CS273750B1 - 2-(phenylthio) phenylalkylamines, their s-oxides and salts with dicarboxylic acids - Google Patents

Abstract

The invention concerns synthetic pharmaceuticals. Its subject is 2-(phenylthio)phenylalkylamines, their S-oxides and salts with dicarboxylic acids. These substances are psychotropically effective and, on the basis of their anti-reserpine effects on animals, they can be characterised as potential antidepressants. They are available from 2-(phenylthio)benzaldehyde and from (2-(phenylthio)phenyl)acetone. In the first case, they are transformed in the appropriate primary amine by reaction with nitromethane and subsequent reduction. By formylation and reduction this is transformed into the secondary amine. The tertiary amine is prepared by methylation with formaldehyde and formic acid. In the second case the Leuckart reaction is used to gain the formamide derivative, which is hydrolysed to a primary amine or reduced to secondary amine. The tertiary amine is prepared by methylation of the primary amine by formaldehyde and formic acid. Sulphoxides are obtained by oxidation of sulphides by hydrogen peroxide at room temperature in acetic acid. All alkaline products are provided by neutralization with maleic acid or oxalic acid.

Description

The invention relates to 2- (phonylthio) phenyl-amines and their S-oxides of the general formula I,

IT. / Wherein R, P / ^C, and R are identical or different and denote hydrogen or methyl, n represents 0 or 1 »1 and of their salts with dicarboxylic acids.

The compounds of formula I in the form of salts show psychotropic activity with predominantly antidepressant character. They show partly mild centrally suppressing effects, partly mild excitatory effects, are antlreserpine-active in animal tests and have a slight affinity for the imipramine and desipramine binding sites (receptors) in the rat brain hypothalamus. Their practical applicability in the treatment of mental depressive states can be assumed.

The following substances were tested:

2- (2- (Penylthio) phenyl) ethylamine (Ia),

N-Methyl-2- (2- (phenylthio) phenyl) ethylamine (Ib), N, N-dimethyl-2- (2- (phenylthio) phenyl) ethylamine (Ic), 1- (2- (Penylthio) phenyl) -2-propylamine (1d),

N-Methyl-1- (2- (phenylthio) phenyl) -2-propylamine (Ie), N, N-Dimethyl-1- (2- (phenylthio) phenyl) -2-propylamine (If), 1- (2 - (Penylsulfinyl) phenyl) -2-propylamine (Ig), N-Methyl-1- (2- (phenylsulfinyl) phenyl) -2-propylamine (Ih) and N, N-Dimethyl-1- (2- (phenylsulfinyl)) phenyl) -2-propylamine (1i).

All agents were administered in the form of hydrogen maleate (except Ib and le, which were used in the form of hydrogenoxalates) and were administered orally unless otherwise indicated.

Acute toxicity in mice, LD ^ ₀ mg / kg: Ia, 525; Ib, 40 i, v .; Ic, 288; Id, 158; le, 216; If, 1,3t Ig, 352; Ih, 377l li, 170.

Further significant effects of several selected substances:

Ia, at a dose of 50 mg / kg, significantly antagonizes reserpine ptosis in mice; in batches

100 to 200 mg / kg protects mice from the hypothermic effect of reserpine. It has a slight affinity for the binding sites for imipramine and desipramine in rat hypothalamus; Inhibition

3 linkages NFI 4 / ^J H / lmipraminu and 4 nM / ^J H / desipramine; 8 ^ θ 873, respectively. 711 nfí,

Ic, at i, p, at a dose of 8 mg / kg shows a slight hypothermic effect in mice.

Ie, at a dose of 25 mg / kg, has a pronounced antireserpine effect in the ptosis test in mice; at a dose of mg / kg, it significantly antagonizes reserpine-induced gastric ulceration in rats; at 10 mg / kg significantly antagonizes reserpine hypothermia in mice; at an oral dose of 100 mg / kg and at a time interval of 1-4 showed anorectic effect in rats.

Ig, following a 100 mg / kg dose, showed a significant anorectic effect (reduced food intake) in rats at 1 hour post-dose.

-in·

...

CS 273750 B1, at a dose of 10 mg / kg significantly reduced the locomotor activity of the mice at an interval h after administration (central suppressive effect).

The compounds of formula I according to the invention are accessible by various methods according to the step of methylation at the carbon of the aliphatic chain and at the nitrogen atom. The compounds of the 2-phenylethylamine series are accessible from 2- (phenylthio) benzaldehyde (M, Hori et al., Tetrahedron Lett. 1978,

255? NSR publication file. 2165 26), which is converted to 1-nitro-2- (2- (phenylthio) phenylene) by its reduction, e.g. lithium aluminum hydride, to give 1a. Its formylation and reduction results in 1b. The preparation of 1-phenyl-2'-propylamine series starting from the new (2- (phenylthio) phenyl) azetone (the preparation of which is described in the example) is obtained from this compound by the Leuckart reaction to give N- (1). - (2- (phenylthio) phenyl) -2-propyl) formamide which provides alkaline hydrolysis with compound ld and reduction with hydride reagents compound 1a. Compound 1f is obtained from compound 1d with methyl formaldehyde and formic acid. Hydrogen peroxide in acetic acid All products are basic in nature and provide acid neutralization to provide salts from which hydrogen maleate (partially hydrogenated oxalates) crystallize well. Their identity was assured by the usual analytical and spectral methods. The following examples illustrate the preparation possibilities of the compounds according to the invention.

