CS225394B1 - S-Substitution Derivatives of 8-chloro- [alpha] (2-chloro-phenyl) -1-mercaptomethyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine - Google Patents

Abstract

The invention relates to S-substituted derivatives of 8-chloro-6-(2-chlorophenyl)-1-mercaptomethyl-4H-s-triazolo(4,3-a)-1,4-benzodiazepine of the general formula I, in which R denotes 2-dimethylaminoethyl, cyclohexyl, phenyl, tolyl, chlorophenyl, benzyl, furfuryl or pyridylmethyl, and their salts with pharmaceutically acceptable inorganic or organic acids.

Description

The present invention relates to 8-chloro-6- (2-chlorophenyl) -1-mercaptomethyl-1H-s-triazolo (4,3-a) -1,4-benzodiazepine derivatives of the general formula I, in which R is 2-dimethylaminoethyl, cyclohexyl, phenyl, tolyl, chlorophenyl, benzyl, furfuryl or pyridylmethyl, and their salts with pharmaceutically acceptable inorganic or organic acids.

The compounds of the invention of formula I and their salts are characterized by a combination of a high degree of discoordination activity and anticonvulsant activity, which makes them useful as anxiolytics, tranquillizers, sedatives, antiepileptics and hypnotics. All substances according to the invention are characterized by very low toxicity; neither acts lethal in mice at the administered maximum dose of 1 g / kg orally. The discoordination effect of the compounds was evaluated in mice in a rotating rod test; The following are the median effective dose (ED ₅₀ j at the time of maximum effect after oral administration to produce ataxia in 50% of animals. Next, as a criterion centrally buffer action in the case of a number of substances used in the inhibition of spontaneous locomotor activity in mice monitored beam method; presents Mean effective doses (D ₅ oj when administered orally, which reduce motility to 50% of the control value. Anti-convulsive efficacy has been studied in mice by oral administration in two tests: (1) as antagonizing convulsive and lethal action of pentetrazole ( (2) as an electroshock seizure inhibition (mean effective doses of ED ₅₀ that reduce seizures to 50% compared to the control group) another).

The individual substances according to the invention and their effects in the tests are given below. Alprazolam, i.e. 6-phenyl-8-chloro-1-methyl-4H-s-triazo2253S4 i

lo (4,3-a) -1,4-benzodiazepine having the pharmacological profile of anxiolytics and hypnotics (Castaner J., Chatterjee S. S., Drugs Future 1, 551, 1976; 2, 826, 1977; 4, 904 , 1979). It also has an LD _{50 of} greater than 1 g / kg when administered orally, and has an ED 50 of 1.0 mg / kg in the discoordination test; in locomotor activity inhibition assay ₅₀ D = 0.1 to 0.5 mg / '/ kg; in the anticonvulsant and lethal antagonist test, pentetrazole has an ED = 0.5-1.0 mg / kg.

8-Chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethylthiomethyl) -4H-s-triazolo (4,3-a) -1,4- benzodiazepine was tested as a base. In the discoordination test, ED ₅₀ = 1.1 mg / kg, in the pentetrazole antagonist test, ED is approximately 0.1 mg / kg, and in the electroshock convulsion inhibition test, PD ₅₀ = 0.26 mg / kg.

1- [Cyclohexylthiomethyl] -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. has been tested as base. In the discoordination test, it has an ED 50 of about 1 mg / kg, in the pentetrazole antagonist test, the ED is about 0.1 mg / kg, and in the electroshock convulsion inhibition test, PD _{5 (} = 0.19 mg / kg).

1- (Phenylthiomethyl) -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine was also tested as a base. 0.8 mg / kg, in the locomotor activity inhibition test it has a D _{50 of} 0.23 mg / kg, in the pentetrazole antagonist test it has an ED of 0.1 mg / kg and in the electroshock convulsion inhibition test it has an ED ₅₀ = = 0, 07 mg / kg.

S-Chloro-6- (2-chlorophenyl) -1- (4-tolylthiomethyl) -4H-triazolo (4,3-a) -1,4-benzodiazepine was also tested as a base. In the discoordination test, it has an ED 50 = 0.35 mg / kg, in the pentetrazole antagonist test ED = 0.01 to 0.1 mg / kg, and in the electroshock seizure inhibition test PD ₅₀ = 0.19 mg / kg.

8-Chloro-6- (2-chlorophenyl) -1- (4-chlorophenylthiomethyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine was tested as a base. In the ED ₅₀ discoordination test = 0.27 mg / kg, in the pentetrazole antagonist test ED = 0.01 to 0.1 mg / kg, in the electroshock seizure inhibition test PD ₅₀ - 0.23 mg / kg.

1- (Benzylthiomethyl) -8-chloro- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine was also tested as a base. In the discoordination test, ED ₅₀ = 0.40 mg / kg, in the locomotor inhibition test, the D50 is about 0.1 mg / kg, in the per.tetrazole antagonist test, the ED is 0.017 mg / kg, and in the electroshock seizure inhibition test PD _{5 (} | 0,31 mg / kg.

1- (2-Furfurylthiomethyl) -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine was tested as a base. In the ED ₅₀ discoordination test = 0.34 mg / kg, in the pentetrazole ED antagonist test 0.01-0.1 mg / kg, and in the electroshock convulsion inhibition test PD ₅₀ = 0.23 mg / kg.

8-Chloro-6- (2-chlorophenyl) -1- (3-pyridylmethylthiomethyl) -4H-s-trlazolo (4,3-a) -1,4-benzodiazepine was also tested as a base. ₅₀ = 0.56 mg / kg, in the pentetrazole antagonist test ED = 0.1 mg / kg, and in the electroshock seizure inhibition test PDsn = 0.15 mg / kg.

The literature discloses a large number of 1-substituted 6-aryl-8-chloro-4H-s-triazolo (4,3-a) -1,4-benzodiazepine derivatives (Hester JB Jr. et al., J. Med. Chem.) 14, 1078, 1971; 22, 1390, 1979; 23, 392, 402, 1980; Org. Chem. 44, 4165 (1979), but very few reports are of substances of this type whose 1-substituent contains a sulfur atom. Thus, the 1-mercapto-, 1-methylthio- and 1- (2-dimethylaminoethylthio) 8-chloro-6-phenyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine derivative (Hester J) has been described. , B, Jr. and VonVoigtlander P, lit. cit.), Which differ from the compounds of the present invention in that the sulfur atom is directly attached to the carbon of the skeleton at the 1-position and the absence of an important substituent at the o-position of the aryl Some disulfides which correspond to the general formula I but wherein R is an alkylthio, aralkylthio, arylthio and aminothio radical, as well as a hydrogen atom, an alkoxycarbonyl or an acyl group have also been described (Hirai K. et al., European Pat. Kokai Tokkyo Koho 79 / 119.449 (Chem. Abstract 92, 94 447, 111 071, 1980) and finally, in the preliminary communication, the table lists 8-chloro-6- (2-chlorophenyl) -1- (methylthiomethyl) -4H-s-triazolo (4,3- and -1,4-benzodiazepine, respectively, without synthesis method and chemical characterization (Hirai K. et al.). Pharmacobiodyn. 4 (6), S 88, 1981).

The compounds of formula I according to the invention can be obtained by the reactions of the known 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (Archer GA, Sternbach LH, J. Org. Chem. 29, 231, 1964) with the hydrazides of acids of formula II,

RSCH ₂ CONHNH ₂ (Π) wherein R is the same as in Formula I, in boiling 1-butanol. Some of the hydrazides are novel and are described in the Examples; others are known and literature references are also given in the examples. The crude products of the reaction of the hydrazides of the formula II with the named thion are obtained after evaporation of 1-butanol, decomposition of the residue with water and extraction with benzene or chloroform. If the starting hydrazides are water-soluble, they can be easily separated and the final product purified directly by crystallization. If the starting hydrazide is insoluble in water, the crude products must be purified by chromatography on alumina columns. In the case where the substituents at the 1-position contain a very basic (dimethylamino, pyridyl) group, the acid neutralization products provide the corresponding salts. The identity of all substances described in the invention, ie both end products and novel intermediates, was assured by analytical and conventional spectral methods. Example 1

8-Chloro-6- (2-chlorophenyl) -1- (2-dimethylaminoethylthiomethyl) -4H-s-triazolo (4,3- and 1,4-benzodiazepine) 4.82 g 7-chloro-5 - (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (lit. cit.), 7.25 g of S- (2-dimethylaminoethyl) thioacethydrazide and 120 ml of 1-butanol are boiled under stirring for 8 hours. The solvent was evaporated under reduced pressure, the residue was quenched with 150 ml of water and the product was extracted with benzene, the extract was washed with water, dried over sodium sulphate and evaporated and the residue crystallized from a mixture of benzene and hexane. Yield: 5.6 g (84%), m.p. 85-86 [deg.] C. This product was analytically identified as a solvate with half of the benzene molecule and gave hygroscopic hydrochloride by neutralizing hydrochloric acid.

The starting S- (2-dimethylaminoethyl) thioacethydrazide is a novel substance which is prepared, for example, as follows:

To a solution of sodium ethoxide prepared by dissolving 3.3 g of sodium in 70 ml of ethanol is added 15.1 g of 2-dimethylaminoethyl mercaptan (Clinton RO et al., J. Amer. Chem. Soc. 70, 950, 1948) and After cooling, 17.5 g of ethyl chloroacetate are added dropwise with stirring. The mixture was heated to reflux for 1 h in a water bath. After cooling, the precipitated sodium chloride is filtered off with suction, the filtrate is evaporated under reduced pressure, the residue is dissolved in benzene, filtered again and the filtrate is distilled under vacuum. Redistillation of the middle fraction yielded 16.8 g (61%) of pure ethyl 2- (2-dimethylaminoethyl ⁾ thioacetate boiling at 122 ° C / 2 kPa, ng ² 1.4711. crystallized from ethanol / ether and melted at 85-86 ° C.

A mixture of 15.8 g of the preceding ester and 5.5 ml of 100% hydrazine hydrate was shaken to form a homogeneous solution, which was then heated at 100 ° C for 1 h and then at the same temperature in a water pump vacuum for 1 h. From the residue (14.7 g, 100%), pure S- (2-dimethylaminoethyl) thioacethydrazide was obtained by distillation, boiling at 144 ° C / 40 Pa, n ²² 1.5345.

Example 2

1- (Cyclohexylthiomethyl) -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. A mixture of 3.21 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (lit. cit.), 5.1 g of cyclohexylthioacethydrazide and 80 ml of 1-butanol with stirring under a nitrogen atmosphere for 8 hours. Then the solvent is evaporated under reduced pressure, the residue is dissolved in 100 ml of benzene, the solution is washed with water and evaporated under reduced pressure. The residue was dissolved in a small amount of benzene and the solution was chromatographed on a column of 75 g alumina (neutral, activity II). The crude product eluted with benzene was crystallized from a mixture of benzene and hexane. The title compound is obtained in a yield of 2.7 g (59%) and melts at 150-151 ° C.

The starting cyclohexylthioacethydrazide is a novel substance which is prepared, for example, by the following procedure: A mixture of 26.0 g of ethyl cyclohexylthioacetate (Mousseron M. et al., Bull. Soc. Chim. Fr. 1947, 616; Chem. Abstr. 42, 1901, 1948 ) and 8.5 ml of 100% hydrazine hydrate are shaken until a homogeneous solution is obtained and heated at 100 DEG C. for 3 hours and then at the same temperature in a water pump vacuum for 1.5 hours. The residual viscous liquid (24.0 g, nearly 100%) was washed with water and dried by heating under vacuum at 70 ° C. The purified hydrazide resulted in a yield of 19.0 g. Neutralization with hydrogen chloride in ethanol gave the hydrochloride, which crystallized from a mixture of ethanol and ether, m.p. 122-123 ° C.

