CS224810B1 - 3-alkyl-9-/3-dimethylaminopropylidene/-thioxanthenes and their salts - Google Patents

Description

The invention relates to 3-alkyl-9- (3-dimethylaminopropylidene) thioxanthenes of Formula L _R (I) in which R represents methyl or ethyl, and ⁿ having I and a pharmaceutically acceptable organic or inorganic acids.

The compounds of formula I, and in particular their salts, possess pharmacodynamic activity which makes them useful as medicaments. Thus, antihistamines are primarily useful in the treatment of allergic diseases. Furthermore, they have the properties of non-cataleptic or weakly cataleptic neuroleptics, so that they are suitable for use in the therapy of schizophrenic psychoses, and are expected to have fewer undesirable side effects than standard drugs of this type. In addition, they also exhibit antireserpine effects, so that they are also potential thymoleptics useful in the treatment of depressive states. In particular, the properties of the compounds according to the invention as found in the pharmacological evaluation in animals are as follows:

3-Methyl-9- (3-dimethylaminopropylidene) thioxanthene was tested as hydrochloride hemihydrate. Acute toxicity was determined in white mice, LD ^ 15 mg / kg i.v. In a rotating rod test in mice, the substance exhibits an incoordinating action; the mean ED50-inducing ataxia active agent is about 3 mg / kg i.v. In i.v. at 3 mg / kg, the substance is ineffective in the catalepsy test in rats. In contrast, it exhibits antihistamine

224 fi effect in guinea pig histamine detoxification test; the median effective dose that protects 50% of the animals from the lethal effect of histamine is between 0.1 and 0.5 mg / kg by subcutaneous administration.

At doses higher than 3 mg / kg i.v. the substance inhibits the activity and reactivity of the mice.

3-Ethyl-9- (3-dimethylaminopropylidene) thioxanthene was tested in the form of hydrogen fumarate, Acute oral toxicity in mice, LD 50 between 200 and 300 mg / kg (toxic symptoms are excitations and signs of convulsions). In the rotating rod test in mice, the compound has an incoordinating effect only at higher doses; ED ^ ₀ is about 135 mg / kg orally. At an oral dose of 50 mg / kg, it induces catalepsy in 40% of rats. Antihistamine effect in the guinea pig detoxification test; PD? Q - 10 mg / kg orally. There is also a high antihistaminic effect in the histamine aerosol test in guinea pigs; PD ^ g - 2 mg / kg orally. At an oral dose of 100 mg / kg, the substance has a statistically significant protective effect in the ulcerogenic effect test of reserpine in rats. Furthermore, it acts antire-. serpin in the reserpine hypothermia antagonist test in mice at an oral dose of 10 mg / kg *

The compounds according to the invention are accessible by acid-catalyzed dehydration of the tertiary alcohols of general formula 11

COT ^h ° ^A W ₃ n (oh ₅ ° (II)).

wherein R is the same as in Formula I. This acid-catalyzed dehydration is performed by heating with dilute sulfuric acid or hydrochloric acid. The resulting mixtures of the geometric isomers of the olefinic amines of formula I, which can be partially separated by crystallizing the salts of the compounds of formula I. The pharmacological values indicated do not relate to the individual Z- or E-isomers, but to mixtures thereof as re-sterilized acids. The compounds of formula II are novel and their preparation methods are described in the examples.

While the bases of formula I - being mixtures of geometric isomers - are mostly oily, their salts, obtained in dehydration reactions in 224 810, are also crystalline in the form of mixtures and by repeated crystallization, substances enriched in one of the possible isomers can be obtained, respectively. even substances homogeneous in this respect. In addition to the analyzes, spectra were used to characterize the products, but even for homogeneous substances they could not decide on the double bond configuration. This would require a crystallographic X-ray diffractometric study, which was not within the scope of the present invention.

