CS263982B1 - 4-/aminoalkoxy/dibenzo/b,e/thiepin-11/6h/-ones and hydrochlorides them - Google Patents

Abstract

The solution is within the synthetic field drugs. Its subject is 4- (aminoalkoxy) dibenzoyl-b, e / thiepin-11 (6H) -ones and their hydrochlorides, wherein the amino group is either dimethylamino or methylamino and alkyl represents - (CH 2) 3 - or · - (CH 2) 4 -. These substances and their hydrochlorides exhibit in pharmacological and biochemical models of activity that pro suggests antidepressant and cerebrotic efficacy for patients, especially higher age categories. Substances are prepared either by the reaction of the alkali salts of 4-hydroxydibenzo / b, ε-thiepin-11 (6H) -one with 3-dimethylaminoalkyl halides, or by 4- (bromoalkoxy) dibenzo / b, e / thiepin-11 (6H) -one reactions with methylamine. Prepared bases with neutralization with hydrogen chloride or hydrochloric acid converted to the hydrochlorides.

Description

The invention relates to 4- (aminoalkoxy) dibenzo [b, e] thiepin-11 (6H) -ones of formula I

wherein R is hydrogen or methyl and n is 3 or 4, and their hydrochlorides.

The compounds of the invention exhibit activity in pharmacological and biochemical-pharmacological models, which are considered to be predictive of antidepressant efficacy and for cerebral activation in patients, particularly of higher age categories. They can therefore be considered antidepressants and geronto-psychopharmaceuticals. A typical compound of the present invention is 4- (3-dimethylaminopropoxy) -dibenzo [eta] thiepin-11 (6H) -one, which has been tested in the form of hydrochlorides. Its acute toxicity in mice by oral administration is relatively low; The LD 50 is 473 mg / kg. In the maximum electroshock test in mice, the substance exhibits a seizure protective effect at an oral dose of 100 mg / kg in 50% of the animals. Furthermore, the compound has antireserpine activity in a rat test to evaluate the inhibitory effect on gastric ulcer induced by reserpiin. At an oral dose of 50 mg / kg, the compound exhibits a significant inhibitory effect (when co-administered with reserpine) .The antihypoxic effect of the compound was tested in a nitrogen anoxia test in mice, and an oral dose of 200 mg / kg increased the survival time. This result suggests a cerebroprotective effect of the substance, which may be useful in disorders of proper oxygenation of brain tissue in the elderly with symptoms of brain sclerosis.

The compounds of formula I are mainly accessible by two synthetic procedures. In the case of tertiary amines, ie compounds of formula I where R - CH3, the method of choice is a 4-hydroxydibenzo [b, e] thiepin-11 (6H) -one process which is converted by treatment with a metal alkoxide % of a lower aliphatic alcohol to the corresponding metal salt, which is then reacted at elevated temperature with dimethylaminoalkyl halides, preferably with 3-dimethylaminopropyl chloride or 4-dimethylaminobutyl bromide. The reaction is preferably carried out at the temperature of the respective solvent, i.e. in particular methanol or ethanol. After completion of the reaction, the formed alkali metal chloride or bromide is removed by filtration and the filtrate is treated on the basis of formula I (R = CH 3). This provides neutralization with hydrochloric acid or hydrochloric acid to provide the corresponding hydrochloride. The starting 4-hydroxydibenzo [b, e] thiepin-11 (6H) -one has not been described in the literature yet and is obtained by demethylation of the known 4-methoxydibenzo [b, e] thiepin-11 (6H) -one (Valenta V. et al. (Collect. Czech. Chem. Commun. 47, 984 (1982)) as described in the example. Of the metal alkoxides, sodium methoxide or ethoxide is preferably used.

For secondary amines of the invention (I, R-H), synthesis is preferred, which consists in reacting 4- (bromoalkoxy) dibenzo [b, e] thiepin-11 (6H) ones with methylamine in aqueous alcohol at room temperature. The starting bromoalkoxy compounds are also unknown and therefore the preparation of 4- (4-bromobutoxy) dibenzo [b, e] thiepin-11 (6H) -one by reaction of 4-hydroxydibenzo [b, e] thiepin-11 (6H) potassium salt is described in the example. -one with 1,4-dibromobutane.

The compounds of the formula I according to the invention are novel and their identity has been assured by both analytical and spectral methods. The following examples are merely intended to illustrate the preparation possibilities of the compounds of the invention and to provide their characteristic physico-chemical data (melting points).

