NO750943L - - Google Patents

Description

The present invention relates to a method for the production of a hitherto unknown class of 2-substituted thio-1,4-benzodiazepine derivatives. Such 2-substituted thio-1,4-benzodiazepine derivatives can be used for medicinal purposes.

More specifically, the present invention relates to a process for the preparation of a hitherto unknown class of 2-substituted thio-1,4-benzodiazepine derivatives of the general formula III

12

where R and R each denote hydrogen, halogen, nitro, amino, cyano, alkyl, haloalkyl, alkoxy, alkylthio, alkanesulfinyl, alkanesulfonyl, alkanoylamino or dialkylamino, R 3 denotes the alkylene,

4 5. 4

and R and R each denote hydrogen or alkyl, in that, when R and R^ denote alkyl groups, the indicated alkyl groups together can form a ring with or without an oxygen atom or an imino group, which ring optionally has one or more substituents, or salts thereof, especially non-toxic pharmaceutically acceptable salts.

The term "alkyl" indicates here in the description and in

the requirements an alkyl group with preferably 1-10 carbon atoms, more

preferably a lower alkyl group, e.g. with 1-6 carbon atoms. In an analogous way, the alkyl and alkane parts denote 1 different 1 2 groups, which are indicated in connection with the definition of R and R , preferably those with 1-10 carbon atoms, more preferably lower alkyl or lower alkane with 1-6 carbon atoms. The alkylene group, which is indicated by the symbol R 3, preferably denotes an alkylene group with 1-18 carbon atoms, more preferably an alkylene group with 1-10 carbon atoms. The process according to the present invention for the production of the previously unknown 2-substituted thio-1,4-benzodiazepine derivatives indicated above is characterized by the fact that a compound of the general formula I

where R 1 and R 2 each have the above meaning, is reacted with a compound of the general formula II 3 4 5 where R , R and R each have the meaning given above, and X denotes an acid residue. The compound with the general formula II is also referred to here as an S-substituent. The turnover that occurs as a result is shown schematically below:

where the symbols have the meaning indicated above.

Among the starting compounds with the general formula I, which are used in the method according to the present invention, are e.g. 1,3-dihydro-5-phenyl-7-chloro-2H-1,4-benzodiazepine-2-thione a known compound. The connection can e.g. is prepared using the method described in the Journal of Organic Chemistry, volume 29, 231-233 (1964), and the other starting compounds with the general formula I can be prepared in an analogous manner.

The method according to the present invention is carried out by reacting a 1,4-benzodiazepine-2-thione derivative of the general formula I with an S-substituent of the general formula II. The starting material, namely the 1,4-benzodiazepine-2-thione derivative used here, is such as is indicated by the above-mentioned general formula I, in particular a compound with 12

the general formula I, where R and R each represent a hydrogen atom, a halogen atom such as fluorine, chlorine or bromine, a nitro group, an amino group, a cyano group, an alkyl group such as

methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl or hexyl, a haloalkyl group such as chloromethyl, bromomethyl, chloropropyl, 1,2-dichloroethyl or trifluoromethyl, an alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy or hexyloxy, an alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, tert-butylthio, pentyltlo or hexylthio, an alkanesulfinyl group such as methanesulfinyl, ethanesulfinyl, propanesulfinyl, isopropanesulfinyl, butansulfinyl, isobutan- sulfinyl, tert.butanesulfinyl, pentanesulfinyl or hexanesulfinyl, an alkanesulfonyl group such as methanesulfonyl, ethanesulfonyl,

propanesulfony1, isopropanesulfonyl, butanesulfonyl, isobutanesulfonyl, tert.butanesulfonyl, pentanesulfonyl or hexanesulfonyl,

an alkanoylamino group such as acetamido, propionamide, butylamido, isobutylamido, valeramido, pivalamido or octanamido or a dialkylamino group such as dimethylamino, diethylamino or methylethylamino.

