CS276004B6 - 2- (Phenylthio) benzyl amines, their salts and processes for their preparation - Google Patents

Abstract

The solution relates to new 2-(phenylthio)benzylamines of the general formula I, in which R denotes hydrogen or methyl, R1 is methoxyl or hydroxyl and n is 1 or 2, their salts and methods of their preparation. The substances of the formula I can be prepared by reduction of amides of the formula II, or by the action of formamides of the formula IV on aldehydes of the general formula III. The substances of the formula I with a free phenolic group are prepared by demethylation of the corresponding methoxy analogues and the methoxylated derivatives are accessible by the reaction of benzyl halides of the general formula V with amines of the general formula IX. The prepared bases are neutralized with acids to give pharmaceutically acceptable salts. The substances are highly selective inhibitors of the reuptake of 5-hydroxytryptamine in brain structures and can be used for the treatment of mental depression.

Description

The invention relates to 2- (phenylthio) benzylamines of the general formula I,

(I) wherein R is hydrogen or methyl, R is methoxyl or hydroxyl and n is 1 or 2, and their pharmaceutically acceptable salts with inorganic or organic acids and methods for their preparation.

The compounds of the formula I, and in particular their salts, are characterized by activity in biochemical, biochemical-pharmacological and pharmacological tests which are used to evaluate potential antidepressants, i.e. drugs for mental depression. According to the following results, it can be concluded that the substances according to the invention have good prospects for use in the therapy of mental depression.

In the field of biochemical and biochemical-pharmacological tests, four standard methods have been used to evaluate the substances according to the invention. The first two characterize the affinity of the compounds for the binding sites for imipramine and desipramine in the hypothalamus of the rat brain. Imipramine and desipramine are two standard tricyclic antidepressants, and the affinity for their binding sites in the brain suggests a similar, i.e. antidepressant, effect. It is known that the higher affinity for imipramine binding sites corresponds to the serotonergic nature of their mechanism of action, while the higher affinity for desipramine binding sites suggests an adrenergic mechanism of action. To allow quantitative evaluation, both ligands were used in the form of tritiated derivatives at a concentration of 4 nM. The higher affinity for imipramine binding sites suggests inhibition of 5-hydroxytryptamine reuptake in brain structures. This mechanism of action is often reported in the literature for so-called second-generation antidepressants, which are mostly non-tricyclics. Some of the compounds of the invention show a large difference in affinity for the imipramine and desipramine binding sites, and these agents have the character of highly selective 5-hydroxytryptamine reuptake inhibitors in brain structures. The effect on 5-hydroxytryptamine reuptake in rat brain can also be detected directly by inhibiting 5-hydroxytryptamine reuptake using (H) 5-hydroxytryptamine as a ligand at a concentration of 10 nM. Using ( ³ H) noradrenaline as a ligand at a concentration of 10 nM and using rat brain cortex as a substrate, the effect of the substances on noradrenaline reuptake in said substrate can be determined. Again, there is no large difference in the inhibition of 5-hydroxytryptamine and noradrenaline reuptake with conventional tricyclic antidepressants. The desired selectivity is manifested by a significant difference in the results in both of these tests. Some of the compounds according to the invention have a much higher inhibitory effect on the reuptake of 5-hydroxytryptamine than on the reuptake of norepinephrine, again in the sense of selectively inhibiting the reuptake of 5-hydroxytryptamine.

Of the in vivo pharmacological tests used in the search for new antidepressants, tests for antireserpine activity have been used in the first characterization of the substances according to the invention; Xi) mouse eyelid ptosis inhibition assay induced by reserpine administration; (ii) a test for antagonism of reserpine-induced hypothermia (lowering of body temperature) in mice and (iii) a test for inhibition of gastric ulcer in rats, also induced by reserpine. The antireserpine efficacy in these assays is the basis for the prediction of an

CS 276004 Θ6 antidepressant effect in patients suffering from mental depression. The compounds of the invention in many cases have significant antireserpine activity in one, two or even all three of these tests. In addition, they also have the ability to potentiate the toxicity of yohimbine in mice, which is. also the basis for predicting the antidepressant effect.

The compounds of the invention were also subjected to a basic toxicological test, i.e. an acute toxicity test in mice; results are reported as mean lethal doses of LD ^ g. In this test and in the other in vivo tests mentioned, the compounds according to the invention were administered in the form of salts orally; the doses given in mg / kg are based on. The following are specific data for selected compounds of the invention. Efficacy in biochemical-pharmacological tests is expressed in terms of IC 50 values, ie mean inhibitory concentrations. In vivo tests indicate doses of ED that elicit statistically significant responses in the desired sense, or in the form of mean effective doses of ED 2, again in mg / kg. The methods used are generally known and therefore their implementation is not described here.

N-Methyl-2- (2-methoxyphenylthio) benzylamine (Compound A) was tested as the hydrochloride. Acute toxicity, LD ^ g = 148 mg / kg. Inhibition of imipramine binding, IC 50 = 34.3 nM. • -Inhibition of desipramine binding, = 48.6 nM. There is no significant difference in the affinity of the substance for the binding sites for imipramine and desipramine. Inhibition of 5-hydroxytryptamine reuptake, IC 50 = 24.2 nM; inhibition of noradrenaline reuptake, ΙΓ ^ θ - 8.16 nM. Here, too, there is no significant difference in the affinities for the respective receptors, but the affinities are generally quite high. In the mouse reserpine ptosis inhibition assay, the dose of ED = 25 mg / kg is significantly effective. In the test affecting the locomotor activity of mice, a dose of 10 mg / kg significantly increased the activity. · ·

N, N-Dimethyl-2- (2-hydroxyphenylthio) benzylamine (Compound 8) was tested as hydrogen maleate. LD ^ g - 467 mg / kg. Inhibition of imipramine binding, IC 50 = 7.68 nM (high affinity). In the reserpine ptosis inhibition test, ED = 25 mg / kg (threshold dose is 10 mg / kg). At a dose of 50 mg / kg, it effectively inhibits the development of gastric ulcers in rats.

N-Methyl-2- (3-methoxyphenylthio) benzylamine (Compound C) was tested as the hydrochloride. LD ^ g = 301 mg / kg. Inhibition of imipramine binding, IC 50 = 29.5 nM. Inhibition of desipramine binding, IC 50 - 293 nM. The selectivity of the effect is evident. Inhibition of 5-HT- (5-hydroxytryptamine) reuptake, IC 50 = 11.8 nM. Inhibition of NA (noradrenaline) reuptake, IC 50 s = 6.95 nM. Thus, selectivity is not apparent here. In the reserpine ptosis inhibition assay, ED = 25 mg / kg. In the reserpine ulcer antagonization test, ED = 50 mg / kg. In the mouse locomotor activity test, a dose of 10 mg / kg again produced a significant increase in activity.

