CS236384B1 - Polychlorinated 9- (3-dimethylaminopropylidane) thioxanthenes, their salts and their method of preparation - Google Patents

Abstract

in which R , Fr and R-^ are the same or different and represent a hydrogen atom or a chlorine atom, their salts with pharmaceutically acceptable acids, as well as a method for their preparation. The substances of formula I and their salts show a high degree of inhibitory activity against microorganisms, especially against cocci, so that they can be considered as potential chemotherapeutics for infectious diseases. The method for preparing the substances of formula I consists in the S-catalyzed dehydration of the correspondingly chlorinated 9-(3-dimethylaminopropyl) thioxanthen-9-ols.

Description

The invention relates to polychlorinated 9- (3-dimethylaminopropylidene) thioxanthenes of the general formula I,

Wherein R, R and R are the same or different and denote a hydrogen atom or a chlorine atom, their salts with pharmaceutically acceptable acids, and the process for their preparation,

Literature (Petersen PV et al., Arzneim-Forsch. 8, 395, 1958; Nielsen IM et al., Acta Pharmaco. Oxicol. 19, 87, 1962; Jílek JO et al., Czech Pharm. 14, 294, 1965; Metyš J. et al., Czech Pharm. 15, 526 (1966) discloses 9- (3-dimethylaminopropylidene) thioxanthene and its 2-chloro derivative as neurotrophic and psychotropic drugs with tranquilizing and neuroleptic activity. For the 2-chloro-6-fluoro derivatives of this series, neuroleptic efficacy lasting longer after administration has been reported (Rajšner M. et al., Collect.Czech.Chem.Commun. 40, 719, 1975; Federal Republic of Germany 2,335,359; Belg. (* / 808,347). It has now been found that by introducing several (at least three) chlorine atoms into the 9- (3-dimethylaminopropylidene) thioxanthene molecule at the positions indicated in formula I, central effects disappear and instead a high degree of antimicrobial activity occurs, easily detectable in in vitro tests. in vitro, which makes these substances potential chemotherapeutic agents for infectious diseases.

A typical compound of the invention is 1,2,4-trichloro-9- (3-di-2,236,384)

2 (methylaminopropylidene) thioxanthene (I, R = Cl, R = R = H), which was evaluated as methanesulfonate (monohydrate). Acute toxicity in mice, LD ₅₀ = 75 mg / kg i.ν.χ At 15 mg / kg iv, it does not show centrally depressant, discoordination and antiamphetamine activity in mice and does not potentiate the effect of thiopental; it does not act cataleptically in rats at the same dose. It has only a short-term hypotensive effect in rats and has mild adrenolytic activity. In in vitro assays it exhibits a high degree of inhibitory activity against several microbial species, particularly cocci. The microorganisms tested and the minimum inhibitory concentrations found in µg / ml are shown: Streptococcus ® haemolyticus, 3; Streptococcus faecalis, 6; Staphylococcus pyogenes aureus, 3; Escherichia co li 12; Proteus vulgaris, 50; Saccharomyces pasterianus, 50; Trichophython menta grophytes, 50. The reliability of activity against Staphylococcus pyogenes aureus has been demonstrated by testing on twenty different strains of this organism; minimum inhibitory concentration from 3 to 6 µg / ml.

The process for the preparation of the compounds of the invention consists of the acidic primary alcohols of the formula

I, which is also subject to catalysed dehydration of terII.

(II)

3, wherein R, R and R are the same as in formula X. As shown in the examples, this reaction is carried out by heating with dilute sulfuric acid or hydrochloric acid, optionally in the presence of a water-miscible organic solvent. As such, acetic acid, tetrahydrofuran, ethanol, methanol and the like can be used. In the manner described in the examples, the compounds of formula I are obtained as bases which are converted into crystalline salts by neutralization with inorganic or organic acids and purified in this form by crystallization. The bases released from the pure salts by alkalization are homogeneous and partly crystallized

- 3 licky. According to the infrared spectra (area of extra-plane vibrations at 700 to 900 cm @ -1) they belong to the (E) -configuration (judged by the position of the branch chain and the chlorine atoms at positions 1 and 2. This means that the acid catalyzed dehydration of alcohol II is predominant sterically advantageous geometric isoraers ·

The starting aminoalcohols of formula (II) are novel, the preparation of which is described in the examples. The examples serve to illustrate the possibilities of the invention, but are not intended to fully describe these possibilities. The identity of all novel compounds of the invention (end products and intermediates) was assured by analyzes and spectra.

