CS252339B1 - 2-/tert.amino/-11(4-methylpiperazino)-10,11-dihydrodibenzo(b,f)thiepines and therir succinates - Google Patents

Abstract

Mowing is within the scope of drug synthesis. His subject is 2- (target) - .11 - (4-Methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepines of formula (I) R N N-CH 3 wherein R is dimethylamino or morpholino, and succinates thereof. Substances according to the invention are highly effective neuroleptics useful in the treatment of schizophrenic psychos. Some are characteristic yet other effects (antihistemic, spasmolytic, edrenolytic, hypotensive, antiapythmic) so they can be designate polyvalent central and peripheral neuropharmaceuticals with some effects cardiovascular system. They can be prepared reduction of the corresponding 2- (tert-amino) -11- (4-methylpiperazino) dibenzo (b, f) - thiepine diborane, generated by the reaction sodium borohydride with acetic acid in tetrahydrofuran. Named default the enamines ee are obtained by three-step synthesis from (1-iodophenyl) acetic acid and the corresponding thiols, i.e. 4- (dimethylamino) - thiophenol and 4-morpholinothiophenol.

Description

thiepines of the general formula I, ^R

N-CH3 / ³ (I) wherein R is a dimethylamino or morpholino residue, and succinates thereof.

The compounds according to the invention are centrally depressant, cataleptically and antiapomorphine highly potent neuroleptics and are useful in the therapy of schizophrenic psychoses. Since they are potent neuroleptics for oral administration, their daily doses range between 10 and 50 mg. Some of them have found other types of effects (hypotensive, adrenolytic, spesmolytic, antihistaminic, antiarrhythmic), so they can be described as multipotent central and peripheral neuropharmaceuticals with some effects on the blood circulation system.

The results of pharmacological tests on animals and isolated organs for both typical substances according to the invention, which show both their neuroleptic quality and the polyvalence of the effects, are given below.

2- (dimethylamino) -1,1- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine (I, H = dimethylamino) was tested in amber form by various routes of administration. The acute toxicity in mice, LDjq, is 48 mg / kg by oral administration and 40 mg / kg by intravenous administration. In the mouse rotating rod test, it exhibits a very strong diecoordination effect which correlates with its centrally depressing activity; mean effective dose at the time of maximum efficacy for oral administration, ED? q - 1.2 mg / kg; at 24 h after dosing at 2.5 and 5.0 mg / kg, they still induced etaxia at 40 and 40 mg / kg, respectively. 50% of the mice (the effect is clearly prolonged). Disco-coordinating action in the rotating rod test in rats ^{= 10} mg / kg po A high degree of central depressant activity is shown by the ray locomotive activity inhibition test (Dews); was administered orally 60 min before evaluation ^D 50 = ^0, 24 mg / kg (in 24 hours after administration is a higher dose of 1 mg / kg, still significantly buffered).

The agent intensively potentiates the duration of thipental sleep in mice; intravenous doses of 0.1 to 1.0 mg / kg extend sleep duration to 200% of control. The substance has a typical hypothermic effect in rats: an intraperitoneal dose of 0.1 mg / kg reduces the rectally measured body temperature by 1 ° C. A massive antiamphetamine effect, assessed by determining a dose that protects 100% of the mice from lethal exposure to a standard amphetamine dose,

ED = 0.05 mg / kg intravenously. In the catalepsy test, the substance is extremely effective; the median effective dose in the test in rats Εΰ ^ θ is 1.4 mg / kg orally (the effect resolves within 24 h). The efficacy in the apomorphine stereotypic antagonist assay in rats when administered orally is also high; for the treatment of apomorphine-induced chewing, the median effective dose is 3.6 mg / kg, for the treatment of apomorphine-induced agitation is = 3.5 mg / kg (effects disappear within 24 h). Spasmolytic effects evaluated on isolated rat duodenum: at concentrations of 0.1 to 1.0 µg / ml the substance reduces acetylcholine-induced contractions by 50%; likewise, concentrations of 1 to 10 µg / ml reduce barium chloride contractions by 50%. The antihistamine effect was evaluated in guinea pigs by a test to determine the dose protecting 50% of the animals from the lethal effect of a 5 mg / kg histamine dose administered intra -ugularly; ED = 0.1 to 1.0 mg / kg subcutaneously. The substance has a high degree of <6-adrenolytic effect.

In the mouse test, the lethal action of adrenaline when administered orally and ^PD 50 ^{= 0.2} very effectively antagonized the rat dose. The dose that inhibited the adrenaline presorption by 50% was determined: ED = 0.001 mg / kg intravenously. These effects appear to be related to the hypotensive effect in normotensive rats: intravenous doses of 0.04 to 0.4 mg / kg cause a long-term decrease in blood pressure of 50 b. Finally, the compound also has a potent antiarrhythmic effect in rats: dose of 1.0 to 2.5 mg / kg iv significantly increase the latency of ventricular extras of the table, induced by a standard dose of aconitine (the effect is five times higher than that of quinidine).

- (4-methylpiperazino) -2-morpholino-10,11-dihydrodibenzo (b, f) thiepine (í, R = morpholino) was also tested as succinate. Acute toxicity in mice, LD ^ _Q = 35 mg / kg iv Discoordinating effect in mice in a rotating rod test: ^ED 50 (max) ⁼ 0.3 mg / kg po · dose of 25 mg / kg induced 24 h after administration ataxia in 40% of animals. Phenotyping of thiopentel sleep in mice: an intravenous dose of 0.5 mg / kg prolongs sleep duration at 200% of control. Antiamphetamine effect in mice: ED = 0.1 to 0.5 mg / kg intravenously. In the catalepsy test in rats, the compound is moderately active: ED 40 = 12.3 mg / kg orally (the effect resolves within 24 h after administration). Also, the anti-apomorphine effect in rats can be described as moderately intensive: ^D 50 = 27.4 mg / kg (chewing) and 25.9 mg / kg (agitation) (both oral administration). Antihistamine effect in guinea pigs evaluated by detox method: ED = 0.5 mg / kg iv The substance effectively antagonizes the lethal action of adrenaline in mice, PD ^ q = 0.14 mg / kg po Bypotency effect in normotensive rats: oral dose decreased blood pressure 16% for 1 h after administration, 10% for 3 h and 12% for 24 h; an oral dose of 10 mg / kg reduced the pressure at the same intervals by 11%, 10% and 7

The compounds of the invention of formula I are prepared by reducing the corresponding enamines of formula I

(11) wherein R is the same as in Formula 1. For example, diborane, which is generated by reacting sodium borohydride with acetic acid in tetrahydrofuran as described in the Examples, is suitable for reduction. The enamines of formula II are novel and their preparation is also described in the examples. It is based on the reaction of (2-iodophenyl) acetic acid (shingle K. 'et al., Collect. Czech. Chem. Commun. JJ, 1734 (1972)) with 4- (dimethylamino) thiophenol (Banfield JE, J Chem. Soc., 1960, 456), respectively. with 4-morpholinothiophenol (Kmoníček V. et al., Collfifi JU-Czech. Chem. Commun. 51, 937 (1986)). The reactions were carried out in boiling aqueous potassium hydroxide solution in the presence of copper as catalyst to give (2- (4-tert.-aminophenylthio) phenyl) acetic acid. Their cyclization with polyphosphoric acid at 130 ° C results in 8- (tert.amino) dibenzo (b, f) thiepin-10 (1 H) -ones which provide the necessary enamines of formula II, ie 2- (tert.amino) 11- (4-methylpiperazino) dibenzo (b, f) thiepines, by reaction with 1-methylpiperazine in boiling benzene in the presence of titanium tetrachloride. Meutralization of bases of formula I with succinic acid yields crystalline succinates.

Except for those exemplified by literature references, all of the compounds described in the examples are novel. Their identity was ensured both by analyzes and by usual spectral methods. The following examples are intended to demonstrate some of the possibilities for preparing the compounds of the invention; they are not intended to exhaustively describe all these possibilities.

Example!