N-Methyl-2- (3-hydroxyphenylthio) benzylamine (Compound D) was tested as hydrogen maleate. LD $ g with 543 mg / kg. Inhibition of imipramine binding, IC $ g = 17.7 nM. Anticeserpine efficacy in the ptosis test, ED = 25 mg / kg.

N, N-Dimethyl-2- (3-hydroxyphenylthio) benzylamine (Compound E) was tested as hydrogen maleate. LD ^ g = 232 mg / kg. Inhibition of imipramine binding, IC 50 _Q = 4.24 nM. Inhibition of desipramine binding, IC $ g = 12,947 nM. As can be seen, the difference in affinities to the binding sites for both ligands is huge; the substance is a highly selective 5-HT reuptake inhibitor. In this sense, its character is far more pronounced than that of citalopram (Hyttel J., Psy = chopharmacology 51, 225 (1977)), which is considered a prototype of potential antidepressants - 5-HT reuptake inhibitors. This quality of substance E was confirmed in further tests. Inhibition of 5-HT reuptake, IC ₅₀ = 0.58 nM. Inhibition of NA reuptake,

IC _5Q = 505 543. Again, a huge difference in values, which indicates a high selectivity of the gloom of the tonergent mechanism. Antireserpine effect (i) in the ptosis test, ED = 25 mg / kg (threshold dose is 3 mg / kg); (ii) in a hypothermia test, ED = 10 mg / kg; (iii) in the reserpine ulcer test, ED = 50 mg / kg. In the yohimbine toxicity potentiation test, ED ₅₀ = 54.7 mg / kg.

N-Methyl 1-2- (4-methoxyphenylthio) benzylamine (Compound F) was tested as the hydrochloride. LD ₅₀ = 189 mg / kg. Inhibition of imipramine binding, IC ₅₀ = 9.4 nM. Inhibition of desipramine binding, IC ₅₀ = 4950 nM. Inhibition of 5-HT reuptake, IC ₅₀ = 8.85 nM. Inhibition of NA reuptake, IC 50 = 2,405. Substance F is also a highly selective inhibitor of 5-hydroxytryptamine reuptake in brain structures. Antireserpine effect in the ptosis test, ED = from 25 mg / kg (threshold dose is 10 mg / kg). Potentiation of yohimbine toxicity ED _5Q = 59 mg / kg.

N-Methyl-2- (4-hydroxyphenylthio) benzylamine (Compound G) was tested as the hydrogen maleate. LD ^ g = 164 mg / kg. Antireserpine effect in the ptosis test, ED = 12.5 mg / kg.

N, N-Dimethyl-2- (4-hydroxyphenylthio) benzylamine (Compound H) was tested as hydrogen maleate. LD ^ g = 209 mg / kg. Inhibition of imipramine binding, ΙΟ ^ θ = 8.22 nM. Inhibition of desipramine binding, IC 50 = 13.82 nM. The affinity is high, but the selectivity of the effect is low. Inhibition of 5-HT reuptake, IC ₅₀ = 2.52 nM. Inhibition of NA uptake, IC ₅₀ = 9.35 nM. Antireserpine effects: (i) in the ptosis test, ED = 25 mg / kg (threshold dose 10 mg / kg); (ii) gastric ulceration, ED = 50 mg / kg. Toxicity potentiation of yohimbine, EDj ₀ = 76.5 mg / kg. '

N, N-O-methyl-2- (2,4-dihydroxyphenylthio) benzylamine (Compound I) was tested as hydrogen maleate dihydrate. LD ^ g = 200 mg / kg. Inhibition of imipramine binding, IC 50 ⁼ 39.6 nM. Inhibition of desipramine binding, IC $ g - 1 198 nM. Again, considerable selectivity of the effect. Inhibition of 5-HT reuptake, IC 50 = 182.9 nM. Inhibition of NA uptake, IC 50 = 1294 nM. The last two data confirm the selectivity of the effect. Antireserpine effect in the ptosis test, ED - 25 mg / kg (threshold dose 10 mg / kg).

N, N-Dimethyl-2- (2,5-dihydroxyphenylthio) benzylamine (Compound J) was tested as hydrogen maleate. LD $ g = 50 mg / kg i.v. Antireserpine effect in the ptosis test, ED with 25 mg / kg.

N-Methyl-2- (3,4-dimethoxyphenylthio) benzylamine (Compound K) was tested as hydrogen maleate. LD ^ g = 153 mg / kg. Inhibition of imipramine binding, IC 50 = 12.2 nM. Inhibition of desipramine binding, IC 50 = 807.1 nM. Again, considerable selectivity of the effect. Inhibition of 5-HT reuptake, IC 50 = 151.7 nM. Inhibition of NA uptake, IC 50 = 11,840 nM. The selectivity of the effect is confirmed in the last two tests. Antireserpine effects: (i) in the ptosis test, ED = 25 mg / kg (threshold dose 3 mg / kg); (ii) in a gastric ulcer test, ED = 50 mg / kg. Toxicity potentiation of yohimbine, ED ^ g'iz 41.0 mg / kg.

N-Methyl-2- (3,4-dihydroxyphenylthio) benzylamine (Compound L) was tested as hydrogen maleate. LD ^ g = 630 mg / kg. Antireserpine effects: (i) in the ptosis test, ED = 25 mg / kg (threshold dose is 6.25 mg / kg); (ii) in a hypothermia test, ED - 10 mg / kg.

N, N-Dimethyl-2- (3,4-dihydroxyphenylthio) benzylamine (Compound M) was tested as hydrogen maleate. LD ^ g = 306 mg / kg. Inhibition of 5-HT reuptake, IC $ g = 4.05 nM. Inhibition of NA uptake = 1425 nM (high degree of selectivity of effect). Antireserpine effects: (i) in the ptosis test, ED = 25 mg / kg; (ii) in the hypothermia test ·, ED = 10 mg / kg; (iii) in a gastric ulcer test, ED = 50 mg / kg. At a dose of 10 mg / kg significantly increased CS 276004 B6

Suje locomotor activity of mice. '

The compounds of formula I according to the invention are accessible by a number of processes, which are also the subject of the invention. These are primarily reductions of amides of formula II,

(II) in which R, R and n have the same meaning as in formula I. The most general method for the reduction of these amides is reduction with lithium aluminum hydride, which - depending on the solubility of the starting amide II - is carried out in boiling ether or boiling tetrahydrofuran. This process for the preparation of compounds of formula I is more common for compounds of formulas I and II in which R1 represents methoxyl and n is 1 or 2. However, it can also be used in the case of compounds with a free hydroxyl group (i.e. I and II, R1 = OH and n = 1 or 2), as evidenced in one example.

