CS211103B1 - Methoxy- and hydroxy-derivatives of 2-chloro-9- (3-dimethylaminopropylene) thioxanthene - Google Patents

Abstract

The invention describes new methoxy- and hydroxy-derivatives of 2-chloro-9-(3-dimethylaminopropylidene)thioxanthene and their salts with pharmaceutically acceptable inorganic or organic acids, both in the form of mixtures of geometric isomers and in the form of isolated individual cis- or trans-isomers. These substances are non-cataleptic tranquilizers with very mild acute toxicity. The examples describe their preparation from methoxy-substituted 2-(4-chlorophenylthio)benzoic acids or methoxy-substituted 2-(arylthio)-5-chlorobenzoic acids. These acids are first cyclized to methoxy-substituted 2-chlorothioxanthones, which are subjected to the action of 3-dimethylaminopropylmagnesium chloride in the second step. methoxy-substituted 2-chloro-9-(3-dimethylaminopropyl)thioxanthen-9-ols are obtained. These alcohols are further converted by acid-catalyzed dehydration to methoxy derivatives of 2-chloro-9-(3-dimethylaminopropylidene)thioxanthene. Demethylation to hydroxy derivatives of 2-chloro-9-(3-dimethylaminopropylidene)thioxanthene can be carried out, for example, with boron tribromide or by heating with pyridine hydrochloride. Using this last reaction, the last two steps of the synthetic process can be combined and hydroxy derivatives of 2-chloro-9-(3-dimethylaminopropyl)thioxanthen-9-ols can be obtained directly.

Description

The present invention relates to novel methoxy and hydroxy derivatives of 2-chloro-9- (3-dimethylaminopropylidene) thioxanthene of the formula I,

CH ₂ CH ₂ N (CH ₃ ) ₂ wherein R represents inethoxyl or hydroxyl at the 3, 4, 6 and 7 position of the aromatic nuclei of the thioxanthene skeleton, and their salts with pharmaceutically acceptable inorganic or organic acids.

Substances of general formula. they are mild tranquillizers, free of cataleptic activity and mostly with very low toxicity. This differs from the compound of formula I where R = H, which is a known neuroleptic preparation of chlorprothixene (see J. 0. Jílek et al., Czech. Farm. Gg,

294, 1965). which has a considerable degree of cataleptic activity and accordingly exhibits undesirable extrapyramidal reactions. Among the compounds according to the invention, for example, 2-chloro-7-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene, which has been tested in the form of hydrogen maleate transformation (in this case and in other cases, the amounts calculated are based on).

It is a very toxic substance; its mean lethal dose of LD 50 when administered orally to mice is greater than 500 mg / kg.

The median effective dose of EDjq, which induces ataxia in mice in the rotating rod test when administered orally, is 55 mg / kg. In the rat catalepsy test, the median effective dose of ED50 is greater than 50 mg / kg when administered orally. 2-Chloro-3-methoxy-9- (3-dimethylaminopropylidene) thioxanthene was tested as the bisulfate of a mixture of cis- and trans-form when administered orally.

LD? Q = 320 mg / kg, ED? Q in the rotating rod test is 115 mg / kg, and in the catalepsy test, ED? Q is greater than 50 mg / kg.

2-Chloro-4-methoxy-9- (3-dimethylaminopropylidene) thioxanthene also tested as hydrogensulphate mixture of cis and trans forms: ^ ₀ LD = 440mg / kg; ED 50 in the rotating rod test = 128 mg / kg; in a catalepsy assay, the ED50 is greater than 50 mg / kg (mostly oral).

2-Chloro-6-methoxy-9- (3-dimethylaminopropylidene) thioxanthene was also tested as cis- and trans-form bisulfate: LD 50 q = 400 mg / kg; ED 50 in the rotating rod test is 110 mg / kg; in a catalepsy assay, the ED50 is greater than 50 mg / kg (mostly oral).

