CS211104B1 - Aminoketone Thioxanthene Series - Google Patents

Abstract

The invention relates to a new 1-(2-chlorothioxanthen-9-yl)-3-dimethylaminopropan- -|-one and its salts with pharmaceutically acceptable acids. The named substances exhibit, with adequate toxicity, a whole range of neurotropic effects, which make them potential neurotropic drugs, in particular local anesthetics and spasmolytics. The example describes one of the possible methods of preparing the named base and its hydrobromide, which consists in a two-stage synthesis. In the first stage, a solution of cis-2-chloro-9-(3-dimethylaminopropylidene) thioxanthene hydrochloride in aqueous acetic acid is treated with hydrochloric acid and then with a bromide-bromate reagent, i.e. a mixture of a bromide solution and potassium bromate. Alkalization yields 9-bromo-2-chloro-9-(1-hydroxy-3-dimethylaminopropyl)thioxanthene, which, upon heating to 130 C, splits off hydrogen bromide and directly provides the hydrobromide of the desired product.

Description

The invention relates to an aminoketone of the thioxanthene series of formula I,

i.e. 1- (2-chlorothioxanthen-9-yl) -3-dimethylaminopropan-1-one, and its salts with pharmaceutically acceptable acids.

The compound of formula I and its salts exhibit a variety of neurotrophic effects that make them potential at reasonable toxicity (LDg _Q when administered intravenously to mice = 60 mg / kg). neurotrophic drugs, especially ocular anesthetics and spasmolytics. Compound I was used as the hydrobromide in in vitro and animal tests. In guinea pig infiltration anesthesia, a 0.25% concentration of the substance in aqueous solution induces complete anesthesia in 50% of the animals; the substance therefore has approximately four times more intense activity than procyin.

In an isolated in vitro cover duodenum assay, the concentration of 0.5 µg / ml was found to induce a 50% reduction in acetylcholine contractions; it is about 10% efficiency compared to atropine. Concerning the muscotropic spasmolytic effect, the compound of formula I is equal to papaverine: both compounds at a concentration of 5 µg / ml reduce the barium chloride contractions of the isolated rat duodenum to 50%.

Further, the compound of Formula I slightly potentiates the effect of thiopental; at doses of 5-12 mg / kg intravenously prolonged sleep duration after a standard dose of thiopental to twice the control value. The substance also significantly inhibits the growth of some microorganisms - minimum inhibitory concentrations with <µg / ml are given: Staphylococcus pyogenes aureus 12.5; Mycobacterium tuberculosis 50; Saccharomyces pasterianus 3.1; Trichophyton mentagrophytes 1.5; Candida albicans

The compound of formula (I) is preparatively accessible by the procedure detailed in the example. It is a two-step synthetic process wherein the starting material is cis-2-chloro-9- (3-dimethylaminopropylidene) thioxanthene, a known neuroleptic preparation of chlorprothixene. To the hydrochloride of this compound of formula II

ΟζΟ, ch (ch ₂ ) ₂ n (ch ₃ ) ₂ is treated with a bromate bromide reagent, ie a mixture of a solution of bromide and potassium bromate, in a mixture of acetic acid and hydrochloric acid, and after alkalization of the reaction mixture -2-chloro-9- (1-hydroxy-3-dimethylaminopropyl) thioxanthene of formula III

(III)

OH

By heating the compound of formula III to 130 ° C - either in the substance or in an inert solvent - dehydrobromination is carried out, resulting in the desired compound, i.e. the aminoketone of formula I.

Example 1 a d

To a solution of 10.0 g of cis-2-chloro-9- (3-dimethylaminopropylidene) thioxanthene hydrochloride (J. 0. Jílek et al., Cesk. Farm. 1, 294, 1965) in 50 ml acetic acid and 50 ml 5 ml of hydrochloric acid and a solution of 10 g of potassium bromide in 20 ml of water are added. To the stirred mixture was then added dropwise a solution of 1.58 g of potassium bromate in 50 ml of water at room temperature over 15 minutes. The solution was stirred for 30 min under ice-cooling, basified with ammonium hydroxide, and the precipitated solid was filtered off with suction, washed with water and dried in vacuo. 11.7 g (100%) of crude 9-bromo-2-chloro-9- (1-hydroxy-3-dimethylaminopropyl) thioxentene are obtained, m.p. Crystallization from ether gave the pure material, melting at 107.0 ° with decomposition.

The product obtained (16.5 g) is heated at 130 DEG C. for 2 hours, the cooled melt is treated with 20 ml of acetone and filtered off with suction. 6.0 g (36S6) of 1- (2-chlorothioxanthen-9-yl) -3-dimethylaminopropan-1-one hydrobromide are obtained, which crystallizes from a mixture of ethanol, acetone and ether and melts in the pure state at 192 DEG-194 DEG. C.

Claims (1)

SUBJECT OF THE INVENTION Aminoketone of the thioxanthene series of formula I, (I) γ COCH ₂ CH ₂ N (CH ₃ ) ₂ ie 1- (2-chlorothioxanthen-9-yl) -3-dimethylaminopropan-1-one, and its salts with pharmaceutically acceptable acids.