. Amides of formula II can be reduced to amines of formula I, especially when R 1 = OCH 2 and n = 1 or 2, with diborane. It is most convenient to generate this reagent in situ by reacting sodium borohydride with boron trifluoride etherate in tetrahydrofuran. To convert the primary amine borane to the amine of formula I, an alkaline hydrolysis step must be included in the process. Furthermore, to reduce the amide of the formula II to the amines of the formula I, it is possible to use methods in which the amides are first treated with phosphorus chloride and the volatile intermediates formed are then reduced with sodium borohydride in ethanol.

All amines of formula I, where R 1 is OH and n = 1 or 2, are accessible by demethylation of amines of formula I, where R 2 = OCH 2 and n = 1 or 2. Various general methods can be used for demethylation, but in particular heating with pyridine hydrochloride to 180-220 ° C, further reaction with boron tribromide in chloroform at room temperature or finally boiling with concentrated hydrobromic acid.

Furthermore, the preparation of amines of the formula I, in particular when R1 is OCH2 and n is 1 or 2, can be based on aldehydes of the formula III

in which R is OCH 2 and n is 1 or 2, which is subjected to a Leuckart reaction, i.e. the action of formamides of general formula IV, (TV)

R

CS 276004 β6

In which R represents a hydrogen atom or a methyl atom, at temperatures of 170 to 180 ° C.

For the same type of amines of the formula I, it is suitable in addition to substituted benzyl halides in the general presence of formic acid in a preparation process in which the formula V,

(V) wherein Hal represents a chlorine or bromine atom, R is methoxyl and n is 1 or 2, which react with dimethylamine or methylamine under various conditions. The reaction can advantageously be carried out in an anhydrous medium, for example in chloroform, either at room temperature or at elevated temperature, optionally also in an autoclave at temperatures up to 75 ° C.

The starting amides of the formula II are in the vast majority new and their preparation is described in the examples. For the only exception where the starting amide is known, it is given in the relevant literature citation example. Amides of formula II, wherein R ⁵ · is OCH 2 and n is 1 or 2, are prepared mostly from acids of formula VI via chlorides of formula VII, as described in the examples.

o (VI, R = COOH) o (VII, R - COCl) (VIII, R - CH ₂ OH)

In formulas VI to VIII, R represents methoxyl and n is 1 or 2. The acids of formula VI are generally known and also a part of the acid chlorides VII is known; literature citations are given in the examples. Otherwise, for the preparation of acids VI, the general method is to react 2-iodobenzoic acid with the appropriate methoxyphenyl in boiling aqueous potassium hydroxide solution in the presence of copper. Hydroxythiophenols can be carried out in a similar manner, as shown in one of the examples, and thus hydroxylated amines of the formula I can be obtained directly (R ⁵ · = OH) without the degree of demethylation. In this case, the acid chlorides are not used, but the free hydroxy acids are directly coupled with methylamine or dimethylamine, for example in the presence of a complex of triphenylphosphine and carbon tetrachloride in tetrahydrofuran. This results in hydroxylated amides of formula II, where R ¹ = OH, which then only needs to be reduced. The acid chlorides of formula VII are obtained from the acids of formula VI by the action of thionyl chloride in boiling benzene, preferably with the addition of a small amount of dimethylformamide. Alcohols of formula VIII, which are obtained by reduction of aldehydes of formula III or acids of formula VI with hybrid reagents, can also be used as intermediates. By reaction with thionyl halides, they are converted into benzyl halides of the formula V, the use of which in the synthesis of amines of the formula I has already been mentioned. .

All the final products, i.e. the amines of the formula I, as well as most of the intermediates, are new substances whose identity has been ensured by customary analytical and spectral methods. The amines of formula I are basic in nature which they give by acid neutralization

CS 276004 Bb 6 crystalline salts. These salts are more advantageous than bases for the preparation of dosage forms and for pharmacological testing due to their better solubility in water. These salts are also a subject of the invention. The following examples describe all of the preparative methods set forth in the preceding paragraphs and describe most combinations of compounds given by Formula I. However, the examples are intended to be merely illustrative of the invention, which is not intended to be exhaustive.

Example 1

N-i-Methyl-2- (2-methoxyphenylthio) benzylamine

A suspension of 18.9 g of N-methyl-2- (2-methoxyphenylthio) benzamide in 400 ml of ether is slowly added to a stirred solution of 7.9 g of lithium aluminum hydride in 200 ml of ether and the mixture is refluxed. After cooling, 8 ml of water, 8 ml of 15% sodium hydroxide solution and finally a further 24 ml of water are slowly added dropwise with stirring. After stirring for 20 minutes, the precipitate is filtered off with suction and washed with ether. Evaporation of the filtrate gave 14.5 g (B1%) of an oily product. This was dissolved in ether and a slight excess of ethereal hydrogen chloride was added to the stirred solution. The hydrochloride precipitates oily at first, but crystallizes rapidly with stirring. It is obtained in a yield of 16.0 g and, after crystallization from pure ethanol, melts at 181-182 ° C.

The starting amide is a novel substance and is prepared from the known 2- (2-methoxyphenylthio) benzoyl chloride (Šindelář K. et al., Collect. Czech. Chern. Commun. 47, 1367 (1982); Czech Author's Certificate No. 202 241 ) as follows: '

A solution of 22 g of 2- (2-methoxyphenylthio) benzoyl chloride in 150 ml of benzene is added dropwise to 10 ml of a 25% aqueous solution of methyl amine at rapidly stirred 150 ml of a 25% aqueous solution of methyl amine. The mixture was stirred vigorously at this temperature for 2 h, then filtered and the benzene phase separated from the filtrate was evaporated. The residue is the crude desired amide, which is recrystallized from 20 ml of ethanol; 19.4 g (90%), m.p. 109-110 ° C.

Example 2

N-Methyl-2- (2-hydroxyphenylthio) benzylamine

A mixture of 2.6 g of N-methyl-2- (2-methoxyphenylthio) benzylamine (see Example 1) and 5.8 g of pyridine hydrochloride was heated with stirring in a bath at 210-220 ° C for 30 minutes. After cooling, it is dissolved in 100 ml of water, the solution is filtered and the filtrate is slightly alkalized with stirring by dropwise addition of 15.5 ml of 10% sodium hydroxide solution (to pH 8-8.5). The precipitated oily product crystallizes on standing. After standing for 12 hours, it is filtered, washed with water and recrystallized from ethanol; 1.5 g (61%); m.p. 116-117 ° C. Neutralised maleic acid in ethanol gives crystalline hydrogen maleate melting at 169 ° C (ethanol).

He added

N, N-Dimethyl-2- (2-methoxyphenylthio) benzylamine

As in Example 1, 49 g of N, N-dimethyl-2- (2-methoxyphenylthio) benzamide are reduced with 19.3 g of lithium aluminum hydride in 800 ml of ether. After decomposition of the mixture, the ether layer was evaporated to give 48 g of an oily residue, which was dissolved in 300 ml of benzene and the base was transferred from this solution by shaking to 300 ml of 1.5M HCl. Acidic aqueous layer

The mixture was separated, basified with aqueous ammonia and the base was isolated by extraction with benzene (300 ml). Work-up of the extract gave 38 g (82%) of a homogeneous oily base. Neutralized hydrogen chloride in ether gives crystalline hydrochloride which crystallizes from a mixture of ethanol and ether and melts in pure form at 174-175 ° C.

The starting N, N-dimethyl-2- (2-methoxyphenylthio) benzamide has been prepared previously (Šindelář K. et al .; Collect. Czech. Chern. Commun. 47, 1367 (1982)).

Example4

N, N-Dimethyl-2- (hydroxyphenylthio) benzylamine.

N, N-Dimethyl-2- (2-methoxyphenylthio) benzylamine (9.5 g, see Example 3) was demethylated as in Example 2 by heating with 20 g of pyridine hydrochloride at 210-220 ° C (30 minutes). Similar work-up and crystallization of the crude product from ethanol gave 7.0 g (78%) of the desired base, m.p. 83-83.5 ° C. Neutralized maleic acid in a mixture of ethanol and ether is prepared to give crystalline hydrogen meelinate, m.p. 107-108 ° C (ethanol-ether).

Example 1 and d 5

N-Methyl-2- (3-methoxyphenylthio) benzylamine

As in Example 1, 23 g of N-methyl-2- (3-methoxyphenylthio) benzamide are reduced with 9.7 g of 1-aluminum hydride in 700 ml of ether. Analogous work-up gave 19.2 g (88%) of the desired oily base. By neutralizing it with hydrogen chloride in ether, a crystalline hydrochloride is prepared which crystallizes from a mixture of ethanol and ether and melts at 130 ° C. .

The required starting N-methyl-2- (3-methoxyphenylthio) benzamide is a new substance which is prepared with the known 2- (3-methoxyphenylthio) benzoic acid (Bartl V. et al., Collect. Czech. Chem. Commun. 38, 2301 (1973)) as follows:

To a stirred solution of 30 g of 2- (3-methoxyphenylthio) benzoic acid in 250 ml of benzene was added 2 drops of dimethylformamide and 45 g of thionyl chloride were added dropwise. The mixture was then refluxed for 2 h. Benzene and excess thionyl chloride are removed by distillation (residues in vacuo) and the still warm residue is dissolved in 55 ml of cyclohexane. The warm solution is quickly filtered and left to crystallize. On standing until the next day, 30.4 g (95%) of 2-3- (methoxyphenylthio) benzoyl chloride are precipitated, m.p. 101-101.5 ° C.

In analogy to Example 1, 28.2 g of 2- (3-methoxyphenylthio) benzoyl chloride are reacted with 180 ml of a 25% aqueous solution of methylamine with vigorous stirring. The product crystallizes after stirring the mixture for 1 h; 20.2 g (73%) of N-methyl-2- (3-methoxyphenylthio) benzamide, m.p. 92 ° C (aqueous ethanol). An example

N-Methyl-2- (3-hydroxyphenylthio) benzylamine

N-Methyl-2- (3-methoxyphenylthio) benzylamine (12.4 g, see Example 5) was demethylated as in Example 2 by heating with 28 g of pyridine hydrochloride at 210-220 ° C (30 min). Similar work-up gave 9.1 g (78%) of the desired product, m.p. 142 DEG-143 DEG C. (ethanol-cyclohexane). By neutralization with maleic acid in ethanol ae is prepared

CS 276004 86 8 crystalline hydrogen maleate, m.p. 138-139 ° C (ethanol ether).

Example 7

N, N-Dimethyl-2- (3-methoxyphenylthio) benzylamine

A solution of 22.1 g of N, N-dimethyl-2- (3-methoxyphenylthio) benzamide in 350 ml of ether is added over 40 minutes to a stirred solution of 8.7 g of 1-aluminum hydride in 150 ml of ether. The mixture is refluxed for 6 h and, after cooling, is quenched by the slow addition of 9 ml of water, 9 ml of 15% sodium hydroxide solution and 27 ml of water. After stirring for 20 minutes, the solid is filtered off with suction and washed on the filter with ether. The filtrate was dried and evaporated. The oily residue (19.5 g, 93%) is an almost homogeneous oily base. Neutralization with a solution of hydrogen chloride in ether gave crystalline hydrochloride, m.p. 149-150 ° C (ethanol ether).

The required starting N, N-dimethyl-2- (3-methoxyphenylthio) benzamide, which is a new substance, is prepared, for example, as follows:

A solution of 24.1 g of 2- (3-methoxyphenylthio) benzoyl chloride (see Example 5) in 180 ml of benzene was added dropwise at 10 DEG C. to 160 ml of 20% aqueous dimethylamine at 10 DEG C. with vigorous stirring. The mixture was stirred at room temperature for 2 h, the benzene layer was separated, washed with water, filtered and evaporated under reduced pressure. The oily residue (23.1 g, 93) crystallizes on standing to give the desired 2- (3-methoxyphenylthio) benzamide, m.p. 42-43 ° C (petroleum ether). ’

Example 8

N, N-O-methyl-2- (3-methoxyphenylthio) benzylamine

To a stirred solution of 68.7 g of N, N-dimethyl-2- (3-methoxyphenylthio) benzylamine in 470 ml of tetrahydrofuran was added 13.1 g of sodium borohydride under nitrogen and then added dropwise over 1 h at 20-27 ° C. 68.7 g (61 ml) of boron trifluoride etherate. The mixture was stirred at room temperature for 1 h and refluxed for 3 h. After cooling, 190 ml of dilute hydrochloric acid (1: 1) are slowly added with stirring (over a period of 30 minutes). The mixture was refluxed for 3 h. It is cooled and basified with 400 ml of 20% sodium hydroxide solution. The aqueous layer was diluted with 200 mL of water, extracted with 1,2-dichloroethane, the organic solutions were combined, dried and evaporated. The residue is dissolved in 40 ml of ethanol, a slight excess of an ethanolic solution of hydrogen chloride in ethanol and 40 ml of cyclohexane is added to the solution. The solution was seeded with a few crystals of the product hydrochloride (see Example 7) and allowed to crystallize in the refrigerator; 58.9 g (80%) of N, N-dimethyl-2- (3-methoxyphenylthio) benzylamine hydrochloride, m.p. 147.5 to 150 ° C.