2- (dimethylamino) -1- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepine (I, R = dimethylamino)

To a stirred solution of 1.9 g of 2- (dimethylamino) -11- (4-methylpiperazino) dibenzo (b, f) thiepine (II, R = dimethylamino) in 20 ml of tetrahydrofuran was added 1.2 g of sodium borohydride and then dropwise solution of 6.3 ml of acetic acid in 10 ml of tetrahydrofuran over 1.5 h. The mixture was stirred at room temperature for 30 min, refluxed for 2 h, diluted with chloroform (20 mL), washed with 5% sodium hydroxide (20 mL) and water. After drying with potassium carbonate, the solvents were evaporated under reduced pressure. The residue (2.4 g of the amino-borane complex) was dissolved in 40 ml of ethanol and the solution was refluxed for 6 hours with 20 ml of 20% sodium hydroxide. After cooling, the mixture was extracted with benzene, the extract was washed with water, dried with potassium carbonate and evaporated. The residue (1.7 g of crude oily base is neutralized with 0.53 g of succinic acid in ethanol and the precipitated salt is crystallized from a mixture of ethanol and ether; 1.0 g (42%) of succinate melting at 130 DEG-130 DEG C.

132 [deg.] C.

The starting 2- (dimethylamino) -1- (4-methylpiperazino) dibenzo (b, f) thiepine, which has not been described in the literature, can be prepared, for example, as follows:

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 DEG C. until a solution is obtained. 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 with charcoal while hot, 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 is 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 8- (dimethylamino) dibenzo (b, f) thiepin-10 (11H) -one.

To a stirred solution of 4.1 g of the previous ketone and 7.5 g of 1-methylpiperazine in 90 ml of benzene is slowly added dropwise a solution of 2.18 g of titanium tetrachloride in 15 ml of benzene and the mixture is refluxed for 24 h. After cooling, the mixture 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 2- (dimethylamino) -11- (4-methylpiperazino) dibenzo (b, f) thiepine are obtained, which are recrystallized from ethanol to give the pure material melting at 155-157 ° C.

I ⁵ \

Example 2

11- (4-methylpiperazino) -2-morpholino-10,11-dihydrodibenzo (b, f) thiepine (I, R = morpholino)

Similar reduction (as in Example 1) of 12.4 g of 11- (4-methylpiperazino) -2-morpholinodibenzo (b, f) thiepine with 8.0 g of sodium borohydride and 30 ml of acetic acid in 170 ml of tetrahydrofuran gives 11.1 g of crude product which is purified by column chromatography on 200 g of neutral alumina (activity II). The benzene yielded 8.1 g (65 homogeneous oily base, which was neutralized with 2.4 g of succinic acid in ethanol. Crystallization of the crude jentarsine from ethanol 8 ether gave 7.5 g of pure succinate, m.p. 169-172 ° C.

The starting 11- (4-methylpiperazino) -2-morpholinodibenzo (b, f) thiepine, which has not been described in the literature, can be prepared, for example, as follows:

Similar to Example 1, by reaction of 6.0 g of 4-morpholinothiophenol (lit. cited),

6.0 g of (2-iodophenyl) acetic acid (lit. cit) and 0.2 g of copper in boiling solution of 6.0 g of potassium hydroxide in 60 ml of water yield 4.0 g (40%) of the acid (2- (4) (morpholinophenylthio) phenyl) acetic, mp 164-166 ° C (ethanol).

Cyclization of 12.4 g of the preceding acid with 125 g of polyphosphoric acid at 125-130 ° 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. By recrystallization from aqueous methanol, a hemihydrate melting at 150-152 ° C is obtained, which is used as the analytical product.

Reaction of 6.6 g of the previous ketone (unsolvated) with 6.4 g of 1-methylpiperazine and 85 g of titanium tetrachloride in 150 ml of boiling benzene gave 4.8 g (58%) of crude 11- (4-methylpiperazino) -2. -morpholinodibenzo (b, f) thiepine, which is purified by crystallization from aqueous ethanol, m.p. 180.5-182.5 ° C. For characterization, monomaleinate hemihydrate can be prepared by neutralization with maleic acid in 95% ethanol and addition of ether, m.p. 17 'to

173 ° C (95% ethanol-ether)

SUBJECT OF THE INVENTION

Claims (2)

SUBJECT OF THE INVENTION 2- (t-amino) -1- (4-methylpiperazino) -10,11-dihydrodibenzo (b, f) thiepines of formula I; (I) wherein R represents a dimethylamino or morpholino residue, and succinates thereof