Example 1

4- (3-dimethylaminopropoxy) dibenzo [b, e] thiepin-11 (6H) -one (I, R = CH3, n = 3) ·

Dissolve 1.9 g of sodium metal in 80 ml of absolute ethanol to prepare a sodium ethoxide solution, to which 6.4 g of 3-dimethylaminopropyl chloride hydrochloride are added and after 10 min. stirring 7.3 g of 4-hydroxydibenzo [b, e] thiepin-11 (6H) -one. The mixture was then refluxed for 11 h. After cooling, the precipitated salt is filtered off with suction and washed with benzene and ethanol. The filtrate was acidified with hydrochloric acid and evaporated to dryness under reduced pressure. The residue was partitioned between water and benzene, the aqueous phase basified with aqueous ammonia and the base extracted with benzene. The extract was dried over anhydrous potassium carbonate and evaporated under reduced pressure. The residue was 8.6 g (88%) of the crude desired base which crystallized on standing; mp 63-65 ^° C (cyclohexane). Neutralization with hydrogen chloride in ethanol / ether yields the hydrochloride, which crystallizes from this mixture and melts in the pure state at 172-175 ° C.

The starting 4-hydroxydibenzo [b, e] thiepin-11 (6H) -oin used is a novel substance which is prepared - as mentioned in the description - from the known 4-methoxydibenzo [b, e] thiepin-11 (6H) - as follows:

A mixture of 29.7 g of 4-methoxydiibenzo [b, e] thiidin-11 (6H) -one and 89 g of pyridine hydrochloride was heated with stirring at a bath temperature of 225-235 ° C for 45 min. After cooling to 60 ° C, the mixture is diluted with 400 g of water and ice and after standing for 1 h the precipitated solid product is filtered off. Dissolve in 500 ml of boiling ethanol, filter the solution with activated carbon and filter

263382 parí. The residue was crystallized from 250 ml of ethanol. There were obtained 24.7 g (88 ° / o J-4 hydroxydlbenzo (b, e) thiepin-ll (6H J-one, which melts at 180-185 C. ^CI completely pure material was obtained by recrystallization from methanol, mp 186th to 189 ° C.

Example 2

4- (4-Methylaminobutoxy) dibenzo [b, e] thiepin-11 (6H) -one (I, R = Η, n = 4)

To a solution of 10.1 g of 4- (4-bromobutoxy) dibenzo [b, e] thiepin-11 (6H) -one in 450 ml of ethanol was added 105 ml of a 41% aqueous methylamine solution and the mixture was stirred at room temperature for 7 h. After standing overnight an additional 95 ml of methylamine solution is added and stirring is continued for another 8 h. Ethanol is evaporated under reduced pressure, excess residue of 10% sodium hydroxide solution is added and the product is extracted with benzene. The extract was washed with 10% sodium hydroxide solution and water, and the base was transferred by shaking into 3M.-HCl. The acidic aqueous layer was separated, basified with aqueous ammonia, and the liberated base was isolated by extraction with chloroform. The extract was worked up to give 7.0 g (80%) of the desired base which crystallized on standing and melted at 73-70 ° C.

Claims (1)

Subject 78 ° C. The pure material is obtained by crystallization from a mixture of cyclohexane and hexane, m.p. 75-78 ° C. Neutralization with hydrogen chloride in methanol / ether gave the hydrochloride, which crystallized from methanol and melted at 215-218 ° C in pure form. The starting 4- (4-bromobutoxy) dibenzo [b, e] thiepin-11 (6H) -one used is a novel compound which is prepared - as indicated in the description - from 4-hydroxydibenzo [b, e] thiepin-11 (6H). ) -one (its preparation is described in Example 1) as follows: To a solution of 2.6 g of potassium hydroxide and 9.7 g of 4-hydroxydibenzo [b, e] thiepiyl-11 (6H-one) in 100 ml of methanol is added 17.6 g of 1,4-dibromobutane and the mixture is boiled under stirring 10.5 h under reflux. The solvent was evaporated under reduced pressure, the residue was partitioned between water and benzene, the benzene layer was washed with 10% sodium hydroxide solution, water, dried over potassium sulfate and evaporated under reduced pressure. Crystallization of the residue from a mixture of benzene and petroleum ether gave 10.1 g (67%) of the desired 4- (4-bromobutoxy) dibenzo [b, e] thlepin-11 (6H) -one, m.p. Completely pure material was obtained by recrystallization from a mixture of benzene and petroleum ether, mp 123-126 C. ^Q VYNALEZU 4- (aminoalkoxy) dibenzo [b, e] thiepin-11 (6H) -ones of formula I wherein R is hydrogen or methyl and n is 3 or 4, and their hydrochlorides.