The S-substituent used in the method according to the present invention is a compound indicated by the general formula II indicated above, in particular the compound can be one that has the indicated general formula II where X denotes an acid residue of a halogen acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, p-toluenesulfonic acid, an alkylsulphuric acid, benzenesulphuric acid or a dialkylcarbamic acid, R 3 denotes a linear or branched alkylene group such as methylene, 1-methylmethylene, ethylene, propylene, trimethylene, tetra-4-methylene, pentamethylene, hexamethylene or decamethylene, and R and R<5>each represents a hydrogen atom or an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl. In the general formula II can, when both

4 5

R and R denote alkyl groups, the alkyl groups together forming a ring with or without an oxygen atom or an imino group. In the case where the ring is formed by the two alkyl groups, there may be one or more substituents on the ring such as hydroxy, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl or hexyl) . hexyloxy), and the number of substituents on the ring may be 1, 2 or more. As examples of groups with the general formula

4 5

where the groups indicated by the symbols R and R are

alkyl groups, which are cyclized in the above-mentioned manner, can be defined as a 5- to 7-membered saturated heterocyclic group containing at least 1 nitrogen atom, which group can have one or more of the above-mentioned substituents. Examples of such heterocyclic groups include a 5- to 7-membered saturated heterocyclic group, which contains one or two nitrogen atoms, and which has one or more of the above-mentioned substituents, such as 1-pyrroldinyl, piperidino, 1-piperazinyl , 1-perhydroazepinyl, 4-methyl-1-piperazinyl, 4-(2-methoxyphenyl)-1-piperazinyl or

4-hydroxy-4-(4-chlorophenyl)piperidino, or a 6-membered saturated heterocyclic group containing a nitrogen atom and a different heteroatom (eg an oxygen atom) such as morpholino.

The method according to the present invention can also be carried out in the presence of a basic condensation agent. Condensing agents applicable to the method according to the present invention are inorganic bases such as hydrides, amides, alkoxides and carbonates of alkali metals such as lithium, sodium and potassium or of alkaline earth metals such as magnesium, calcium and barium or organic bases such as pyridine, trimethylamine, triethylamine or dimethylaniline.

The desired reaction can usually be carried out in a solvent such as water, methanol, ethanol, ether, benzene, toluene,

xylene, acetone, dimethylformamide and dimethylsulfoxide. Solvents that can be used for the reaction are not limited to those indicated above, and any other solvent that does not participate in the reaction can be used. The solvents can also be used in the form of a solvent mixture.

The reaction often proceeds advantageously when a quaternary ammonium compound is used as catalyst. Examples of such quaternary ammonium compounds are N,N,N*,N'-tetramethylpiperazine pmdichloride, benzyltriethylammonium chloride, tetramethylammonium chloride, tetraethylammonium bromide and tetrabutylammonium chloride, and any other quaternary ammonium compound which does not have a disruptive impact on turnover.

The reaction temperature used may vary depending on the nature of the 1,4-benzodiazepine-2-thione derivative of the general formula I, the S-substituent of the general formula II, the basic condensing agent, the catalyst and the solvent used as starting material. However, the reaction is usually carried out at room temperature or by heating to a temperature close to the boiling temperature of the solvent used.

The prepared compound with the general formula III can, if desired, be converted into a corresponding inorganic acid addition salt, such as the hydrochloride or sulfate, or into a corresponding organic acid addition salt such as the maleate, oxalate, lactate, tartrate, citrate or sulfonate. Such salt formation can be used to promote crystallization. It should be noted, however, that a pharmaceutically acceptable salt, which can be prepared using a non-toxic acid, is as effective and useful as a medicine as the underlying compound.

Compounds of the general formula III and acid addition salts thereof exhibit psychotropic activity, particularly minor sedative effects. For therapeutic purposes, acid addition salts of compounds of the general formula III are administered

in practice in the form of pharmaceutically acceptable salts thereof.

Compounds of the general formula III and pharmaceutically acceptable salts thereof can be administered in a manner known per se using conventional unit doses or together with conventional pharmaceutical carriers to achieve a minor sedative effect in humans and mammals. They can thus be used in the form of pharmaceutical preparations, which contain them in admixture with a pharmaceutical organic or inorganic carrier, which is suitable for external or parenteral use. Oral administration using tablets, capsules or in liquid form such as suspensions, solutions or emulsions is particularly advantageous.

The method according to the present invention is illustrated in more detail by the following examples:

Examplell

3.6 g of sodium hydride (50% ig oil suspension), and the resulting mixture is stirred at room temperature for 15 minutes. To this mixture is added dropwise at room temperature with stirring during approx. 1 hour 13.2 g of N,N-dimethyl-2-chloroethylamine, after which the mixture is stirred for 1 hour. The reaction mixture is poured into ice-cooled water and then extracted with chloroform. The extract is washed with water and dried over magnesium sulfate, and the solvent is then distilled off under reduced pressure. An oily product, which is obtained in the form of the residue, is chromatographed on a column of alumina, which is eluted with benzene/chloroform (5:1). The eluate is concentrated under reduced pressure, whereby oily 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro-3H-1,4-benzodiazepine is obtained. The oily product obtained in this way is treated in a manner known per se with maleic acid and is then recrystallized from a mixture of anhydrous ethanol and acetone, whereby 9.0 g of 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro are obtained -3H-1,4-benzodiazepine maleate with melting point 131-134°C. Analysis:

Example 2

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under ice-cooling with stirring 1.2 g sodium hydride (50% oil suspension), and the resulting mixture is stirred at room temperature for 20 minutes. 6.6 g of N,N-dimethyl-2-chloroethylamine are added dropwise over 10 minutes to the mixture, after which the mixture is stirred at room temperature for 1 hour. The reaction mixture is poured into ice-cooled water and then extracted with chloroform. The extract is washed with water and dried over magnesium sulphate, and the solvent is distilled off. The oily product, which is obtained as a residue, is chromatographed on a column of aluminum oxide, which is eluted with benzene. The eluate is concentrated, whereby crude 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The crude product obtained in this way is treated in a manner known per se with maleic acid and is then recrystallized from a mixture of anhydrous isopropyl alcohol and acetone, whereby 4.8 g of 2-(2-dimethylamino-ethylthio)-5-(2-chlorophenyl) are obtained )-7-chloro-3H-1,4-benzodiazepine maleate with melting point 140-142°C.

Analysis:

Example 3

To a solution of 2.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 10 ml of 10% aqueous sodium hydroxide solution and 10 ml methanol is added dropwise under ice-cooling with stirring to an aqueous solution of 1.7 g of N,N-dimethyl-2-chloroethylamine hydrochloride, and the resulting mixture is stirred at room temperature for 2.5 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and then dried over magnesium sulfate. The solvent is distilled off from the solution, thereby obtaining 2.7 g of crude 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine in the form of a residue. The oily product obtained in this way is treated in a manner known per se with maleic acid and recrystallized from a mixture of isopropyl alcohol and acetone, whereby 2.6 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7 are obtained -chloro-3H-lyl-benzodiazepine maleate with melting point 140-142°C.

Example 4

To a solution of 3.2 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 17 ml of 10% aqueous potassium hydroxide solution and 1 .2 ml of tetrahydrofuran are added at room temperature with stirring to 2.16 g of N,N-dimethyl-2-chloroethylamine hydrochloride in powdered form. The resulting mixture is stirred at room temperature for 3 hours, and then the reaction mixture is diluted with water and extracted

with ethyl acetate. The extract is washed with water, dried and then distilled under reduced pressure to remove the solvent, whereby oily 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The oily product produced in this way is treated in a manner known per se with maleic acid and recrystallized from a mixture of isopropyl alcohol and

acetone, whereby 4.50 g of 2-(2-dimethylaminoethylthio)-5-(2-chloro-phenyl)-7-chloro-3H-1,4-benzodiazepine maleate with melting point 140-142°C are obtained.

Example 5

A solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is placed under cooling while stirring 1/2 g sodium hydride (50% oil suspension), and the resulting mixture is stirred at room temperature for 20 minutes. 7.6 g of N,N-dimethyl-3-chloropropylamine are added dropwise to the mixture, and the mixture is stirred at room temperature for 1.5 hours. The reaction mixture is poured into ice-cooled water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulphate, and then the solvent is distilled off under reduced pressure. The oily product obtained in this way in the form of a residue is chromatographed on a column of aluminum oxide, which is eluted with a benzene-chloroform mixture. The eluate is treated in the usual way, whereby oily 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The oily product obtained in this way is treated in a manner known per se with fumaric acid and recrystallized from anhydrous ethanol and acetone, thereby obtaining 4.3 g of 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro -3H-1,4-benzo-diazepine fumarate with melting point 154-156°C.

Analysis:

Example 6

To a solution of 3.2 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 17 ml of 10% aqueous potassium hydroxide solution and 1 .2 ml of tetrahydrofuran are added at room temperature with stirring, 1.75 g of N,N-dimethyl-3-chloropropylamine hydrochloride and 100 mg of benzyltriethylammonium chloride, and the resulting mixture is stirred for 4 hours in a water bath at 40°C. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure, whereby oily 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The oily product obtained in this way is treated in a known manner with fumaric acid and recrystallized from isopropyl alcohol, whereby 4.40 g of 2-(3-dimethylaminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H are obtained -1,4-benzodiazepine fumarate with melting point 154-156°C.

Example 7

To a solution of 9.6 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture

containing 40 ml of 10% aqueous sodium hydroxide solution and 40 ml of methanol are added at room temperature to 4.4 g of 1-chloro-2-(1-pyrrolidinyl)-ethane hydrochloride, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure, whereby oily 2-[2-(1-pyrrolidinyl)-ethylthio]-5-(2-chlorophenyl)-7-chloro-3H-1, 4-benzodiazepine. The oily product obtained in this way is treated in a manner known per se with fumaric acid and recrystallized from isopropyl alcohol, thereby obtaining 6.9 g of 2-[2-(1-pyrrolidinyl)ethylthio]-5-(2-chlorophenyl)-7 -chloro-3B>1,4-benzodiazepine fumarate with melting point 184-188°C.

Analysis:

Example 8

To a solution of 9.6 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 40 ml of 10% aqueous sodium hydroxide solution and 40 ml of methanol is added dropwise over 15 minutes to a solution of 5.5 g of 1-chloro-2-piperidinoethane hydrochloride in 20 ml of water, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure, whereby oily 2-(2-piperidinoethylthio)-5-(2-chloro-phenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The oily product obtained in this way is treated in a manner known per se with fumaric acid and recrystallized from 99% ethanol, thereby obtaining 10.5 g of 2-(2-piperidinoethylthio)-5-(2-chlorophenyl)-7-chloro -3H-1,4-benzo-diazepine fumarate with melting point 196-198°C.

Analysis:

Example 9

To a solution of 7.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thipne in a solvent mixture containing 30 ml of 10% aqueous sodium hydroxide solution and 30 ml of methanol is added drop by drop over approx. 10 minutes under ice-cooling with stirring an aqueous solution of 7.0 g of 1-chloro-2-(perhydroazepin-1-yl)ethane hydrochloride, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with 5% aqueous sodium hydroxide solution, washed with water and dried. The solvent is then distilled off, whereby 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained in the form of an oily residue. The oily product obtained in this way is treated in a manner known per se with 2.74 g of fumaric acid and recrystallized from isopropyl alcohol, thereby obtaining 9.9 g of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl) )-7-chloro-3H-1,4-benzodiazepine fumarate with melting point 170-171°C.

Analysis:

Example 10

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 34 ml of 10% lg aqueous potassium hydroxide solution and 2 4.5 g of 1-chloro-2-morphoicinoethane hydrochloride are added to .5 ml of tetrahydrofurah, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure, whereby oily 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is obtained. The oily product obtained in this way is treated in a known manner with fumaric acid and recrystallized from isopropyl alcohol, whereby 7.5 g of 2-(2-morpholinoethylthio)-5-(2-chlorophenyl)-7-chloro-3B- 1,4-benzodiazepine fumarate with melting point 191-193°C.

Analysis:

Example 11

To a solution of 11.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 100 ml of anhydrous dimethylformamide is added under ice-cooling with stirring 2.1 g of sodium hydride (50% oil suspension), and the resulting mixture is stirred at 30°C for 1 hour. A solution of 12.5 g of 1-chloro-3-[4-(2-methoxyphenyl)-i-piperazinyl]propane hydrochloride in 50 ml of dimethylformamide is added dropwise over 15 minutes to the mixture, and the resulting mixture is stirred at room temperature for 3 hours. The reaction mixture is poured into ice-cooled water and extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and then the solvent is distilled off under reduced pressure, whereby oily 2-(3-[4-(2-methoxyphenyl)-1-piperazinyl]-propylthio)-5-(2-chlorophenyl)- 7-chloro-3H-1,4-benzodiazepine. The oily product obtained in this way is treated in a manner known per se with fumaric acid and recrystallized from isopropyl alcohol, thereby obtaining 10.5 g of 2-(3-[4-(2-methoxyphenyl)-1-piperazinyl]propylthio)-5 -(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate with melting point 189-191°C.

Analysis:

Example 12

To a solution of 4.4 g of 1,3-dihydro-5-(2-fluorophenyl)-7-brora-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 21.5 ml of 10% aqueous potassium hydroxide solution and 1.4 ml of tetrahydrofuran are added at room temperature with stirring to 2.74 g of N,N-dimethyl-2-chloroethylamine hydrochloride, and the resulting mixture is then stirred at room temperature for 2 hours. The reaction mixture is diluted with an aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure, whereby crude crystalline 2-(2-diraethylaminoethylthio)-5-(2-fluorophenyl)- 7-bromo-3H-1,4-benzo-diazepih.. By recrystallization from an ether-n-hexane mixture, 4.05 g of 2-(2-dimethylaminoethylthio)-5-(2-fluorophenyl)-7-bromo-3H are obtained -1,4-benzodiazepine with melting point 105-107.5°C.

Analysis:

Example 13

To a solution of 4.8 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro^-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 28 ml of 10% aqueous potassium hydroxide solution and 1 ml of tetrahydrofuran is added at room temperature with stirring to 3.6 g of N,N-dimethyl-2-chloropropylamine hydrochloride, and the resulting mixture is stirred at room temperature for 2 hours and 30 minutes. The mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ether. The extract is washed with water and dried, and the solvent is removed by distillation under reduced pressure. The resulting residue in the form of an oily product is chromatographed on a column of silica gel, whereby 3.9 g of crude 2-(1-methyl-2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1 are obtained ,4-benzodiazepine in the form of the free base. The crude product is dissolved in acetone and 1.1 g of fumaric acid is added. The solvent is removed by distillation under reduced pressure, whereby crude 2-(1-methyl-2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate is obtained. By recrystallization from a mixture of isopropyl alcohol, methyl alcohol and ether, 4.1 g of 2-(2-dimethylamino-1-methylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate are obtained with melting point 178-180°C (yield 52.5%). Analysis:

Example 14

To a solution of 5.7 g of 1,3-dihydro-5-phenyl-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture containing 57 ml of 10% aqueous potassium hydroxide solution and 6 ml of tetrahydrofuran is added at room temperature with stirring 7.0 g of 1-chloro-2-(4-methyl-1-piperazinyl)ethane dihydrochloride, and the resulting mixture is stirred at 40°C for 4 hours. The reaction mixture is diluted with an aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure. The resulting residue in the form of an oily product is dissolved in ethyl alcohol, 3.8 g of fumaric acid is added, and the solvent is distilled off under reduced pressure, whereby a crystalline product is obtained. Recrystallization from tetrahydrofuran gives 5.4 g of 2-[2-(4-methyl-1-piperazinyl)ethylthio]-5-phenyl-7-chloro-3H-1,4-benzodiazepine-di-fumarate with melting point 193-194 °C (cleavage, yield 42%). Analysis:

Example 15

To a solution of 1.6 g of 1,3-dihydroxySro-5-(phenyl)-7-trifluoromethyl-2H-benzodiazepine-2-thione in a solvent mixture containing 8.5 ml of 10% aqueous potassium hydroxide solution and 1.5 ml of tetrahydrofuran are added at room temperature with stirring to 1.1 g of piperidinoethyl chloride hydrochloride, and the resulting mixture is stirred at 50°C for 4 hours. The reaction mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure. The resulting oily product is converted using 510 mg of fumaric acid to the fumarate. By recrystallization from a mixture of acetone and ether, 1.5 g of 2-(2-piperidinoethylthio)-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine fumarate with melting point 132-134°C is obtained.

Analysis:

Example 16

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-benzodiazepine-2-thione in a solvent mixture containing 34 ml of 10% aqueous potassium hydroxide solution and 5 ml of tetrahydrofuran is added at room temperature with stirring 4.79 g of pyrrolidinopropyl chloride hydrochloride, and the resulting mixture is then stirred at 50°C for 5 hours. The reaction mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure. The resulting oily product re-

is formed using 2.6 g of fumaric acid for the fumarate. By recrystallization from isopropyl alcohol, 7.0 g of 2-[3-(1-pyrrolidinyl)propylthio]~5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate with a melting point of 148-151°C are obtained . Analysis:

Example 17

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-benzodiazepine-2-thione in a solvent mixture containing 34 ml of 10% aqueous potassium hydroxide solution and 5 ml of tetrahydrofuran is added at room temperature with stirring 5.15 g of piperidinopropyl chloride hydrochloride, and the resulting mixture is stirred at 50°C for 4 hours. The reaction mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulphate, and the solvent is removed by distillation under reduced pressure. The resulting oily product is converted using 2.0 g of fumaric acid to the fumarate. Recrystallization from a mixture of tetrahydrofuran and ether yields 8.6 g of 2-(3-piperidinopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate with melting point 110-112°C .

Analysis:

Example 18

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-benzdiazepine-2-thione in a solvent mixture containing 34 ml of 10% aqueous potassium hydroxide solution and 5 ml of tetrahydrofuran is added at room temperature with stirring 5.2 g

morpholinopropyl chloride-hydrochloride, and the resulting mixture is stirred at 50°C for 2.5 hours. The reaction mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation

under reduced pressure. The resulting oily product is converted using 2.38 g of fumaric acid to the fumarate. Recrystallization from isopropyl alcohol yields 6.8 g of 2-(3-morpholino-propylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate

with melting point 169-171°C.

Analysis:

Example 19

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-benzodiazepine-2-thione in a solvent mixture containing 34 ml of 10% aqueous potassium hydroxide solution and 5 ml of tetrahydrofuran is added at room temperature with stirring 5.5 g of hexamethyleneiminopropyl chloride hydrochloride, and the resulting mixture is then stirred at 50°C for 4 hours. The reaction mixture is diluted with a saturated aqueous sodium chloride solution and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation under reduced pressure. The resulting oily product is converted using 2.8 g of fumaric acid to the fumarate. By recrystallization from a mixture of tetrahydrofuran and ether, 9.2 g of 2-(3-perhydroazepin-1-ylpropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate are obtained with a melting point of 164 -167°C. Analysis:

Example 20

To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-benzodiazepine-2-thione in a solvent mixture containing 20 ml of an aqueous potassium hydroxide solution (prepared by dissolving 2.65 g of potassium hydroxide in water, until the total volume is 20 ml) and 20 ml of tetrahydrofuran are added at room temperature with stirring 5.0 g of N,N-di-n-hexylaminoethyl chloride. After stirring for 2 hours at room temperature, stirring is continued at 50°C for 4 hours. After completion of the reaction, the tetrahydrofuran is removed by distillation under reduced pressure, and the residue is diluted with water and then extracted with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the solvent is removed by distillation. The resulting oily product is converted using 2.3 g of fumaric acid to the fumarate. Recrystallization from ether yields 7.6 g of 2-(2-dihexylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine fumarate with a melting point of 113-115°C.

Analysis

Example 21

The following compounds can be prepared in an analogous manner to that described in the above examples: 1) 2-(10-dimethylaminodecylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine, NMR spectrum in CDC13: 6 (ppm) = 1.2 - 1.7 (16H, m) , 2.18 (6H, s) 2.0 - 2.4 (2H, m) 3.10 (2H, t) 4, 20 (2H, s) 7.0 - 7.4 (7H, m), 2) 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine, 3 ). 2-(3-dimethylaminopropylthio)-5-(2-methoxyphenyl)-7-chloro-3H-1,4-benzodiazepine, 4) 2-(4-dimethylaminobutylthio)-5-(2-chlorophenyl)-7-chloro- 3H-1,4-benzodiazepine, 5) 2-(6-dimethylaminohexylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine, 6) 2-(2-dibutylaminoethylthio)-5- (2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine and 7) 2-(2^[4-hydroxy-4-(4-chlorophenyl)piperidino]ethylthio)-5-(2-chlorophenyl)- 7-chloro-3H-1,4-benzodiazepine.

Claims (1)

1. Process for the production of 2-substituted thio-1,4-benzodiazepine derivatives of the general formula III where R 1 and R 2 each denote hydrogen, halogen, nitro, amino, cyano, alkyl, haloalkyl, alkoxy, alkylthio, alkanesulfinyl, alkane-sulfonyl, alkanoylamino or dialkylamino, R<3> denotes the alkylene, 4 5 4 and R and R each denotes hydrogen or alkyl, wherein, when R and 5 R denotes alkyl groups, the aforementioned alkyl groups together can form a ring with or without an oxygen atom or an imino group, which ring optionally has<*>one or more substituents, or salts thereof, characterized in that a 1,4-benzodiazepine-2-thione derivative with the general formula I 12 where R and R each have the above meaning, react with a compound of the general formula II; where R<3>, R4 and R5 each have the above meaning, and X denotes an acid residue.;2. Method according to claim 1, characterized in that compounds 1 2 are prepared where R denotes a halogen atom or a nitro group, R denotes a hydrogen atom, a halogen atom or an alkoxy group, R<3>4 5 denotes an alkylene group, and R and R denote alkyl groups, or non-toxic pharmaceutically acceptable salts thereof,;3. Method according to claim 2, characterized in that compounds 1 2 are produced where R represents chlorine, bromine or nitro, R represents hydrogen, 3 chlorine, fluorine or methoxy, R represents ethylene, trimethylene, 4 propylene, tetramethylene, hexamethylene or octamethylene, and R and R represent methyl, butyl or hexyl, or non-toxic , pharmaceutically acceptable salts thereof.;4. Method according to claim 3, characterized in that 2-(2-dimethylaminoethylthio)-5-phenyl-7-nitro-3H-1,4-benzodiazepine or its maleate is produced.;5. Method according to claim 3, characterized in that 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine or its maleate is produced.;6. - Process according to claim 3, characterized in that 2-(3-dimethyl-aminopropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine or its fumarate is produced.;7. Method according to claim 3, characterized in that 2-(2-dimethylaminoethylthio)-5-(2-fluorophenyl)-7-bromo-3H-1,4-benzodiazepine is produced.;8. Process according to claim 3, characterized in that 2-(1-methyl-2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine or its fumarate is produced.;9. Method according to claim 3. characterized in that 2-(2-dihexyl-amirioethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine or its fumarate is produced.;10. Method according to claim 3, characterized in that 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-nitro-3H-1,4-benzodiazepine is produced.; 11. Method according to claim 3, characterized in that 2-(3-dimethylaminopropylthio)-5-(2-methoxyphenyl)-7-chloro-3H-1,4-benzodiazepine is produced. 12o Method according to claim 3, characterized in that 2-(4-[dimethylaminobutylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is produced.;13. Process according to claim 3, characterized in that 2-(6-dimethylaminohexylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is produced.; 14. Method according to claim 3, characterized in that 2-(10-dimethylaminodecylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is produced.;15; Method according to claim 3, characterized in that 2-(2-dibutyl-aminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1/4-benzodiazepine is produced.;16. Method according to claim 1, characterized in that compounds 1 2 are produced where R denotes a halogen atom or a haloalkyl group, R 3 denotes a hydrogen atom or a halogen atom, R denotes a 4 5 alkylene group, and R and R denote alkyl groups, the alkyl groups together forming a ring with or without an oxygen atom or an imino group, and the ring may have "one or more substituents, or non-toxic pharmaceutically acceptable salts thereof." 17. Method according to claim 16 , characterized in that compounds are prepared where R 1 denotes a halogen atom or a haloalkyl group, R<2> denotes a hydrogen atom or a halogen atom, R 3 denotes an alkylene group, and the group with the general formula ; denotes a 5- to 7-membered saturated heterocyclic group containing at least 1 nitrogen atom, which group may have "one or more substituents, or non-toxic pharmaceutically acceptable salts thereof.; 18. Method according to claim 17, characterized in that R"*" denotes a halogen atom or a haloalkyl group, R<2> denotes a hydrogen atom or a halogen atom, R 3 denotes an alkylene group, and the group with the general formula denotes a 5- - 7-membered saturated heterocyclic group containing one or two nitrogen atoms, which group can have one or more substituents, or non-toxic, pharmaceutically acceptable alters thereof. 19. Process according to claim 18, characterized in that a<1> denotes a chlorine or broHs&toiB «sils a trifluoroethyl group, R denotes a hydrogen or chloratroa, R denotes em ethylene-«lier trimethylene group, and the group with the general formula denotes 1-pyrrolidinyl, piperidino, 1-piperazinyl, i-assejyinyl, 4-ethyl 1- 1-piperazinyl, 4-(2-methoxyf onyl)-1-piperainyl «Iler 4-bydrokay-4-(4-chlorophen< y>l)pi<p>eridino, or non-toxic©pharmaceutically acceptable salts thereof. 20. Freragangøtnåt© according to claim 19, characterized in that 2-12-(1-pyrrolidinyl)-ethylthio)-S-{2-chlorophenyl)-7-chloro-3H-1,4-benzodlaaepin <3>11 is the fuaxate thereof is produced. 21. Method according to claim 19, characterized in that 2-(2-pip©Eidino~ethylthio)~5-(2-chiorphen<y>1)-7-chloro-3H-1,4-benzodiazepln or the fumarate dexav is produced. 22. Procedure according to claim 19, characterized in that one prepares" 2-(2-per-hydroazepin-1-ylethylthio)(2-chlorophenyl)~7~chloro-3H-1,4-benao~ diazzepine or its fumarate. 23. Fresgang seat according to claim 19, characterized in that it is methylated 2-(3-14-(2-ethoxy phenyl) 1-piperainylpropylthio)-5-(2-chlorophenyl)-7-chloro-3M-1,4-benzodiazepine or its fumarate. 24. Method according to claim 19, characterized in that 2-[3-(1-pyrralidiayl)propylthio]-5~{2-chlorophenyl)-7-chloro-3S-1,4-1>@nao-diaaepi» or its derivative is produced. 25. Method According to claim 19, characterized in that 2- (3-piper i d i nopropy1 tio) - 5- (2-chlorophenyl)-7-chloro-3n-1, 4-bea«odlas<Bpine or the fumarate dexav is produced. 26. Procedure According to requirement 1$, characterized in that 2-(2-pipeoxy&iiio&t<y>ltio)-5-phenyl-7-tri£lttorsBethyl-3B-i# 4-ben8odlaaepi» or its fumarate is produced. 27. Method according to claim 19, characterized in that 2-(3-perhydro-azepin-1-ylpropylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzo-diazepine or its fumarate is produced. 28. Method according to claim 19, characterized in that 2-[2-(4-methyl-1-piperazinyl)ethylthio]-5-phenyl-7-chloro-3H-1,4-benzodiazepine or its fumarate is produced. 29. Method according to claim 19, characterized in that 2-(2-[4-hydroxy-4-(4-chlorophenyl)piperidino]ethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine is produced. 30. Method according to claim 17, character! s is t in that compounds 1 2 3 are produced where R denotes a halogen atom, R denotes a halogen atom, R denotes an alkylene group, and the group with the general formula denotes a 6-membered saturated heterocyclic group with a nitrogen atom and a heteroatom different therefrom, or non-toxic pharmaceutically acceptable salts thereof. 31. Method according to claim 30, characterized in that compounds are prepared where R and R denote chlorine atoms, R denotes an ethylene or trimethylene group, and the group with the general formula denotes morpholino, or non-toxic pharmaceutically acceptable salts thereof. 32. Method according to claim 31, characterized in that 2-(2-morpholino-ethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine or its fumarate is produced. 33. Method according to claim 31, characterized in that 2-(3-morpholino-propylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepineyl fumarate thereof is produced. 34. Process for the production of 2-substituted thio-1,4-benzodiazepine derivatives according to claim 1, characterized in that the reaction is carried out in the presence of a condensing agent.