CS202337B1 - Method of proparing pharmacodynamically effective 11-/dimethylamino-alkylthio/-6,11dihydro-dibenzo/b,e/thiepine - Google Patents

Description

The present invention relates to a process for the preparation of the pharmacodynamically active 11- (dimethylamino-alkylthio) -6,11-dihydrodibenzo (b, e) thiepines of the general formula I

s (GH ₂ ) n (CH ₃ ) _and wherein n represents 2 or 3, as well as their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of formula I and their salts are characterized by peripheral neurotrophic activity and as such are useful as pharmaceuticals. They were tested in the form of hydrochloride by parenteral administration. The acute toxicity of the hydrochlorides of the two compounds of the invention in mice is expressed by the mean lethal dose LD ₅₀ - = 50 mg / kg when administered iv. Both compounds in the form of a 1% solution show a significant local anesthetic effect in the corneal anesthesia test. Both have anticholinergic effects, manifested in their mydriatic effect (effective dose of 5-10 mg ip) and their spasmolytic effect on isolated rat duodenum against acetylcholine spasms (effective concentration 0.1 to 1.0 µg / ml) . In a similar test, they also show a spasmolytic effect of papaverine character, i.e. against spasms induced by barium chloride (effective concentration 1 to 10 µg / ml). The compound of formula I wherein n is 2 furthermore exhibits a useful antihistamine effect in a guinea pig histamine detoxification test (a dose of 5 mg / kg sc protects 50% of guinea pigs from a lethal dose of histamine, i.e. 5 mg / kg, administered intra -ugularly). The same compound shows some potentiation of thiopental sleep in mice, suggesting a centrally depressant effect (a dose of 0.5-1.0 mg / kg iv prolongs thiopental sleep to twice the control value).

The preparation of some compounds of the formula I has already been described in the literature (P. Dostert, M. Jalfre, Eur. J. Med. Chem.-Chim. Therap. 9, 259, 1974). The preparation method used consisted of reacting 11-chloro-6,11-dihydrodibenzo (b, e) thiepines with dimethylaminoalkanethiols. This process had the disadvantage that in the preparation of a series of substances it was necessary to separately synthesize the appropriate dimethylamino monoalkanothiols from the corresponding aminoalkyl halides by at least two steps.

It has now been found that it is preferable to use the unwritten 6,11-dihydrodibenzo (b, ejthiepine-11-thiol of formula II) as a universal intermediate

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202 337, which then condense with easily accessible dimetylaminoalkylchloridy formula III (CH _3/2 N / _{CH2) n} Cl (III) in which n means the same as in formula I according to the invention.

The desired thiol of formula II is obtained from the known 11-chloro-6,11-dihydrodibenzo (b, e) thiepine (V. Seidlová et al., Monatsch. Chem. 96, 650, 1965), which first alkylates the thiourea and the hydrochloride obtained. S- (6,11-dihydrodibenzo (b, e) thiepin-11-yl) isothioureas of formula IV

is cleaved by heating with an aqueous alkali metal hydroxide solution. The resulting aqueous solution provides the desired thiol of formula II by acidification.

The process according to the invention is characterized in that the 6,11-dihydrodibenzo (b, ejthiepine-11-thiol of the formula II in the form of an alkali metal salt, preferably sodium salt) is reacted with the dimethylaminoalkyl chlorides of the formula III in an organic solvent, for example in a mixture of ethanol and ether, at the boiling point of the reaction mixture, whereupon the oily bases of the formula I obtained are converted into salts by neutralization with pharmaceutically acceptable inorganic acids.

Particularly preferred for pharmacological tests and for the preparation of dosage forms are the hydrochlorides, which crystallize well, have excellent water-solubility and are sufficiently stable.

The following examples are only illustrative of the preparation possibilities of the present invention but are not intended to exhaust all of these possibilities.

