CS252336B1 - 2- (tert-amino) -11- (4-methylpiperazino) dibenzo (b, f) thiepines and their maleates - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is 2-(tert.amino)-11-(4- -methylpiperazino)dibenzo(b,f)thiepines of the general formula I in which R is a dimethylamino, piperidino or morpholino residue, and their maleates. These substances have the properties of moderately effective cataleptic neuroleptics and are therefore useful in the therapy of schizophrenic psychoses. Their preparation consists in the reactions of 8-(tert.amino)dibenzo(b,f)thiepin-10(11h)- -ones with 1-methylpiperazine in the presence of titanium tetrachloride in boiling benzene. The starting ketones are prepared by the reactions of (2-iodophenyl)acetic acid with 4-(tert.amino)thiophenols in boiling aqueous potassium hydroxide solution in the presence of copper and with the formation of (2-(4-tert.aminophenylthio)phenyl)acetic acids, which are cyclized by the action of polyphosphoric acid at 130 °C

Description

The present invention relates to 2- (tertiamino) -11- (4-methylpiperazino) dibenzo [b, f] thiepines of formula X

(I) wherein R is a dimethylamino, piperidino or morpholino residue, and their maleate.

The compounds according to the invention are centrally depressant, cataleptically and antiapomorphine-active neuroleptics and are useful in the therapy of schizophrenic psychoses. These are moderately potent neuroleptics intended for oral administration and their daily doses are between 20 and 100 mg.

The results of animal pharmacological tests for two typical substances according to the invention which demonstrate their neuroleptic quality are presented below.

11- (4-methylpiperazino) -2-piperidinodibenzo (b, f) thiepine (I, R = piperidino) was tested as monomaleinate hemihydrate by oral administration. In a rotating rod test in mice, it exhibits a relatively strong discoordinating action that correlates with its centrally depressing activity; the mean effective dose of ED50 at the time of maximum efficacy is 8.4 mg / kg.

A higher dose of 25 mg / kg induces ataxia in 24% of the mice 24 h after 48 hours and 20 h in 48 h. The efficacy is therefore clearly prolonged. Also in the rat catalepsy test, the substance is relatively highly effective; the mean effective dose of ED50 is 7.1 mg / kg (within 24 hours after administration the effect subsides). The substance exhibits high potency in an apomorphine stereotyping antagonist assay in rats; for influencing apomorphine-induced chewing, the median effective dose of Dj _{0 is} 3.6 mg / kg, for influenced apomorphine-induced agitation is = 3.5 mg / kg. Furthermore, the substance has an adrenolytic effect which is typical of most neuroleptics; effectively antagonizes the lethal action of adrenaline in mice, FD? q = ϋ, 12 mg / kg. At concentrations of 12.5 to 50 µg / ml, they inhibit the growth of the following microorganisms in vitro: Streptococcus xj-heemolyticus, Staphylococcus pyogenes aureus, Seccheromyces pssterianus, Irichophyton mentagrophytes.

11- (4-methylpiperazino) -2-morpholinodibenzo (b, f) thiepine (I, R = morpholino) was also tested in the form of monomaleinate hemihydrate when administered orally. Discoordination effect in the rotating rod test in mice, ΕΒ ^ θ = 5.3 mg / kg (the effect subsides within 24 h). Cataleptic effect in rats, ED ^ = 7.5 mg / kg (within 24 hours the effect subsides). Antagonism against apomorphine stereotypes in rats; D ^ ₀ = 14.4 mg / kg (chewing) and 12.3 mg / kg (agitation). Antagonism to the lethal action of adrenaline in mice, PB- ₀ = 0.11 mg / kg.

The compounds of the invention of formula I having the character of enamines are prepared by one of the general methods for preparing this type of substance. Particularly preferred are the reactions of ketones of formula II,

Wherein R is the same as in Formula I, s, -methylpiperazine in boiling benzene in the presence of titanium tetrachloride as described in the Examples. The ketones of formula II are novel and are obtained by a two-step procedure also described in the Examples. In the first step, reactions of (2-iodophenyl) acetic acid (Shindelar K. et al., Collect.Czeoh.Chem. Commun. 21, 734) (1972)} with the appropriate thiols, i.e. 4- (dimethylamino) thiophenol (Banfield JE, J. Chem. Soc. 1960. 456), 4-piperidinothiophenol and 4-morpholinothiophenol (for the latter, see Kmoníček V. et al. 51, 937, (1986)) to give the corresponding (2- (4-tertiaminophenylthio) phenyl) acetic acid. The reaction is carried out in boiling aqueous potassium hydroxide in the presence of copper as a catalyst. In the second step, the acids obtained are cyclized by treatment of the ketones of formula II with polyphosphoric acid at 130 ° C.

In addition to the substances for which the literature is cited, all the substances in the present invention are novel. Analyzes and spectral methods were used for their safe identification.

The following examples are merely illustrative of the preparation possibilities of the compounds of the present invention, but are not intended to limit the scope of the present invention to the present invention.

Example 1

2- (dimethylamino) -11- (4-methylpiperazino) dibenzo (b, f) thiepine (I, R = dimethylamino)

To a stirred solution of 4.1 g of 8- (dimethylamino) chibenzo (b, f) thiepin-10 (11H) -one (II, R = dimethylamino) and 7.5 g of 1-methylpiperazine in 90 ml of benzene was slowly added a solution of 2.18 g of titanium tetrachloride in 15 ml of benzene and refluxed for 24 h.

