CS261295B1 - Amidines and amidoximes of diphenylsulphide series and their salts - Google Patents

Abstract

The solution is in the synthetic field drugs. Its subject matter is (2- (phenylthio) - phenyl) acetamidines, 2- (phenylthio) benzamidines, the corresponding amidoximes, and sulfoxides derived by oxidation to a sulfur atom as well and salts thereof. These substances show in tests pharmacodynamic in animals and are potential antidepressants and tranquilizers. They are synthetically accessible from the respective nitriles which react with hydrogen chloride and ethanol hydrochlorides of the respective acetimidates and benzimidates. Their reactions with ammonia and amines result in amidines. Direct reaction of nitriles with a base of hydroxylamine in boiling methanol to give amidoximes. All these are sulfides that can be oxidized with hydrogen peroxide in acetic acid at room temperature to the appropriate sulfoxides. All amidines and amidoximes are basic and inorganic neutralization or organic acids that are pharmaceutically acceptable, provide salts, which are also solved.

Description

The present invention relates to amidines and amidoximes of the diphenylsulfide series of formula (I)

wherein R is hydrogen or OH, R ⁴ is NH 3, 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl or 4- (2-hydroxyethyl) -1-piperazinyl, m is 0 or 1 and also n denotes 0 or 1, and their salts with inorganic or organic, pharmaceutically acceptable acids.

The compounds of formula (I) and their salts possess different types of therapeutically useful pharmacodynamic activities, which make them potential drugs. The main directions of their effect are neurotrophic and psychotropic. First of all, they appear to be antidepressants and mild tranquillizers. Some also have local anesthetic, antihistamine and antiarrhythmic effects. Specific results of the pharmacological tests are given by several examples of representative compounds of the invention.

(2- (phenylthio) phenyl) acetamidine was tested as naleinate. Its acute toxicity in mice by intravenous administration, LD ^ g is 25 mg / kg. The substance shows a significant effect in the yohimbine toxicity potentiation model in mice; = 55.3 mg / kg p.o. This effect is typical of antidepressants. It is preferred that the agent is simultaneously ineffective incoordination in the rotating rod test in mice up to an oral dose of 250 mg / kg.

Ν, Ν-Pentamethylene- (2-phenylthio) phenyl) acetamidine was evaluated as hydrochloride. Its acute toxic in mice by oral administration, LD ^ g = 356 mg / kg. At an oral dose of 10 mg / kg, it suppresses the mild but statistically significant spontaneous locomotor activity of the mouse, which is typical of tranquillizers.

N, N- (3-oxapentan-1,5-diyl) - (2- (phenylthio) phenyl) acetamidine was also evaluated as hydrochloride. Its LD ₅₀ for oral administration in mice is 273 mg / kg. Like the former, this oral dose of 10 mg / kg inhibits spontaneous locomotor activity in mice slightly but statistically significantly. Further, at an oral dose of 50 mg / kg it exhibits a significant inhibitory effect on gastric ulceration in rats induced by reserpine. It can therefore be described as a mildly depressant antidepressant.

(2-phenylthio) phenyl) acetamidoxime was tested as the maleate. Its acute toxicity in oral Ι50 mice is 212 mg / kg and intravenously 100 mg / kg. At an intraperitoneal dose of 5 mg / kg, ptosis suppresses the eyelids of mice induced by reserpine.

In i.p. doses of 5 to 10 mg / kg inhibit the hypothermic effect of reserpine in mice. It therefore has the properties of an antidepressant. Furthermore, it has an antihistamine effect in guinea pigs: a subcutaneous dose of 1 mg / kg protects 50% of the animals in the experiment against the lethal effect of a standard dose of histamine administered intra -ugularly. In the form of a 1% solution, it acts as a local anesthetic in guinea pigs in an infiltration anesthesia test. Finally, at doses of 10 to 20 mg / kg i.v. shows an antiarrhythmic effect in rats against aconitine.

2- (phenylthio) benzamidoxime was evaluated as hydrochloride. At an oral dose of 100 mg / kg, it potentiates the toxicity of yohimbine in mice, while at the same dose it is ineffective discoordinating in mice.

The compounds of the formula I according to the invention are accessible from the nitriles of the formula II (CH ₂ ) _n CN

(II), in which n denotes the same as in formula I. The preparation of the nitrile of formula II, wherein n-1, has been described in the literature (see Jílek J.O. et al .: Monatsh. Chem. 96, 182, 1965). The compound of formula II, where n = 0, was only a moderator in the literature (Chem. Abstr. 58, 10 823, 1963) and therefore its preparation is described in the respective example. The synthesis of amidines of formula I (R = H) is based on nitriles of formula II which are first converted by reaction with ethanol and hydrogen chloride to ethyl 2- (phenylthio) benzimidate and ethyl (2-phenylthio) phenylaetimidate. These are then reacted with ammonia and amines to form the appropriate amidines as described in the Examples. In order to prepare the amidoximes, the nitriles of the formula II are reacted with a hydroxylamine base, most often in boiling methanol. In order to obtain sulfoxides, i.e. compounds of formula I wherein m = 1, the corresponding sulfides of formula I, where m = 0, must be oxidized. For this, oxidation of hydrogen peroxide in acetic acid at room temperature is also most appropriate. examples described. The examples are to be understood as illustrative of the possibilities for preparing the compounds of formula (I); it is not the purpose of describing all the preparation options. All substances described in the invention are novel; their identity was assured by analytical and spectral methods.

Example 1 (2-phenylthio) phenyl) acetamidine

To 50 ml of an 8% solution of ammonia in ethanol was added 10.0 g of ethyl (2-phenylthio) phenyl) acetimidate hydrochloride with stirring and cooling (0 ° C), the mixture was stirred for 30 minutes and evaporated under reduced pressure. 25 ml of a 10% solution of potassium hydroxide in ethanol are added to the residue, the mixture is stirred for 30 minutes, evaporated again in vacuo and the residue is extracted with ether. Workup of the extract yielded 7.8 g (98%) of the desired base which crystallized from benzene and melted at 76-77 ° C. Neutralization with calculated amounts of maleic acid in ethanol yields either monomaleinate melting at 179-180 ° C or hemimaleinate with m.p. Mp 166-168 ° C.

The starting ethyl (2-phenylthio) phenyl) acetimidate hydrochloride, which has not been described in the literature, is prepared, for example, by the following procedure:

A mixture of 45 g of (2-phenylthio) phenyl) acetonitrile and 12 ml of ethanol was saturated with anhydrous hydrogen chloride for 1.5 h under external cooling (0 ° C). It is then diluted with 25 ml of ether and left overnight at 0 ° C. The precipitated product hydroxide is filtered off with suction, washed with 15 ml of a mixture of ethanol and ether J: 3, and dried under vacuum. 37 g (69%) of the desired compound of m.p. Mp 111-112 ° C (ethanol ether).

Example 2

N, N, pentamethylene- (2-phenylthio) phenyl) acetamidine

A mixture of 4.6 g of ethyl 2- (phenylthio) phenyl) acetimidate hydrochloride, 30 ml of ethanol and 1.3 g of piperidine is stirred and refluxed for 7 hours. The ethanol was evaporated under reduced pressure, the residue was dissolved in a small amount of ethanol and an equal volume of ether was added. 0.20 g of piperidine hydrochloride (m.p. 243 DEG C.) crystallized and was removed by suction. The filtrate was further diluted with ether to crystallize the hydrochloride of the desired compound. It is suction filtered overnight, washed with ether and dried in vacuo; 4.28 g (83%), m.p. Mp 131-135 ° C.

Example 3

N, N- (3-oxapentane-1,5-diyl) - (2- (phenylthio) phenyl) acetamidine

A mixture of 4.6 g of ethyl (2-phenylthio) phenyl) acetamidate hydrochloride, 30 ml of ethanol and 1.3 g of morpholine was refluxed for 7 h and evaporated in vacuo. The residue was dissolved in ethanol (15 ml) and ether (100 ml) was added. 3.55 g (68%) of the hydrochloride of the title compound crystallized. 195-196 ° C (ethanol-ether).

Example 4

Ν, Ν- (N-methyl-3-azapentan-1,5-diyl) - (2- (phenylthio) phenyl) acetamidine

A mixture of 4.6 g of ethyl (2-phenylthio) phenyl) acetimidate hydrochloride, 30 ml of ethanol and 1.5 g of 1-methylpiperazine is refluxed for 7.5 hours. The solvent was evaporated in vacuo and the residue was partitioned between 20% sodium hydroxide solution and ether. The organic phase was separated, dried and evaporated. The oily residue (4.7 g) was dissolved in acetone and 3.4 g of maleic acid was added to the solution at boiling. The salt precipitated by cooling is crystallized from ethanol; 5.0 g (58%) of the dimaleinate monohydrate of the desired base are obtained, m.p. Mp 173-175 ° C.

Example 5

Ν, Ν- (N- (2-hydroxyethyl) -3-azapentane-1,5-diyl) - (2- (phenylthio) phenyl) acetamidine

The preparation is carried out as in the previous example from 5.8 g of ethyl 2- (phenylthio) phenyl) acetamidate hydrochloride and 2.5 g of 1- (2-hydroxyethyllpiperazine) in 30 ml of ethanol. g of maleic acid yielded 6.0 g (53%) of the desired dimaleinate monohydrate, mp 133-135 and again 145-148 ° C.

Example 6 (2- (phenylthio) phenyl) acetamidoxime

To a solution of sodium methoxide in methanol (3.3 g of sodium in 50 ml of methanol) was added 9.9 g of hydroxylamine hydrochloride, followed by a solution of 27.0 g of (2- (phenylthio) phenyl) acetonitrile in 100 ml of methanol. The mixture was stirred and refluxed for 5 g. The precipitated sodium chloride is filtered off, washed with methanol and the filtrate is evaporated. The residue (37.4 g) was dissolved in 150 ml of chloroform, washed with water, dried and evaporated. The oily residue was crystallized from a mixture of 15 ml of benzene and 15 ml of hexane to give 13.5 g (44%) of the desired base, m.p. Mp 93-94 ° C (benzene). Neutralization with maleic acid affords the maleate, which crystallizes from ethanol and melts at 140-141 ° C.

Example '7

2- (phenylthio) phenyl) acetamidoxime-S-oxide

To a solution of 3.9 g of the previous base in 40 ml of acetic acid was added 1.7 ml of 30% hydrogen peroxide and the mixture was allowed to stand at room temperature for 60 hours. Dilute with 300 ml of water, wash with 50 ml of benzene and leave to crystallize overnight; 2.6 g (63%), m.p. Mp 167-168 ° C (ethanol). Neutralization with maleic acid in aqueous ethanol yields crystalline maleate monohydrate, m.p. 143 DEG-144 DEG C. (aqueous ethanol).

Example

2- (phenylthio) benzamidokim

To a solution of sodium methoxide (from 1.5 g of sodium and 30 ml of methanol) was added 4.2 g of hydroxylamine hydrochloride and 12.6 g of 2- (phenylthio) benzonitrile in 60 ml of ethanol, and the mixture was refluxed for 10 h. The sodium chloride is filtered off with suction and the filtrate is evaporated. The residue was diluted with 250 mL of water and extracted with chloroform. