DERIVATES OF N,N-DIMETHYL-2-(ARYLTHIO)BENZYLAMINE, THEIR SALTS, METHODS OF PREPARATION AND THEIR USE IN PHARMACEUTICAL MEDICAMENTS

Abstract: Derivatives of N,N-dimethyl-2-(arylthio)benzylamine of general formula (I), wherein the substituents R1 and R2 in the A ring in the 4 and 5 positions are hydrogen, fluorine, or chlorine atoms, while at least one of them must be a hydrogen atom and further, among the substituents R<3> to R<6> in the B ring two to three are hydrogen atoms, another one is either one fluorine or chlorine atom (only if at least one of the substituents R1 to R2 in the A ring is a fluorine or chlorine atom), further, two fluorine or two chlorine atoms, an alkyl with one to three carbon atoms, trifluoromethyl, methylthio, methylsulfinyl, methoxyl or hydroxyl (only if in the B ring there is also a fluorine or chlorine atoms as a substituent), nitro, amino, hydroxymethyl - except the 2 position, carboxyl - except the 3 position, methoxycarbonyl or ethoxycarbonyl group, as well as their salts with pharmacodynamically harmless acids. Methods of preparation of these compounds have been described, as well as some of their pharmacological characteristics and ways of their use in pharmaceutical medicaments based on their ability to selectively influence serotonin transport in the central nervous system.

Description: Derivatives of N,N-Dimethyl-2- (arylthio)benzylamine, Their Salts, Methods of Preparation and Their Use in Pharmaceutical Medicaments. Field of Technique The invention relates to the derivatives of N ,N-dimeτhyl -2- (arylthio) benzylamine and their salts, which selectively inhibit serotonin re-uptake in the brain structures It is also concerned with the methods of preparation and pharma¬ ceutical medicaments on their basis suitable for treatment of depression and other diseases of the central nervous sys¬ tem, based on serotonin transport defects and serotonin me¬ tabolism imbalance in the brain. Background of the Invention Besides other compounds, in depression pharmacoτherapy tri- cyclic amines are also used, recently plus some tetracyclic compounds, with a characteristic complex of behavioural fea¬ tures expressed in the term "thymoleptic activity" These compounds, some of which have undesirable cardiotoxic and anticholinergic side effects, are still widely used and are called First-Generation Anτidepressants The progress in biochemical pharmacology, which has led to the knowledge that the influence of anτidepressanτs on the fate of some biogennic amines in brain, noradrenaline in particular, plays its role in the anτidepressant effect mechanism, re¬ sulted in the synthesis and testing of a large number of mo- nocyclic and bicyclic amines; some of them came to be used in pharmacotherapy of depression and are called Second- Generation Anτidepressants. Since the second half of the 70s, the serotonin transport role in the brain structures in depression ethiology have become understood, and compounds, which besides inhibiting noradrenaline presynaptic re-uptake also substantially inhi¬ bit serotonin re-uptake, have been gradually discovered. There has been an effort to find selective inhibitors of se¬ rotonin re-uptake with minimum influence on noradrenaline re-uptake. This type of anτidepressanτs is called Third- Generation Antidepressanτs , and also here a number of mono- cyclic or bicyclic amines have been found, e.g. citalopram, fluoxetine, paroxetine, fluvoxamine and sertraline (Owen R.T. : Drugs of Today, 28, 439 (1992)), which have been al¬ ready applied in pharmacotherapy of depression. An acciden¬ tal discovery of serotonin and noradrenaline re-uptake inhi¬ bition (non-selective effect) in case of the plain N,N-dimethyl-2- (phenylthio) benzyla ines (Jilek J. et al . Collect. Czech. Chem. Commun. 54, 1995 (1989)) aroused a bigger interest concerning compounds of this type and manipulation of the structure of the above mentioned basic compound first led to the series of N,N-dimethyl-2- ( ethoxy- and hydroxyphenylthio)benzylamines , (Jilek J. et . al : Col¬ lect. Czech. Chem. Commun. 54, 3294 (1989)) , where some com¬ pounds clearly suggested selectivity in effect. It was a case of N,N-dimethyl-2- (3-hydroxyphenylthio) benzyla ine , in particular, called "moxifeτin" (Protiva . Drugs of the Future 16, 911 (1991); CS 276004; EP 396,827) . Another selective inhibitor of serotonin re-uptake in the brain structures is N,N-dimethyl-2- (2-hydroxymethyl)phenyl¬ thio)benzylamine (VO 93/12080, and particularly N,N-dimethyl- 2- (4- (trifluoromethyl) -2- (hydroxymethyl) phenylthio) benzyl¬ amine . However, even in case of this compound, [ H] serotonin and •a [ HJnoradrenaline re-uptake inhibition in synaptosomal frac- tions in particular e.g. of rat cerebral cortex, is not sufficient . The aim of the invention is to find the modification of the compound on the basis of N,N-dimethyl -2- (pheny1 thi o) benzy1 - amine, which would show higher selectivity and better ef¬ fects than compounds having been applied up to the present. Disclosure of the Invention The grounds of the invention lie in the new derivatives of N,N-dimethyl-2- (ary thio)benzylamine of general formula (I) or their salts with inorganic or organic acids which are pharmacodynamical 1y harmless, wherein at least one of the substituents R or R in the A ring in 4 and 5 positions is an hydrogen atom, while the other substituent R or R in the A ring is either a fluorine atom or chlorine atom and wherein two to three among the substituents R to R in the B ring in the 2 to 5 positions are hydrogen atoms, while if the both substituents in the A ring are hydrogen atoms, the substituents in the D ring are either three hydrogen atoms and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulf nyl , or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxy- carbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms, one fluorine or chlorine atom and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxy¬ methyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl , or methylthio, or nitro, or amino, or methoxy, or hydroxyl group, or are two hydrogen atoms and each of the two remai¬ ning substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms and two fluorine or chlorine atoms, or in case that one substituent in the A ring is either an fluorine atom or chlorine atom, the substituents in the B ring are either two hydrogen atoms and two fluorine or chlorine atoms, or two hydrogen atoms and one fluorine or chlorine atom and one subsituenτ formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxy¬ methyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino, or methoxy, or hydroxyl group, or are three hydrogen atoms and one fluorine or chlorine atom, or one of the substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl , or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group. The anvantageous derivatives of the compound of general formula (I) according to the invention are: N,N-dimethyl-2- (2-amino-4- (trifluorome hyl) phenylthio)benzyl amine , N,N-dimethyl-5-chloro-2- (4- (methylthio)phenylthio)benzyl- amine , N,N-dimethyl-5-fluoro-2- (4- (methylthio)phenylthio) benzyl- amine , N,N-dimethyl-2- (2,4-d ichloropheny1thio) -5-fluorobenzyla ine , N,N-dimethyl-2-(3,4-dichlorophenylthio) -5-fluorobenzylamine, or N.N-dimethyl -2- (2-anιi no-4- (trifl uoromethy1 ) henyI thi o) -5- fluorobenzylamine and their salts wi th inorganic, or organic acids which are pharmacodynamically harmless. The structure of the above mentioned compounds suggests that the said specificity of substituents on a diphenylsulfide fragment lies particularly in the presence of a halogen atom in the 5 position of the A ring and in the presence of a 2-amino group or a 4- (methylthio) group in the B ring. According to the invention, the advantageous compound is N,N-dimethyl-2- (2-am no-4- (trif1uoromethyI ) pheny1 thi o) benzy1 - amine, and among its salts particularly oxalate, dihydro- chloride and maleate. This compound shows the highest selec¬ tivity regarding the comparison of inhibition of serotonin re-uptake and noradrenaline re-uptake in the brain structu¬ res, which is apparent from the Table of biological activity (see bel ow) . Derivatives of the compound of general formula (I) can be prepared via various procedures which use the methods of organic synthesis. As for the fundamental procedure, the key intermediate products are N,N-dimethylamides of general formula (II) wherein the subst i tuents R to R are identical to tliosc in formula (I) , and besides that, in the B ring can also he a formyl or dimethylaminocarbonyl group. In the last step of synthesis these amides are reduced by e.g. complex hydrides of the lithium aluminium hydride type, or by diborane, which is advantageously used "in situ", so that in the reaction mixture it is generated by the reaction of so ium boro- hydride with boron trifluoride etherate. If any of the sub¬ stituents R 3 to R in the B ring is a formyl , dimethylamino¬ carbonyl or carboxyl group, according to the invention also such a group is reduced at the same time and provide the de¬ rivative of the compound of general formula (I) with a hydroxyl or dimethylaminomethyl group. Another method of preparation of the derivatives of the com¬ pound (I) according to the invention, uses benzylhalogenides of general formula (III) as an intermediate product in the last step wherein Hal is an chlorine or bromine atom and the substitu¬ ents R to R are identical to the substituents in formula (I) . These benzylhalogenides are brought into reaction with dimethylamine in an organic solvent - advantageously in toluene at room temperature. In yet another advantageous procedure according to the invention, the benzaldehydes of general formula IV (IV) wherein the substituents R to R are identical to the sub¬ stituents in formula (I) , in the last step react with dimethylformamide and formic acid at higher temperatures - the advantageous temperature is between 110 and 120 C. If one of the substituents on the B ring of the compound of general formula (I) according to the invention, shall be methylsulfinyl, the corresponding methylthioderivative is oxidised by hydrogen peroxide in acetic acid at room tempe¬ rature. If one of the substituents on the B ring of the compound of general formula (I) according to the invention, shall be esterified carbonyl , i.e. methoxycarbonyl or ethoxycarbonyl, the corresponding carboxyderivative is esterified by metha- nol or ethanol - advantageously in the presence of hydrogen chloride, or the corresponding trifluoromethylderivative is used, which is hydrolysed with sulfuric acid at 90 to 110 C and then is esterified with the corresponding alcohol. Finally, if one of the substituents R to R in the B ring of the compound of general formula (I) according to the in¬ vention, is hydroxyl, the corresponding methoxyderivative demethylates - anvantageously via heating with hydrobromic acid . Further, the salts of compounds of general formula (I) according to the invention can anvantageously be prepared via neutralisation of bases with phar acodynamically harm¬ less inorganic or organic acids. All derivatives of the compound of general formula (I) ac¬ cording to the invention are of an alkaline nature and their bases are insoluble in water, and mostly are of oily appea¬ rance. Neutralisation of all of them with suitable acids yields their crystalline salts, usually also badly soluble in water; their examples can be hydrochlorides , oxalates or maleates . Providing one substituent on the B ring is carb¬ oxyl, the final products are amphoteric, but, however, they also provide the crystalline salts due to the presence of a strong basic amino group. These salts, or the above mentioned amphoteric "amino acids" are suitable for preparation of oral medical forms, which can be used advantageously in human pharmacotherapy . The affinity of the compounds according to the invention, to serotonergic system conditions the potential use of com¬ pounds according to the invention not only in treatment of depression, but also in treatment of migraine, fear or anxiety states, or as anorectics in treatment of obesity. Examples of the Methods According to the Invention Some advantageous methods of preparation of the derivatives of compound of general formula (I) according to the inventi¬ on are demonstrated in the following examples. Example 1 : N,N-Dimethyl-4-fluoro-2- (3-fluorophenylthio) benzylamine . a) 8.0 g of 3-fluorothiophenol (Rajsner . and Protiva M. Collect. Czech. Chem. Commun. 32, 2021 (1967)) was gradually added to a solution of 9.0 g of potassium hydroxide in 80 ml water and after 10 min of stirring, 1.0 g of powdered copper and 10.6 g of 4-fluoro-2-iodobenzoic acid (Rajsner M. et . al: Collect. Czech. Chem. Commun. 40, 719 (1975)) were added and the mixture was refluxed under stirring for 6 h. After partial cooling, the insoluble fractions were filtered off by suction and the filtrate was acidified with diluted hydro¬ chloric acid (1:1) under stirring. After 16 h of standing, the product was filtered, washed with water and dried, which yielded 7.5 g of 4-fluoro-2- (3-fluorophenylthio)benzoic acid, which after crystallisation from eτhanol melted at 198.5-200°C. b) 7.6 g of thionylchloride was added under stirring drop- wise to a suspension of 7.35 g of 4-fluoro-2- (3-fluoro¬ phenylthio)benzoic acid in 60 ml of benzene. After adding two drops of dimethylformamide , the mixture was refluxed for 2 h. The volatile constituents evaporated off i n vacuo , the residue was added 2x80 ml of benzene and evaporated i n vacuo . Crystallisation of the residue from cyclohexane yielded 7.3 g of 4-fluoro-2- (3-fluorophenylthio) benzoyl chloride with the melting point 91-93°C. c) A solution of 7.2 g of 4-fluoro-2- (3-fluorophenylthio) - benzoyl chloride in 50 ml of benzene was added dropwise under intensive stirring at 20 C over a period of 5 min to 25 ml of 40% aqueous solution of dimethylamine and the mix¬ ture was stirred at room temperature for 3 h. The benzene layer was separated, washed with 2x40 ml of water, dried with potassium carbonate and evaporated i n vacuo , which yielded 8.2 g of crude oily N,N-dimethyl-4-fluoro-2- (3- fluorophenylthio)benzamide . d) 2.8 g of sodium borohydride was added to a solution of 8.2 g of crude N,N-dimethyl-4-fluoro-2- (3-fluorophenylthio) - benzamide in 70 ml of teτrahydrofuran and then 10.4 g of boron trifluoride etherate was added dropwise under stirring at room temperature over a period of 15 min. The mixture was stirred at room temperature for 1 h and then was refluxed for 3 h. After cooling, 30 ml of diluted hydrochloric acid (1:1) was added dropwise and the mixture was refluxed for a further 3 h. After cooling, the mixture was alkalised with 20% solution of sodium hydroxide and the product was extrac- ted with ether. The extract was dried with anhydrous potas¬ sium carbonate and was evaporated. The residue (9.2 g) was dissolved in ether and the solution was neutralised with a solution of maleic acid in ether. After 16 h of standing, 6.3 g of N,N-dimethyl-4-fluoro-2- (3-fluorophenylthio) benzyl- amine hydrogen maleate precipitated. This, after recrystal- lisation from a mixture of acetone and ether, melted at 159-160°C. Example 2: N ,N-dimethyl-2- (3 , 4-difluorophenylthio) benzylamine . 10.0 g (0.068 mol) of 3 , 4-difluoroτhiophenol (Cervena I.et al . : Collect. Czech. Chem. Commun. 41, 881 (1976)) was gra¬ dually added to a solution of 12.65 g of potassium hydroxide in 135 ml of water at 50°C. After 10 min of stirring, 1.0 g of powdered copper and 16.62 g of 2- iodobenzoic acid were added to the mixture. The mixture was refluxed under stir¬ ring for 9 h and processed in analogy to example 1/a to obtain 14.20 g (80%) of 2- (3 , 4-difluorophenylthio)benzoic acid, which after recrystallisation from ethanol melted at 196-198°C. 20.3 g of thionylchloride was added dropwise under stirring to a suspension of 14.0 g of 2- (3 , 4-difluorophenylthio) - benzoic acid (0.052 mol) in 115 ml of benzene and after adding two drops of dimethylformamide, it was processed in analogy to example 1/b. Crystall sation of the residue (16.7 g) from cyclohexane yielded 13.9 g (93%) of 2-(3,4-di- fluorophenylthio) benzoyl chloride with the melting point 73-74°C. A solution of 13.8 g of 2- (3 ,4-difluorophenylthio)benzoyl- chloride in 96 ml of benzene was added dropwise at tempera¬ ture not exceeding 8 C and under intensive stirring to 22 ml of 40% aqueous solution of dimethylamine . Then it was pro- cessed in analogy to example 1/c, which yielded 13.9 g of (98%) crude N,N-dimethyl-2- (3 , 4-difluorophenylthio)benzamide . 3.4 g of sodium borohydride was added to a solution of 13.8 g of crude N,N-dimethyl-2- (3 , 4-difluorophenylthio)benz¬ amide (0.047 mol) in 90 ml of τetrahydrofuran and then 13.9 g of boron trifluoride etherate was added dropwise under stirring at 27 C. The mixture was processed in analogy to example 1/d. The residue (15.0 g) of the crude base was dissolved in ether, the solution was filtered and the fil¬ trate was neutralised with a solution of hydrogen chloride in ethanol. 13.3 g of N,N-dimethyl-2- (3 , 4-difluorophenylthio) benzylamine hydrochloride was obtained as a result of cry¬ stallisation, which after recrystallisation from a mixture of ethanol and ether melted at 153-154°C. Example 3 : N,N-Dimethy1-4-fluoro-2- (4-fluorophenylthio)benzylamine . A reaction of 8.6 g of 4-fluoro-2- (4- fluorophenylthio) - benzoic acid (Ger .Offen.2, 545 , 841) in 70 ml of benzene with 12.5 g of thionylchloride and dimethylformamide in analogy to example 1/b, yielded 9.2 g (100%) of 4-fluoro-2- (4-fluoro¬ phenylthio)benzoylchloride , which after crystallisation and recrystallisation from a mixture of benzene and petroleum ether melted at 105-106 °C. A reaction of 9.0 g of 4-fluoro-2- (4-fluorophenylthio) - benzoyl chloride in 60 ml benzene and 14.5 ml of 40% aqueous solution of dimethylamine , in analogy to example 1/c, yiel¬ ded 9.26 g (100%) of crude oily N,N-dimethyl-4-fluoro-2- (4-fluorophenylthio)benzamide . A reaction of crude N,N-dimethyl-4-fluoro-2- (4-fluorophenyl¬ thio)benzamide in 60 ml of tetrahydrofuran with 2.3 g of sodium borohydride and 9.3 g of boron trifluoride etherate, in analogy to example 1/d, yielded 8.7 g of oily base, which provided 8.7 g N,N-dimethyl-4-fluoro-2- (4-fluorophenylthio) - 12 benzylamine hydrogen maleate with the melting point 183-184°C (95% ethanol) . Example 4 : N,N-Dimethyl-5-fluoro-2- (3-fluoropheny1 hio) benzylamine . 9.0 g of potassium hydroxide in 80 ml of water, 10.6 g of 5-fluoro-2-iodobenzoic acid (Rajsner et al . Collect. Czech. Chem. Commun. 40, 719 (1975)) , 6.3 g 3-fluorothiophenol (Rajsner M. and Protiva M. : Collect. Czech. Chem. Commun. 32, 2021 (1967)) and 1.0 g of copper were refluxed under stirring for 6.5 h and then the mixture was processed in analogy to example 1/a, which after crystallisation from aqueous ethanol yielded 8.9 g of 5-fluoro-2- (3-fluorophenyl- thio)benzoic acid, melted at 157.5-159°C. A reaction of 8.75 g of 5-fluoro-2- (3- fluorophenylthio) - benzoic acid with 9.6 g of thionylchl ride in 80 ml of benzene, in analogy to example 1/b, yielded 8.2 g of oily 5-fluoro-2- (3-fluorophenylthio)benzoy 1 chloride. A solution of 8.0 g of 5-fluoro-2- (3- fluorophenylthio) - benzoyl chloride in 60 ml of benzene and 30 g of 40% aqueous solution of dimethylamine was processed in analogy to exam¬ ple 1/c, which yielded 8.6 g of oily N,N-dimethyl-5-fluoro- 2- (3-fluorophenylthio)benzamide. A reaction of 8.6 g of N,N-dimethyl-5- fluoro-2- (3-fluoro¬ phenylthio)benzamide in 70 ml of tetrahydrofuran with 2.8 g of sodium borohydride and 12 g of boron trifluoride etherate and then through neutralisation with a solution of maleic acid in ether, in analogy to example 1/d, yielded 5.3 g of N,N-dimethyl-5-fluoro-2- (3-fluorophenyIthio) benzylamine hydrogen maleate, which after crystal isation from a mixture of acetone and ether melted at 117.5-118.5 C. Example 5 N,N-Dimethyl-5-fluoro-2- (4-fluorophenylthio)benzylamine . 9.0 g of potassium hydroxide in 80 ml of water, 10.6 g of 5-fluoro-2-iodobenzoic acid, 5.5 g of 4-fluorothiophenol (Rajsner et . al : Cesk . Farm. 11, 451 (1962)) , and 1.0 g of copper were refluxed for 7 h and proccesed in analogy to example 1/a. After crystallisation from ethanol, 9.3 g of 5-fluoro-2- (4-fluorophenylthio)benzoic acid was obtained, which melted at 206-207.5°C. A reaction of 9.15 g of 5-fluoro-2- (4-fluorophenylthio) - benzoic acid with 11.7 g of thionylchloride in 100 ml of benzene and dimethylformamide , in analogy to example 1/b and crystallisation from cyclohexane yielded 9.85 g of 5-fluoro- 2- (4-fluorophenylthio)benzoyl chloride, .p. 90-91.5 C. A reaction of 9.7 g of 5-fluoro-2- (4-fluorophenylthio) - benzoyl chloride in 50 ml of benzene with 31 g of 40% aqueous dimethylamine , in analogy to example 1/c, yielded 10.1 g of oily N,N-dimethyl-5-fluoro-2- (4-fluorophenylthio) - benzamide. A reaction of 10.1 g of oily N,N-dimethyl-5-fluoro-2- (4- fluorophenylthio) benzamide in 70 ml of tetrahydrofuran with 2.8 g of sodium borohydride and 10.0 g of boron trifluoride etherate, in analogy to example 1/d, yielded 6.6 g of crys¬ talline N,N-dimethyl-5-fluoro-2- (4-fluorophenylthio) benzyl¬ amine hydrogen maleate, which after recrystallisation from a mixture of acetone and ether melted at 135.5-136.5 C. Example 6 : N,N-Dimeτhyl-5-fluoro-2- (3 ,4-difluorophenylthio)benzylamine . a) A reaction of 5.7 g of potassium hydroxide in 62 ml of water with 4.50 g of 3.4-difluorothiophenol , 7.98 g of 5- luoro-2-iodobenzoic acid, 0.45 g of copper, in analogy to example 1/a, yielded 7.22 g of 5-fluoro-2- (3 , 4-difluoro¬ phenylthio)benzoic acid with melting point 181-182 C. b) A reaction of 7.0 g of 5-fluoro-2- (3 , 4-di luorophenyl- thio)benzoic acid with 7.4 g of thionylchloride in 60 ml of benzene, in analogy to the example 1/b, yielded 7.2 g (97%) of crystalline 5-fluoro-2- (3 , 4-difluorophenylthio) benzoyl chloride, melting at 77-78°C. c) A reaction of 7.0 g of 5-fluoro-2- (3 , 4-difluoropheny1- thio) benzoyl chloride in 50 ml of benzene with 12 ml of 40% aqueous dimethylamine , in analogy to example 1/c, yielded 6.9 g (96%) of oily N,N-dimethyl-5-fluoro-2- (3 , 4-difluoro¬ phenylthio)benzamide . d) 6.8 g of oily N,N-dimethyl-5-fluoro-2- (3 , 4-difluoro¬ phenylthio) benzamide in 42 ml of tetrahydrofuran with 1.56 g of sodium borohydride and 6.45 g of boron trifluoride etherate were brought into reaction in analogy to example 1/d. The obtained crude base was extracted from an aqueous solution of 3x25 ml of benzene. Neutralisation with a solu¬ tion of hydrogen chloride in ethanol yielded 6.4 g of cry¬ stalline N,N-dimethyl-5-fluoro-2- (3 , 4-difluorophenylthio) - benzylamine hydrochloride , which after crystallisation from ethanol melted at 148-150°C. Example 7 : N,N-Dimethyl-2- (2, 4-dichlorophenylthio) benzylamine . a) 20 ml of thionylchloride was added to a solution of 13.6 g of 2- (2 , 4-dichlorophenylthio)benzoic acid (Sindelaf K. et al. : Collect. Czech. Chem. Commun. 38, 3321 (1973)) in 100 ml of toluene and the mixture was refluxed for 3 h. The volatile constituents evaporated off i n vacuo , which yielded 14.3 g of crystalline crude 2- (2 , 4-dichlorophenylthio) - benzoyl chloride, which after crystallisation from petroleum ether melted at 91-93°C. b) A solution of 14.3 g of 2- (2, 4-dichlorophenylthio) - benzoyl chloride in 200 ml of dioxane was saturated with gaseous dimethylamine over a period of 2 h under occasional external cooling with icy water. After 16 h of standing, the volatile constituents evaporated off i n vacuo and the resi¬ due was extracted between water and benzene. The benzene phase was dried with magnesium sulfate and evaporated i n va¬ cuo , to obtain 13.7 g of N,N-dimethyl-2- (2 , 4-dichloropheny1 - thio) benzamide , which after crystallisation from a mixture of benzene and petroleum ether melted at 120-122 C. c) 3.0 g of sodium borohydride was added to a solution of 11.83 g of N,N-dimethyl-2- (2, 4-dichlorophenylthio) benzamide in 60 ml of tetrahydrofuran and then 10 ml of boron tri¬ fluoride etherate was added dropwise over a period of 40 min. The reaction mixture was processed in analogy to example pie 1/d. The crude base was dissolved in chloroform and purified by filtration on a 150 g silica gel column. After evapora¬ ting the chloroform, the obtained crude base was neutralised using 5.0 g of oxalic acid dihydrate in 50 ml of ethanol, which yielded 10.6 g of crystalline N, N-dimethyl-2- (2 , 4-di - chlorophenylthio)benzylamine hydrogen oxalate, melting at 208-211°C. Example 8: N,N-Dimethy1-2- (2, 5-dichlorophenylthio)benzylamine . A reaction of 11.0 g of 2- (2, 5-dichlorophenylthio) benzoic acid (Sindelaf K. et . al : Collect. Czech. Chem. Commun. 38, 3321 (1973)) in a mixture of 100 ml of toluene and 20 ml of thionylchloride was carried out in analogy to example 1/b, which yielded 12.0 g of 2- (2 , 5-dichlorophenylthio) benzoyl chloride, which after crystallisation from cyclohexane mel¬ ted at 104-105.5°C. A reaction of 12.0 g of 2- (2 , 5-dichlorophenylthio) benzoyl chloride in 200 ml of dioxane with gaseous dimethylamine carried out in analogy to example 7/b, yielded 11.2 g (93%) of crystalline N,N-dimethyl-2- (2 , 5-dichlorophenylthio)benz¬ amide, which after crystallisation from a mixture of benzene and petroleum ether melted at 124-126 C. 2.6 g of sodium borohydride was added to a solution of 10.2 g of N,N-dimethyl-2- (2 , 5-dichlorophenylthio) benzamide in 60 ml of tetrahydrofuran and then 8 6 ml of boron tri¬ fluoride etherate was added dropwise at room temperature under nitrogen over a period of 30 min The reaction mixture was processed in analogical procedure to example 1/d to ob¬ tain the crude oily base (9.7 g) . The base was neutralised using 4.7 g of oxalic acid dihydrate in ethanol. The subse¬ quent crystallisation yielded 9.0 g (73 %) N,N-dimethyl-2- (2 , 5-dichlorophenylthio) benzylamine hydrogen oxalate which melted at 180-182.5°C. Example 9 : N,N-Dimethyl-2- (3 , 4-dichlorophenylthi o) benzylamine . A reaction of 14.2 g of 2- (3 , 4-dichlorophenylthio)benzoic acid (Cervena I. and others: Collect. Czech. Chem. Commun. 41, 881 (1976)) in 180 ml of benzene with 15.2 g of thionyl¬ chloride, carried out in analogy to example 1/b, yielded 15.5 g of crude crystalline 2- (3 , 4-dichlorophenylthio)benzoyl chloride, which after crystallisation from cyclohexane mel¬ ted at 104.5-105.5°C. 15.3 g of 2- (3 , 4-dichlorophenylthio) benzoyl chloride in 100 ml of benzene was mixed with 32 g of 40% aqueous solu¬ tion of dimethylamine under mild cooling over a period of 10 min. The mixture was stirred for 4 h at room temperature and evaporated i n vacuo . The residue contained 15.3 g of oily N,N-dimethyl-2- (3 , 4-dichlorophenylthio) benzamide . A reaction of 15.3 g of oily N,N-dimethyl-2- (3 , 4-dichloro- phenylthio) benzamide in 100 ml of tetrahydrofuran with 4.5 g of sodium borohydride and 15.0 g of boron trifluoride etherate under nitrogen and the procedure carried out in analogy to example 1/d yielded crystalline N,N-dimethyl-2- (3 , 4-dichlorophenylthio)benzylamine hydrogen maleate, which after crystallisation from a mixture of acetone and ether melted at 127.5-128.5°C. Example 10: N,N-Dimethyl-2-(3, 5-dichlorophenylthio)benzylamine . A suspension of 3 , 5-dichloroaniline hydrochloride obtained from 29.0 g of 3 , 5-dichloroaniline and 75 ml of diluted hydrochloric acid (1:1) was diazotized under stirring at 0-5 C with a solution of 13.7 g of sodium nitrite in 30 ml of water. 0.2 g of nickel sulfate was added to a solution of the diazonium salt and the cooled mixture was added in small amounts to a solution of 35 g of potassium xanthaτe in 45 ml of water kept between 40-45 C. After having added every¬ thing, this temperature was kept for a further 1 h. After cooling, the mixture was extracted with ether, the ethereal extract was washed with 50 ml of 10% solution of sodium hydroxide, dried with calcium chloride and ether evaporated off. The residue was dissolved in 115 ml of ethanol and 45 g of potassium hydroxide was slowly added to the boiling solu¬ tion. The mixture was refluxed for 8 h, the ethanol was distilled off and 160 ml of 3M sulfuric acid was added to the residue at a temperature of 25 C maximum. The oily pro¬ duct was extracted with the ether and the extract was evapo¬ rated, which yielded 16.1 g of semicrystalline crude 3,5-di- chlorothiophenol . A reaction of 16.1 g of crude 3 , 5-dichlorothiophenol , 24 g of 2-iodobenzoic acid and 1.65 g of copper with 20.8 g of potassium hydroxide in 225 ml of water at 50-60 C, refluxing under stirring for 9 h and then processing in analogy to example 1/a, yielded 24 g (90%) of 2- (3 , 5-dichlorophenyl- thio)benzoic acid, which after crystallisation from ethanol melted at 198-200°C. 22 ml of thionylchloride was added under stirring over a period of 1.5 h to a suspension of 24.0 g of 2-(3,5-di- chlorophenylthio)benzoic acid in 220 ml of benzene heated up to 70 C. The mixture was then processed in analogy to exam¬ ple 1/b. Crystallisation from cyclohexane yielded 23.2 g of 2- (3 , 5-dichlorophenylthio)benzoyl chloride with melting point 104-107°C. A solution of 23.2 g of 2- (3 , 5-dichlorophenylthio) benzoyl chloride in 160 ml of toluene was added under intensive stirring at 4-6 υ C over a period of 1 h to 80 ml of 40% aque¬ ous solution of dimethylamine. The filtrate was stirred a further 2 h at room temperature. The toluene phase was se¬ parated, washed with water and dried with potassium carbona¬ te which was filtered off. The mixture was evaporated i n va¬ cuo , which yielded 17.5 g of oily N,N-dimethyl-2- (3 , 5-di- chlorophenylthio)benzamide , which crystallised on standing and after recrystallisation from a mixture of benzene and petroleum ether melted at 120-122°C. 3.6 g of sodium borohydride was added to a solution of 18.0 g N,N-dimethyl-2- (3 , 5-dichlorophenylτhio) benzamide in 125 ml of tetrahydrofuran and then 18.3 g of boron trifluo¬ ride etherate was added dropwise under nitrogen at 20-27 C over a period of 1 h. The mixture was then processed in ana¬ logy to example 1/d. The residue of the crude base was dis¬ solved in ether, the solution was filtered and the filtrate was neutralised with a solution of hydrogen chloride in ether. The precipitated crystalline N,N-dimethyl-2- (3 , 5-di- chlorophenylthio)benzylamine hydrochloride after recrystal¬ lisation from a mixture of ethanol and ether melted at 185-189°C. Example 11 : N,N-Dimethyl-5-chloro-2- (2 , 4-dichlorophenylthio) benzylamine . 8.95 g of 2, 4-dichlorothiophenol (Sparke M.B. et . al : J. Am. Chem. Soc . 75, 4907 (1953)) , 14.1 g of 5-chloro-2-iodo¬ benzoic acid (Pelz K. et . al : Collect. Czech. Chem. Commun. 33, 1852 (1968)) and 2.5 g of copper were step by step added to a solution of 9.1 g of potassium hydroxide in 100 ml of water and the mixture was refluxed under stirring for 7.5 h. Then the mixture was diluted with 150 ml of hot water, fil¬ tered and further processed in analogy to example 1/a. Crys¬ tallisation from ethanol yielded 14.9 g (89%) of 5-chloro-2- (2, 4-dichlorophenylthio) benzoic acid, m.p 188-191 C. A mixture of 14.8 g of 5-chloro-2- (2 , 4-dichlorophenylthio) - benzoic acid in 100 ml of toluene and 20 ml of thionylchlo¬ ride was heated up to 80 C under stirring under reflux con¬ denser and then was processed in analogy to example 1/b, which yielded 12.4 g (80%) of crude crystalline 5-chloro-2- (2, 4-dichlorophenylthio)benzoylchloride , which after crystal¬ lisation from cyclohexane melted at 129-132 C. A reaction of 12.0 g of crude 5-chloro-2- (2 , 4-dichloro- phenylthio)benzoyl chloride in 200 ml of dioxane with gase¬ ous dimethylamine in analogy to example 7/b yielded the cru¬ de amide, which was dissolved in 60 ml of chloroform and filtered on a 130 g silica gel column. The column was eluted with chloroform, the solvent evaporated off to obtain 10.3 g (84%) of crystalline N,N-dimethyl-5-chloro-2- (2 , 4-dichloro- phenylthio)benzamide, which after crystallisation from a mixture of benzene and petroleum ether melted at 96-97 C. 8.6 g of N,N-dimethyl-5-chloro-2- (2,4-dichlorσphenylthio) - benzamide in 50 ml of tetrahydrofuran, 2.0 g of sodium boro¬ hydride and 6.6 ml of boron trifluoride etherate was proces¬ sed in analogy to example 1/d, which yielded 7.4 g of oily N,N-dimethyl-5-chloro-2- (2 ,4-dichlorophenylthio)benzylamine . This was dissolved in ethanol and neutralised with a solu¬ tion of hydrogen chloride in ether, which yielded 6.86 g of the crystalline hydrochloride . This, after crystallisation from a mixture of methanol and ethanol, melted at 258-261 C. Example 12: N ,N-Dimethyl-5-chloro-2- (2 , 5-dichloropheny1 thio)benzylamine . a) 2.95 g of 2 , 5-dichlorothiophenol (Sindelaf K. et al . Collect. Czech. Chem. Commun. 38, 3321 (1973)) , 14.12 g of 5-chloro-2-iodobenzoic acid and 2.5 g of copper were step by step added to a solution of 9.1 g of potassium hydroxide in 100 ml of water and the mixture was refluxed for 9 h. Vhile still hot, it was diluted with 50 ml of hot water and filte¬ red. After cooling, the filtrate was acidified with 18 ml of diluted hydrochloric acid (1:1) and left standing for 16 h at 0 C. The precipitated crude 5-chloro-2- (2 , 5-dichloro- phenylthio)benzoic acid was filtered by suction and dissol¬ ved in 100 ml of dimethylformamide at 80 C. The solution was filtered, and the pure acid precipitated by diluting of the cold filtrate with 500 ml of water. This was filtered by suction and its recrystallisation from ethanol yielded 10.90 g (65%) of 5-chloro-2- (2 ,5-dichlorophenylthio)benzoic acid, m.p. 216-218°C. b) A reaction of 10.9 g of 5-chloro-2- (2 , 5-dichloropheny1- thio)benzoic acid in 100 ml of toluene with 20 ml of thionyl¬ chloride carried out in analogy to example 1/b and after crystallisation yielded 11.0 g of 5-chloro-2- (2 , 5-dichloro- phenylthio)benzoyl chloride, which melted at 105-106 C. c) A reaction of 11.0 g of 5-chloro-2- (2 , 5-dichlorophenyl- thio)benzoyl chloride in 200 ml of dioxane with gaseous di¬ methylamine, carried out in analogy to example 7/b, yielded 10.7 g (90%) of crystalline N,N-dimethyl-5-chloro-2- (2 , 5-di- chlorophenylthio)benzamide , which after crystallisation from a mixture of cyclohexane and petroleum ether melted at 92-93°C. d) A reaction of 10.2 g of N,N-dimethyl-5-chloro-2- (2 , 5- dichlorophenylthio)benzamide in 60 ml of tetrahydrofuran with 2.58 g of sodium borohydride and 8.6 ml of boron tri¬ fluoride etherate, carried out in analogy to example 1/d, yielded the oily base, which was dissolved in 12 ml of ethanol and neutralised by the addition of 10 ml of hydrogen chloride in ether. Crystallisation from ethanol yielded 8.1 g (75%) of N,N-dimethyl-5-chloro-2- (2, 5-dichlorophenyl- thio)benzylamine hydrochloride , m.p. 252-255 C (in sealed capillary) . Example 13 : N,N-Di ethyl-5-chloro-2- (3 , 4-dichlorophenylthio) benzylamine . A reaction of 5.6 g of potassium hydroxide in 100 ml of water with 5.37 g of 3 ,4-dichlorothiophenol (Cervena I. et al. : Collect. Czech. Chem. Commun. 41, 881 (1976)) , 8.48 g of 5-chloro-2-iodobenzoic acid and 2.5 g of copper, carried out in analogy to example 1/a, yielded 9.1 g (91%) of 5-chloro-2- (3 , 4-dichlorophenylthio)benzoic acid (m.p. 223- 227 C) , which after crystallisation from ethanol melted at 225-227° C. A reaction of 8.6 g of 5-chloro-2- (3 , 4-dichlorophenylthio) - benzoic acid with 20 ml of thionylchloride, carried out in analogy to example 1/b, yielded crystalline 5-chloro-2- (3 ,4- dichlorophenylthio) benzoyl chloride (100% yield) , which after crystallisation from cyclohexane melted at 98-101 . A solution of 9.0 g of 5-chloro-2- (3 ,4-dichlorophenylthio) - benzoyl chloride in 150 ml of dioxane was saturated with ga¬ seous dimethylamine over a period 1.5 h and processed in analogy to example 7/b. The benzene phase was washed with diluted solution of sodium carbonate and with water, dried with magnesium sulfate, then filtered and evaporated i n va¬ cuo . The residue was dissolved in chloroform and the soluti¬ on was filtered on a 75 g silica gel column. Evaporating of the filtrate yielded 7.43 g (80%) of oily N,N-dimethyl-5- chloro-2- (3 , 4-dichlorophenylthio)benzamide . 1.6 g of sodium borohydride was added to a solution of 6.8 g of oily N,N-dimethyl-5-chloro-2- (3 , 4-dichlorophenyl- thio)benzamide in 60 ml of tetrahydrofuran and then 8 ml of boron trifluoride etherate was added dropwise under nitrogen and under stirring over a period of 1 h . The mixture was processed in analogy to example 1/d. Neutralisation with a solution of hydrogen chloride in ether yielded 5.25 g (74%) of crystalline N,N-dimethyl-5-chloro-2- (3 , 4-dichloro- phenylthio)benzylamine hydrochloride , which after recrystal¬ lisation from a mixture of ethanol and ether melted at 203-207°C. Example 14: N,N-Dimethy1-2- (2 , 4-dichlorophenylthio) -5-fluorobenzylamine . a) A reaction of 5.7 g of potassium hydroxide in 65 ml of water with 5.52 g of 2 ,4-dichlorothiophenol , 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper, carried out in analogy to example 1/a, yielded2- (2, 4-dichlorophenyl- thio) -5-fluorobenzoic acid, which was filtered by suction and recrystallised from ethanol, which yielded 8.32 g of the acid, m.p. 198.5-199.5°C. b) 9.92 g of thionylchloride was added dropwise under stirring at 60 C to a suspension of 8.15 g of 2- (2, 4-di - chlorophenylthio) -5-fluorobenzoic acid in 55 ml of benzene, and the resulting solution was processed in analogy to exam¬ ple 1/b. Crystallisation from cyclohexane yielded 8.3 g of 2- (2, 4-dichlorophenylthio) -5-fluorobenzoyl chloride, m.p. 85-86°C. c) A solution of 8.1 g of 2- (2 ,4-dichlorophenylthio) -5- fluorobenzoyl chloride in 50 ml of benzene was added dropwi¬ se under intensive stirring at 8°C to 11 ml of 40% aqueous solution of dimethylamine. The mixture was stirred for a further 2 h at 15 C and then was processed in analogy to example 1/c, which yielded 8.3 g (100%) of oily N,N-dimethyl- 2- (2 , 4-dichlorophenylthio) -5-fluorobenzamide . d) 7.6 g of oily N,N-dimethyl-2- (2 , 4-dichlorophenylthio) -5- fluorobenzamide in 45 ml of tetrahydrofuran , 1.6 g of sodium borohydride and 6.51 g of boron trifluoride etherate reacted in analogy to example 1/d, the gained residue of the crude base was dissolved in ether, the solution was filtered and the filtrate neutralised with a solution of hydrogen chlori¬ de in ether. Crystallisation from ethanol yielded 7.05 g of N,N-dimethyl-2- (2,4-dichlorophenylthio) -5-fluorobenzamine hydrochloride, which after crystallisation from ethanol mel¬ ted at 209-212°C. Example 15: N,N-Dimethy1-2- (2, 5-dichlorophenylthio) -5-fluorobenzamine . A reaction of 5.7 g of potassium hydroxide in 65 ml of water with 5.52 g of 2 , 5-dichlorothiophenol , 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper, carried out in analogy to example la, yielded 9.05 g (95%) of 2- (2, 5- dichlorophenylthio) -5-fluorobenzoic acid, m. p. 224-227 C. In analogy to example 1/b, a reaction of 8.9 g of 2- (2, 5- dichlorophenylthio) -5-fluorobenzoic acid with 10.8 g of thionylchloride in 60 ml of benzene and dimethylformamide provided 8.45 g (90%) of crystalline 2- (2, 5-dichlorophenyl- thio) -5-fluorobenzoyl chloride, which after recrystallisation from cyclohexane melted at 110-111 C. In analogy to example 1/c, a reaction of a solution of 8.2 g of 2- (2 , 5-dichlorophenylthio) -5-fluorobenzoyl chloride with 11 ml of 40% aqueous dimethylamine and crystallisation from methanol yielded 7.87 g (94%) of crystalline N,N-di- methyl-2- (2 , 