxic neuroleptics with a favorable pharmacological profile, useful in the treatment of schizophrenic-type psychoses. The method of preparation consists of a two-stage process starting from 2-chloro- and 2-trifluoromethyl- -11H-dibena(b,f)-1,4-oxathiepine. In the first stage, chlorination to position 11 is carried out with sulfuryl chloride or N-chlorosuccinimide, and in the second stage, the crude 11-chloro derivatives are subjected to a reaction with 1-methyl-4-piperidylmagnesium chloride in the presence of tetrahydrofuran. The bases are converted into salts by neutralization with acids.

Description

The invention relates to 2-substituted 11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepihes (the 2-substituent being chlorine or trifluoromethyl), their salts and pharmaceutically acceptable acids, and method of their preparation. The compounds are poorly toxic neuroleptics with a favorable pharmacological profile useful in the treatment of schizophrenic-type psychoses. The process consists of a two-step process starting from 2-chloro- and 2-trifluoromethyl-11H-dibena (b, f) -1,4-oxathiepine. In the first step, the sulfuryl chloride or N-chlorosuccinimide is chlorinated to the 11-position, and in the second step the crude 11-chloro derivatives are reacted with 1-methyl-4-piperidylmagnesium chloride in the presence of tetrahydrofuran. The bases are converted into salts by acid neutralization.

The present invention relates to 2-substituted-oxathiepines of the general formula I, s 11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4 (I) nch ₃ in which R represents a chlorine atom or trifluoromethyl, and their salts with pharmaceutically acceptable inorganic or organic acids, and processes for their preparation.

The compounds of formula I and their salts are low toxic neuroleptics with a favorable pharmacological profile, useful in the treatment of schizophrenic-type psychoses. They are characterized by a mild tranquilizing effect, which is partially prolonged (in animal tests the effect persists over 24 h after administration). Their ketaleptic activity is partly mild, partly intense, and the antiapomorphine effect is of a high degree, which makes it possible to predict the properties of incisive neuroleptics. Thus, 2-chloro-11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine, which has been tested as hydrogen maleate, has low oral toxicity in mice,

LD ₅₀ = 299 mg / kg.

In the mouse rotating rod test, it exhibits an incoordinating action which is of the protracted type; mean effective dose at 2 h post administration, ED? q = 14 mg / kg po; at 24 h, an oral dose of 25 mg / kg induced ataxia in 30% of the mice. The cataleptic effect was determined in an oral rat test; medium effective dose ED ^ _Q = 41 mg / kg. 2-Trifluoromethyl-11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine was tested by oral administration as hydrogen oxalate monohydrate.

Toxicity LD 50 = 384 mg / kg. Incoordination effect in rotating rod test in mice = 2 mg / kg. Inhibition of locomotor activity in a dishwasher using the beam method according to

Dewee, Djq = 5.7 mg / kg. Cataleptic effect in rat test, ED? Q = 4.7 mg / kg. In an anti-apomorphine effect test in rats, the effects of apomorphine-induced atherotypes (chewing) and agitation were observed, with reported values (Β ^ θ) being doses of a neuroleptic that cause 50% inhibition of said apomorphine reactions; it is 1.7 mg / kg for apomorphine stereotypes and 1.4 mg / kg for apomorphine agitation. This substance is therefore a very effective euroleptic with relatively low central buffering activity.

The process for the preparation of the compounds of the formula I according to the invention consists of a two-stage process, in which in the first step the 2-substituted 11H-dibenz (b, f) -1,4-oxathiepines of the formula II are chlorinated to the 1,1-chloro derivatives of the formula XII.

(II, R ¹ = H) (III, R ¹ = Cl) wherein in formulas II and III R is the same as in formula I. Chlorination * can be carried out with various chlorinating agents, sulfuryl chloride is particularly preferred and N- chlorsuccinimide. In the case of sulfuryl chloride, the reaction is preferably carried out in carbon tetrachloride, benzene being used as solvent when working with chlorosuccinimide. The chloro derivatives 111 are not isolated in the pure state but in the crude state are treated in the second step by treatment with 1-methyl-4-piperidylmangnesium chloride in a mixture of tetrahydrofuran and benzene. The resulting oily bases of formula I are optionally converted into crystalline salts by neutralization with pharmaceutically acceptable inorganic or organic acids, of which maleate or oxalate is particularly preferred.

The starting materials of formula (II) are novel and the methods for their preparation are described in the Examples, which contain further details on the preparation of the compounds of formula (I).

All products and new intermediates were characterized by analyzes and spectra (UF, IR,

NIIR, IIS) to ensure their identity.