The starting N, N-dimethyl-2- (3-methoxyphenylthio) benzamide can also be prepared by the following modified procedure:

A stirred solution of 37.9 g of 2- (3-methoxyphenylthio) benzoyl chloride (see Example 5) was saturated with 24.5 g of dimethylamine at 25 DEG C. and the mixture was allowed to stand at room temperature for 48 hours. It is then washed with 250 ml of water, 200 ml of 1M-HCl, 200 ml of 5% sodium hydroxide and finally a further 200 ml of water. Work-up gave 38.3 g (98%) of an oily amide which crystallized on standing and was identical to the product of the previous example, m.p. 42-43 ° C.

CS 276004 .έ

Example 9

N, N-Dimethyl-2- (3-methoxyphenylthio) benzylamine

A mixture of 5.75 g of N, N-dimethyl-2- (3-methoxyphenylthio) benzamide and 20 ml of phosphorus oxychloride is stirred for 3 hours at room temperature and then evaporated to dryness in vacuo. The residue is diluted with 20 ml of toluene, which is also evaporated in vacuo to remove the last traces of phosphorus oxychloride. The residue (8.6 g) was dissolved in 15 ml of tetrahydrofuran, the solution was cooled to 0 ° C, and a suspension of 1.5 g of sodium borohydride in 40 ml of ethanol was added thereto over 1 hour with stirring. The mixture was stirred at room temperature for 1 h, 5 ml of dilute hydrochloric acid (1: 1) was added and refluxed for 6 h. The ethanol was evaporated under reduced pressure and the residue partitioned between benzene and dilute aqueous ammonia. The benzene solution was dried and evaporated, the residue was dissolved in 7 ml of ethanol, and a slight excess of ethanolic hydrogen chloride solution was added to the solution. 1.1 g (18%) of the hydrochloride of the desired amine crystallize out, m.p. 148-150.5 ° C (ethanol ether).

The starting N, N-dimethyl-2- (3-methoxyphenylthio) benzamide used can be prepared by the following further modified procedure:

To a solution of 226 g of dimethylamine hydrochloride in 150 ml of water is slowly added at 4-7 ° C a solution of 89 g of sodium hydroxide in 200 ml of water (with stirring for 45 minutes). A solution of 83.2 g of 2- (3-methoxyphenylthio) benzoyl chloride (see Example 5) in 640 ml of toluene is then added over a period of 45 minutes at the same temperature with vigorous stirring. The mixture was stirred at room temperature for 2 h, allowed to stand overnight, the toluene layer was separated, washed with water and evaporated under reduced pressure. The oily residue (84.2 g, 97%) crystallizes on standing, m.p. 42-43 ° C. '

Example 10

N, N-Dimethyl-2- (3-methoxyphenylthio) benzylamine

A mixture of 28.5 g of 2- (3-methoxyphenylthio) benzaldehyde, 43 g of dimethylformamide and 26.8 g of formic acid was stirred and refluxed for 6.5 h (bath temperature 180 ° C). After cooling, 170 ml of 5% hydrochloric acid and the solution is washed with ether. The acidic aqueous solution was basified with 20% sodium hydroxide and the base was isolated by extraction with 1,2-dichloroethane. Work-up of the extract gave 30.3 g of crude desired amine, which was converted to the hydrochloride (27.1 g, 75%), m.p. 149-150 ° C

The starting 2- (3-methoxyphenylthio) benzaldehyde, which is a new substance, is prepared as follows:

A mixture of 20.0 g of 3-methoxythiophenol (Mauthner F., Ber. Dtsch. Chem. Ges. 39, 3596 (1906)), 40 ml of dimethylformamide, 20 g of potassium carbonate and 20.1 g of 2-chlorobenzaldehyde is stirred and heated. h at 90 ° C. It is then diluted with 200 ml of water and the product is extracted with benzene. Work-up of the extract and crystallization of the crude product from 25 ml of methanol gave 28.5 g (82%) of the title compound, m.p. 63.5 to 64.5 ° C.

Example 1 and d 11

N, N-Dimethyl-2- (3-methoxyphenylthio) benzylamine

To a solution of 13.2 g of 2- (3-methoxyphenylthio) benzyl chloride (8-art. V. Collect. Czech. Chem. Commun. 38, 2301 (1973)) in 50 ml of chloroform was added 9.0 g of dimethylamine gas and the mixture was heated. 12 h in an autoclave at 75 ° C. After cooling, chloroform was removed

CS 2760004 Bb and the residue is partitioned between 150 ml of benzene and 150 ml of water. The benzene layer was washed with water and the product was taken up in 150 mL of 1.5 M-HCl. The acidic aqueous solution and the oily hydrochloride at the bottom were basified with dilute aqueous ammonia (1: 1) and the precipitated oily base was extracted with 150 ml of benzene. Work-up of the extract gave 11.9 g (87%) of the oily desired base, which was converted to the hydrochloride, m.p. 149-150 ° C. .

Example 1 and d 12 '

N, N-Dimethyl-2- (3-hydroxyphenylthio) benzylamine

A mixture of 7.0 g of N, N-dimethyl-2- (3-methoxyphenylthio) benzylamine (Examples 7 to 11) and 14.8 g of pyridine hydrochloride was stirred and heated at 210 DEG-220 DEG C. for 30 minutes (bath temperature). Work-up as in the previous examples gave 5.6 g (84%) of an oily base, which was converted into these salts by neutralization reactions; hydrogen maleate, m.p. 123-124 ° C (ethanol ether); hydrochloride, m.p. 165-166 ° C (ethanol); hydrobromide, m.p. 150-151 ° C (ethanol ether). Decomposition of the pure salts with aqueous ammonia and extraction with ether gave a crystalline base, m.p. 106-107 ° C (cyclohexane).

Example 13

N, N-O-methyl-2- (3-hydroxyphenylthio) benzylamine

A solution of 7.7 g of N, N-dimethyl-2- (3-methoxyphenylthio) benzylamine (see Examples 7 to 11) in 60 ml of chloroform was cooled to 10 DEG C. and solution 14 was added over 15 minutes with stirring. 0 g of boron tribromide, in 20 ml of chloroform. The mixture was stirred at room temperature for 6 h, allowed to stand overnight and diluted dropwise at 10-15 ° C with 65 ml of ethanol. The resulting clear solution was stirred at room temperature for 8 h and the solvents were evaporated at 50-60 ° C under reduced pressure. The oily residue crystallizes after trituration with ether; 7.7 g (75%) of the hydrobromide of the desired substance, m.p. 150 ° C (ethanol).

Example 14

N, N-Dimethyl-2- (3-hydroxyphenylthio) benzylamine

A mixture of 214 g of N, N-dimethyl-2- (3-methoxyphenylthio) benzylamine hydrochloride (see Examples 7 to 11) and 850 ml of 47% hydrobromic acid was stirred and heated at 120 ° C for 8 hours. After cooling, it is poured into 1.85 l of water and made slightly basic by the slow addition of 1.2 l of 20% sodium hydroxide solution (pH 9). Extract with 2.5 l of 1,2-dichloroethane. Work-up of the extract gave 170 g (95%) of the crystalline desired base, m.p. 107-108 ° C (methanol).

Example 1 and d 15 ·

N, N-Dimethyl-2- (3-hydroxyphenylthio) benzylamine

A solution of 1.4 g of N, N-dimethyl-2- (3-hydroxyphenylthio) benzamide in 20 ml of tetrahydrofuran is added over 10 minutes to a stirred solution of 1.0 g of lithium aluminum hydride in 20 ml of tetrahydrofuran and the mixture is boiled for 6 hours under reflux condenser. After cooling, it is decomposed with stirring by adding 5 ml of water dropwise. The precipitated solid is filtered off and washed with tetrahydrofuran, the filtrate is dried and evaporated. 1.0 g (76%) of an oily base are obtained, which is converted into crystalline hydrogen maleate, m.p. 123-127 ° C, corresponding to the product described in Example 12.

The starting N, N-dimethyl-2- (3-hydroxyphenylthio) benzamide used is a new substance which can be prepared by the following two-step process:

A mixture of 20.3 g of 75S 3-hydroxythiophenol (Watson ER, Dutt S., J. Chem. Soc. 121, 2415, (1922)), 39.7 g of 2-iodobenzoic acid and 3.0 g of copper is added to the solution. 25 g of potassium hydroxide in 250 ml of water and the mixture is refluxed with stirring for 6.5 h. After cooling, it is filtered and the filtrate is acidified with hydrochloric acid. After standing overnight, the precipitated product is filtered off and purified by crystallization from ethanol; 22.15 g (75) of 2- (3-hydroxyphenylthio) benzoic acid, m.p. 209-211 ° C.

A mixture of 13.1 g of triphenylphosphine, 20 ml of carbon tetrachloride and 100 ml of tetrahydrofuran is stirred for 1 hour. Then 12.1 g of the above acid are added and 7.0 g of dimethylamine gas are introduced. The mixture was stirred for 4 h, allowed to stand overnight, stirred for a further 3 h, filtered and the filtrate evaporated. The inhomogeneous residue was chromatographed on a 150 g silica gel column eluting with chloroform. The first fractions contain the less polar components of the mixture and only the last fractions represent the desired amide; 3.62 g (27), m.p. 124.5-125.5 ° C (ether).

Example 16

N-Methyl-2- (4-methoxyphenylthio) benzylamine

As in the previous examples, 23.2 g of N-methyl-2- (4-methoxyphenylthio) benzamide are reduced with 9.7 g of 1-aluminum hydride in 850 ml of ether. The crude amine obtained is converted directly in ethereal solution by treatment with hydrogen chloride into crystalline hydrochloride; 21 g (84%), m.p. 133-134 ° C (ethanol-ether). '

The starting N-methyl-2- (4-methoxyphenylthio) benzamide is obtained, similarly to the previous examples, by reacting 27 g of 2- (4-methoxyphenylthio) benzoyl chloride (shingler K. st al., Collect. Czech. Chem. Commun. 38 , 1579 (1973)) in 250 ml of benzene with 170 ml of aqueous methylamine; 24.6 g (93%), m.p. 140.5-141 ° C (ethanol).

Example 17

N-Methyl-2- (4-hydroxyphenylthio) benzylamine

Demethylation of 8.2 g of N-methyl-2- (4-methoxyphenylthio) benzyl amine (Example 16) is carried out by heating with 18.3 g of pyridine hydrochloride in analogy to the preceding examples. 6.7 g (86) of the desired crystalline base, melting at 129 DEG-131 DEG C. (ethanol-petroleum ether), are obtained. It gives a crystalline hydrogen maleate with m.p. 143-143.5 ° C (ethanol).

Example 1S _;

N, N-O-methyl-2- (4-methoxyphenylthio) benzylamine

N, N-Dimethyl-2- (4-methoxyphenylthio) benzamide (23.1 g) was reduced with 9.1 g of lithium aluminum hydride in 500 ml of ether as in the previous examples. 20.6 g (94%) of the desired crystalline base are obtained, m.p. 60 ° C (petroleum ether). It gives crystalline hydrochloride, m.p. 158-159 ° C (ethanol ether).

CS 276004 06

The starting N, N-dimethyl-2- (4-methoxyphenylthio) benzamide was prepared analogously to the previous examples by reacting 28.6 g of 2- (4-methoxyphenylthio) benzoyl chloride in 180 ml of benzene with an excess of 20% aqueous dimethylamine solution. Ee 23.6 g (80%) of the desired amide are obtained, m.p. 81.5 ° C (cyclohexane).

Example 19

N, N-Dimethyl-2- (4-hydroxyphenylthio) benzylamine

Demethylation of 6.0 g of N, N-dimethyl-2- (4-methoxyphenylthio) benzylamine (Example 18) is carried out analogously to the preceding examples by heating with 12.7 g of pyridine hydrochloride at 210-220 ° C. 4.7 g (83%) of crystalline base are obtained, m.p. 119-121 ° C (cyclohexane). It gives a crystalline hydrogen maleate, m.p. 153-154 ° C (ethanol).

Example 20

N-Methyl-2- (2,4-dimethoxyphenylthio) benzylamine

As in the previous examples, 19.7 g of N-methyl-2- (2,4-dimethoxyphenylthio) benzamide are reduced with 7.7 g of 1-aluminum hydride in 540 ml of ether. 16.6 g (88) of crystalline base are obtained, m.p. 46-47 ° C (benzene-hexane). It gives a crystalline hydrogen maleate melting at 137-138 ° C (ethanol).

The starting N-methyl-2- (2,4-dimethoxyphenylthio) benzamide has not yet been described and is obtained as follows:

To a solution of 62 g of potassium hydroxide in 570 ml of water is added 50 g of 2,4-dimethoxythiophenol (Suter CM, Hansen HL, J. Am. Chern. Soc. 55, 2080 (1933); Jacob III P. et al., J Med. Chem. 20, 1235 (1977)), 72 g of 2-iodobenzoic acid and 1.5 g of copper and the mixture is refluxed with stirring for 14 hours. After cooling, it is filtered with activated charcoal and 2- (2,4-dimethoxyphenylthio) benzoic acid is precipitated from the filtrate by acidification with 350 ml of dilute hydrochloric acid (1: 1). After standing for 12 hours, the precipitated product is filtered off with suction, washed with water and purified by boiling with ethanol. 70.8 g (84%), m.p. 215-217 ° C (ethanol).

To a suspension of 71 g of the previous acid in 520 ml of benzene, 4 drops of dimethylformamide are added and then 96 g of thionyl chloride are added dropwise over 15 minutes with stirring. The mixture is refluxed for 2 hours, benzene and excess thionyl chloride are removed from the resulting solution by distillation and the residue is taken up in 160 ml of cyclohexane. 71.5 g (95%) of 2- (2,4-dimethoxyphenylthio) benzoyl chloride are obtained, m.p. 119-121 ° C (cyclohexane).

A solution of 24 g of the above chloride in 250 ml of benzene is added dropwise to 100 ml of 40% aqueous methylamine with vigorous stirring at 10 ° C. The mixture is stirred and worked up as in the previous examples. 21 g (93%) of the desired amide are obtained, m.p. 151-152 ° C (benzene-petroleum ether).

Example 21

N-Methyl-2- (2,4-dihydroxyphenylthio) benzylamine.

Demethylation of 7.0 g of N-methyl-2- (2,44-dimethoxyphenylthio) benzylamine (Example 20) is carried out analogously to Example 13 by reaction with 12.5 g of boron tribromide in 65 ml of chloroform. Work-up gave 4.1 g (50%) of the hydrobromide of the title compound, 11.1. 225-226 ° C (ethanol). The liberated base is crystalline and melts at 195 ° C (ethanol-petroleum ether).

Example 22

N, N-N-methyl-2- (2,4-dimethoxyphenylthio) benzylamine.

As in the previous examples, 23.6 g of N, N-dimethyl-2- (2,4-dimethoxyphenylthio] isamide were reduced with 8.6 g of 1-aluminum hydride in 600 ml of ether to give 18.4 g (82%) of an oily base. which is converted to the hydrogen maleate, mp 117-118 ° C (ethanol).

The starting amide is prepared by reacting a solution of 24 g of 2- (2,4-dimethoxyphenylthio) benzoyl chloride in 250 ml of benzene with 150 ml of 25% aqueous dimethylamine. 24.1 g (98) of crystalline amide are obtained, m.p. 126-127 ° C (benzene).

Example 23

N, N-O-methyl-2- (2,4-dimethoxyphenylthio) benzylamine

A solution of 18.0 g of 2- (2,4-dimethoxyphenylthio) benzyl chloride in 30 ml of chloroform was charged with 11 g of dimethylamine gas under external cooling, and the resulting mixture was heated in an autoclave at 75 ° C for 12 hours. After cooling, the chloroform was evaporated, and the residue was partitioned between 150 ml of benzene and 150 ml of 2% sodium hydroxide solution. The base is extracted from the benzene layer to 300 ml of 1.5M-HCl. The base is liberated from the acidic aqueous solution with aqueous ammonia and extracted with benzene. Work-up of the extract gave 17.5 g (95%) of an oily base, which was characterized by conversion to picran, m.p. 180-181 ° C (acetone).

The starting 2- (2,4-dimethoxyphenylthio) benzyl chloride is a new substance which is prepared as follows:

By reacting 30 g of 2,4-dimethoxythiophenol (cited) with 24.3 g of 2-chlorobenzaldehyde in 50 ml of dimethylformamide in the presence of 18.7 g of anhydrous sodium carbonate at 100 DEG C. (3.5 h), 42 g of 2- ( 2,4-dimethoxyphenylthio) benzaldehyde (89%), m.p. 129-130 ° C (ethanol).

The aldehyde obtained (27.6 g) in 400 ml of ethanol is reduced with 1.9 g of sodium borohydride in 18 ml of water (with the addition of 0.2 ml of 20% sodium hydroxide). The mixture is refluxed for 6 h, the ethanol is distilled off and the residue is diluted with water. Extraction with benzene gave 27.2 g of 2- (2,4-dimethoxyphenylthio) benzyl alcohol, m.p. 87-88 ° C.

To a solution of 27 g of the preceding alcohol in 60 ml of benzene was added dropwise 17.5 g of thionyl chloride, and the mixture was refluxed for 15 minutes. After evaporation of the volatiles in vacuo, 24 g of a crystalline residue are obtained, representing a yield of 33% on the desired 2- (2,4-dimethoxyphenylthio) benzyl chloride, m.p. 91-93 ° C (benzene-petroleum ether).

CS 276004 06 '

Example 24

N, N-Dimethyl-2- (2,4-dihydroxyphenylthio) benzylamine

As in Example 13, 6.06 g of N, N-dimethyl-2- (2,4-dimethoxyphenylthiol) benzylamine (Examples 22 and 23) were demethylated with 15 g of boron tribromide in 100 ml of chlorobenzene to give 3.9 g of ( 64%) of a crystalline base, mp 166-170 ° C (benzene), to give hydrogen maleate, which crystallizes from aqueous ethanol as a dihydrate, mp 141 ° C.

Example 1 and d 25

N-Methyl-2- (2,5-dimethoxyphenylthio) benzylamine

As in the previous examples, 16 g of N-methyl 1-2- (2,5-dimethoxyphenylthio) benzaipine are reduced with 6.0 g of lithium aluminum hydride in 400 ml of ether. Workup gave 14.5 g (95) of an oily base which was converted to crystalline hydrogen maleate, m.p. 119-121 ° C (ethanol). . The starting N-methyl-2- (2,5-dimethoxyphenylthio) benzamide (m.p. 82-3 ° C (benzene · petroleum ether) was prepared from 2,5-dimethoxythiophenol (Burton H., Hoggarth E., J. Chem. Soc. 1945, 14) via the following intermediates (procedure as in Example 20):

2- (2,5-Dimethoxyphenylthiolbenzoic acid, yield 94, mp 204-205 ° C (ethanol);

2- (2,5-Dimethoxyphenylthio) benzoyl chloride, yield 97, m.p. 101-102 ° C (cyclohexane).

Example 26. of

N-Methyl 1-2- (2,5-dihydroxyphenylthio) benzylamine

As in Example 13, 9.2 g of N-methyl-2- (2,5-dimethoxyphenylthio) benzylamine (Example 25) were demethylated with 16 g of boron tribromide in 85 ml of chloroform. 5.8 g of crude base are obtained, which is converted into crystalline hydrogen maleate, m.p. 163-164 ° C (ethanol). The base liberated from this salt is crystalline and melts at 168-172 ° C.