Example 1

2- (2- (Penylthio) phenyl) ethylamine (1a)

To a stirred solution of 18.7 g of thiophenol in 42 ml of hexamethylphosphoric triamide was added a solution of 6.8 g of Bodium hydroxide in 13 ml of water and after 10 minutes still

22.5 g of 2-chlorobenzaldehyde. The mixture was refluxed at 100 ° C for 3.5 h in a nitrogen atmosphere. After partial cooling, it is poured into 300 ml of ice-water and the product is isolated by extraction with benzene. Workup of the residue and distillation of the residue in vacuo afforded 29.4 g (85%) of 2- (phenylthio) benzaldehyde, m.p. The compound gives eemicarbazone, which crystallizes from ethanol and melts at 212-215 ° C.

A mixture of 30.0 g of the previous aldehyde, 12.8 g of nitromethane, 120 ml of acetic acid and 12 g of ammonium acetate is stirred and refluxed for 4 hours. After cooling, it is poured into water and the product is extracted with ether. The extract was washed with 5% sodium carbonate solution and water, dried and evaporated. The residue was 34.7 g (96%) of an almost homogeneous oily 1-nitro-2- (2- (phenylthio) phenyl) ethene. Can the sample be analyzed by distillation? mp 180 ° C / 0.2 kPa.

A solution of 25.0 g of the above nitrostyrene in 150 ml of ether was added dropwise over 3 hours to a stirred solution of 19 g of lithium aluminum hydride in 300 ml of ether. The mixture is allowed to stand at room temperature for 2 days, then quenched by the slow addition of ethanol and water, the solid is filtered off, the filtrate is separated and the organic layer is evaporated.

18.8 g (84%) of crude amine 1a. Dissolve in ether, neutralize with 9.0 g maleic acid in ethanol and dilute with ether. Crystallize 13.2 g of hydrogen maleate, m.p. 154-155 ° C (ethanol ether).

Example 2

N-Methyl-2- (2-phenylthio) phenyl) ethylamine (1b)

A mixture of 16.4 g of amine 1a and 45 ml of ethyl formate is heated in an autoclave for 6 hours

Mp 125-130 ° C. The reaction mixture was dissolved in ether, washed with dilute hydrochloric acid and 5% sodium bicarbonate solution, dried and evaporated. It is obtained

16.2 (88%) of the corresponding formamide derivative used in this state for the next reactions. It was dissolved in 80 ml of benzene and the solution was added dropwise to a stirred solution of 6.0 g

Ί &

Ά

F.'

A.,

CS 273750 B1 lithium aluminum hydride in 70 ml ether. The mixture 09 is stirred and refluxed for 5 h.

After cooling and decomposing by the slow addition of ethanol and water, the organic phase of the filtrate is filtered and evaporated. The residue (14.5 g, 95%) is an almost homogeneous amine 1b.

Neutralize with oxalic acid dihydrate in ethanol and dilute the solution with ether. 6.4 g of hydrogen oxalate crystallized, m.p. 190 DEG C. (ethanol-ether).

Example 3

N, N-Dimethyl-2- (2- (phenylthio) phenyl) ethylamine (IC)

A mixture of 13.0 g of amine Ia, 12 ml of 00% formic acid, 21.5 ml of 20% formaldehyde and 10 ml of water is stirred and refluxed for 11 hours. After cooling, it is poured into dilute sodium hydroxide solution, extracted with ether, the extract is washed with water, dried and evaporated. 12.7 g (Θ7%) of an almost homogeneous amine 1c are obtained, which is converted to maleeate, m.p. 100 DEG-102 DEG C. (ethanol-ether).

Example 4 1- (2- (Penylthio) phenyl) -2-propylamine (1d)

To a stirred suspension of 3.5 g of 00% sodium hydride in 50 ml of toluene at 70 ° C was added dropwise 13.3 ml of ethanol. A mixture of 20 g of (2- (phenylthio) phenyl) acetonitrile (J.O. Jílek et al., Monatsh, Chem. 96, 182 (1965)) and 13.3 ml of ethyl acetate are added to the resulting sodium othoxide suspension. The mixture was refluxed for 2 h. After cooling, the reaction is quenched by the addition of 110 ml of water, the toluene solution is washed with water, the combined aqueous solutions are cooled to 0 ° C and acidified with hydrochloric acid at pH 2 to 3. The oil which has precipitated is extracted with toluene. 5 g (57%) of 3-oxo-2- (2- (phonylthio) phenyl) butyronitrile, mp 157-158 ° C / 70 Pa.