Examples:

He did

2-Chloro-11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine (I, R = Cl)

To a solution of 6.45 g of 2-chloro-11H-dibenz (b, f) -1,4-oxathlepine in 100 ml of carbon tetrachloride, a solution of 3.54 g of sulfuryl chloride in 100 ml was added dropwise over 4.5 hours at 60 ° C. carbon tetrachloride. The mixture was stirred for 1 hour at 60 ° C, then the carbon tetrachloride was evaporated, the residue was dissolved in 20 ml of benzene, and the solution was added dropwise to a stirred solution of the Grignard reagent, which was reacted with 7.0 g of 4-chloro-1-. methylpiperidine with 1.3 g magnesium in 45 ml tetrahydrofuran. The mixture was refluxed for 3.5 h, quenched with 20% ammonium chloride solution and extracted with benzene.

The extract was washed with water and the basic product was extracted by shaking with excess dilute hydrochloric acid. The acidic solution was basified with aqueous ammonia and the base was isolated by extraction with ether. After drying the extract with potassium carbonate, the benzene was evaporated. The residue (3.7 g) was ehromethoxylated on a column of 400 g of neutral alumina (activity II). Elution with benzene separates the less polar material and then elutes with a mixture of benzene and chloroform from the column to elute 1.47 g of the desired base, which is oily and neutralized with maleic acid in a mixture of acetone and ether to give 1.73 g of hydrogen maleate. Crystallization from the solvent mixture gave a pure material, m.p. 184-186.5 ° C.

The used starting 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine is a novel substance obtained, for example, by the following procedure:

To a solution of 120 g of 5-chloro-2-iodobenzoic acid (K. Pelz et al., Colletft. Czech. Chem. Commun. JJ, 1852, 1968) in 145 ml of tetrahydrofuran is added under stirring at 45 ° C for 45 min. C 16.1 g of sodium borohydride. The mixture was stirred at this temperature for 30 min and then a solution of 80.3 g (71.4 mL) of boron trifluoride etherate in 40 mL of tetrahydrofuran was added dropwise. Stirring is continued for 3 h and, under cooling with ice water, decomposed at a maximum of 8 ° C by the dropwise addition of 50 ml of 5% hydrochloric acid.

Dilute with water and extract with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. 110 g (96%) of crude 5-chloro-2-iodobenzyl alcohol of m.p. 115 DEG-117 DEG C. are obtained. The analytically pure material was obtained by crystallization from ethanol, m.p. 116-117 ° C.

A mixture of 41.6 g of phosphorus tribromide, 25 ml of benzene and 8.2 ml of pyridine is prepared under cooling, 108.3 g of 5-chloro-2-iodobenzyl alcohol are added dropwise with stirring at a maximum of 10 ° C, diluted. with 40 ml of benzene, stirred for 4 h at room temperature and 1 h at 50 ° C. After cooling, it is diluted with 120 ml of chloroform, washed with 25 ml of 5% hydrochloric acid, 5% sodium hydroxide solution and water, dried over magnesium sulphate and evaporated. 126 g (95%) of crude 5-chloro-2-iodobenzyl bromide melting at 75-79 ° C are obtained. The pure product is obtained by crystallization from a mixture of benzene and petroleum ether, m.p. 77-79 ° C.

To a mixture of 640 ml of dimethylformamide, 52.4 g of potassium carbonate and 47.8 g of 2-hydroxythiophenol (R, Leuckart, J. Prakt. Chem. / 2/41 '92, 1890) is added a solution of 125.6 g of 5-chloro 2-iodobenzyl bromide in 500 ml of dimethylformamide, stirred for 1 h at room temperature, then 57 g of potassium carbonate and 4.5 g of copper are added and refluxed for 6 h. Dimethylformamide was distilled off under reduced pressure, the residue was diluted with water and shaken with benzene. After aspiration, the benzene layer was separated, washed with water, dried over potassium carbonate and evaporated. Distillation of the residue gave 42.5 g (45%) of 2-chloro-11H-dibenz (b, f) 217879

M.p. 148-168 ° C (65 Pa, m.p. 66-76 ° C) The pure product is obtained by crystallization from methanol and melts at 78-79 ° C.

Example 2

2-Chloro-11- (1-methyl-4-piperidyl) -41H-dibenz (b, f) -1,4-oxathiepine

To a solution of 7.05 g of 2-chloro-11H-dibenz (b, f) -1,4-oxathiepine (see Example 1) in 30 ml of benzene was added 3.85 g of N-chlorosuccinimide. The mixture was stirred for 5 hours, while initially maintaining a maximum temperature of 25 ° C. After standing overnight, the mixture was added dropwise with stirring to a solution of the Grignard reagent prepared by reacting 7.0 g of 4-chloro-1-methylpiperidine with 1.3 g of magnesium in 40 ml of tetrahydrofuran at 20-25 ° C. The mixture was stirred for 5 h at room temperature, allowed to stand for 48 h and then quenched with 20% ammonium chloride solution. Extract with benzene, wash the extract with water and remove the basic product by shaking with excess dilute hydrochloric acid.

The acidic aqueous solution was basified with aqueous ammonia and the base isolated by extraction with benzene. After drying with potassium carbonate, the extract was evaporated and the residual oil (6.4 g) was chromatographed on a column of 400 g of neutral alumina (activity II). Elution with benzene separates a small amount of less polar contaminant and then elutes 4.16 g of the desired homogeneous base with a mixture of benzene and chloroform. Neutralization with maleic acid affords hydrogen maleate, mp 183.5-186.5 ° C, identical to the product prepared according to the preceding example.

Example 3

2-Trifluoromethyl-11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepine

To a solution of 7.4 g of 2-trifluoromethyl-11H-dibenz (b, f) -1,4-oxathiepine in 100 ml of carbon tetrachloride Be stirred for 4 h at 60 ° C a solution of 3.54 g of sulfuryl chloride in 100 ml of carbon tetrachloride. The mixture was stirred at 60 ° C for 1.5 h, left to stand overnight and the carbon tetrachloride was evaporated under reduced pressure. The residue was dissolved in 20 ml of tetrahydrofuran and the solution was added dropwise over 15 minutes to a solution of the Grignard reagent, which was prepared by reacting 7.0 g of 4-chloro-1-methylpiperidine with 1.3 g of magnesium in 30 ml of tetrahydrofuran.

The mixture was refluxed for 3 hours and quenched overnight with 20% ammonium chloride solution. Extract with ether, wash the extract with water and remove the basic product by shaking it with excess dilute hydrochloric acid.

The acidic aqueous solution was basified with aqueous ammonia and the base isolated by extraction with benzene. The extract was dried over potassium carbonate and evaporated. The residue (5.0 g) was chromatographed on a column of 200 g of neutral alumina (activity II). Benzene elutes a minor amount of the less polar component and elutes 1.8 g of homogeneous desired base from the column with benzene / chloroform. Neutralization with oxalic acid in acetone gave the hydrogen oxalate crystallizing as a hemihydrate, mp 193-197 ° C with decomposition (wet acetone).

v 2-Trifluoromethyl-11H-dibenz (b, f) -1,4-oxathiepine starting material is a novel substance obtained by the following procedure:

To a solution of 45 g of 2-chloro-5-trifluoromethylbenzyl chloride (B. Pecherer, U.S. Pat. No. 3,465,051} Chem. Abstr. JI., 123,885, 1969) and 27.6 g of 2-hydroxythiophenol (R. Leuckart, cited) in Dimethylformamide (800 ml) was added with potassium carbonate (27.2 g) and the mixture was stirred at room temperature under nitrogen for 3 h. DMF was then distilled off in vacuo and the residue was partitioned between water and benzene. It is filtered off with suction, the benzene layer of the filtrate is separated off, dried with potassium carbonate and treated by distillation. 40.2 g (73%) of 2-trifluoromethyl-11H-dibenz (b, f) -1,4-oxathiepine boiling at 135-137 ° C / 0.1 kPa were obtained.

The distillate crystallized from petroleum ether and melted at 70-71 ° C in pure state.

Claims (2)

SUBJECT OF THE INVENTION 1. 2-Substituted 11- (1-methyl-4-piperidyl) -11H-dibenz (b, f) -1,4-oxathiepines of formula I, The NCH ₃ benz (b, f) -1,4-oxathiepines of formula II chlorinate, preferably N-chlorosuccinimide, to the 11-chloro derivatives of general formula III in which R is chlorine or trifluoromethyl, and their salts with pharmaceutically acceptable inorganic or organic acids. 2. Process for preparing compounds according to claim 1, characterized in that the 2-substituted-11H didou or sulfuryl chloride (II, R ¹ = H) (III, R ¹ = Cl), where in the formulas II and III, R is the same in formula I JEKO The crude compounds of formula III are reacted with t-methyl-4-piperidylmagnesium chloride in the presence of tetrahydrofuran, and the bases obtained are optionally converted into salts by neutralization with pharmaceutically acceptable acids.