Examples

1. 11- (2-Dimethylaminoethylthio) -6,11-dihydrodibenzofb, (e) thiepine (I, n = 2)

0.83 g of sodium metal is dissolved in 30 ml of absolute ethanol and a solution of 8.7 g of 6,11-dihydrodibenzo (b, e) thiepine-11-thiol (II) in 30 ml of anhydrous ether is added under stirring. After stirring at room temperature for 15 minutes, a solution of 8.5 g of 2-dimethylaminoethyl chloride in an additional 30 ml of ether was added dropwise over 40 minutes. The reaction mixture was then refluxed for 4 hours and evaporated under reduced pressure. The residue is quenched with 100 ml of water and extracted with benzene. From the benzene extract, the basic portion is transferred to the aqueous phase by shaking with dilute hydrochloric acid, released again by alkalization with excess 5M sodium hydroxide, and isolated by extraction with dichloromethane. The extract was dried over anhydrous potassium carbonate and evaporated. 8.1 g (72%) of an oily desired base are obtained, which does not crystallize after prolonged standing. It is dissolved in 30 ml of ethanol and neutralized with ethereal hydrogen chloride solution. On standing, 8.1 g of the hydrochloride precipitated, which crystallized from a mixture of ethanol and ether in the pure state at 201-202 ° C.

The required starting 6,11-dihydrodibenzo (b, e) thiepine-11-thiol is prepared as follows:

To a solution of 17.0 g of thiourea in 260 ml of ethanol was added 38.5 g of 11-chloro-6,11-dihydrodibenzo (b, e) thiepine, and the mixture was refluxed for 8.5 hours with stirring. After standing overnight, the precipitated S- (6,11-dihydrodibenzo (b, e) thiepin-11-yl) isothiourea hydrochloride was filtered off with suction, washed with a small amount of ether and dried in vacuo to give a yield of 37.0 g (72 g). It melts at 169-172 ° C and is analytically pure because recrystallization from a mixture of ethanol and ether does not increase the melting point.

A mixture of 16.2 g of S- (6,11-dihydrodibenzo (b, e) thiepin-11-yl) isothiourea hydrochloride and 80 ml of 5M sodium hydroxide is refluxed under a hydrogen atmosphere for 5 hours. After shaking, the benzene layer was separated, dried over magnesium sulphate and evaporated in vacuo to give 8.7 g (71%) of a viscous liquid which was a crude 6,11-dihydrodibenzoate ( b, e) thiepine-11-thiol, which is used for further work in this state, suitable for its characterization is the appropriate disulfide, which is formed very easily by oxidation with atmospheric oxygen, it is a crystalline substance with mp 198 ° C with decomposition (benzene- petroleter).

2. 11- (3-Dimethylaminopropylthio) -6,11-dihydrodibenzo {b, ej-thiepine

0.49 g of sodium is dissolved in 10 ml of absolute ethanol and the solution is added

5.2 g of crude 6,11-dihydrodibenzo (b, e) thiepine-11-thiol in a mixture of 5 ml of ether and 5 ml of ethanol, and after stirring for 10 minutes, a solution of 2.6 g of 3-dimethylaminopropyl chloride in 10 ml eteru. The mixture was refluxed for 6 hours and then worked up analogously to Example 1. 3.3 g of an oily base were obtained, which was neutralized with hydrogen chloride in a mixture of ethanol and ether. Crystalline hydrochloride is obtained, which crystallizes from a mixture of ethanol and ether and melts in the pure state at 208-208.5 ° C.

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SUBJECT OF THE INVENTION

Claims (1)

SUBJECT OF THE INVENTION A process for the preparation of pharmacodynamically active 11- (dimethylaminoalkylthio) -6,11-dihydrodibenzo (b, ejthiepines of the general formula I with (οη _ζ ) ν (οη ₃ ) _α in which n denotes 2 or 3, and their salts with pharmaceutically acceptable inorganic or organic acids, characterized in that the 6, ll-dihydro-dibenzo (b, ejthiepin-l-thiol of the formula II in the form of an alkali metal salt, preferably a sodium salt, is fed to the reaction with dimetylalkylchloridy formula III [CH _3/2 N / CH _{2) n} Cl (III) in which n has the same meaning as in formula I, in an organic solvent, for example a mixture of ethanol and ether, at the boiling temperature of the reaction mixture and then the obtained oily base of formula I optionally are converted by neutralization pharmaceutically harmless inorganic or organic acids for salts.