2-Chloro-7-methoxy-9- (3-dimethylaminopropylidene) thioxanthene was tested as the hydrogen maleate of the mixture of cis and trans forms: LD ^ ₀ = 350 mg / kg, ΕΏ ^ θ in the rotating rod test is 80 mg / kg in catalepsy test is greater than 50 mg / kg (all oral administration). 2-Chloro-4-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene, tested in the form of the cis-form hydrogen maleate, showed some cataleptic activity: LD = 250 mg / kg; in the catalepsy test ΕΏ ^ θ = 50 mg / kg (oral administration). 50

The preparation of the compounds of formula (I) is described in the Examples. They are four to five-step synthetic procedures, based on the methoxy substituted 2- (4-chlorophenylthio) benzoic IX (II) CH ₃ o

COOH

Cl or from the methoxy-substituted 2- (arylthio) -5-chlorobenzoic acids of formula III

HOOC Cl

Acids of formulas II and III which are already cyclized from the step by treatment with sulfuric acid or 2-chlorothioxanthone-fatty acid of formula IV

O

The cyclization with sulfuric acid is slowly carried out already in (III) literature known in the first polyphosphoric on the methoxysubstate (IV) at room temperature and relatively rapidly at elevated temperature, e.g. at 100 ° C. At elevated temperatures, however, sulfonation leading to water-soluble by-products is sometimes used as a side reaction. Thus, while at lower temperatures ketones IV are obtained in low yield and some of the starting acids of formulas II and III are regenerated, lower yields due to side reactions tend to be lower at higher temperatures. Polyphosphoric acid cyclization proceeds smoothly at temperatures of 100 to 50 ° C and is not accompanied by undesirable side reactions.

In the second step, the ketones of formula IV are treated with 3-dimethylaminopropylmagnesium chloride, i.e., a Grignard reagent prepared from 3-dimethylaminopropyl chloride and magnesium. The preparation of this Grignard reagent in tetrahydrofuran has been described in the literature (M. Protiva et al., Collect. Czech. Chem. Commun. JJ, 2161, 1964). After decomposition of the reaction mixture with ammonium chloride solution, the tertiary alcohols of formula V are obtained as products

HO (CH ₂ ) ₃ N (CH ₃ ) ₂

These alcohols of formula (V) can then be converted to acid-catalyzed dehydration to compounds of formula (I) wherein R = OCH 2. The acid-catalyzed dehydration is preferably performed by heating with dilute mineral acids, e.g., 10% sulfuric acid. The compounds of formula I, R = OCH2, are formed as mixtures of the cis and trans forms (geometric isomers). These mixtures can be separated by fractional crystallization of bases or salts or can be used as such.

Different demethylation methods can be used to convert the compounds of formula I, R = OCHp to compounds of formula I, R = OH, for example. · For example, demethylation can be carried out by reaction with boron tribromide in dichloromethane or chloroform at room temperature; This can be accomplished by heating with pyridine hydrochloride at 190 to 200 ° C or can also be achieved by heating with hydrogen bromide in acetic acid.

Aminoalcohols of the formula I can also be dehydrated and demethylated simultaneously by heating with pyridine hydrochloride, so that the compounds of the formula I, R = OH, are formed directly. These phenolic bases also result in the form of mixtures of geometric isomers, which can either be used in the form of salts as such, or of crystalline bases or salts, or else by chromatography of the bases into the pure cis and trans forms.

The final compounds of formula (I) are basic in nature and provide neutralization by acids to provide salts which are generally more advantageous than the free bases for pharmacological testing and for the preparation of dosage forms. Salts with pharmaceutically acceptable inorganic or organic acids which simultaneously crystallize well are particularly suitable for this purpose. The examples describe hydrochlorides, sulfates, maleates, oxalates, etc.

He did

2-Chloro-3-methoxy-9- (3-dimethylaminopropylidene) thioxanthene

A mixture of 9.06 g of 2-chloro-3-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol, 60 ml of water and 6.4 ml of sulfuric acid is refluxed for 1.5 hours. After cooling, the solution was basified with 50 ml of 20% aqueous sodium hydroxide solution and the crude base was isolated by extraction with benzene. Treatment of the extract gave 8.4 g (98%) of the desired base as a mixture of geometric isomers. It is dissolved in 25 ml of ethanol and neutralized by the addition of 2.42 g of sulfuric acid. On standing, 9.6 g of hydrogen sulphate with m.p. 192-197 ° C crystallized. Crystallization from ethanol gave a melting point of 199 - 201 ° C.

The starting material 2-chloro-3-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol is new and is best obtained as follows:

A mixture of 39.2 g of 2- (4-chloro-3-methoxyphenylthio) benzoic acid (I. Red et al.,

Collect. Czech. Chem. Commun. 42. 1705. 1977) and 225 ml of sulfuric acid are stirred for 2 hours at 40 DEG C. and then poured into a mixture of 900 g of ice and 900 ml of water. The precipitated solid is filtered off with suction, suspended in 10% sodium hydroxide solution and stirred for 10 min at 50 ° C. It is then filtered again, washed with water, dried in vacuo and crystallized from 4.5 l of benzene. 30.9 g (84%) of 2-chloro-3-methoxythioxanthone, melting at 233-234 ° C, is obtained.

