CS202229B1 - 2-isopropyl-6-fluor-9-/3-dimethylaminopropyliden/thioxanthene - Google Patents

Description

This invention relates to 2-isopropyl-6-fluoro-3- (3-dimethylaminopropylidene) thioxanthene of formula I (I)

and its salts.

Compound I and its salts have central neurotrophic activity and are useful as drugs in psychiatry and neurology. Their typical property is centrally damping activity, which is not accompanied by cataleptic effect. They are therefore tranquilizers for which minimal side effects can be expected. They are useful for calming restless neurotic patients and counteract phobias, fear and anxiety.

For the pharmacological evaluation in animals (mice, rats), hydrogen maleate of substance I was used. It is a substance of low toxicity. Its mean lethal dose for mice by oral administration of LD ₅₀ is 280 mg / kg. The centrally depressant effect can be found primarily in a rotating rod test in mice in which an oral dose of 6.3 mg / kg induces ataxia (impaired locomotor coordination) in 50% of the animals (ED ₅₀ dose). This effect of the substance is prolonged because at 24 hours after administration, ataxia is detectable in 20% of animals (dose range, 2.5 to 20 mg / kg). Another test that can demonstrate the depressant effect of a substance is the beam method of monitoring the effect of spontaneous locomotor activity in mice. In this test, the median effective dose of D ₅₀ is equal to

1.5 mg / kg; this dose reduces the locomotor activity of the animals to 50%. At the same time, Compound I is virtually ineffective cataleptically since, in the rat catalepsy test, its median effective dose is greater than 50 mg / kg when administered orally. Accordingly, an oral dose of 40 mg / kg did not affect apomorphine stereotype and agitation in rats. Both indicate that the substance is not a neuroleptic but a non-cataleptic tranquilizer.

Furthermore, compound I (in the form of said hydrogen maleate) has some antimicrobial activity. In in vitro assays it has an antimicrobial action against the following microorganisms, with the appended numbers being the minimum inhibitory concentration in µg / ml: Streptococcus faecalis, 25; Staphylococcus pyogenes aureus, 25; Mycobacterium tuberculosis H37Rv.5; Saccharomyces pasterianus, 6.2; Trichophyton mentagrophytes, 25; Candida alblcans 100; Aspergillus niger, 50.

In an exemplary embodiment, one possible method of preparing Compound I and its salts is described. This method is based on the known

202 229

202 229 2-bromo-4-fluorobenzoic acid (M. Rajšner et al., Collect. Czech. Chem. Commun. 40, 728, 1975) and also known 4-isopropylthiophenol (V. Valenta et al., Collect. Chem. Commun. 39, 797 (1974). In the first step, both compounds are condensed by heating in dimethylformamide in the presence of anhydrous potassium carbonate and copper catalyst. There was thus obtained 4-fluoro-2- (4-isopropylphenylthio) benzoic acid, which was cyclized by treatment with concentrated sulfuric acid at 100 DEG C. to give 2-isopropyl-6-fluorothioxanthone. Hydrolysis of the primary product yields crystalline 2-isopropyl-6-fluoro-9- (3-dimethylaminopropyl) thioxanthen-9-ol. Base I, i.e. 2-isopropyl-6-fluoro-9- (3-dimethylaminopropylidene) thioxanthene, is obtained as an oily mixture of geometric isomers, i.e. cis and trans isomers. The oily base provides crystalline hydrogen by neutralization with maleic acid maleate, which is obtained in practically uniform form by repeated crystallization and, owing to the absence of a cataleptic effect, can be attributed to the trans configuration. 127 DEG-132 DEG C. and dissolved in water at room temperature to a 2% solution. It is better soluble in ethanol and is eliminated from the solution by addition of ether. The second geometric isomer, ie the cis isomer, accumulates in the mother liquors.

Example

15 g of 4-isopropylthiophenol are dissolved in 40 ml of dimethylformamide and 19.6 g of 2-bromo-4-fluorobenzoic acid, 25 g of anhydrous potassium carbonate and 1.5 g of freshly reduced copper are gradually added. The mixture was heated to 150 ° C with stirring for 3 hours. After cooling, it is strongly diluted with water, acidified with dilute hydrochloric acid and the precipitated product is isolated by extraction with chloroform. The extract was dried over sodium sulfate and evaporated. Crystallization of the residue from a mixture of benzene and petroleum ether or cyclohexane gave 18.3 g (71%) of 4-fluoro-2- (4-isopropylphenylthio) benzoic acid which, after recrystallization from ethanol, had mp 201-202 degrees Celsius.

A mixture of 18.2 g of the previous acid and 100 ml of conc. of sulfuric acid was heated to 100 ° C for 35 minutes. After cooling, it is poured into 750 ml of water, the precipitated solid product is filtered off with suction, dissolved in chloroform, washed with 5% sodium hydroxide solution, dried over potassium carbonate and evaporated. 16.1 (94%) of 2-isopropyl-6-fluorothioxanthone are obtained, which, after crystallization from ethanol, has a melting point of 116-117 ° C.

Reaction of 2.7 g of magnesium with 14 g of 3-dimethylaminopropyl chloride in 35 ml of absolute tetrahydrofuran gives a solution of the Grignard reagent, i.e. 3-dimethylaminopropylmagnesium chloride. To this solution was added dropwise at room temperature with stirring

15.6 g of the previous ketone in another 35 ml of tetrahydrofuran. The mixture was stirred at room temperature for 30 minutes and quenched by dropwise addition of 100 ml of 20% ammonium chloride solution under cooling with water. The mixture is then extracted with benzene. The aqueous phase is separated, the organic phase is dried over potassium carbonate and evaporated under reduced pressure. Crystallization of the residue from a mixture of 42 ml of benzene and 100 ml of petroleum ether gave 12.0 g (58%) of 2-isopropyl-6-fluoro-9- (3-dimethylaminopropyl) thioxanthen-9-ol, which melted at 146 DEG C. up to 148 ° C.

To a solution of 9 ml of sulfuric acid in 90 ml of water was added 11.5 g of the preceding aminoalcohol and the mixture was refluxed for 1 hour. After cooling, it is diluted with water, basified with ammonium hydroxide and the base isolated by extraction with ether. The extract was dried over potassium carbonate and evaporated. 11 g of an oily mixture of cis- and trans-2-isopropyl-6-fluoro-9- (3-dimethylaminopropylidene) thioxanthene are obtained. By neutralization with maleic acid in ethanol and addition of ether, 10.0 g of crystalline hydrogen maleate having a melting point of 125 DEG-130 DEG C. were obtained. After recrystallization from a mixture of ethanol and ether, the salt is practically homogeneous and melts at 127-132 ° C.

Claims (2)

OBJECT OF THE INVENTION and salts thereof with pharmaceutically acceptable inorganic or organic acids, preferably hydrogen maleate. 2-Isopropyl-6-fluoro-9- (3-dimethylaminopropylidene) thioxanthene of the formula