5-dichlorophenylthio) -5-fluorobenzamide , m. p. 98-99°C. A reaction of 7.6 g of N,N-dimethyl-2- (2 , 5-dichlorophenyl- thio) -5-fluorobenzamide in 45 ml of tetrahydrofuran with 1.6 g of sodium borohydride and 6.51 g of boron trifluoride etherate, carried out in analogy to example 14/d, yielded 7.05 g of N,N-dimethyl-2- (2, 5-dichlorophenylthio) -5-fluoro- benzylamine hydrochloride , which after crystallisation from ethanol melted at 198-201 °C. Example 16 : N,N-Ddimethyl-2- (3 , 4-dichlorophenylthio) -5- fluorobenzyla ine . In analogy to example la, a reaction of 5.7 g of potassium hydroxide in 70 ml of water with 5.52 g of 3 , 4-trichlorothio- phenol , 7.98 g of 5-fluoro-2-iodobenzoic acid and 0.45 g of copper yielded 8.2 g (86%) of crystalline 2- (3 , 4-dichloro- phenylthio) -5-fluorobenzoic acid, which after crystallisation from ethanol melted at 196-197°C. In analogy to example 1/b, a reaction of a suspension of 8.0 g of 2- (3 , 4-dichlorophenylthio) -5-fluorobenzoic acid in 60 ml of benzene with 9.7 g of thionylchloride and dimethyl - formamide yielded 8.3 g (98%) of crystalline 2- (3 , 4-dichloro- phenylthio) -5-fluorobenzoyl chloride, which after crystalli¬ sation from cyclohexane melted at 72-73 C. A reaction of 8.1 g of 2- (3 , 4-dichlorophenylthio) -5-fluoro¬ benzoyl chloride in 50 ml of benzene with 13 ml of 40% aque¬ ous dimethylamine, carried out in analogy to example 1/c, yielded 7.6 g (92%) of oily N,N-dimethyl-2- (3 , 4-dichloro- phenylthio) -5-fluorobenzamide. A reaction of 7.6 g of oily N,N-dimethyl-2- (3 , 4-dichloro- phenylthio) -5-fluorobenzamide in 50 ml of tetrahydrogen- furan, 1.57 g of sodium borohydride and 6.5 g of boron tri- fluoride etherate was carried out in analogy to example 14/d and after 16 h of standing, the precipitated crude hydrochloride was filtered by suction and crystallised from ethanol, which yielded 5.5 g of N,N-dimethyl-2- (3 , 4-dichloro- phenylthio) -5-fluorobenzylamine , m.p. 178-180 C. Example 17: N,N-Dimethyl-2- (3-methylphenylthio) -5-fluorobenzylamine . 60 g of thionylchloride was added dropwise under stirring over a period of 20 min to a solution of 42.6 g of 2- (3- methylphenylthio)benzoic acid (Protiva . et . al : Collect. Czech. Chem. Commun. 47, 3134 (1982)) in 300 ml of benzene and was processed in analogy to example 1/b. Crystallisation from cyclohexane yielded 45.9 g of 2- (3-methylphenylthio) - benzoyl chloride, m.p. 78-79°C. A solution of 13.5 g of 2- (3-methylphenylthio) benzoyl chloride was mixed with 50 ml of 40% aqueous dimethylamine under intensive stirring at 10 C over a period of 20 min. The solution was stirred for 3 h at room temperature and was processed in analogy to example 1/c, which yielded 13.9 g of crude N,N-dimethyl-2- (3-methylphenylthio)benzamide . 4.3 g of 90% sodium borohydride was added to a solution of 13.90 g of crude N,N-dimethyl-2- (3-methylphenylthio)benzamide in 90 ml of tetrahydrofuran, then 15 g of boron trifluoride etherate was added dropwise at room temperature over a peri¬ od 20 min and the mixture was processed in analogy to exam¬ ple 1/d. The crude base was dissolved in ether and neutrali¬ sed with a solution of maleic acid in acetone. On standing there crystallised 9.83 g of N,N-dimethyl-2- (3-methylphenyl- thio) benzylamine hydrogen maleate, m.p. 109-111 C. Example 18: N,N-Dimethy1-4-fluoro-2- (4-isopropylphenylthio)benzylamine . One drop of dimethylformamide was added to a suspension of 22.0 g of 4-fluoro-2- (4-isopropylphenylthio)benzoic acid (Protiva M. et al . : Collect. Czech. Chem. Commun. 51, 698 (1986)) in 200 ml of benzene, then 30 g of thionylchloride was added dropwise under stirring over a period of 5 min and the mixture was processed in analogy to example lb, which yielded 21.4 g (91%) of crude oily 4-fluoro-2- (4-isopropyl- phenylthio)benzoyl chloride. A solution of 20.0 g of crude 4-fluoro-2- (4-isopropylphenyl- thio)benzoyl chloride in 160 ml of benzene was saturated with gaseous dimethylamine at 12-16 C until its weight addi¬ tion was 22.5 g (lh) . The mixture was stirred for a further 1 h at 12-16 C and then washed with water, dried with calcium chloride and filtered. The filtrate was evaporated i n vacuo . The oily residue was left standing to crystallise (14 days) . After addition of petroleum ether it was filtered by suction, which yielded 13.2 g (64%) of N,N-dimethyl-4- fluoro-2- (4-isopropylphenylthio)benzamide , which after re¬ crystallisation from n-hexane melted at 54-55 C. 2.25 g of sodium borohydride was added to a solution of 12.2 g of N,N-dimethyl-4-fluoro-2- (4-isopropylphenylthio) - benzamide, then 11.2 g of boron trifluoride etherate was ad¬ ded dropwise under nitrogen at 20-25 C over a period of 30 min and the mixture was processed in analogy to example 1/d, which yielded 12.0 g (100%) of oily base. This was dis¬ solved in 20 ml of ether and the solution was mixed with a solution of 4.5 g of maleic acid in 10 ml of ethanol. By cooling 13.8 g of N,N-dimethyl-4-fluoro-2- (4-isopropylphenyl¬ thio)benzylamine hydrogen maleate crystallised, which after recrystallisation from a mixture of ethanol and ether melted at 117-118°C. Example 19: N,N-Dimethyl-2- (2- (trifluoromethyl)phenylthio)benzylamine . 7.0 g of 2- (trifluoromethyl)thiophenol (Sharghi N. and Lalezari I. : J. Chem. Eng. Data 11, 612 (1966), Chem. Abstr. 66, 10690 (1967)) , 9.75 g of 2-iodobenzoic acid and 2.2 g of copper were step by step added to a solution of 7.3 g of po¬ tassium hydroxide in 80 ml of water, the mixture was reflu¬ xed under stirring for 10 h and then was processed in analo¬ gy to example 12/a. 11.4 g of 2- (2- (trifluoromethyl)phenyl¬ thio)benzoic acid was obtained, which after recrystallisation from benzene melted at 170-174 C. A reaction of 10.5 g of 2- (2- (trifluoromethyl) phenylthio) - benzoic acid in 100 ml of benzene with 10 ml of thionyl¬ chloride, carried out in analogy to example 1/b, yielded 10.0 g crude 2- (2- (trifluoromethyl)phenylthio) benzyol chlo¬ ride, which after crystallisation from cyclohexane melted at 70-73°C. A solution of 10.0 g of 2- (2- (trifluoromethyl)phenylthio) - benzoyl chloride in 100 ml of dioxane was saturated with ga¬ seous dimethylamine under external cooling over a period of 1 h. After 16 h of standing, the solvent evaporated i n vacuo and the oily residue was crude N,N-dimethyl-2- (2- (trifluoro¬ methyl)phenylthio)benzamide. A reaction of 9.5 g of oily N,N-dimethyl-2- (2- (trifluoro¬ methyl)phenylthio)benzamide in 50 ml of tetrahydrofuran with 2.42 g of sodium borohydride and 9.0 g of boron trifluoride etherate, carried out in analogy to example 1/d, yielded the crude base, which was purified by filtration on a 200 g si¬ lica gel column - for eluting a mixture of toluene, chloro¬ form and chloroform saturated with ammonia was used. Evapo¬ rating the filtrate yielded 8.7 g (96%) of the chromatogra- phically homogeneous base. Its neutralisation with oxalic acid dihydrate in ethanol yielded 8.5 g of crystalline N,N- dimethyl-2- (2- (trifluoromethyl)phenylthio)benzylamine , which after crystallisation from ethanol melted at 145-147 C. Example 20 : N,N-Dimethyl-2- (3- (trifluoromethyl)phenylthio)benzylamine . 82.4 g of thionylchloride was added at 60 C to a suspensi¬ on of 63.4 g of 2- (3- (trifluoromethy1 ) phenylthio)benzoic acid (Peltz K. et al. : Collect. Czech. Chem. Commun. 34, 3936 (1969)) in 470 ml of benzene. The mixture was refluxed for 2 h and processed in analogy to example 1/b. The product was crystallised from cyclohexane, which yielded 63.2 g (94%) of crystalline 2- (3- (trifluoromethyl) pheny1 thio)benzoyl chlo¬ ride, m. p. 85-86°C. A solution of 63.2 g of 2- (3- (trif1uoromethyl) phenylthio) - benzoyl chloride in 400 ml of benzene was mixed together with 90 g of 40% aqueous dimethylamine under intensive stir¬ ring at 5°C. The mixture was stirred for 1 h and after stan¬ ding for 1 h at room temperature, it was processed in analo¬ gy to example 1/c, which yielded 64.6 g (100%) of oily N,N-dimethyl-2- (3- (trifluoromethyl)phenylthio) benzamide . A reaction of 64.6 g of oily N,N-dimethyl -2- (3- (trifluoro¬ methyl)phenylthio)benzamide in 400 ml of tetrahydrofuran with 11.2 g of sodium borohydride and 58.6 g of boron tri¬ fluoride etherate, carried out in analogy to example 1/d, yielded the crude base, which was dissolved in ether, filte¬ red and neutralised with a solution of hydrogen chloride in ether. 62.6 g (90%) of N,N-dimethyl-2- (3- (trifluoromethyl) - phenylthio)benzylamine hydrochloride precipitated, which after crystallisation from a mixture of ethanol and ether melted at 165-167°C. Example 21 : N,N-Dimethyl-2- (4- (trifluoromethyl) phenylthio) benzylamine . A reaction of 7.6 g of crude 2- (4- (trifluoromethyl)phenyl- thio)benzoic acid (GB 925,539) in 50 ml of toluene with 20 ml of thionylchloride, carried out in analogy to example 7/a, yielded 8.1 g of crude 2- (4- (trifluoromethyl)phenylthio) - benzoyl chloride, which after crystallisation from cyclo¬ hexane melted at 66-68 C. A reaction of 8.1 g of crude 2- (4- (trifluoromethyl)phenyl¬ thio) benzoyl chloride in 75 ml of dioxane with gaseous di¬ methylamine, carried out in analogy to example 7/b, yielded 7.52 g of oily N,N-dimethyl-2- (4- (trifluoromethyl) pheny1- thio) benzamide . A solution of 7.5 g of N,N-dimethyl-2- (4- (trifluoromethyl) - phenylthio)benzamide in 45 ml of tetrahydrofuran was reduced by 1.3 g of sodium borohydride and 6.8 ml of boron trifluo¬ ride etherate. The reaction mixture was processed in analogy to example 1/d to obtain the oily base. The base was neutra¬ lised with a solution of 4.1 g of oxalic acid dihydrate in 30 ml of ethanol. By addition of 50 ml of ether, crystalline N,N-dimethyl-2- (4- (trifluoromethyl)phenylthio)benzylamine hydrogenoxalate was obtained, which crystallised in two crystalline modifications: the lower melting one - m.p. 166-170°C, and the higher melting one - m.p. 178-182°C. Example 22 : N,N-Dimethyl-5-fluoro-2- (4- (trifluoromethyl)phenylthio) - benzylamine. A reaction of 11.2 g of potassium hydroxide in 120 g of water with 14.4 g of crude 4- (trifluoromethyl) -2-nitrothio- phenol [obtained by reduction of bis(4- (trifluoromethyl) -2- nitrophenyl)disulfide (Sindelaf . et. al: Collect. Czech. Chem. Commun. 46, 118 (1981)) by glucose when using descri¬ bed procedure (DRP 204,450)], 17.1 g of 5-fluoro-2-iodo¬ benzoic acid and 1.5 g cooper, carried out in analogy to example 1/a, and crystallisation from a mixture of benzene and cyclohexane yielded 10.5 g (45%) of 5-fluoro-2- (4- (tri- fluoromethyl) -2-nitrophenylthio) benzoic acid with melting point 156-159°C. A mixture of 10.1 g of 5-fluoro-2- (4- (trifluoromethyl) -2- nitrophenylthio)benzoic acid, 60 ml of ethanol, 5.1 g of hydrazine hydrate, 0.6 g of filtration charcoal and 0.2 g of ferric chloride hexahydrate was refluxed for 11 h and filte¬ red. Ethanol contained in the filtrate evaporated off i n va¬ cuo . The residue was dissolved in a diluted solution of so¬ dium hydroxide and acidified with acetic acid to obtain 8.4 g of 2- (2-amino-4- (trifluoromethyl)phenylthio) -5-fluoro¬ benzoic acid, which after crystallisation from a mixture of benzene, ethanol and petroleum ether melted at 191-193 C. A solution of 2.2 g of sodium nitrite in 5 ml of water was slowly added dropwise under stirring at 0 C to a solution of 8.0 g of 2- (2-amino-4- (trifluoromethyl)phenylthio) -5-fluoro¬ benzoic acid and 4.2 ml of sulfuric acid in 70 ml of etha¬ nol. The mixture was stirred at the given temperature for a further 15 min, then 4.5 g of sodium hypophosphite mono- hydrate in 5 ml of water, 0.2 g of copper and 30 ml of etha¬ nol were added and the mixture was refluxed for 1.5 h. After filtration, the filtrate was evaporated i n vacuo , the resi¬ due was combined with water and filtered by suction. The so¬ lid phase was extracted with boiling ethanol, the insoluble fraction was filtered off and the filtrate was evaporated again. The residue was extracted with boiling benzene and the insoluble fraction was again filtered off. The filtrate was evaporated and crystallisation of the residue from petroleum ether yielded 4.4 g of 5-fluoro-2- (4- (trifluoromethyl) phenyl - thio)benzoic acid with melting point 127-129.5 C. A mixture of 4.2 g of 5-fluoro-2- (4- (trifluoromethyl) - phenylthio)benzoic acid, 40 ml of benzene and 4.8 g of thio¬ nylchloride was refluxed for 1.5 h and processed in analogy to example 1/b, which yielded 3.9 g of oily 5-fluoro-2- (4- (trifluoromethyl) phenylthio)benzoyl chloride . A solution of 3.9 g of 5-fluoro-2- (4- (trifluoromethyl) - phenylthio) benzoylchloride was dissolved in 30 ml of benzene and was mixed under intensive stirring over a period of 15 min with 10 ml of 40% aqueous dimethylamine and processed in analogy to example 1/c, which yielded 4.0 g of oily N,N-di-methyl-5-fluoro-2- (4- (trifluoromethyl) phenylthio) - benzamide. 1.0 g of sodium borohydride was added to a solution of 4.0 g of oily N,N-dimethyl-5-fluoro-2- (4- (trifluoromethyl) - phenylthio)benzamide in 30 ml of tetrahydrofuran and then 4.5 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring over a period of 10 min. The mixture was processed in analogy to example 1/d to obtain the crude base (3.5 g) . This was dissolved in ether and the solution was neutralised with a solution of 1.5 g of oxalic acid dihydrate in acetone. The precipitated crude N,N-dime¬ thyl-5-fluoro-2- (4- (trifluoromethyl)phenylthio)benzylamine hydrogen oxalate recrystallised from ethanol to obtain 3.25 g of the pure salt with melting point 177.5-179.5°C. Example 23 : N,N-Dimethy1-2- (4- (methylthio) phenylthio)benzylamine . a) A reaction of 12.4 g of 2- (4- (methylthio)phenylthio) - benzoic acid (Pelz K. et. al : Collect. Czech. Chem. Commun. 33, 1895 (1968)) in 100 ml of benzene with 11 ml of thionyl¬ chloride, carried out in analogy to example 1/b, yielded 13.0 g of crude 2- (4- (methylthio)phenylthio) benzoyl chloride as a yellowish oil. b) A reaction of 13.0 g of crude 2- (4- (methylthio)phenyl¬ thio)benzoyl chloride in 80 ml of benzene with 40 ml of 40% aqueous dimethylamine, carried out in analogy to example 1/c, yielded 13.2 g of oily N,N-dimethyl-2- (4- (methylthio) - phenylthio)benzamide . c) 3.0 g of sodium borohydride was added to a solution of 13.6 g of oily N,N-dimethyl-2- (4- (methylthio) phenylthio) - benzamide in 80 ml of tetrahydrofuran and then 12.0 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring over a period of 30 min. The mixture was processed in analogy to example 1/d, which provided 14 g of the crude base. This was neutralised with a solution of hydrogen chloride in ether, and after crystallisation from a mixture of acetone and ethanol 8.3 g of N ,N-dimethyl-2- (4- (methylthio)phenylthio)benzylamine hydrochloride was yiel¬ ded, with melting point 141-144°C. Example 24: N,N-Dimethy1-5-fluoro-2- (4- (methylthio) phenylthio) - benzylamine . A reaction of 12.4 g of 5-fluoro-2- (4- (methylthio)phenyl- thio)benzoic acid (Kopicova Z. et . al : Collect. Czech. Chem. Commun. 40. 3519 (1975)) , 90 ml of benzene and 16 g of thio¬ nylchloride, carried out in analogy to example 1/b and crystallisation from cyclohexane yielded 11.1 g of 5-fluoro- 2- (4- (methylthio)phenylthio)benzoyl chloride with melting point 77-78°C. A reaction of 11.1 g of 5-fluoro-2- (4- (methylthio)phenyl¬ thio)benzoyl chloride in 60 ml of benzene with 20 ml of 40% aqueous dimethylamine, carried out in analogy to example 1/c, yielded oily N,N-dimethyl-5-fluoro-2- (4- (methylthio) - phenylthio)benzamide . A reaction of 12.2 g of oily N,N-dimethyl-5-fluoro-2- (4- (methylthio)phenylthio)benzamide in 70 ml of tetrahydrofuran with 2.8 g of sodium borohydride and 12.5 g of boron tri¬ fluoride etherate, carried out in analogy to example 1/d, yielded 12.0 g of crude base. This was neutralised with a solution of hydrogen chloride in ether, which yielded 11.6 g of N,N-dimethyl-5-fluoro-2- (4- (methylthio)phenylthio) - benzylamine hydrochloride, which after crystallisation from a mixture of ethanol and ether melted at 160.5- 162.5 C. Example 25 : N,N-Dimethyl-5-fluoro-2- (4- (methylsulfinyl) phenylthio) - benzylamine. 5 ml of 15% hydrogenperoxide was added to a solution of 2.6 g of N,N-dimethyl-5-fluoro-2- (4- (methylthio)phenylthio) - benzylamine hydrochloride (see example 24) in 12 ml of ace¬ tic acid and the mixture was left standing at room tempera¬ ture for 4 days. After diluting with water, it was made al¬ kaline by aqueous ammonium and extracted with ether. The ex¬ tract was dried with potassium carbonate, filtered and the filtrate was evaporated, which yielded 2.3 g of the base of N,N-dimethyl-5-fluoro-2- (4- (methylsulfinyl)phenylthio) benzyl¬ amine base, which after crystallisation from a mixture of benzene and petroleum ether melted at 94-97 C. Neutralisa¬ tion of this base with a solution of hydrogen chloride in ether yielded the hydrochloride, which after crystallisation from a mixture of acetone, ethanol and ether melted at 221-223°C. Example 26 : N,N-Dimethyl-5-chloro-2- (4- (methylthio)phenylthio) - benzylamine. 5.0 g of 4- (methylthio)thiophenol , (Pelz K. et . al : Col¬ lect. Czech. Chem. Commun. 33, 1895 (1968)) , 11.3 g of 5-chloro-2-iodobenzoic acid and 3.0 g of copper were step by step added to a solution of 6.8 g of potassium hydroxide in 120 ml of water and the mixture was refluxed for 8.5 h and processed in analogy to example 1/a. The product was re- crystallised from 400 ml of mixture of benzene and petroleum ether (1:1) , filtered by suction and dried, yielding 8.9 g of 5-chloro-2- (4- (methylthio)phenylthiobenzoic acid (72%) , which melted at 193-195°C. A reaction of 10.1 g of 5-chloro-2- (4- (methylthio) phenyl¬ thiobenzoic acid in 100 ml of toluene with 20 ml of thionyl¬ chloride (1 h under stirring at 80 C) and processing in ana¬ logy to example 7/a yielded 9.8 g (95%) of 5-chloro-2- (4- (methylthio) phenylthiobenzoylchloride , which after crystal¬ lisation from a mixture of cyclohexane and petroleum ether melted at 78-81°C. 9.4 g of 5-chloro-2- (4- (methylthio)phenylthionbenzoyl chloride in 50 ml of toluene reacted under intensive stirring and cooling with cold water with 30 ml of 40% aqueous di¬ methylamine. The mixture was stirred at room temperature for a further 2 h, the toluene phase was separated, washed with water and evaporated i n vacuo . The residue was dissolved in chloroform and was purified by filtration on a silica gel column, which was eluted with chloroform. The filtrate eva¬ porated i n vacuo again, which yielded 7.55 g of oily N,N-di¬ methyl-5-chloro-2- (4- (methylthio)phenyl hio)benzamide . A reaction of 7.41 g of oily N,N-dimethyl-5-chloro-2- (4- (methylthio)phenylthio)benzamide in 60 ml of tetrahydrofuran with 3.0 g of sodium borohydride and 10 ml of boron trifluo¬ ride etherate, carried out in analogy to example 1/d, yiel¬ ded the crude base, which was neutralised with a solution of 3.0 g of oxalic acid dihydrate in 80 ml of ethanol. After 16 h of standing, the precipitated product was filtered by suction, washed with ethanol and dried, which yielded 5.05 g (53%) of N,N-dimethyl-5-chloro-2- (4- (methylthio) phenylthio) - benzylamine hydrogen oxalate, m.p. 131-134 C. Example 27 : N,N-Dimethy1-2- (4- (fluoro-3-methoxyphenylthio)benzylamine . - 35 - A mixture of 18.5 g of thiosalicylic acid, 150 ml of di¬ methylformamide, 33.15 g of potassium carbonate, 24.6 g of 5-bromo-2-fluoroanisole (EP 175,452; JP 61/27,768; Chem. Abstr. 105, 42658 (1986)) and 2.2 g of copper was refluxed for 12 h. After cooling, the reaction mixture was diluted with 1.1 1 of water, filtered and washed with benzene. The water phase was acidified with hydrochloric acid, the preci¬ pitated crude 2- (4- (fluoro-3-methoxyphenylthio)benzoic acid (20.6 g) was filtered by suction and after crystallisation from ethanol melted at 222-224°C. A reaction of 8.82 g of 2- (4- (fluoro-3-methoxyphenylthio) - benzoic acid in 70 ml of benzene with 12.3 g of thionyl¬ chloride, carried out in analogy to example 1/b, yielded 8.6 g (91%) of 2- (4- (fluoro-3-methoxyphenylthio) benzoyl- chloride, which after crystallisation from a mixture of benzene and cyclohexane melted at 113-114.5 C. A reaction of 8.45 g of 2- (4- (fluoro-3-methoxyphenylthio) - benzoyl chloride in 60 ml of benzene with 13 ml of 40% aque¬ ous dimethylamine, carried out in analogy to example 1/c, yielded 7.3 g of crystalline N,N-dimethyl-2- (4-fluoro-3- methoxyphenylthio)benzamide , which after recrystallisation from methanol melted at 97-98, 5°C. 1.75 g of sodium borohydride was added to a solution of 7.0 g of N,N-dimethyl-2- (4- (fluoro-3-methoxyphenylthio) benz¬ amide in 45 ml of tetrahydrofuran and then 6.8 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring. The mixture was processed in analogy to example 6/d, except for the use of a solution of hydrogen chloride in ether for neutralisation. The procedure yielded 6.52 g of N,N-dimethyl-2- (4- (fluoro-3-methoxyphenylthio) - benzylamine hydrochloride, which after recrystallisation from a mixture of acetone and ether melted at 146-148 C. Example 28 : N,N-Dimethyl-2- (4-fluoro-3-hydroxyphenylthio)benzylamine . A solution of 7.0 g of N,N-dimethy -2- (4-fluoro-3-methoxy- phenylthio)benzylamine hydrochloride (see example 27) in 50 ml of 46% hydrobromic acid was heated up to 120 C under stirring for 8 h. After cooling, the mixture was diluted with 100 ml of water, its pH was adjusted up to 8 using 20% solution of sodium hydroxide, and the mixture was extracted with chloroform. The extract was filtered over a 100 g sili¬ ca gel column, which was eluted with chloroform. The filtra¬ te was evaporated, which yielded 4 71 g of the base of oily N,N-dimethyl-2- (4- (fluoro-3-hydroxyphenylthio)benzyl¬ amine. Its neutralisation with the corresponding acids and crystallisation from benzene, or a mixture of ethanol and ether, respectively, yielded the hydrochl ride with melting point 172-175 C, and hydrogen maleate with melting point 148-150°C. Example 29: N,N-Dimethyl-2- (4-chloro-3- ethoxypheny1 thi ) benzylamine . A reaction of 4.7 g of 2- (4-chloro-3-methoxyphenylthio) - benzoic acid (Cervena I. et . al : Collect Czech. Chem. Com¬ mun. 42, 1705 (1977)) in 35 ml of benzene and 3.8 ml of thionylchloride, carried out in analogy to example 1/b, yielded 4.1 g (82%) of crystalline 2- (4-chloro-3-methoxy- phenylthio)benzoylchloride , which after recrystallisation from cyclohexane melted at 117-118.5 C. A solution of 3.6 g of 2- (4-chloro-3-methoxyphenylthio) - benzoyl chloride in 45 ml of toluene was under stirring and external cooling by water and ice saturated with gaseous di¬ methylamine for 1 h. The mixture was stirred for a further 2 h and evaporated i n vacuo . The oily residue was mixed with a small amount of a mixture of cyclohexane and hexane (1:1) and crystallised. The product's filtration by suction yiel¬ ded 3.0 g of N,N-dimethyl-2- (4-chloro-3-methoxyphenylthio) - benzamide, which after recrystallisation from a mixture of hexane and cyclohexane melted at 84-86 C. 0.7 g of sodium borohydride was added to a solution of 2.65 g of N,N-dimethyl-2- (4-chloro-3-methoxyphenylthio)benz¬ amide in 20 ml of tetrahydrofuran and then 2.26 g of boron trifluoride etherate was added dropwise under nitrogen and under stirring. The mixture was processed in analogy to example 1/d, which yielded 2.35 g (92%) of the oily crude base. Using hydrogen chloride in ether yielded N, N-dimethyl- 2- (4-chloro-3-methoxyphenylthio) benzylamine hydrochloride , which after crystallisation from 2-propanol melted at 162-164°C. Example 30: N,N-Dimethyl-2- (4-trifluoromethyl) -2-nitrophenylthio) - benzylamine . 22.8 g of 2-methylτhiophenol , 41.4 g of 2-chloro-5- (tri- fluoromethyl)nitrobenzene and 2.0 g of copper were added to a solution of 30.6 g of potassium hydroxide in 325 ml of wa¬ ter. The mixture was refluxed under stirring for 9 h, and after cooling extracted with toluene. The extract was dried with magnesium sulfate, filtered and evaporated, which yiel¬ ded 50 g of the oily crude 2- (4-trifluoromethyl)-2-nitro- phenylthio)toluene of orange colour. After cooling to 0 C, the product crystallised and after recrystallisation from hexane melted at 55-56 C. 37 g of N-bromosuccinimide and 0.5 g of 2,2 -azobis(2- methylpropionitrile) were added to a solution of 54.2 g of 2- (4-trifluoromethyl) -2-nitrophenylthio)toluene in 400 ml of tetrachloromethane and the mixture was refluxed under stirring for 4 h. After cooling the precipitated solid com¬ pound was filtered off and washed with tetrachloromethane, which yielded 470 ml of filtrate containing 2- (4-trifluoro- methyl) -2-nitrophenylthio)benzylbromide . For its characteri¬ sation this was isolated from a part of the filtrate as fol¬ lows: 45 ml of the filtrate was evaporated i n vacuo , then chromatographed on a 100 g silica gel column and the column was eluted by petroleum ether, then cyclohexane and 5% tolu¬ ene in cyclohexane. After isolation and crystallisation from a mixture of petroleum ether and cyclohexane, the product melted at 77-79°C. The filtrate (302 ml) containing 2- (4-trifluoromethyl) -2- nitrophenylthio) benzylbromide was cooled to -10 C and a so¬ lution of excess dimethylamine in tetrachloromethane was ad¬ ded little by little under stirring. The mixture was stirred at room temperature for 3 h and the precipitated dimethyl¬ amine hydrobromide was filtered off. The filtrate was washed with water, dried with magnesium sulfate and evaporated, which yielded 40 g of the crude oily base of N,N-dimethyl-2- (4-trifluoromethyl)-2-nitrophenylthio)benzylamine , which crystallised on standing and after recrystallisation from hexane melted at 59-60 C. Its neutralisation and crystalli¬ sation from a mixture of ethanol and ether, or aqueous etha¬ nol, respectively, yielded the following salts: the hydro¬ bromide melting at 193-195 C and hydrogen oxalate melting at 218-219°C. Example 31 : N,N-Dimethy1-2- (2-aminophenylthio) benzylamine. a) A solution of 4.9 g of 2- (2-aminophenylthio)benzoic acid (Mayer F. : Ber . Dtsch. Chem. Ges. 42, 3046 (1909)) in 50 ml of tetrahydrofuran was added dropwise under stirring over a period of 30 min to a solution of 1.7 g of lithium aluminium hydride in 70 ml of tetrahydrofuran and after an exothermic reaction the mixture was refluxed for 5 h. After 16 h of standing, the mixture was decomposed under stirring by adding dropwise 6.7 ml of 4% solution of sodium hydroxi¬ de. The precipitated solid was filtered off and the filtrate was dried with magnesium sulfate and evaporated i n vacuo , which yielded 4.3 g (93%) of 2- (2-aminophenylthio)benzyl alcohol. This crystallised on standing and after recrystal¬ lisation from cyclohexane melted at 107-108.5 C. It provides hydrochloride, which after recrystallisation from a mixture of 2-propanol and ethanol melted at 143-147 C. b) 2.6 g of 2- (2-aminophenylthio)benzyl alcohol was slowly mixed at room temperature with 2.7 g of thionylchloride and the mixture was left standing at room temperature for 1 h. Then it was diluted with 20 ml of benzene and all volatile constituents absolutely evaporated off i n vacuo . The residue was 2.7 g of oily crude 2- (2-aminophenylthio) benzyl chlori¬ de. c) A solution of 1.4 g of dimethylamine in 3 ml of toluene was added to a solution of 1.15 g of 2- (2-aminophenylthio) - benzyl chloride in 8 ml of toluene and the mixture was under external cooling by water and ice stirred for 1.5 h. After 16 h of standing, the precipitated dimethylamine hydro¬ chloride was filtered off and the filtrate was evaporated, which yielded 1.1 g (92%) of the base as a brown oil. Neu¬ tralisation of 1.0 g of this base with 0.7 g oxalic acid di¬ hydrate in 5 ml of heated ethanol yielded crystalline N,N-dimethyl-2- (2-aminophenylthio)benzylamine hydrogen oxa- late , which after crystallisation from aqueous methanol mel¬ ted at 182-186°C. Example 32: N,N-Dimethy1-2- (3-aminophenylthio)benzylamine . 7.15 g of crude 3-aminothiophenol (Zincke T. , Mϋller J. : Ber. Dtsch. Chem. Ges . 46, 775 (1913)) was added to a solu¬ tion of 8.9 g of potassium hydroxide in 80 ml of water and after 20 min of stirring at 50 C also 14.1 g of 2- iodobenzoic acid and 0.2 g of copper as catalyst were added. The mixture was refluxed for 12 h. After adding of filtration charcoal, the mixture was filtered hot, and the partially cooled fil¬ trate was acidified with diluted hydrochloric acid (1:1). The product was filtered by suction and crystallised from aqueous 2-propanol, which yielded 7.7 g of 2- (3-aminophenyl- thio)benzoic acid with melting point 160-163 C. 3.66 g of absolutely dry 2- (3-aminopheny 1 thio) benzoic acid was slowly added to a solution of 3.0 g of lithium aluminium hydride in 100 ml of tetrahydrofuran. The mixture was stir¬ red at room temperature for 30 min, then refluxed for 3.5 h and processed in analogy to example 31/a, which yielded 3.1 g (89%) of crystalline 2- (3-aminopheny1thio) benzyl alco¬ hol, which after crystallisation from cyclohexane melted at 69-71°C. Under cooling by ice and water 3.0 g of 2- (3-aminophenyl- thio)benzyl alcohol and 2.5 ml of thionylchloride were slowly mixed and the mixture was left standing at room temperature for 1 h. The excess thionylchloride evaporated off i n vacuo and the gained crude 2- (3-aminopheny1 thio) benzyl chloride hydrochloride was suspended in 20 ml of toluene. 4.5 ml of dimethylamine in 10 ml of toluene was added dropwise under stirring and under external cooling by ice and water. The mixture was left standing at room temperature for 2 h, and was then stirred for a further 2 h. The precipitated di¬ methylamine hydrochloride was filtered off by suction and the filtrate was evaporated i n vacuo . The residue was 3.0 g of the oily crude base, which was dissolved in a small amount of ethanol and neutralised with a solution of 2.8 g of the oxalic acid dihydrate in ethanol . On standing there precipitated 3.4 g of N,N-dimethyl-2- (3-aminophenylτhio) - benzylamine bis(hydrogen oxalate) , which after crystallisa¬ tion from methanol melted at 161-162 U C. Examp l e 33 : N,N-Dimethyl-2- (4-aminophenylthio)benzylamine . A mixture of 3.7 g of 2- (4-aminophenylthio)benzyl alcohol (Adlerova E. et . al : Collect. Czech. Chem. Commun. 33, 2666 (1968)) and 3.8 g of thionylchloride was processed in analo¬ gy to example 31/b. The procedure yielded 3.8 g of crude 2- (4-aminophenylthio)benzyl chloride hydrochloride. A solution of 4.6 ml of dimethylamine in 10 ml of toluene was added dropwise under stirring to a suspension of 3.8 g of crude 2- (4-aminophenylthio)benzylchloride hydrochloride in 25 ml of toluene and the mixture was processed in analogy to example 31/c, which yielded 3.8 g of the oily base. This was dissolved in 10 ml of ethanol and neutralised with a so¬ lution of 3.7 g of oxalic acid dihydrate in 15 ml of etha¬ nol. After 16 h of standing in cold, 3.2 g of N,N-dimethyl-2- (4-aminophenylthio)benzylamine bis(hydrogen oxalate) crystal¬ lised, which after subsequent crystallisation from methanol melted at 164-166°C. Example 34: N,N-Dimethyl-2- (2-amino-4- (trifluoromethyl) phenylthio) - benzylamine . 9.4 g of hydrazinehydrate , 1.3 g of filtration charcoal and a solution of 9.4 g of ferric chloride hexahydraτe in 15 ml of ethanol were added under stirring to a suspension of 26.0 g of 2- (4- (trifluoromethyl) -2-nitrophenylthio)benzoic acid (GB 925,539) . The mixture was refluxed for 8.5 h. After 16 h of standing, ethanol evaporated off i n vacuo . A solu¬ tion of 8.6 g of sodium hydroxide in 45 ml of water was ad¬ ded to the residue, the mixture was diluted with 115 ml of water and 1.3 g of filtration charcoal was added. After hea- ting up to 90 C, the mixture was filtered, the filtrate was cooled to 15 C and under stirring was acidified with 22 g of acetic acid added dropwise. The precipitated product was filtered by suction, washed with water and dried, which yielded 19.9 g (81%) of 2- (2-amino(-4- (trifluoromethyl) - phenylthio) benzoic acid, which after crystallisation from benzene melted at 188-190°C. A solution of 37.6 g of 2- (2-amino(-4- (trifluoromethyl) - phenylthio)benzoic acid in 350 ml of tetrahydrofuran was under stirring slowly added dropwise to a solution of 11.6 g of lithium aluminium hydride in 400 ml of tetrahydrofuran and the mixture was refluxed for 5 h. After cooling, the mixture was decomposed by slow adding dropwise of 4% solu¬ tion of sodium hydroxide (47 ml) under external cooling. Then the mixture was stirred at room temperature for 1.5 h and the precipitated compound was filtered by suction and washed with ether. The filtrate was dried with magnesium sulfate and evaporated i n vacuo . The oily residue crystal¬ lised on standing and recrystallisation from cyclohexane yielded 21.8 g (61%) of 2- (2-amino-4- (trifluoromethyl) phenyl - thio)benzyl alcohol with melting point 88-89 C. Vhen working with bigger charges, the reduction of the acid into alcohol is more suitably carried out in the follo¬ wing way: 323 g of 70% solution (toluen) of sodium dihydridobis(2-methoxyethoxo)aluminate (NaAlH 2 (OCH2CH2OCH3) 2 in 300 ml of toluene was under stirring over a period of 75 min added dropwise to a solution of 125 g of 2- (2-amino-4- (trifluoromethyl)phenylthio)benzoic acid in 2 1 of toluene and the mixture was stirred at room temperature for 4 h. Under external cooling and under stirring then it was decom¬ posed by adding 2000 ml of 10% solution of sodium hydroxide. The toluene phase was separated, the aqueous phase was ex¬ tracted with toluene and the toluene solutions were put to¬ gether, dried with magnesium sulfate and after filtration the toluene evaporated off i n vacuo . The residue was 101 g (92%) of crude 2- (2-amino-4- (trifluoromethyl)phenylthio) - benzyl alcohol, which after crystallisation from cyclohexane melted at 88-89 C and was identical to the product of the previous reduction. 59.8 g of 2- (2-amino-4- (trifluoromethyl)phenylthio) benzyl alcohol was added under stirring at 5-8 C over a period of 1 h to 29.2 ml of thionylchloride and the mixture was then stirred at room temperature for 2 h. The excess thionylchlo¬ ride was absolutely evaporated off i n vacuo and the solid product was stirred up with cyclohexane and filtered by suc¬ tion, which yielded 70.8 g (100%) of 2- (2-amino-4- (trifluoro¬ methyl)phenylthio)benzyl chloride hydrochloride, which melted at 89-93°C. A solution of 40 ml of dimethylamine in 40 ml of toluene was added dropwise under stirring and under external cooling to a suspension of 70.8 g of 2- (2-amino-4- (trifluoromethyl) - phenylthio)benzyl chloride in 100 ml of toluene. The mixture was stirred at room temperature for a further 1 h and was processed in analogy to example 31/c, which yielded 57.4 g (88%) of the oily crude base of N,N-dimethyl-2- (2-amino-4- (trifluoromethyl)phenylthio)benzylamine , which after crystal¬ lisation melted at 58-59 C. Its neutralisation with hydro- genchloride in a mixture of ethanol and ether yielded di- hydrochloride , which crystallised from a mixture of ethanol and ethylacetate as monohydrate with melting point 180-183 . Neutralisation of the base with oxalic acid di¬ hydrate in hot ethanol and its subsequent cooling yielded the oxalate , which after crystallisation from aqueous etha¬ nol melted at 213-216°C. Example 35: N,N-Dimethy1-2- (2-amino-4- (trifluoromethyl)phenylthio) -5- fluorobenzylamine . A solution of 40.0 g of 2- (2-amino-4- (trifluoromethyl) - phenylthio) -5-fluorobenzoic acid (see example 22) in 200 ml of tetrahydrofuran was added dropwise under stirring over a period of 15 min to a solution of 13.2 g of lithium alumi¬ nium hydride in 100 ml of tetrahydrofuran and the mixture was refluxed under stirring for 4 h After 16 h of standing, the mixture decomposed by adding dropwise of 10% solution of sodium hydroxide (40 ml) under stirring. After 2.5 h of stirring, the precipitated compound was filtered off by suc¬ tion, the filtrate was dried with potassium carbonate and was evaporated. The residue was 41 g of crude 2- (2-amino-4- (trifluoromethyl)phenylthio) -5-fluorobenzy1alcohol to which 40 ml of thionylchloride was added dropwise under cooling with ice and under stirring. The mixture was stirred at room temperature for 2 h and left standing for 16 h The excess thionylchloride evaporated off i n vacuo The residue was crude 2- (2-amino-4- (trifluoromethyl)phenyl thio) -5-fluoro- benzyl chloride hydrochloride. This was dissolved in 50 ml of benzene and a solution of 40 g of dimethylamine in 50 ml of benzene was added dropwise under stirring and under coo¬ ling. The mixture was stirred for 6 h and after 48 h of standing the precipitated dimethylamine hydrochloride was filtered off by suction. The filtrate was evaporated i n va¬ cuo and the residue was chromatographed on a 150 g silica gel column. Elution with chloroform yielded 23.5 g of the oily base, which with hydrogen chloride in ether provided N,N-dimethyl-2- (2-amino-4- (trifluoromethyl ) phenylthio) -5- fluorobenzylamine hydrochloride hemihydrate This crystal¬ lised from a mixture of ethanol and ether as a crystalline modification melting at 181-184 υ C, and from a mixture of 2-propanol and ethylacetate as another crystalline modifica¬ tion melting at 124-128°C. Example 36: N,N-Dimethyl-2- (4-amino-2- (trifluoromethyl) phenylthio) - benzylamine 0.93 g of thiosalicylic acid and 1.6 g of 2-bromo-5-nitro- benzotrifluoride (Filler R. , Novar H. : J. Org. Chem. 26, 2707 (1961)) were added to a solution of 0.48 g of sodium hydroxide in 25 ml of ethanol and the mixture was refluxed under stirring for 2.5 h. The ethanol evaporated off i n va¬ cuo and the residue was dissolved in 25 ml of hot water. After cooling, the mixture was acidified under stirring with 2.5 ml of 3M hydrochloric acid. Filtration, washing with wa¬ ter and drying yielded 1.85 g (92%) of crude 2- (2- (trifluoro¬ methyl) -4-nitrophenylthio)benzoic acid, which after crystal¬ lisation from aqueous methanol melted at 150-152 C. 0.2 g of filtration charcoal and a solution of 0.1 g of ferric chloride hexahydrate in 5 ml of ethanol were added to a solution of 2.92 g 2- (2- (trifluoromethy1) -4-niτrophenyl- thio)benzoic acid in 15 ml of 96% ethanol. The mixture was refluxed for 7.5 h, the ethanol evaporated off i n vacuo and the residue was dissolved at 60 C in 1M solution of sodium hydroxide. The solution was filtered using filtration char¬ coal, cooled and made slightly acid with acetic acid. The precipitate was filtered by suction, washed with water and dried, which yielded 1.26 g (47%) of 2- (4-amino-2- (trifluoro¬ methyl)phenylthio)benzoic acid, which after crystallisation from a mixture of benzene and petroleum ether melted at 210-214°C. A solution of 3.13 g of 2- (4-amino-2- (trifluoromethyl) - phenylthio)benzoic acid in 30 ml of ether was under stirring slowly added dropwise to a solution of 1.52 g of lithium aluminium hydride in a mixture of 15 ml of ether and 15 ml of tetrahydrofuran and was refluxed for 1.5 h. After 16 h of standing, it decomposed by adding dropwise of 5% sodium hydroxide (6 ml) under stirring. The precipitated compound was filtered off by suction and the filtrate was evaporated i n vacuo . The residue was chromatographed on a 25 g silica gel column, which was eluted with benzene. The procedure yielded 2.7 g of 2- (4-amino-2- (trifluoromethyl)phenylthio) - benzyl alcohol, which provided crystalline hydrochloride. This after crystallisation from a mixture of ethanol and ether melted at 160-162°C. A solution of hydrogen chloride in ether (2 ml containing 5.5 mmol of hydrogen chloride) was added to a solution of 1.61 g of 2- (4-amino-2- (trifluoromethyl) phenylthio) benzyl alcohol in 5.5 ml of benzene and then 5.2 ml of thionylchlo¬ ride was added dropwise under stirring over a period of 20 min. The reaction mixture was stirred at 24 C for 1.5 h and the volatile constituents absolutely evaporated off i n vacuo . The residue was 1.7 g (100%) of 2- (4-amino-2-tri- fluoromethyl)phenylthio) benzyl chloride hydrochloride. which was dissolved in 15 ml of toluene and then a solution of di¬ methylamine (5x in excess) in 10 ml of toluene was added. The mixture was stirred at room temperature for 1 h and after 16 h of standing it was washed with water. The toluene solution was dried with potassium carbonate and was evapora¬ ted i n vacuo . The residue was 1.65 g of the base as an oily liquid. Neutralisation with oxalic acid dihydrate in ethanol hot followed by cooling yielded 1.53 g (88%) of N,N-dimethyl- 2- (4-amino-2- (trifluoromethyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from 2-propanol melted at 161-163.5°C. Example 37: N,N-Dimethyl-2- (3- (hydroxymethyl)phenylthio)benzylamine . A mixture of 200 ml of dimethylformamide , 24 g of N,N-di¬ methyl-2-iodobenzamide (Cohen T. et . al : Tetrahedron Lett. 40, 3555 (1974)), 13.7 g of 3-mercaptobenzoic acid, 25 g of potassium carbonate and 1 g of copper was refluxed in the bath heated up to 150 C under stirring for 9 h. Di ethylfor- mamide was distilled off i n vacuo , the residue was diluted with 200 ml of water, the resulting liquid was filtered and the filtrate was acidified with diluted hydrochloric acid (1:1). After 30 min of standing, the precipitate was filte¬ red by suction, dissolved in hot ethanol, the insoluble fraction was filtered off and the filtrate was evaporated. The residue was chromatographed on a 150 g silica gel co¬ lumn, which was gradually eluted with benzene, chloroform, ethylacetate and ethanol. The ethylacetate eluaτes were eva¬ porated, which yielded 12.4 g of homogenous oily N,N-di¬ methyl-2- (3- (carboxy phenylthio)benzamide . 