The Grignard reagent is prepared by reacting 27.2 g of 3-dimethylaminopropyl chloride with 5.4 g of magnesium in 70 ml of tetrahydrofuran using small amounts of iodine and 1,2-dibromoethane to start the reaction. The finished Grignard reagent was cooled with a mixture of ice and water and a suspension of 31 g of 2-chloro-3-methoxythioxanthone in 150 ml of tetrahydrofuran was added over 15 minutes with stirring. The mixture was then stirred for 1 h at room temperature and allowed to stand overnight at room temperature. It is decanted by pouring into 120 ml of 20% ammonium chloride solution and the product is extracted with chloroform. The extract was dried over magnesium sulfate, evaporated and the residue crystallized from ethanol. 31.5 g of the desired 2-chloro-3-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol, melting at 179-181 ° C, is obtained.

Example 2

2-Chloro-3-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene

A mixture of 210 g of pyridine hydrochloride and 16.0 g of 2-chloro-3-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol (see Example 1) was heated at 190 ° C for 1 h and the melt partially cooled Dilute with water, filter, filter the filtrate with a solution of 80 g of sodium hydroxide in 150 ml of water and extract with benzene. The extract was dried (MgSO4), evaporated and the residue crystallized from aqueous acetone. 9.7 g (6%) of the desired base solvate with half of the acetone molecule melting at 98-103 ° C are obtained. The infrared spectrum indicates that it is predominantly a trans-isomer. Neutralization with sulfuric acid yields crystalline hydrogen sulfate, which crystallizes from a mixture of acetone and ether and melts at 182-190 ° C.

Example 3

2-Chloro-4-methoxy-9- (3-dimethylaminopropylidene) thioxanthene

2-Chloro-4-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol (9.1 g) was dehydrated similarly to Example 1 by boiling with a solution of 18 g sulfuric acid in 70 ml water. Similar work-up gave 8.6 g (99%) of a glassy mixture of geometric base isomers. By neutralizing with sulfuric acid, this mixture provides crystalline hydrogen sulfate, melting at 188-190 ° C (ethanol).

r

The starting material 2-chloro-4-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol is new and is best obtained by the following procedure:

A mixture of 70 g of 2- (4-chloro-2-methoxyphenylthio) benzoic acid (J. 0. Jílek et al .;

Collect. Czech. Chem. Commun. (1978, 1747, 1978) and 600 g of polyphosphoric acid are stirred at 135 ° C for 3 h. It is then quenched with 3 L of water, left to stand overnight, the precipitated product is filtered, suspended in 1.2 L of 5% sodium hydroxide solution at 100 ° C, after cooling it is filtered again, washed with water and dried. The crude product is crystallized from 950 ml of xylene. 50 g (76%) of 2-chloro-4-methoxythioxanthone crystallized, melting at 209-210 ° C.

Reaction of 11.0 g of 2-chloro-4-methoxythioxanthone with 3-dimethylaminopropylmagnesium chloride (from 12.0 g of 3-dimethylaminopropyl chloride and 2.4 g of magnesium) in 100 ml of tetrahydrofuran was carried out similarly as described in Example 1 for the isomeric compound. The mixture was refluxed for 1 h, allowed to stand overnight and the tetrahydrofuran was evaporated completely in vacuo. The residue was dissolved in 100 ml of benzene, quenched with 50 ml of 5% ammonium chloride solution and separated ee. The organic layer was shaken vigorously with 225 ml of dilute hydrochloric acid (containing 25 ml of concentrated acid) and the benzene layer was separated. The aqueous phase containing the oily hydrochloride precipitated is made alkaline with ammonium hydroxide, the precipitated crystalline base is filtered and dried; 12.8 g (88%) of 2-chloro-4-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol, melting at 141-145 ° C. Crystallization from ethanol gave a pure material, melting at 146 ° C.

Example 4

2-Chloro-4-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene

A solution of 2-chloro-4-methoxy-9- (3-dimethylaminopropylidene) thioxanthene (3.45 g) in 30 ml of dichloromethane was added dropwise over 30 minutes to a stirred solution of 6.25 g of boron tribromide in 30 ml of dichloromethane under external ice cooling. The mixture was allowed to stand at room temperature for 2 days, quenched with 60 mL of water, stirred for 1 h, basified with 10% sodium carbonate solution and extracted with dichloromethane. The extract was evaporated and the residue dissolved in 70 ml of 3% sodium hydroxide solution. The solution was heated at 100 ° C for 1 h, filtered and the filtrate was neutralized dropwise with acetic acid. The precipitated solid is filtered off with suction after standing overnight, washed with water, dissolved in 70 ml of boiling ethanol, filtered and the filtrate is evaporated in vacuo. The residue is 2.3 g (66%) of the desired base monohydrate, melting at 20 to 25 ° C.

