CS236549B1 - Piperazinoalkanoles of dibenzo (b,e)thiepine series and their salts with maleic acid - Google Patents

Abstract

The invention is within the scope of synthetic drugs. Its subject matter is piperazinoalkanols dibenzo (b, e) thiepine series general formula I, wherein R is hydrogen or chloro, and salts thereof with maleic acid. Compounds of the invention and their maleates are characterized by antihistaminic and musculotropic spasmolytic activity, so can be used as medicines for the elimination of symptoms of allergic diseases and further as painkillers muscle spasm. They are accessible by reduction the corresponding unsaturated piperezinoalkanols (double bond between skeleton and first branch chain), preferably. hydroiodic acid in boiling acid acetic acid in the presence of red phosphorus. The crude oily bases are converted by neutralization maleic acid to crystalline maleate and in this form are purified by crystallization.

Description

The present invention relates to novel piperazinoalkanols of the dibenzo (b, e) thiepine series of formula I,

(CH ₂ ) ₃ CH ₂ CH ₂ OH wherein R is a hydrogen atom or a chlorine atom and their maleic acid salts.

The compounds of the formula I according to the invention and their salts with maleic acid are characterized by antihistamine and musculotropic spasmolytic activity and can be used as medicaments for controlling the symptoms of allergic diseases and also as medicaments against painful muscular spasms. When administered intravenously, their effect is accompanied by a short-term decrease in blood pressure and an adrenolytic effect. Higher doses cause short-term central depression and ataxia. Pharmacodynamic effects can be demonstrated on the test animals as well as on their isolated organs. An example of a compound of the invention is 1 '(3- / 6,11-dihydrodibenao (b, e) thiepin-11-yl / propyl) -4- (2-hydroxyethyl) piperazine (I, R = H) which has been tested in in the form of bis (hydrogen maleate). Its acute toxicity in mice by intravenous administration, LDj ₀ = 70 mg / kg.

At a subcutaneous dose of 5 mg / kg, the substance protects 50% of guinea pigs in the experiment from the lethal effect of a 5 mg / kg dose of histamine administered intra -ugularly. At concentrations of 1 to 10µg / ml it reduces to 50% the spasms of isolated rat duodenum induced by standard barium chloride concentration. values. At doses higher than 4 mg / kg i.v. induces ataxia in mice and reduced locomotor activity for 30 min.

The compounds of the invention of formula 1 are accessible by reducing the corresponding unsaturated piperazinoalkanols of formula 11,

(II), wherein R is the same as in Formula 1. For the reduction, hydroiodic acid in boiling acetic acid in the presence of red phosphorus is preferably used. The resulting oily bases of formula (I) are purified either by chromatography or by crystallization in the form of a maleic acid salt, obtained by neutralizing the crude bases with this acid. The starting materials of the formula II are partly known, partly new. Substance 11, R = H, has been described (Dutch Pat. Appl. 64/7758; Fr.pat. 88 751, 3rd Amendment to Pat. 1,449,569), but is poor in the literature cited. characterized, its method of preparation is described in the example.

Compound II, R = Cl, is novel and its preparation is also described in the example.

All of the novel compounds described in the invention - both end products and intermediate products - were analytically and spectrally assured. The following examples are merely illustrative of the preparative methods that can be used to synthesize the compounds of the invention; it is not intended to describe all possible preparative methods.

Example 1

1- (3- / 6,11-Dihydrodibenzo (b, e) thiepin-11-yl / propyl) -4- (2-hydroxyethyl) piperazine

A mixture of 5.0 g of (E) -1- (3- / 6,1 1-dihydrodibenzo (b, e) thiepin-11-ylidene) propyl-4- (2-hydroxyethyl) oiperazine, 15 ml of acetic acid, 5 ml of 55 ® hydroiodic acid and 2.0 g of red phosphorus were refluxed for 5 hours, after cooling, the mixture was filtered, the filtrate was diluted with water and extracted with benzene, washed with water, sodium carbonate solution and water again, dried The inhomogeneous residue is dissolved in 25 ml of ethanol and a solution of 3.0 g of maleic acid in 15 ml of ethanol is added to the hot solution, and after standing overnight, the precipitated bis (hydrogen maleate) is filtered off with suction and purified by crystallization from ethanol; 2.4 g (30%), m.p. 145-146.5 ° C.

Although the initial unsaturated amino alcohol has been described (cited) in the literature, it is better to proceed as follows:

A mixture of 25.0 g of (E) -11- (3-bromopropyl) -6,11-dihydrodibenzo (b, e) thiepine (Rajsner M. et al., Gollect. Czech. Chem. Commun. 44. 2536, 1979) . 34.0 g of 1- (2-hydroxyethyl) piperazine and 65 ml of chloroform are stirred and refluxed for 3 hours. The mixture is diluted with 100 ml of chloroform, filtered with charcoal, the filtrate is washed with water and the bases are extracted by shaking into a solution of 25 ml of hydrochloric acid in 175 ml of water. The aqueous layer was again filtered with charcoal, the filtrate basified with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue, which is crude (E) -1- (3- / 6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine, is dissolved in 150 ml of ethanol. and the solution was neutralized with 16.8 g of maleic acid in 60 ml of ethanol. On standing and cooling, 28.2 g (61%) of bis (hydrogenic maleate) melting at 154-155 ° C crystallized. An analytical sample was obtained by recrystallization from ethanol, m.p. Mp 155-156 ° C. Pure oily base was prepared in theoretical yield by decomposition of this salt with aqueous ammonia, extraction with ether and evaporation of the extract.