Example 1

3-Methyl-9- (3-dimethylaminopropylidene) thioxanthene

To a solution of 8.4 g sulfuric acid in 42 ml water was added 6.0 g 3-methyl-9- (3-dimethylaminopropyl) thioxanthen-9-ol and the mixture was refluxed for 1.5 h. After cooling, the solution was basified with 20% sodium hydroxide solution and the product was extracted with benzene. The extract was washed with water, dried (MgSO4) and filtered with charcoal. Evaporation of the filtrate gave 5.5 g (97%) of an oily base (mixture of Z- and E-isomer). Dissolve in 10 ml of ethanol and neutralize with

2.2 ml of hydrochloric acid. By adding 12 ml of ether, 3.5 g of crystalline hydrochloride melting at 156 DEG-161 DEG C. were formed. In this form the substance was used for pharmacological tests. Repeated crystallization from ethanol / ether gives a homogeneous hydrochloride melting at 175-177 ° C; according to the analysis it is a hemihydrate. Decomposition of this homogeneous hydrochloride with ammonium hydroxide and extraction with ether yields a homogeneous base which is still oily.

The starting 3-methyl-9- (3-dimethylaminopropyl) thioxanthene-9ol is a novel compound which can be prepared as follows:

To a stirred solution of 118 g of 85% potassium hydroxide in 1100 ml of water was added successively 68 g of 3-methylthiofepol (D.S, Tarbell and D.K.Pukushima, Org.Syn ,, Coll. Vol. J, 809, 1955).

133 g of 2-iodobenzoic acid (W. Wachter, Ber.Deut.Chem, Ges.

26, 1744, 1893) and 2 g of copper catalyst and the mixture was refluxed for 14 h. After cooling, it is filtered with charcoal and the filtrate is acidified with hydrochloric acid. After cooling and standing overnight, the product was filtered, washed with water and recrystallized from 330 ml of ethanol. 85 g (65%) of 2- (3-methylphenylthio) benzoic acid, melting at 172 DEG-172 DEG, were obtained

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175 ° C, Recrystallization from ethanol gave a pure material melting at 178-179 ° C,

A mixture of 73 g of the previous acid and 680 g of sulfuric acid was stirred for 30 min and heated to 95 ° C. After cooling, it is poured onto 4 kg of ice, the solid product is filtered, washed with water, suspended in 350 ml of 5% sodium hydroxide solution, the suspension is stirred for 20 minutes, filtered again and washed with water. After drying under vacuum, 35 g (52%) of 3-methylthioxanthone are obtained, which contains a minor amount of isomeric 1-methylthioxanthone.

By reaction of 1.8 g of magnesium with 9.0 g of 3-dimethylaminopropyl chloride in 60 ml of ether (starting the reaction with an iodine bead and 0.2 g of ethyl bromide), a Grignard reagent solution was prepared. Its preparation is completed under reflux for 4 hours. After cooling, the solution is diluted with 50 ml of ether and 8.4 g of the previous ketone are added with stirring over 10 minutes. The mixture was diluted with 80 ml of benzene and refluxed for 18 h. After cooling, the reaction is quenched by the dropwise addition of 100 ml of 10% ammonium chloride solution, stirred for 10 min, the aqueous solution is separated and extracted with ether. The organic phases were combined, washed with water and shaken with excess 1: 9 dilute hydrochloric acid. The separated aqueous hydrochloride solution was immediately basified with 20% sodium hydroxide solution and the product was extracted with benzene. The extract was dried (MgSO4) and evaporated. The residue (7.3 g, 63%), which crystallized on standing, was crude 3-methyl-9- (3-dimethylaminopropyl) thioxanthen-9-ol, m.p. Mp 113-118 ° C. Recrystallization from ethanol gave the pure product melting at 126-127 ° C, Example 2

3-Ethyl-9- (3-dimethylaminopropyl) thioxanthen-9-ol (11.8 g) was dehydrated by boiling with a solution of 17 g sulfuric acid in 85 ml water for 1.5 h. A similar treatment as in Example 1 was obtained

9.9 g (89%) of an oily base which is a mixture of the Z and E isomers. Neutralization with fumaric acid in ethanol yielded 9.3 g of hydrogen fumarate (mixture of isomers) melting at 163-166 ° C, which was used in pharmacological tests. Repeated crystallization from ethanol gave a homogeneous hydrogen fumarate melting at 182-184 ° C. By decomposing this homogeneous fumarate '5'

A sample of homogeneous base was prepared by 224 810 ammonium hydroxide and ether extraction, but was again oily. Its infrared spectrum shows a satellite band at 775 cm in the extra-plane vibration region, suggesting an E-configuration for this base.

