CS229076B1 - Process for preparing 3-alkyl-11-piperazino-10,11-dihydrodibenzo (b, f) thiepines and their salts - Google Patents

Abstract

The invention belongs to the field of synthetic drugs. Its subject is a process for the preparation of 3- -alkyl-11-piperazino-10,11-dihydrodibenzo-(b,f)thiepines of the general formula I i — 2 in which R denotes methyl or ethyl and R methyl or 2-hydroxyethyl, and their salts with pharmaceutically acceptable inorganic and organic acids. The substances according to the invention are obtained by the substitution reaction of 3-alkyl-11-chloro-10,11-dihydrodibenzo(b,f)thiepines with 1-methylpiperazine or 1-(2-hydroxyethyl)piperazine in boiling chloroform. The salts of the base formula I are obtained by the usual neutralization reaction. The substances of the formula I and especially their salts are antihistamines and non-cataleptic or weakly cataleptic neuroleptics. They are therefore used in the therapy of allergic diseases and, more recently, in the therapy of psychoses of the schizophrenic type.

Description

The invention falls within the field of synthetic drugs. Its subject is a process for the preparation of 3-alkyl-11-piperazino-10,11-dihydrodibenzo(b,f)thiepines of the general formula I

i — 2 in which R denotes methyl or ethyl and R denotes methyl or 2-hydroxyethyl, and their salts with pharmaceutically acceptable inorganic and organic acids.

The compounds of the invention are obtained by the substitution reaction of 3-alkyl-11-chloro-10,11-dihydrodibenzo[b,f]thiepines with 1-methylpiperazine or 1-(2-hydroxyethyl)piperazine in boiling chloroform. The salts of the base of formula I are obtained by the usual neutralization reaction.

The compounds of formula I and especially their salts are antihistamines and non-cataleptic or weakly cataleptic neuroleptics. They are therefore useful in the therapy of allergic diseases and, to a greater extent, in the therapy of psychoses of the schizophrenic type.

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

In which R represents methyl or ethyl and R represents methyl or 2-hydroxyethyl, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of the formula X according to the invention and especially their salts are characterized by pharmacodynamic activity, which makes them useful in therapy. They have a significant antihistamine activity, for which they are useful in the therapy of allergic diseases, and are also low-cataleptic or non-cataleptic neuroleptics, so that they can be used in the treatment of psychoses of the schizophrenic circuit as substances with a low incidence of undesirable side effects.

The following properties were found in animal tests for individual substances according to the Invention:

3-Methyl-11-(4-methylpiperazino)-,0,11-dihydro-benzo(b,f)thiepih was tested as monomethanesulfonate. The doses given are in all cases converted to the base. Acute toxicity was determined in white mice by i. v. administration, LD^q = 37.5 mg/kg. Antihistamine activity in the histamine detoxification test in guinea pigs, ED^q = 0.1 to 0.5 mg/kg s. c. In the rotating rod test in mice, the median effective dose (ED^q) that causes ataxia is between 2.5 and 7.0 mg/kg i. v. An intravenous dose of 7 mg/kg does not produce a cataleptic effect in rats.

At doses above 7 mg/kg 1st v. in mice, the substance causes a decrease in activity and reactivity.

3-Ethyl-11-(4-methylpiperazine)-10,11-dihydrodibenzo(b,f)thiepine was tested in the form of monomethanesulfonate hemihydrate. Acute toxicity in mice by oral administration, LD^q = 265 mg/kg. XncoOrdinal effect on the rotating rod in mice by oral administration,' ED^q = 54 mg/kg. An oral dose of 50 mg/kg induces a cataleptic state in 40% of rats. Antihistaminic effect in the histamine detoxification test in guinea pigs; an oral dose of 10 mg/kg has a protective effect against the lethal effect of histamine in 62.5% of animals. Antihistamine effect in the histamine aerosol test in guinea pigs: PD _cn ³ 0.8 mg/kg p. 0. (the substance is therefore more effective than the standard preparation mebrophenhydramine, known under the trademark Bromadryl, whose PU^q = 1.3 mg/kg p. 0.).

3-Ethyl-11-[4-(2-hydroxyethyl)piperazino]-,0,11-dihydrodibenzo(b,f)thlepine was tested in the form of bis(hydrogenmaleate). Acute toxicity in mice when administered orally, LU50 - 360 mg/kg. Incoordination effect on the rotating rod in mice when administered orally, = 100 mg/kg. An oral dose of 50 mg/kg induces a cataleptic state in 80% of mice. Antihistamine effect in the histamine detoxification test in guinea pigs: an oral dose of .0 mg/kg administered 1 h before histamine has a protective effect against the lethal effect of histamine in 50% of animals. Antihistamine effect in the histamine aerosol test In guinea pigs: an oral dose of 10 mg/kg has a protective effect against histamine bronchospasm in 11 60% of animals.

The compounds of formula I can be prepared according to the invention by the substitution reaction of 3-ethyl-11-chloro-10,11-dihydrodibenzo(b,f)thieples of general formula IX

Cl in which R ¹ means the same as in formula I, with 1-methylpiperazine or 2-hydroxyethylpiperazine in boiling chloroform. The starting materials of formula II are new and their preparation is described in detail in the examples. The preparation of salts of formula I consists in neutralizing the base of formula I with pharmaceutically acceptable (non-toxic) inorganic or organic acids. Salts with methsulfonic acid are very advantageous because they are readily soluble in water, which allows their parenteral administration. Salts with maleic acid crystallize well, are less soluble in water and are suitable for the production of dosage forms for oral use.

The bases of general formula .1 and their salts are crystalline substances with characteristic melting points. All new substances mentioned in the invention have been characterized in terms of their identity by analyses and all conventional spectra (ultraviolet, infrared, ’h NMR spectra).