Example 3

1- (Phenylthiomethyl) -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. A mixture of 5.0 g of phenylthioacethydrazide (Rose F. L. Wilson B. R. Brit. Pat. 782.420), 3.21 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4- of benzodiazepine-2-thione and 80 ml of 1-butanol are refluxed under nitrogen for 7 hours. The solvent was then evaporated under reduced pressure, the residue was evaporated in benzene and chromatographed on a 160 g neutral alumina column (activity II). The chloroform eluted product was crystallized from a mixture of benzene and hexane. 3.0 g (67%) of a homogeneous title compound are obtained, m.p. 138-140 ° C.

Example 4

8-Chloro-6- (2-chlorophenyl) -1- (4-tolylthiomethyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. A mixture of 3.21 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydrol-4-benzodiazepine-2-thione (lit. cit.), 5.39 g of 4-tolylthioacethydrazide (Rose FL, Wilson) BR, lit. cit.) And 80 ml of 1-butanol are refluxed under nitrogen for 8 hours under stirring. After evaporation of the butanol in vacuo, the residue is chromatographed on a column of 160 g of neutral alumina (activity II). The benzene eluates are discarded, then the desired product is washed with chloroform and recrystallized from a mixture of benzene and hexane; 3.3 g (71%), mp 199-200 ° C. Example 5

8-Chloro-6- (2-chlorophenyl) -1- (4-chlorophenylthiomethyl) -4H-s-triazolo (4,3-a) -1,4-benzo-

diazepine. A mixture of 3.21 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (lit. cit.), 5.94 g of 4-chlorophenylthioacethydrazide (Rose FL, Wilson BR, cited) and 80 ml of 1-butanol are refluxed under nitrogen for 7 hours with stirring. After evaporating butanol in vacuo, the residue is dissolved in 18 ml of hot benzene. On standing overnight 3.4 g of the starting hydrazide precipitated, which was removed by filtration. The filtrate is chromatographed on a 140 g neutral alumina column (activity II). The benzene eluates were discarded and the chloroform eluates were crystallized from benzene / hexane after evaporation. 3.10 g (62%) of the desired product is obtained, m.p. Mp 198-199 ° C.

Example 6

1- (Benzylthiomethyl) -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. A mixture of 3.21 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (lit. cit.), 5.4 g of benzylthioacethydrazide (Rose FL, Wilson BR , lit. cited) and 80 ml of 1-butanol are refluxed under a nitrogen atmosphere for 8 hours with stirring. After evaporation of the butanol under reduced pressure, the residue is dissolved in 100 ml of benzene, the solution is filtered with carboraffin and the filtrate is evaporated again. The residual oil (7.1 g) was dissolved in a small amount of benzene and the solution was chromatographed on a column of 150 g of neutral alumina. The first benzene eluates containing less polar contaminants are discarded. The desired product is then eluted with chloroform and crystallized. Crystallization from benzene / hexane gave 3.70 g (80%) of pure product melting at 168-169 ° C.

Example 7

1- (2-Furfurylthiomethyl) -8-chloro-6- (2-chlorophenyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. A mixture of 3.21 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (cited), 5.1 g of 2-furfurylthioacethydrazide and 80 ml of 1-butanol is added. with stirring under reflux in a nitrogen atmosphere for 8 hours. The butanol was evaporated under reduced pressure and the residue was partitioned by shaking between 100 ml of water and 100 ml of benzene. The benzene solution was washed with water, dried over sodium sulfate and evaporated. The residue is chromatographed on a 120 g neutral alumina column (activity II). The first benzene eluates containing less polar impurities are discarded, and then 3.5 g (77%) of a homogeneous product is eluted with chloroform, which crystallizes from a mixture of benzene and hexane and melts in the pure state at 154-155 ° C.

The starting 2-furfurylthioacethydrazide is a new substance and is prepared, for example, by the following procedure:

Dissolving 3.3 g of sodium in 70 ml of ethanol gives a solution of sodium ethoxide, to which 16.3 g of 2-furfuryl mercaptan (Kofod H., Org. Syn., Coll. Vol. 4, 491, 1963) is added and min. After stirring and cooling, 17.5 g of ethyl chloroacetate are added dropwise. The mixture was refluxed for 1 hour, after cooling, the precipitated sodium chloride was removed by filtration and washed with ethanol. The filtrate was evaporated under reduced pressure and the residue was partitioned by shaking between 100 ml of water and 200 ml of ether. The ether solution was dried over sodium sulfate, the ether was evaporated and the residue distilled. 24.6 g of ethyl 2-furfurylthioacetate of 145-146 ° C / 2.4 kPa, ng ^δ 1.5093 are obtained.