Example 27

N, N-Dimethyl-2- (2,5-dimethoxyphenylthio) benzylamine

As in the previous examples, 16.8 g of N, N-dimethyl-2- (2,5-dimethoxyphenylthio) benzamide are reduced with 6.0 g of lithium aluminum hydride in 400 ml of ether; 14.7 g (91%) of an oily base which gives crystalline hydrogen maleate, m.p. 101-103 ° C (ethanol).

The starting N, N-dimethyl-2- (2,5-dimethoxyphenylthio) benzamide (m.p. 72-73 ° C (benzene-petroleum ether) was prepared almost in theoretical yield by reacting a benzene solution of 2- (2,5-dimethoxyphenylthio) benzoyl chloride (Example 25) with an aqueous solution of dimethylamine.

CS 276004 06

Example 28

N, N-Dimethyl-2- (2,5-dihydroxyphenylthio) benzylamine

As in Example 13, 10 g of N, N-dimethyl-2- (2,5-dimethoxyphenylthio) benzylamine (Example 27) were demethylated with 16.7 g of boron tribromide in 100 ml of chloroform. Yield, 74%. Bases, m.p. 126-127 ° C. Hydrogen maleate, tVt. 159 ° C (ethanol).

Example 29

N-Methyl-2- (3,4-dimethoxy phenylthio) benzylamine

Reduction of 44 g of n-methyl-2- (3,4-dimethoxyphenylthio) benzamide with 16.3 g of lithium aluminum hydride is carried out as in the previous examples, but using 750 ml of tetrahydrofuran as the reaction medium. Yield, 33.0 g (79%) of an oily base which gives crystalline hydrogen maleate, m.p. 151-152 ° C (ethanol).

The starting N-methyl-2- (3,4-dimethoxyphenylthio) benzamide (mp 146 ° C (ethanol) was prepared from 3,4-dimethoxythiophenol (Protiva M. et al., Collect. Czech. Chern. Commun. 46, 1808). (1981)) via the following intermediates (procedure as in Example 20):

2- (3,4-Dimethoxyphenylthio) benzoic acid, yield 89 Si, m.p. 215-217 ° C (ethanol).

2- (3,4-dimethoxyphenylthio) benzoyl chloride, yield 82 m.p. 133-134 ° C (benzene-cyclohexane).

Example 30

N-Methyl 1-2- (3,4-dihydroxyphenylthio) benzylamine ~

As in Example 13, 10.0 g of N-methyl-2- (3,4-dimethoxyphenylthio) benzylamine (Example 29) were demethylated with 17.5 g of boron tribromide in 90 ml of chloroform. 6.7 g (74%) of base are obtained, m.p. 85-86 ° C. Hydrogen maleate, m.p. 160 ° C (ethanol ether).

Example 1 and d 31

N, N-Dimethyl-2- (3,4-dimethoxyphenylthio) benzylamine

As in Example 29, 23.2 g of N, N-dimethyl-2- (3,4-dimethoxyphenylthio) benzamide are reduced with 7.2 g of lithium aluminum hydride in 350 ml of tetrahydrofuran. Yield, 19.1 g (86% of an oily base which gives crystalline hydrochloride, mp 175-176 ^° C (ethanol-ether).

The starting N, N-dimethyl-2- (3,4-dimethoxyphenylthio) benzamide (m.p. 119-120 ° C (ethanol)) is obtained in 95% yield by reaction of a benzene solution of 2- (3,4-dimethoxyphenylthio) benzoyl chloride (Example 29) with a 20% aqueous solution of dimethylamine.

Example 1 and d 32.

N, N-Dimethyl-2- (3,4-dihydroxyphenylthio) benzylamine

As in Examples 13, 7.0 g of N, N-dimethyl-2- (3,4-dimethoxyphenylthio) benzylamine (Example 31) were demethylated with 11.6 g of boron tribromide in 65 ml of chloroform. 5.1 g (80%) of base melting at 149 DEG-152 DEG C. are obtained; hydrogen maleate, m.p. 152 DEG-153 DEG C. (ethanol ether). .

Claims (15)

PATENTALLY 2. 2- (Phenylthio) benzylamines of the general formula I, in which R represents a hydrogen atom or a methyl, R is methoxyl or hydroxyl and n is 1 or 2, and their pharmaceutically acceptable salts with inorganic or organic acids. 2. N, N-O-methyl-2- (3-hydroxyphenylthio) benzylamine and its salts. 3. N, N-O-methyl-2- (3,4-dihydroxyphenylthio) benzylamine and its hydrogen maleate. 4. N-Methyl-2- (4-methoxyphenylthio) benzylamine and its hydrochloride id. 5. N-Methyl 1-2- (3,4-dimethoxyphenylthio) benzylamine and its hydrogen maleate. 6. A process for the preparation of the compounds of formula I according to claim 1, characterized in that the amides of formula II, in which · R, R and n denote the same as in formula I, undergo a reduction. 7. The process according to item 6, characterized in that the amides of the formula II are reduced with lithium aluminum hydride. 8. The process according to item 6, characterized in that the amides of formula II are reduced with diborane, preferably generated in situ by the reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran. 9. The process of claim 6, wherein the amides of formula II are pre-treated with phosphorus chloride and the resulting volatile intermediates are reduced with sodium borohydride. 10. A process for the preparation of the compounds of formula I, in which R is hydrogen or methyl, R is hydroxyl and n is 1 or 2, characterized in that the compounds of formula I in which R is hydrogen or methyl, R is ³ is methoxyl and n is 1 or 2,0-demethylated. . CS 276004 θ6 11. The process of claim 10, wherein the demethylation is performed by heating with pyridine hydrochloride to 180-220 ° C. 12. The process of claim 10, wherein the demethylation is performed by reaction with boron tribromide. 13. The process of claim 10, wherein the demethylation is performed by boiling with concentrated hydrobromic acid. 14. A process for the preparation of compounds according to claim 1 of the general formula T, characterized in that the aldehydes of the general formula III · _{(ni) are used} . in which R ¹ and n are the same as in formula I, they are treated with formamides of general formula IV) · (iv) 'R.' in which R denotes the same as in formula I, in a mixture with formic acid at the boiling point of this mixture. 15. A process for the preparation of the compounds of formula I, wherein R is hydrogen or methyl, R is methoxyl and n is 1 or 2, wherein the benzyl halides of formula V are: (V) in which Hal represents a chlorine or bromine atom, R is methoxyl and n is 1 or 2, reacted with amines of formula IX, R-NH-CH 2 in which R denotes the same as in formula I.