Example 2

1- (3- / 2-Chloro-6,1) -hydrodibenzo (b, e) thiepin-11-yl / propyl) -4- (2-hydroxyethyl) piperazine

A mixture of 13.5 g of (E) -1- (3- / 2-chloro-6,11-dihydrodibenzo (b, e) thiepin-11-ylidene / propyl) -4- (2-hydroxyethyl) piperazine, 60 ml of acid acetic acid, 42 ml of 55% hydroiodic acid and 5.6 g of red phosphorus were stirred and refluxed for 5 h. After standing overnight, it is filtered, the filtrate is diluted with water, basified with 20% sodium hydroxide solution and extracted with chloroform. The extract was washed with water and evaporated under reduced pressure.

A hot solution of 8.0 g of maleic acid in 45 ml of ethanol was added to the residue, and after standing overnight the maleate precipitate was filtered off with suction and recrystallized from water.

The product (inhomogeneous) melting at 162-164 ° C is obtained. Quench with aqueous ammonia, isolate the base with chloroform extraction and chromatograph on a 150 g neutral alumina column (activity II). Elution with benzene gave 4.5 g (33%) of a homogeneous base, yielding 4.8 g of bis (hydrogen maleate), m.p. 182 DEG-184 DEG C. (80% aqueous ethanol).

The starting aminoalcohol is a novel compound which can be prepared as described above from the known 2-chlorodibenzo (b, e) thiepin-11 (6H) -one (Rajner M. et al., Czech Farm. 11. 45 ', 1226). :

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A solution of Grignard's reagent is prepared by reacting 4.7 g of magnesium with 25.0 g of cyclopropyl bromide (Meek JS, Osuga D. Τ., Org. Syn., Coll. Vol. 5 '26, 1973) in 100 ml of tetrehydrofuran (see Register). M. et al., Collect. Czech. Chem. Commun. 44, 2536, 1979). The reagent solution was cooled to room temperature and a warm solution of 25.9 g of 2-chlorodibenzo (b, e) thiepin-11 (6H) -one in 100 ml of tetrahydrofuran was added dropwise over 1 h with stirring. The mixture was refluxed for 1 h, cooled in an ice bath, and quenched with slow addition of 135 mL of saturated ammonium chloride solution with stirring. The mixture was extracted with ether, extract. It is washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated.

Upon standing the residue crystallized overnight to give 26.7 g (92%) of crystalline 2-chloro-: 11-cyclopropyl-6,11-dihydrodibenzo (b, e) thiepin-11-ol melting at 124-127 ° C. Recrystallization of the sample from a mixture of benzene and patrol ether gave an analytically pure material, m.p. 129-131 ° C.

A stirred solution of 10.0 g of the preceding alcohol in 170 ml of acetic acid was added dropwise over 30 minutes at 10-15 ° C with 85 ml of a 15% solution of hydrogen bromide in acetic acid. The mixture is left at room temperature for 24 h, filtered with charcoal, the filtrate is diluted with 200 ml of water and extracted with benzene. The extract was washed with water, dried (MgSO4) and evaporated. The residue crystallizes upon dilution with cyclohexane. 9.0 g (75%) of crude (E) -11- (3-bromopropyl) -2-chloro-6,11-dihydrodibenzo (b, e) thiepine are obtained, which is recrystallized from a mixture of cyclohexane and hexane to give then in the pure state as melting at 109-111 ° C.

A mixture of 5.0 g of the above bromo derivative, 6.0 g of 1- (2-hydroxyethyl) piperazine and 10 ml of chloroform was stirred and refluxed for 3 hours. The mixture is then diluted with 50 ml of chloroform, filtered with charcoal, the filtrate is washed with water and then extracted with a solution of 10 ml of hydrochloric acid in 60 ml of water. The aqueous layer was filtered with charcoal, the filtrate was basified with aqueous ammonia, and the product was extracted with dichloromethane. The extract was dried over potassium carbonate and evaporated. The oily residue is dissolved in 50 ml of ethanol and the residue is neutralized with a solution of a calculated amount of maleic acid in ethanol. Standing and cooling led to crystallization, yielding 5.2 g (59%) of bis (hydrogen maleate) (S) -1- (3- (2-chloro-6,11-dihydrodibenzo) (b, e) thispin-11-ylldene) propyl) -4- (2-hydroxyethyl) piperazine; Zine, m.p. Mp 163-165 ° C. crystallization from a mixture of ethanol and ether ss gives pure melting at 165-166 ° C. Decomposition of this salt with aqueous ammonia and extraction with chloroform gave a base melting at 121-122 ° C (benzene-petroleum ether). By neutralizing this base with methanesulfonic acid in ethanol, a dimethanesulfonate melting at 206 DEG-208 DEG C. (ethanol-ether) can be obtained.

Claims (1)

P fi E D U £ T IN THE INVENTION Piperazinoalkanols dibenzo (b, e) thiapine series of formula I, R (I). wherein R is a hydrogen atom or a chlorine atom, and their salts with malelic acid. Severography, n. P., MOST Price 2,40 Kčs