Example I

1.2.4-Trichloro-9- (3-dimethylaminopropylidene) thioxanthene.

1.2.4-Trichloro-9- (3-dimethylaminopropyl) thioxanthen-9-ol (8.5 g) was refluxed for 1.5 h with a solution of 13 g sulfuric acid in 60 ml water. After cooling the mixture was basified with 10% sodium hydroxide solution and the base was extracted with benzene ₀ extract was washed with water, dried over magnesium sulfate, filtered with charcoal and the filtrate is evaporated under reduced pressure. The residue was dissolved in 25 ml of ethanol, a small amount of insoluble matter was removed by filtration, and the filtrate was again evaporated in vacuo. 6.6 g (81%) of an oily mixture of geometric isomers of the desired compound are obtained. Dissolve in 11 ml of ethanol, add 2.1 ml of 34% hydrochloric acid and 20 ml of ether. The precipitated hydrochloride is filtered off after 30 minutes and recrystallized from a mixture of ethanol and ether. 4.1 g (46%) of the hydrochloride (E% isomeku * mp 254 DEG-256 DEG C.) are obtained.

113 DEG-114 DEG C. (benzene-petroleum ether). Neutralization of this base with methanfulphonic acid gave a crystalline methanesulfonate which crystallized from a mixture of 96% ethanol and ether as the monohydrate, m.p. Mp 88-90 ° C.

The starting 1,2,4-trichloro-9- (3-dimethylaminopropyl) thioxanthen-9-ol is a novel and not yet described substance which can be prepared from known starting materials by the following procedure:

To a stirred solution of 31 g of potassium hydroxide in 300 ml

238,384 water was added successively with 25 g 2,4,5-trichlorothiophenol (D.R.P.

562 503; BritJ '72 87 178; Cherntsov O.M., Mur V.I., Zh.Ochsch.Chim.

29, 2271 (1959), 29.1 g of 2-iodobenzoic acid and 1.0 g of copper catalyst and the mixture is refluxed for 14 h.

After standing overnight, the solid was filtered and dried. Acidification of the filtrate gave 4.0 g of the desired compound (fraction A). The dried solid is boiled several times with benzene, the undissolved potassium salt is finally filtered and decomposed by heating with 80 ml of hydrochloric acid to 80 ° C. After dilution with water, the mixture is left overnight at room temperature, fraction A is added, sucked off, washed with water and recrystallized from acetone by filtering the warm solution to remove the copper. 32.0 g (82%) of 2- (2,4,5-trichlorophenylthio) benzoic acid melting at 248-252 ° C is obtained. The analytical product was obtained by further crystallization from acetone, m.p. 253 DEG-254 DEG.

To 300 g of sulfuric acid heated to 95 ° C was added with stirring 30 g of the previous acid and the mixture was heated and stirred for 30 min. After cooling, it is poured into 2.5 l of ice-cold water and allowed to stand overnight. The precipitated product is isolated by filtration, washed with water and dried. 27.0 g (95%) of crude are obtained

1,2,4-trichlorothioxanthone, m.p. 190-195 ° C. The pure product is obtained by crystallization from acetic acid, m.p. Mp 203-206 ° C.

Reaction of 3.2 g of magnesium and 16.0 g of 3-dimethylaminopropyl chloride in 80 ml of tetrahydrofuran was prepared by Grignard reagent (a small amount of iodine and ethyl iodide was used to start the reaction). A suspension of 20.8 g of the previous ketone in 120 ml of tetrahydrofuran was added to the prepared reagent solution over 1 h at room temperature, and the mixture was then refluxed for 12 h. The solvent was evaporated, the residue was quenched with 400 mL of 10% ammonium chloride solution and extracted with benzene. The extract was washed with water, dried over magnesium sulfate, filtered with charcoal, and the filtrate was evaporated. The residue was dissolved in 50 ml of warm benzene and a small amount of solid which precipitated by cooling was removed by filtration. The filtrate was then evaporated under reduced pressure and the residue crystallized from a small volume of benzene. 15.0 g (68%) of 1,2,4-trichloro-9- (3-dimethylaminopropyl) thioxanthen-9-ol, melting at 102 DEG-106 DEG C., is obtained. to 125 ° C.