After cooling, it is shaken with water, the precipitated hydrated titanium dioxide is removed by filtration, the filtrate is washed with saturated sodium bicarbonate solution, dried over potassium carbonate and evaporated. The oily residue crystallizes after trituration with petroleum ether. 3.6 g (61%) of crude product are obtained, which recrystallization from ethanol gives the pure desired base melting at 155-157 ° C.

The starting 8- (dimethylamino) dibenzo (b, f) thiepin-10 (11H) -one is preferably prepared by the following procedure:

A solution of 4.0 g of potassium hydroxide in 40 ml of water is deoxygenated by the addition of 0.2 g of sodium dithionite, 5.1 g of 4- (dimethylamino) thiophenol (lithium citrate) is added, the mixture is heated to 60 ° C until a solution is formed. and with stirring 8.4 g of (2-iodophenyl) acetic acid (lit. cit.) and 0.2 g of copper catalyst were added. The mixture is refluxed for 20 h, filtered while hot: with activated carbon, the filtrate is neutralized with acetic acid to pH 5-6 and, after standing overnight, the precipitated product is filtered off with suction, washed with water and dried in vacuo; 6.1 g (67%) of almost pure (2- (4-dimethylaminophenylthio) phenyl) acetic acid, m.p. Mp 112-116 ° C. Crystallization from ethanol gave the pure product, m.p. Mp 114-117 ° C.

A mixture of 24.0 g of the previous acid and 240 g of polyphosphoric acid was heated to 135 ° C and stirred at this temperature for 3 h. After partial cooling, the mixture was poured on ice, neutralized with 20% sodium hydroxide solution to about pH 7 and left overnight at room temperature. The product is filtered, washed with water and dried in vacuo; 22.1 g (93%), m.p.

Mp 112-115 ° C. An analytical sample was obtained by crystallization from ethanol, m.p. Mp 125-127 ° C. The product is the desired 8- (dimethylamino) dibenzo (b, f) thiepin-10 (11H) -one.

Example 2

- (4-Methylpiperazino) -2-piperidinodibenzo (b, f) thiepine (I, R = piperidino)

Similar to Example 1, 6.9 g of 8-piperidinodibenzo [b, f] thiepin-10 (11H) -one (II, R = piperidino) is reacted with 11.5 g of 1-methylpiperazine and 2.2 g of titanium tetrachloride in 170 g. ml of benzene to give 7.4 g of crude product which is chromatographed on a column of 150 g of neutral alumina (activity II) to yield 2.7 g (31%) of the homogeneous desired base, mp 152-154 ° C ( By neutralizing maleic acid in 95% ethanol and adding ether, monomaleinate hemihydrate is obtained, mp 132.5-134.5 ° C (ethanol-ether).

The starting 8-piperidinodibenzo (b, f) thiepin-10 (11H) -one was prepared analogously to a similar ketone in Example 1 by this method;

Reaction of 6.7 g of 4-piperidinothiophenol (lithium citrate) with 7.9 g of (2-iodophenyl) acetic acid (lithium citrate) in boiling solution of 8.4 g of sodium hydroxide in 85 ml of water in the presence of 0.2 g of medium 4.1 g (42%) of (2- (4-piperidinophenylthio) phenyl) acetic acid, m.p.

146-148 ° C (aqueous ethanol).

Cyclization of 13.9 g of this acid with 140 g of polyphosphoric acid at 130 ° C (3 h) yielded 12 g of an inhomogeneous product, which was extracted with methanol (separated from the non-dissolving polymeric substance), the extract was evaporated under reduced pressure and. the residue crystallizes from aqueous methanol; 3.5 g (27%) of 8-piperidinodibenzo (b, f) thiepin-10 (11H) -one, m.p. 105-107 ° C.

Example 3

11- (4-methylpiperazino) -2-morpholinodibenzo (b, f) thiepine (I, R = raorfolino)

Similar to Example 1, 6.6 g of 8-morpholinodibenzo (b, f) thiepin-10 (IIH) -one are reacted with 6.4 g of 1-methylpiperazine and 1.85 g of titanium tetrachloride in 150 ml of benzene.

4.8 g (58%) of crude product are obtained, which product is purified by crystallization from aqueous ethanol, m.p. 180.5-182.5 ° C. By neutralizing maleic acid in 95% ethanol and adding ether, monomaleinate hemihydrate, m.p. Mp 171-173 ° C (95% ethanol-ether).

The starting 8-morpholinodibenzo (b, f) thiepin-10 (11H) -one was prepared similarly to the analogous ketones in Examples 1 and 2 as follows:

Reaction of 6.0 g of 4-morpholinothiophenol (lithium citrate), 6.0 g of (2-iodophenyl) acetic acid (lithium citrate) and 0.2 g of medium in a boiling solution of 6.0 g of potassium hydroxide in 60 ml of water are added. 4.0 g (40%) of (2- (4-morpholinophenylthio) phenyl) acetic acid, m.p. Mp 164-166 ° C (ethanol).

Cyclization of 12.4 g of the preceding acid with 125 g of polyphosphoric acid at 125 to 130 ° C (3 h) yielded 7.0 g (60%) of crude 8-morpholinodibenzo (b, f) thiepin-10 (11 H) -one, which crystallizes from methanol and melts at 135-139 ° C. Recrystallization from aqueous methanol yielded a hemihydrate melting at 150-152 ° C, which was used as the analytical product.

Claims (2)

SUBJECT OF THE INVENTION 2- (t-amino) -11- (4-methylpiperazino) dibenzo (b, f) thiepines of formula I V / (I) wherein fl is a residue of dimethylamino, piperidino or morpholino, and their maleate