A mixture of 25.0 g of the preceding ester and 8.7 ml of 100% hydrazine hydrate was shaken to form a homogeneous solution, then heated at 100 ° C for 3 h and finally at the same temperature in a water pump vacuum for 2 h. The colorless oil obtained (23.3 g, theoretical amount) is the desired crude 2-furfurylthioacethydrazide which is used in the reaction in this form. For characterization, the hydrochloride is prepared by neutralizing the sample with hydrogen chloride in ethanol, followed by evaporation in vacuo and crystallization from a mixture of ethanol and ether, melting at 101-102 ° C.

Example 8

8-Chloro-6- (2-chlorophenyl) -1- (3-pyridylmethylthiomethyl) -4H-s-triazolo (4,3-a) -1,4-benzodiazepine. A mixture of 4.82 g of 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepine-2-thione (cited), 8.1 g of 3-pyridylmethylthioacethydrazide and 120 ml of 1-butanol are added. with stirring under reflux in a nitrogen atmosphere for 8 hours. The butanol is evaporated under reduced pressure, the residue is partitioned by shaking between 150 ml of water and 200 ml of benzene, the benzene solution is washed with water, dried over sodium sulphate and evaporated. The residue was dissolved in 25 ml of benzene and the solution was chromatographed on a column of 160 g of neutral alumina (activity II). Benzene elutes less polar contaminants and then elutes the desired product with chloroform. Crystallization from benzene / hexane gave 5.4 g (77%) of pure material, melting at 149-150 ° C. Neutralization with hydrogen chloride in ethanol, evaporation of the solution and crystallization of the residue from a mixture of aqueous ethanol and ether gives the dihydrochloride solvated by half of the water molecule, m.p. 197-199 ° C.

The starting 3-pyridylmethylthioacethydrazide is a novel substance which is prepared, for example, by the following procedure:

To a solution of sodium ethoxide prepared by dissolving 3.3 g of sodium in 70 ml of ethanol is added 18 g of 3-pyridylmethyl mercaptan (Vejdelek Z. J. and Protiva M., Chem. Listy 45, 451, 1951), stirred for 5 min. and then within 10 min. 17.5 g of ethyl chloroacetate are added dropwise. The mixture was refluxed for 1 hour, after cooling, the precipitated sodium chloride was removed by filtration, the filtrate was evaporated, the residue was dissolved in benzene and filtered again. The filtrate is worked up by distillation. There was obtained 27.0 g (89%) of ethyl 3-pyridylmethylthioacetate boiling at 145-148 ° C / 0.2 kPa, i.e. 1.5390. For characterization, a picran can be prepared by neutralizing this base with plklic acid in ethanol, which crystallizes from a mixture of ethanol and acetone and melts at 86-87 ° C.

A mixture of 25.0 g of the preceding ester and 7.7 ml of 100% hydrazine hydrate was shaken to form a homogeneous solution, then heated at 100 ° C for 4 h and finally at the same temperature in vacuo for 1 h. The residue is the theoretical amount of 3-pyridylmethylthioacethydrazide (oil) which is used in this form for the next reaction. For characterization, crystalline dihydrochloride, m.p. 177 DEG-178 DEG C. [aqueous ethanol], was prepared by neutralization with hydrogen chloride in ethanol.

Claims (1)

8-Chloro-6- (2-chlorophenyl) -1-mercaptomethyl-4H-s-triazolo (4,3-a) -1,4-benzodiazepine S-substituted derivatives of formula I wherein R is 2-dimethylaminoethyl , cyclohexyl, phenyl, tolyl, chlorophenyl, benzyl, furfuryl or pyridylmethyl, and their salts with pharmaceutically acceptable inorganic or organic acids.