According to the spectra, it is a mixture of geometric isomers.

Example 5

2-Chloro-4-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene

The mixture, 70 g pyridine hydrochloride α, 5 g 2-chloro-4-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol (Example 3) was heated at 190 ° C for 1 h. After partial cooling, the melt is dissolved in 400 ml of water, the solution is filtered, a solution of 55 g of sodium hydroxide in 100 ml of water is added and extracted with benzene. The extract is shaken with excess dilute hydrochloric acid, the oily hydrochloride precipitated is collected by decantation, quenched with 5% sodium hydrogen carbonate solution and the product is extracted with dichloromethane. The extract was evaporated, the residue was dissolved in benzene and petroleum ether was added. On standing, 4.0 g (29%) of the trans-base crystallized, which melted in the pure state at 187 DEG -90 DEG C. (benzene-ethanol). Neutralization with maleic acid affords crystalline hydrogen maleate crystallizing from a mixture of acetone and ether and melting at 92-195 ° C.

1.2 g (9%) of cis-base having a melting point of 82-84 ° C (benzene), which gives the hydrogen maleate, melting at 190-192 ° C (acetone-ether), is precipitated from the benzenetretrol ether mother liquor.

Examples

2-Chloro-6-methoxy-9- (3-dimethylaminopropylidene) thioxanthene

2-Chloro-6-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol (10.0 g) was refluxed with a solution of 20 mL sulfuric acid in 100 mL water for 1.5 h. The mixture is worked up as in the previous examples. The crude product obtained (9.5 g) was crystallized from petroleum ether; 3.45 g (36%) of the trans isomer are obtained, m.p. 76-79 ° C. Neutralization with sulfuric acid gives crystalline hydrogen sulfate sulfate hemihydrate, melting at 181-183 ° C (ethanol).

The starting 2-chloro-6-methyl-9- (3-dimethylaminopropyl) thioxenthen-9-ol is new and is best obtained as follows:

A mixture of 30 g of 2- (4-chlorophenylthio) -4-methoxybenzoic acid (K. Šindelář et al.,

Collect. Czech. Chem. Commun. 22, 3548 (1974)) and 240 g of polyphosphoric acid are stirred for 3 hours at 125-135 [deg.] C. and treated similarly to the synthesis of the 4-methoxyisomer (Example 3). 25.3 g (90%) of 2-chloro-6-methoxythioxanthone, melting at 211 DEG-212 DEG C. (xylene), are obtained.

The reaction of 16.6 g of 2-chloro-6-methoxythioxanthone with 3-dimethylaminopropylmagnesium chloride (from 18.0 g of 3-dimethylaminopropyl chloride and 3.5 g of magnesium) in 150 ml of tetrahydrofuran was carried out similarly to the previous examples. 19.9 g (90%) of 2-chloro-6-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol melting at 153-154 ° C (ethanol) is obtained.

Example 7

2-Chloro-6-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene

A solution of 3.45 g of 2-chloro-6-methoxy-9- (3-dimethylaminopropylidene) thioxanthene in 30 ml of dichloromethane is added dropwise over 45 min to a stirred and cooled solution of 7.5 g of boron tribromide in another 30 ml of dichloromethane. The mixture was stirred at room temperature for 6 h and, after standing overnight, quenched with cooling with 60 ml of water, stirred for 1 h and slightly basified with 10% sodium carbonate solution. The layers were separated, the organic phase was evaporated and the residue was heated to 100 ° C with 70 ml of 3% sodium hydroxide solution for 1 h. After cooling, the solid was filtered off and the filtrate was neutralized with acetic acid. The precipitated product is filtered off with suction, extracted with 100 ml of boiling ethanol, the insoluble material is removed by filtration and the filtrate is evaporated.

1.2 g (34%) of cis-base monohydrate are obtained, melting at 98-105 ° C.

Example

2-Chloro-6-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene

A mixture of pyridine hydrochloride (16 g) and 2-chloro-6-methoxy-9- (3-dimethylaminopropylidene) thioxanthene (Example 6) (1.60 g) was heated at 200 ° C for 1.5 h. The melt is dissolved in 100 ml of water, the solution is filtered, 20% sodium carbonate solution is added to the filtrate until neutral and the product is extracted with dichloromethane. The extract is evaporated and the residue is crystallized by mixing with a small amount of benzene; 0.40 g (26%) of cis-base, mp 200-202 ° C (benzene). Neutralization provides a) a hydrochloride which crystallizes from a mixture of benzene and ethanol as a half-molecule solvate of benzene, mp 217-218 ° C, b) hydrogen maleate, mp 188-190 ° C (acetone-ethanol-ether).

Example 9

2-Chloro-6-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene.

• 'i

11103

A solution of 5.0 g of 2-chloro-6-methoxy-9- (3-dimethyleminopropyl) thioxanthen-9-ol (Example 6) in 30 ml of acetic acid is saturated with anhydrous hydrogen bromide for 10 min and the mixture is refluxed for 3 h. continuous saturation with hydrogen bromide. After standing overnight, boil for a further 3 hours, dilute with 70 ml of acetic acid and cool. The precipitated crystals are filtered off with suction, dissolved in water and the solution is neutralized with 20% sodium carbonate solution. The precipitated product is filtered and recrystallized from benzene; 0.58 g (13%) of cis-base, m.p. 200-202 ° C (benzene).

Example, 0

2-Chloro-7-methoxy-9- (3-dimethylaminopropylidene) thioxanthene

2-Chloro-7-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol (19.7 g) was dehydrated by boiling for 2 h with a solution of 20.5 ml sulfuric acid in 200 ml water. Working up as in the previous examples yielded 17.1 g (9.1%) of an oily mixture of geometric base isomers. Neutralization with hydrogen chloride gives the hydrochloride monohydrate, which crystallizes from a mixture of 2-propanol and ether and melts at 145-52 ° C. In addition, crystalline hydrogen maleate, melting at-130 to 35 ° C (2-propanol-ether), can be prepared by neutralizing the base. Crystalline is hydrogen hydrogel oxalate, m.p. 82-86 ° C (ethanol-ether).

The starting 2-chloro-7-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol is new and can be prepared, for example, by the following procedure:

A mixture of 22.7 g of 5-chloro-2- (4-methoxyphenylthio) benzoic acid (V. Valenta et al., Collect. Czech. Chem. Commun., ±, 3607, 1976) and 110 ml of sulfuric acid is stirred for 4 hours. 5 h at 20 ° C. It is then poured into 0.75 kg of ice-water and the product is extracted with chloroform. The extract was washed with 2.5M sodium hydroxide, dried over potassium carbonate and evaporated. 7.5 g (35%) of 2-chloro-7-methoxythioxanthone, melting at 88 DEG-89 DEG C. (ethanol-toluene), are obtained.

The reaction of 16.0 g of 2-chloro-7-methoxythioxanthone with 3-dimethylaminopropylmagnesium chloride (from 22 g of 3-dimethylaminopropyl chloride and 4.3 g of magnesium) in 110 ml of tetrahydrofuran was carried out similarly to the previous examples. The mixture was quenched with 150 ml of 20% ammonium chloride solution and extracted with benzene. 20.2 g (9%) of 2-chloro-7-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol, melting at 72 DEG-175 DEG C. (ethanol), was obtained.

They did

2-Chloro-7-hydroxy-9- (3-dimethylaminopropylidene) thioxanthene

A mixture of 100 g of pyridine hydrochloride and 10 g of 2-chloro-7-methoxy-9- (3-dimethylaminopropyl) thioxanthen-9-ol was heated at 190 ° C for 1 h. The melt is dissolved in 300 ml of water, the solution is filtered, basified with 20% sodium carbonate solution and the product is extracted with benzene. The extract is dried over magnesium sulphate, evaporated and the residue crystallized from benzene. 2.6 g (29%) of trans-base are obtained, melting at 2.6-217 ° C (benzene-ethanol). Neutralization with maleic acid affords crystalline hydrogen maleate, melting at 41-44 ° C (acetone-ether).

Claims (1)

SUBJECT OF THE INVENTION Methoxy and hydroxy derivatives of 2-chloro-9- (3-dimethylaminopropylidene) thioxanthene of the general formula I, CHCHCH ₂ n (CH ₃ ) ₂ wherein R stands for methoxy or hydroxyl at the 3, 4, 6 and 7 position of the aromatic nuclei of the thioxanthene skeleton , and salts thereof with pharmaceutically acceptable inorganic or organic acids.