The starting 3-ethyl-9- (3-dimethylaminopropyl) thioxanthen-9-ol is a novel compound which can be prepared by the following procedure.

With the exception of the first stage, this procedure is analogous to that described in Example 1.

By reacting 169 g of 3-ethylbromobenzene (Z-Horii, S. Yamamura, H. Hakusui, T. Hishikado and T. Momos, Chem.Pharm.Bull, 16, 2456, 1968) with 22.8 g of magnesium in 470 ml of ether. prepare a solution of Grignard reagent in a conventional manner; The reaction is completed by boiling the mixture for 2 h. Ib cooling to 5 to 7 ° C is added to the stirred solution under nitrogen atmosphere over 1 h a total of 22 g of sulfur flower in small portions. Stirring is continued for 2 h at room temperature, allowed to stand overnight and is quenched by stirring slowly by adding 320 ml of 1: 1 dilute hydrochloric acid. The organic layer was separated and the product was extracted into excess 10% sodium hydroxide solution. The aqueous alkaline phase is cooled to 5 to 8 ° C, overlaid with ether and slowly acidified with dilute hydrochloric acid 1 with stirring. The product was extracted with ether, dried over magnesium sulphate and distilled. 81 g (64%) of 3-ethylthiophenol boiling at 103-107 ° C / 50 mbar are obtained.

A mixture of a solution of 59 g of potassium hydroxide in 300 ml of water, g of 3-ethylthiophenol, 69.5 g of 2-iodobenzoic acid (literature cited) and 1 g of copper was refluxed for 19 h and worked up analogously to Example 1. 49 g (68%) of 2- (3-ethylphenylthio) benzoic acid melting at 125-127 ° C are obtained. Crystallization from a mixture of benzene and petroleum ether gave a pure material, melting at 128-130 ° C.

The previous acid (43.7 g) was cyclized by heating 400 g of sulfuric acid to 95 ° C for ‘30 min. After cooling and pouring into a mixture of 1.2 kg of ice and 0.8 kg of water, the product is extracted with benzene. The extract was washed with 5% sodium hydroxide solution and water, dried over magnesium sulfate and evaporated. The oily residue (38.5 g) is a mixture of the desired 3-ethylthioxanthone with isomeric

1-ethylthioxanthone. Dissolve in 40 ml of benzene and dissolve

224 810 'is chromatographed on a column of 540 g of neutral alumina (activity II). The petroleum ether is first eluted with 12.0 g

1-ethylthioxanthohu, m.p. Mp 74-78 ° C. Thereafter, 15.4 g (38%) of the somewhat more polar and desired 3-ethylthioxanthone are eluted with a mixture of petroleum ether and benzene, which crystallizes from petroleum ether and melts in the pure state at 54 to 56 ° C.

The reaction of the Grignard reagent, prepared from 3.6 g of magnesium and 18 g of 3-dimethylarainopropyl chloride in 200 ml of ether, with 18 g of the previous ketone in 100 ml of ether was carried out as in Example 1. ethyl-9 (3-dimethylaminopropyl) thioxanthen-9-ol, which crystallizes on standing. Crystallization from benzene is obtained pure and then melts at 112-113 ° C.

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Claims (2)

BACKGROUND OF THE INVENTION 3-Alkyl-9- (3-dimethylaminopropylidene) thioxanthenes (I), wherein R is methyl or ethyl, and their salts with pharmaceutically acceptable, inorganic or organic acids. Price: 2, M Kffs Printed by Moravian Printing Works, plant 12, Leninova 21, Olomouc