A mixture of 12.0 g of the previous nitrile and 10.4 g of phosphoric acid was refluxed for 8 hours in a 200 ° C bath. After cooling, the mixture was diluted with 50 ml of water and the product Be extracted with toluene. Treatment of the extract and distillation gave 7.1 g (65%) of (2- (phenylthio) phenyl) acetone, mp 128-130 ° C / 90 Pa, which crystallized from ethanol and melted at 50-51.5 ° C. C,

A mixture of 6.0 g of the preceding acetone derivative, 15 g of formamide and 3.0 g of 98% formic acid is heated under reflux in a bath at 190 to 200 ° C for 12 h. After partial cooling, the mixture is poured into water and the product is extracted ether. Working up the extract yielded 6.6 g (almost theoretical amount) of oily N- (1- (2- (phenylthio) phenyl) -2-propyl) formamide, which was used as such. For characterization, a sample (5.0 g) can be purified by chromatography on 70 g silica gel. Chloroform eluted with 4.2 g of a homogeneous product which crystallized from petroleum ether, mp 66-68 ° C (benzene-hexane).

The crude previous amide (6.6 g) was added to a solution of 6.6 g potassium hydroxide in 8.0 ml ethanol and the mixture was refluxed for 4.5 h (bath 120-130 ° C). Cooling is diluted with 129 ml of water, extracted with ether and the extract is worked up by drying and evaporation. The residue was dissolved in excess 5% hydrochloric acid, the acidic solution was washed with ether, basified with aqueous ammonia and the base extracted again with ether. Treatment of the extract yielded 4.2 g (70%) of the oily amine Id, which was converted by neutralization to the following non-hydrogen halon, mp, 1-10 ° C to 141 ° C (ethanol): hydro-chloride, t, t, 168-171 ° C (ethanol-ether).

Example 5

N-Methyl-1- (2- (phenylthio) phenyl) -2-propylamine (1e)

A solution of 17.3 g of oily N- (1- (2- (phenylthio) phanyl) -2-propyl) formamide in 75 ml of ether was added dropwise to a stirred solution of 7.2 g of lithium aluminum hydride in 75 ml of ether and the mixture was boiled for 6 h. under reflux. It is decomposed under cooling by the slow addition of 7.2 ml

15% sodium hydroxide ¹ and 30 ml water. Stir for 30 min, filter the solid, filter with CS 273750 B1

He teaches magnesium magnesium, filtered and vaporized on activated carbon. The residue is 15.7 g (83%) of an almost homogeneous oily amine Ie. It covers a crystalline hydrogen oxalate melting at 137-139 ° C (ethanol-ether).

Example 6

N, N-Dimethyl-1- (2- (phenylthio) phenyl) -2-propylamine (If)

Shift 11.0 g of nin Id, 0 ml of water, 11.0 ml of 00% formic acid with 19 ml of 2β% formaldehyde are stirred and refluxed for 12 hours. After cooling, it is poured into 330 ml of 5% sodium hydroxide solution and the product is extracted with ether. The extract was washed with water, dried, filtered with charcoal and evaporated. 10.8 g (88%) of a practically homogeneous oily amine If are obtained, which is converted to hydrogen maleate, mp 84-86 ° C (ethanol-ether).

Example 7

1- (2- (Phenylsulfinyl) phenyl) -2-propylamine (Ig)

A solution of 1.2 g of amine Id in 12 ml of acetic acid is oxidized with 0.8 g of hydrogen peroxide and the mixture is left at room temperature for 24 h. It is then diluted with 150 ml of water, acidified with 45 ml of 20% sodium hydroxide and isolated by extraction with benzene; 0.90 g (70%) of oily Ig, Hydrogen maleate, m.p. 176-177 ° C (ethanol).

Example 8

N-Methyl-1- (2- (phenylaulfinyl) phenyl) -2-propylamine (Ih)

Similar oxidation of 1.29 g of amine Ie in 13 ml of acetic acid with 0.8 g of hydrogen peroxide gave, as in the previous example, 1.3 g (94%) of an oily base Ih which was converted to hydrogen maleate, m.p. 134 ° C (ethanol).

Example 9

N, N-Dimethyl-1- (2- (phenylaulfinyl) phenyl) -2-propylamine (li)

As in the previous examples, ae is oxidized by 1.4 g of amine If in 14 ml of acetic acid with 0.7 g of 30% hydrogen peroxide. 1.4 g (97%) of an oily amine 11 are obtained, which is converted to the hydrogen maleate, m.p. 108-101 ° C (ethanol-ether).

Claims (1)

2- (Phenylthio) phenylakylamines and their S-oxides of general formula I, TO Wherein R, R and R are the same or different and are hydrogen or methyl and n is Or a salt thereof with dicarboxylic acids.