Example II ^236,384

2,4,5,6-Tetrachloro-9- (3-di-ethylaminopropylidene) thioxanthene

To a solution of crude 2,4,5,6-tetrachloro-9- (3-dimethylaminopropyl) thioxanthen-9-ol prepared from 3.6 g 2,4,5,6-tetrachlorothioxanthone in 25 ml tetrahydrofuran was added 60 ml 1: 3 dilute hydrochloric acid was added and the mixture was refluxed for 1 h. After cooling, it was basified with 20% sodium hydroxide solution and extracted with chloroform. The extract was dried over potassium carbonate and evaporated. The crude oily base obtained (2.6 g, 60%) was dissolved in 5 ml of ethanol and 0.4 g of oxalic acid dihydrate was added. The mixture is briefly heated to boiling and then allowed to crystallize at room temperature.

After standing to the next day, 1.2 was obtained by filtration. g of hydrogen oxalate melting at 160-165 ° C. The other three crystallizations from ethanol yield a homogeneous salt with a melting point of 180-182 ° C. A sample of this salt is decomposed with 5% sodium hydroxide solution and the homogeneous oily base is isolated by extraction with ether; its IR spectrum showed (E) -configuration.

The starting 2,4,5,6-tetrachloro-9- (3-dimethylaminopropyl) thioxanthen-9-ol is a novel and not yet described substance which can be prepared from the starting materials described as follows:

10.2 g of sodium are dissolved in 220 ml of tert-butyl alcohol, and 40.8 g of 2,3-dichlorothiophenol (Mahajanshetti CS et al., J. Karnatak Univ. 6, 9, 1961; (59, 8636, 1963), 73 g of acid

3,5-dichloro-2-iodobenzoic acid (Valenta V. et al., Collect. Chem. Chem. Commun. 46, 781, 1981) and 3.4 g of copper as catalyst. The mixture was stirred and refluxed for 8 h. It is then partially evaporated under reduced pressure, filtered with activated carbon, the filtrate is diluted with water and acidified with hydrochloric acid. The precipitated product is filtered after standing overnight and purified by crystallization from aqueous ethanol. 49.0 g (62%) of 3,5-dichloro-2- (2,3-dichlorophenylthio) benzoic acid melting at 177-180 ° C is obtained. Analytically pure sample, m.p. 183 DEG-185 DEG C. (benzene).

A mixture of 10.0 g of the previous acid and 100 g of polyphosphoric acid was heated to 150 ° C with vigorous stirring for 1 h. After cooling, it is diluted with water and ice, the precipitated product is isolated by filtration, washed with water and dried. 9.6 g (96%) of 2,438,6,6-tetrachlorothioxanthone melting at 254 DEG-259 DEG C. were obtained. This product can be used for further work without further purification.

To obtain a pure substance, a sample (1.0 g) was crystallized from 500 ml of acetic acid; m.p. M.p. 277-278 ° C.

A solution of Grignard reagent was prepared from 0.88 g of magnesium and 3.9 g of 3-dimethylaminopropyl chloride in 20 ml of tetrahydrofuran, to which 5.6 g of the previous ketone was added with stirring.

The mixture was refluxed for 2 h and left at room temperature overnight. Quench with a solution of 8.0 g of ammonium chloride in 30 ml of water and extract with benzene. The extract was washed with water, dried (MgSO4) and evaporated. On standing, 5.4 g (77%) of 2,4,5,6-tetrachlor-9- (3-dimethylaminopropyl) thioxanthen-9-ol crystallized, melting at 205-211 ° C. An analytical sample was obtained by recrystallization from a mixture of benzene and petroleum ether, m.p. Mp 212-214 ° C.

Claims (2)

SUBJECT OF THE INVENTION 236 384 1. Polychlorinated 9- (3-dimethylaminopropylidene) thioxanthenes of the general formula I, CL (i) Wherein R, R and R are the same or different and represent a hydrogen atom or a chlorine atom, and their salts with pharmaceutically acceptable acids. 2. A process according to claim 1, characterized in that the tertiary compounds of the formula I according to item 1 are characterized by Wherein R, R and R are the same as in Formula I, they undergo acid catalysed dehydration, preferably by heating with dilute mineral acid solutions.