12.4 g of oily N,N-dimethyl-2- (3- (carboxyphenylthio) benz¬ amide in 100 ml of tetrahydrofuran, 4.8 g of sodium boro¬ hydride and 18.8 g of boron trifluoride etherate were pro¬ cessed in analogy to example 23/c, which yielded 9.8 g of oily base. Its neutralisation with oxalic acid dihydrate in acetone yielded crystalline N,N-dimethyl-2- (3- (hydroxy¬ methyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from a mixture of acetone, ethanol and ether melted at 111.5-113°C. Example 38: N,N-Dimethy1-2- (4- (hydroxymethyl)phenylthio)benzylamine . 3.98 g of crude N,N-dimethyl-2-mercaptobenzamide (Schindl- bauer H. : Monatsh. Chem. 99, 1799 (1968)) , 3.04 g potassium carbonate and 2.63 g of 4-chlorobenzaldehyde were added under stirring to 40 ml of dimethylformamide and the mixture was refluxed for 8 h up to the boiling point. It was diluted with 200 ml of water and extracted with a mixture of ether and ethylacetate. After filtration with filtration charcoal, the extract was dried with potassium carbonate and evapora¬ ted i n vacuo . 5.06 g (95%) of oily crude N, N-dimethyl-2- (4- formylphenylthio)benzamide was obtained, which was purified by chromatography on a silica gel column eluted with a mix¬ ture of ethylacetate and benzene . 2.27 g of sodium borohydride was added to a solution of 5.14 g of N,N-dimethyl-2- (4-formylphenylthio)benzamide in 30 ml of tetrahydrofuran and after 16 h of standing, 7.67 g of boron trifluoride etherate was added dropwise under stir¬ ring in nitrogen atmosphere at 17-24 C over a period of 0.5 h. After 1 h of stirring at room temperature, the mixtu¬ re was refluxed for 8 h. After 16 h of standing at room tem¬ perature, the mixture was diluted with 10 ml of tetrahydro¬ furan and then was acidified under stirring at 20-30 C by adding dropwise of 60 ml of 6M HC1. The mixture was refluxed for a further 3.5 h. After cooling it was made alkaline with 10M solution of sodium hydroxide and extracted with chloro¬ form. The extract was dried with potassium carbonate and evaporated i n vacuo . The residue was 4.42 g (90%) of the crude base, which was purified by crystallisation on a sili¬ ca gel column gradually eluted with a mixture of chloroform and ethylacetate, chloroform and a mixture of methanol and chloroform saturated with ammonium at last. The residue of the chloroform eluate was an oily base whose neutralisation with oxalic acid dihydrate in acetone yielded crystalline N,N-dimethyl-2- (4- (hydroxymethyl) heny1thio) benzylamine hydrogen oxalate, which after crystallisation from a mixture of acetone, ethanol and ether melted at 96-98 C. Example 39: N,N-Dimethy1-2- (4- (hydroxymethyl)phenylthio) benzylamine . This is an alternative method of preparation of the com¬ pound according to example 38. A mixture of 25 ml of dimethylformamide , 4.15 g of 4-mercaptobenzyl alcohol (Pelz et al . : Collect. Czech. Chem. Commun. 33, 1895 (1968)), 3.73 g 2-chlorobenzaldehyde , 3.95 g of potassium carbonate and 0.16 g of copper, as a ca¬ talyst, was refluxed under stirring at 98-109 C for 8 h. After 16 h of standing, the insoluble fractions were filte¬ red off and still on the filter were washed with ethanol. The filtrate was filtered with 1 g of filtration charcoal and evaporated i n vacuo . The residue was divided into 10 ml of water and 3 x 3 ml of ether. The ether phases were put together and were evaporated. The residue reacted with a so¬ lution of 10.4 g of potassium pyrosulfite in 26 ml of water. The precipitated "bisulfite adduct" was filtered off by suc¬ tion, decomposed by 10 ml of 3M sulfuric acid and the free aldehyde was extracted with ether and chloroform. 4.42 g of oily 2- (4- (hydroxymethyl)phenylthio)benzaldehyde was obtai¬ ned from the extract. For its characterisation this aldehyde can be converted to crystalline 2, 4-dinitrophenylhydrazon in a familiar way, which after crystallisation from a mixture of ethylacetate and ethanol melted at 216-222°C. A mixture of 3.82 g of 2- (4- (hydroxymethyl)phenylthio) - benzaldehyde, 8 ml of dimethyformamide (7.5 g) and 4.6 g of formic acid was refluxed under stirring for 7.5 h (bath tem¬ perature was 160-170 C) . After cooling, the mixture was aci¬ dified with an addition of 30 ml of 5% hydrochloric acid and the fractions which were not basic were removed by washing with ether. The aqueous solution was filtered with filtra¬ tion charcoal, the filtrate was made alkaline with 15 ml of 5M solution of sodium hydroxide and the product was extrac¬ ted with dichloroethane. The extract was dried with potas¬ sium carbonate and evaporated i n vacuo . The residue was 3.96 g (93%) of the oily base, whose neutralisation with oxalic acid dihydrate in ethanol yielded crystalline N,N-di- methyl-2- (4- (hydroxymethyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from ethanol melted at 96-98 C and was identical to the compound prepared as de¬ scribed in example 38. Example 40 : N,N-Dimethyl-2- (2- (dimethylaminomethyl)phenylthio) - benzylamine . a) 12.2 ml of thionylchloride in 20 ml of benzene was ad¬ ded dropwise under stirring to a solution of 4.11 g of diphenylsulfido-2-2 -dicarboxylic acid (Mayer F. : Ber . Dtsch. Chem. Ges . 43, 588 (1910)) in 40 ml of benzene and the mixture was refluxed for 4 h. After evaporating and coo¬ ling, the solid residue was mixed with a small amount of cyclohexane and isolated by filtration, which yielded 4.28 g (92%) of crystalline diphenylsulfide-2-2 -dicarboxylic acid dichloride, which after crystallisation from cyclohexane melted at 80-83°C. b) A solution of 3.60 g of diphenylsulfide-2-2 -dicarboxy¬ lic acid dichloride in 40 ml of benzene was mixed with 17 ml of 40% aqueous dimethylamine over a period of 1 h under in¬ tensive stirring and external cooling with ice and water. The mixture was stirred at room temperature for 3 h and then was processed in analogy to example 1/c. The procedure yiel¬ ded 3.52 g (93%) of oily N,N-dimethyl-2- (2- (dimethylamino¬ carbonyl)phenylthio) benzamide , which crystallised on stan¬ ding (m.p. 95-102°C) . c) A reaction of oily N,N-dimethyl-2- (2- (dimethylaminocar¬ bonyl)phenylthio)benzamide in 40 ml of tetrahydrofuran, 1.84 g of sodium borohydride and 6.4 g of boron trifluoride etherate, in analogy to example 1/d, yielded 3.08 g (96%) of the oily base. This was dissolved in 50 ml of ether and the solution was acidified with 8 ml of ether containing 1.0 g of hydrogen chloride. The precipitated crude N,N-dimethyl-2- (2- (dimethylaminomethyl)phenylthio)benzylamine dihydrochlo- ride crystallised from 2-propanol containing a small amount of water as hemihydrate (m.p. 205-206°C) . Example 41 : N,N-Dimethy1-2- (3- (dimethylaminomethyl)phenylthio) - benzylamine. a) 6.16 g of thiosalicylic acid, 9.92 g of 3-iodobenzoic acid and 0.66 g of copper were gradually added to a solution of 9.0 g of potassium hydroxide in 90 ml of water. The mix¬ ture was refluxed for 6 h under stirring. After cooling, pH of the mixture was adjusted up to 9 by addition of 5 ml of diluted hydrochloric acid (1:1). Filtration charcoal was ad¬ ded and the mixture was stirred at 80 C for 10 min, then filtered hot and after cooling the filtrate was acidified with hydrochloric acid up to pH=l . After dilution with 200 ml of water, the fine precipitate was filtered off by suction, washed with water and dried to obtain 10.62 g (97%) of crude diphenylsulfide-2 , 3 -dicarboxylic acid, which after crystallisation from aqueous ethanol melted at 308-310 C. b) A reaction of 9.68 g of crude diphenylsulfide-2 , 3 -di¬ carboxylic acid in 110 ml of benzene with 46 g of thionyl¬ chloride (4 h of refluxing) in analogy to example 40/a, yielded 9.83 g (90%) of crude diphenylsulfide-2.3 -di¬ carboxylic acid dichloride, which after crystallisation from cyclohexane melted at 112-113°C. c) A reaction of 8.8 g of diphenylsulfide-2 , 3 -dicarboxy¬ lic acid dichloride in 160 ml of benzene with 36.6 g of 40% aqueous dimethylamine in analogy to example 40/b, yielded 9.28 g (100%) of oily N,N-dimethyl-2- (3- (dimethylaminocarbo¬ nyl)phenylthio)benzamide, which crystallised on standing and after recrystallisation from ethanol melted at 129-130 C. d) In analogy to example 40/c, a reaction of 9.28 g of N,N-dimethyl-2- (3- (dimethylaminocarbonyl)phenyl hio)benzamide with 4.88 g of sodium borohydride and 15.5 ml of boron tri¬ fluoride etherate in 80 ml of tetrahydrofuran yielded 6.33 g (75%) of the oily base. This was converted into N,N-dimethyl- 2- (3- (dimethylaminomethyl) -phenylthio) benzylamine dihydro- chloride, which crystallised from 2-propanol as the solvate containing 1/2 of molecule of this solvent (m.p. 138-141 ). Example 42: N,N-Dimethyl-2- (4- (dimethylaminomethyl)phenylthio) - benzylamine . In analogy to example 41/a, a reaction of 4.5 g of potas¬ sium hydroxide in 45 ml of water, 3.08 g of thiosalicylic acid, 4.96 g of 4-iodobenzoic acid and 0.35 g of copper yielded 4.61 g (84%) of diphenylsul fide- 2 , 4 -dicarboxylic acid, which after crystallisation from 50% aqueous ethanol melted at 234-236°C. A reaction of 4.11 g of diphenylsulfide- 2 , 4 -dicarboxylic acid in 50 ml of benzene with 13.2 g of thionylchloride (2.5 h of refluxing) in analogy to example 40/a, yielded 4.31 g (92%) of solid diphenylsulfide-2 , 4 -dicarboxylic acid dichloride, which after crystallisation from cyclohexane melted at 104-106°C. A reaction of 4.3 g of diphenylsulfide-2 , 4 -dicarboxylic acid dichloride in 25 ml of benzene with 12.5 g of 40% aque¬ ous dimethylamine in analogy to example 40/b, yielded 3.6 g (79%) of oily N,N-dimethyl-2- (4- (dimethylaminocarbonyl) - phenylthio)benzamide . In analogy to example 40/c, a reaction of 3.6 g of N,N-di- methyl-2- (4- (di ethylaniinocarbonyl)phenylthio)benzamide with 1.8 g of sodium borohydride and 6.4 g of boron trifluoride etherate in 40 ml of tetrahydrofuran yielded 3.3 g (100%) of the oily base. This was converted to crystalline N,N-di¬ methyl-2- (4- (dimethylaminomethyl) phenylthio) benzylamine di- hydrochloride, which crystallised from 2-propanol (m.p. 233-235°C) . Example 43 : N,N-Dimethy1-2- (2-carboxyphenylthio)benzylamine . a) A mixture of 30 ml of dimethylformamide, 7.7 g of thio¬ salicylic acid, 7.0 g of 2-chlorobenzaldehyde , 14 g of potassium carbonate and 1.2 g of copper (I) chloride was hea¬ ted up to 100 C under stirring in 5 min and then stirred at 110-120 C for 6 h. After 16 h of standing, the mixture was diluted with 220 ml of water at 60 υ C and the resulting clou¬ dy liquid was filtered with 1 g of filtration charcoal. After cooling, the filtrate was acidified with 5M HCl under stirring. The precipitate was filtered off by suction, was¬ hed with water and dried, which yielded 9.11 g of crude 2- (2-carboxyphenylthio)benzaldehyde with melting point 167-169°C. b) A mixture of 5.1 g of 2- (2-carboxyphenylthio)benz¬ aldehyde, 7.3 g of dimethylformamide and 4.5 g of formic acid was refluxed under stirring up to 110-120 υ C for 15 h. After cooling, the mixture was acidified with a solution of 6 ml of hydrochloric acid in 60 ml of water and the resul¬ ting liquid was washed with toluene. After filtration, the aqueous solution was evaporated to dryness i n vacuo . The re¬ sidue was crystallised from a mixture of 2-propanol and ethylacetate, which yielded 6.0 g of crystalline N,N-di- methyl-2- (2-carboxyphenylthio)benzylamine hydrochloride mono- hydrate with melting point 96-99 C. Example 44: N,N-Dimethyl-2- (4-carboxyphenylthio) benzylamine . In analogy to example 43/a - except for the use of 4-mercaptobenzoic acid instead of thiosalicylic acid (the same amount) , 10.6 g (82%) of 2- (4-carboxyphenylthio)benz- aldehyde with melting point 178-181 C, which crystallised from 80% aqueous ethanol or toluene. In analogy to example 43/b, a reaction of 5.5 g of di¬ methylformamide , 3.88 g of 2- (4-carboxyphenylthio) benz¬ aldehyde and 3.5 g of formic acid yielded 3.7 g (76%) of N,N-dimethyl-2- (4-carboxyphenylthio)benzylamine hydro¬ chloride, which after crystallisation from a mixture of ethanol and ether melted at 209-211°C. Example 45 : N,N-Dimethyl-2- (2- (ethoxycarbonyl)phenylthio) benzylamine . 6.4 g of N,N-dimethyl-2- (2-carboxyphenylthio) benzylamine hydrochloride monohydrate (see example 43) was dried at 80 C i n vacuo . The anhydrous compound was dissolved in 160 ml of ethanol and the solution was saturated with anhy¬ drous gaseous hydrogenchloride at room temperature for 6 h. After 2 h of refluxing, the solution was evaporated to dryness i n vacuo . The residue was added 50 ml of water and 15 ml of aqueous ammonium and the free base was extracted with chloroform. After drying with magnesium sulfate. the extract was evaporated i n vacuo , which yielded 5.0 g of the oily base. Its neutralisation with oxalic acid dihydrate in 2-propanol yielded N,N-dimethyl-2- (2- (ethoxycarbonyl)phenyl- thio)benzylamine hydrogen oxalate, which after crystallisa¬ tion from 2-propanol melted at 151-154°C. Example 46 : N,N-Dimethy1-2- (3- (ethoxycarbonyl)phenylthio)benzylamine A solution of 5.0 g of N,N-dimethyl-2- (3-carboxyphenyl- thio)benzylamine hydrochloride (Kmonicek V. et al. : Collect. Czech. Chem. Commun. 56, 2468 (1991)) in 200 ml of ethanol was saturated with anhydrous gaseous hydrogenchloride for 8 h. The mixture was refluxed for 4 h and processed in ana¬ logy to example 45, which yielded 4.35 g (69%) of N,N-di- methyl-2- (3- (ethoxycarbonyl)phenylthio)benzylamine hydrogen oxalate, which after crystallisation from 2-propanol melted at 145-148°C. Example 47: N,N-Dimethy1-2- (4- (ethoxycarbonyl)phenylthio)benzylamine. A solution of 3.24 g of N,N-dimethyl-2- (4-carboxyphenyl- thio)benzylamine hydrochloride (see example 44) was satura¬ ted with anhydrous gaseous hydrogen chloride at 70-75 C and under stirring for 3.5 h. The mixture was evaporated i n va¬ cuo , the oily residue was added 12 ml of 1.2M NaHCO j and the free base was extracted with ether. Drying and evaporating yielded 3.17 g of the oily base, which was neutralised with 1.26 g of oxalic acid dihydrate in 20 ml of ethanol at 60°C. After cooling and adding of 2 ml of ether, 3.48 g (86%) of N,N-dimethyl-2-(4- (ethoxycarbonyl)phenylthio)benzylamine hydrogen oxalate crystallised, which after recrystallisation from 98% ethanol melted at 172-173.5°C. Example 48 : N,N-Dimethyl-2- (2-amino-4- (methoxycarbonyl)phenylthio) - benzylamine. A suspension of 5.0 g of N,N-dimethyl-2- (2- (amino-4- (tri- fluoromethyl)phenylthio)benzylamine oxalate (see example 34) was made alkaline with aqueous ammonium and the free ba¬ se was extracted with chloroform. The extract was dried with magnesium sulfate and evaporated. The residue base was hea¬ ted with 8 ml sulfuric acid for 3 h up to 100°C. After 16 h 56 of standing, 40 ml of methanol was added and the mixture was refluxed for 9 h. After pouring on the ice, it was made alkaline with aqueous ammonium and the free base was extrac¬ ted with ether. From the extract 3.5 g of the oily base of N,N-dimethyl-2- (2-amino-4- (methoxycarbonyl)phenylthio)benzyl¬ amine was obtained. Its reaction with a solution of hydrogen chloride in ether provided the monohydrochloride , which after crystallisation from a mixture of ethanol and 2-propanol melted at 200-205°C. The following Table contains the values of serotonin re-uptake inhibition (5HT) , noradrenaline re-uptake inhibi¬ tion (NA) and paroxetine binding inhibition (PA) for some compounds prepared via the methods described in Examples hereinbefore in relation to the known compounds mentioned in the Background of the Invention hereinbefore. T A B L E Serotonin re-uptake inhibition (5HT) and noradrenaline re-uptake inhibition (NA) and paroxetine binding inhibition (PA) , IC 50 (nmol/1) Ratio IC 50 where -ICCQ is the concentration causing 50% inhibition of [ H]paroxetine binding, - a ' means the IC^Q values reached while repeated tests, -compounds according to the invention are identified with example numbers and for testing are used in the form of their salts mentioned in Examples (Table values were calcu¬ lated for the bases) , -and compounds A and B mean the known compounds; A-compound = 1- (3-dimethylaminopropyl) -1- (4-fluorophenyl) - phthalato-5-carbonitrile) and B-compound=N,N-dimethyl-2- (4- (trifluoromethyl) -2- (hydroxy¬ methyl)phenylthio)benzylamine. It is apparent that e.g. in case of the compound prepared via procedure according to example 34, that, in regard to the data concerning paroxetine binding inhibition in membra¬ ne fraction of rat brain, the corresponding compound accor¬ ding to the invention shows a good penetration through the blood-brain barrier. Further, it is apparent that this compound does not show the affinity towards alpha-adrenergic muskarine and benzo- diazepine receptors, so that it does not inhibit binding of [ H] preparatives (prazosin, quinuclidinnyl benzilate and flunitrazepam) onto the receptors in the corresponding brain structures. This suggests a low probability of occurrence of some cardiovascular anticholinergic and central neurotropic effects of the benzodiazepine type compounds . Derivatives of general formula (I) and their pharmaceuti¬ cally acceptable salts are suitable for the production of pharmaceutical medicaments designed primarily for treatment and prophylaxis of depression, anxious states, migraine and other diseases of the central nervous system, in which the brain serotonin plays an important role.

Claims: - 58 - C L A I M S 1. Derivatives of N,N-dimethyl-2- (aryl hio)benzylamine of general formula ( 1 ) or their salts with inorganic or organic acids which are pharmacodynamically harmless, wherein at least one of the substituents R 1and R2 in the A ring in the 4 and 5 positions is a hydrogen atom, while the other substituent R or R in the A ring is either a fluorine or chlorine atom, and wherein two to three of the substituents R to R in the B ring in the 2 to 5 positi¬ ons are hydrogen atoms, while if the both substituents in the A ring are hydrogen atoms, the substituents in the B ring are either three hydrogen atoms and one of the substituents for¬ med by an alkyl with one to three carbon atoms, or tri¬ fluoromethyl , or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms, one fluorine or chlorine atom and one substituent formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxy¬ methyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or ethyl- methylthio, or nitrt), or amino, or methoxy, or hydroxyl grou or are two hydrogen atoms and each of the remaining two sub¬ stituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 posi¬ tion, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino group, or are two hydrogen atoms and two fluorine or chlorine atoms ; or in case that one substituent in the A ring is either a fluorine or chlorine atom, the substituents in the B ring are either two hydrogen atoms and two fluorine or chlorine atoms. or two hydrogen atoms and one fluorine or chlorine atom and one of the subsituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxycarbonyl, or methylthio, or nitro, or amino, or methoxy, or hydroxyl group, or three hydrogen atoms and one fluorine or chlorine atom, or one of the substituents formed by an alkyl with one to three carbon atoms, or trifluoromethyl, or methylsulfinyl, or hydroxymethyl - except the 2 position, or carboxyl - except the 3 position, or methoxycarbonyl, or ethoxy¬ carbonyl, or methylthio, or nitro, or amino group. 2. N,N-Dimethyl-2- (2-amino-4- (trifluoromethyl) phenylthio) - benzylamine and its salts with pharmacodynamically harmless inorganic or organic acids. 3. N,N-Dimethyl-5-chloro-2- (4- ethylthio)phenylthio)benzyl¬ amine and its salts with pharmacodynamically harmless inor¬ ganic or organic acids. 4. N,N-Dimethyl-5-fluoro-2- (4-methylthio) phenylthio)benzyl¬ amine and its salts with pharmacodynamically harmless inor¬ ganic or organic acids. 5. N,N-Dimethy1-2- (2 , 4-dichloropheny1 thio) - 5- fluorobenzy1- amine and its salts with pharmacodynamically harmless inor¬ ganic or organic acids. 6. N,N- imethyl-2- (3 ,4-dichlorophenylthio) -5-fluorobenzyl¬ amine and its salts with pharmacodynamically harmless inor¬ ganic or organic acids . 7. N,N-Dimethyl-2- (2-amino-4- (trifluoromethyl) -5-fluoro¬ phenylthio)benzylamine and its salts with pharmacodynami cally harmless inorganic or organic acids. 8. Pharmaceutical medicament, designed primarily for treat¬ ment or prophylaxis of depressive states, characterized in that, that as an effective component contains a derivative of the compound of formula (I) according to claim 1, in the mixture with additives for pharmaceutical medicaments. 9. Methods of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is charac¬ teristic, that N,N-dimethylbenzamides of formula (II) 61 wherein the substituents R to R are identical to those in the formula (I) , and besides that, in the B ring there can also be formyl or dimethylaminocarbonyl, are reduced by diborane generated i n s i tu by the reaction of sodium boro¬ hydride with boron trifluoride etherate. 10. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the sub- stituents R to R is an hydroxymethyl or dimethylamino¬ methyl group, by reduction of the compounds with formula (II) according to claim 9, wherein one of the substituents R to R in the B ring is an formyl, dimethylaminocarbonyl or carboxyl group, for which it is characteristic that an formyl, dimethylaminocarbonyl or carboxyl group is reduced at the same ti e. 11. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is charac¬ teristic that benzylhalogenides of formula (III) wherein the substituents R to R are identical to those in formula (I) and Hal is a chlorine or bromine atom, react wi h dimethylamine in an organic solvent at room temperature 62 12. Method according to claim 11, characterized by that that the reaction is carried out in toluene. 13. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is charac¬ teristic that benzaldehydes of formula (IV) , wherein the substituents R to R" are identical to those in formula (I) , react with dimethylformamide and formic acid at 110 to 120°C. 14. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the sub¬ stituents R to R in the B ring is an methylsulfinyl group, for which it is characteristic that the corresponding methylthioderivative is oxidised by hydrogen peroxide in acetic acid at room temperature. 15. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the sub¬ stituents R to R is ethoxycarbonyl, for which it is cha¬ racteristic that the corresponding carboxyderivative is esterified by ethanol . 16. Method according to claim 15, for which it is characte¬ ristic that esterification is carried out in the presence of hydrogen chloride. 63 17. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the sub¬ stituents R to R is an methoxycarbonyl group, for which it is characteristic that the corresponding trifluoro methyl- ddeerriivvaattiivvee iiss hhyyddrroollyysseedd wwiitthh ssuullffuurriicc acid at 90 to 110 C and subsequently esterified by methanol. 18. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, wherein one of the sub¬ stituents R to R is an hydroxyl group, for which it is characteristic that the derivative of the compound of formu¬ la I , wherein one of the substituents R to R is an methoxyl group, demethylates . 19. Method according to claim 18, for which de ethylation by heating with hydrobromic acid is characteristic. 20. Method of preparation of the derivatives of the compound of formula (I) according to claim 1, for which it is charac¬ teristic that the bases of derivatives of the compound of formula (I) are neutralised with pharmacodynamically harm¬ less inorganic or organic acids. 21. Use of derivatives of the compound of formula (I) accor¬ ding to claim 1, in production of pharmaceutical medicaments designed particularly for treatment and prophylaxis of de¬ pressions, anxious states, migraine and other diseases of the central nervous system, in which brain serotonin plays an important role.

Inventors: DOBROVSK KAREL, KREJCI IVAN, MICKOVA RUZENA, POLIVKA ZDENEK, SILHANKOVA ALEXANDRA, SINDELAR KAREL, VALENTA VLADIMIR, DOBROVSK, KAREL, KREJCI, IVAN, MICKOVA, RUZENA, POLIVKA, ZDENEK, SILHANKOVA, ALEXANDRA, SINDELAR, KAREL, VALENTA, VLADIMIR
Applicants: DOBROVSK KAREL, FARMAK A S, KREJCI IVAN, MICKOVA RUZENA, POLIVKA ZDENEK, SILHANKOVA ALEXANDRA, SINDELAR KAREL, VALENTA VLADIMIR, DOBROVSK, KAREL, FARMAK A.S., KREJCI, IVAN, MICKOVA, RUZENA, POLIVKA, ZDENEK, SILHANKOVA, ALEXANDRA, SINDELAR, KAREL, VALENTA, VLADIMIR
Application year: 1996
Main classification: C07C323
IPC codes: A61K31, C07C323