Example 1

3-methyl-1-(4-methylpiperazine)-10,1,-dihydrodibenzct b,f)thiepine

A solution of 5.0 g of 11-chloro-3-methyl-10,11-dihydrodibenzo(b,f)thiepine and 5.7 g of 1-methylpiperazine in 12 µl of chloroform was refluxed for 7 h. The chloroform was evaporated, the residue was dissolved in 200 µl of benzene, and the solution was washed with 3% sodium hydroxide solution and water. The base was then extracted into an excess of 1.25 M H2SO4. The benzene solution was separated and the acidic aqueous solution of the product sulfate was made alkaline with ammonium hydroxide. The precipitated base was extracted with benzene. The extract was dried over magnesium sulfate, filtered with activated carbon, and the filtrate was evaporated. 4.5 g (72%) of the crude base melting at 130-131 °C was obtained. Recrystallization from benzene gave a pure substance with a m.p. of 132-133 °C. Neutralization with methanesulfonic acid in ethanol and addition of ether yields crystalline monomethanesulfonate, which crystallizes from a mixture of ethanol and ether and melts at 205 to 206 °C in the pure state.

The starting material 11-chloro-3-methyl-10,11-dihydrodibenzo(b,f)thiepine is a new substance and can be prepared by the following procedure:

In a solution of 26 g of 85% potassium hydroxide in 270 ml of water, 30 g of 3-methylthiophenol are dissolved at 50 °C with stirring (D. S. Tarbell and D. K. Fukushima, Org. Syn., Coll. Vol.

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

J. Metyěové and M. Protiva, Collect. Czech. Chem. Commun. 37. 1 734 1972). and 1 g of copper catalyst and the mixture is refluxed for 16 h. The hot solution is filtered with activated carbon, the filtrate is cooled and acidified with hydrochloric acid. The separated crude oily product is extracted with chloroform, the extract is dried with magnesium sulfate and evaporated. The residue (51 g) slowly crystallizes 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 yields a pure substance melting at 108-110 °C.

A mixture of 7.2 g of the above acid, 72 g of polyphosphoric acid and 40 ml of toluene is stirred and refluxed for 6 h. After standing overnight, the mixture is poured into 250 ml of ice water and the product is extracted with benzene. The extract is 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 is obtained, melting at 78-82 °C. Crystallization from ethanol gives a pure substance with a melting point of 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 is refluxed for 5 h, filtered and the filtrate is evaporated under reduced pressure. The residue is dissolved in benzene, the solution is washed with water, dried with magnesium sulfate, filtered with activated carbon and evaporated. 5.4 g (92 X) of crude 7-methyl-10,11-dihydrodibenzo(b,f)thiepin-10-ol is obtained, melting at 115-1.7 °C. Crystallization from benzene gives a pure substance with a m.p. of .18-.20 °C.

To a solution of 5.0 g of the previous alcohol in .50 ml of benzene is added 6.0 g of powdered anhydrous calcium chloride and the stirred suspension is saturated with anhydrous hydrogen chloride for 4 h. The mixture is left to stand overnight, diluted with 50 ml of benzene and filtered with activated carbon. The filtrate is 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 is obtained. Crystallization from benzene gives a pure substance melting at 93-95 °C.

Example 2

3-Ethyl-11-(4-methylplperezino)-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 gives a pure substance melting at 85-86°C. It gives a monomethanesulfonate which crystallizes from a mixture of 95% ethanol and ether as a hemihydrate and melts in the pure state at 179-180°C.

The starting material 3-ethyl-11-chloro-10,11-dihydrodibenzo(b,f)thiepine is a new compound, which is prepared by the procedure described above: this procedure - with the exception of the first step - is analogous to the procedure described in Example 1.

A solution of the Grignard reagent is prepared in the usual manner by reacting 169 g of 3-ethylbromobenzene (Z. Horli, S. Yamamura, H. Hakusui, T. Idshikado β T. Momose, Chem. Pharm. Bull. £6, 2 456 1968) with 22.8 g of magnesium in 470 ml of ether; the reaction is completed by boiling the mixture for 2 h.

After cooling to 5 to 7 °C, a total of 22 g of sulfur flowers are added in small portions to the stirred solution under a nitrogen atmosphere over 1 h. The mixture is stirred for another 2 h at room temperature, left undisturbed overnight, and decomposed by slowly adding 320 ml of 1:1 diluted hydrochloric acid while stirring.

The organic layer is separated and the product is extracted into excess 10% sodium hydroxide solution. The aqueous alkaline phase is cooled to 5-8 °C, layered with ether and slowly acidified with 1:1 dilute hydrochloric acid while stirring. The product is extracted with ether, the extract is dried over magnesium sulfate and worked up by distillation. 81 g (64%) of 3-ethylthiophenol boiling at 103-107 °C/3 kPa 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. Similar treatment yields 68 g (66%) of crude [2-(3-ethylphenylthio)phenyl]acetic acid melting at 65 to 67 °C. Crystallization from aqueous acetic acid yields a pure substance with a melting point of 68 to 69 °C.

The above acid (63 g) was cyclized by boiling with 6j0 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 was obtained. Crystallization from ethanol gave a pure substance 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 gives 23.7 g (93%) of oily 7-ethyl-10,11-dihydro-benzo(b,f)thic-pin-10-ol, which crystallizes from petroleum ether, m.p. 91-92 °C.

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

22907 b.

p r i c 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) was reacted with 19 g of 1-(2-hydroxyethyl)piperazine in 20 ml of boiling chloroform.

15.9 g (87 A) of crude base are obtained, which is purified by crystallization from ethanol, m.p. 121-122 °C. Neutralization with maleic acid in ethanol and addition of ether gives bishydrogenmaleate, 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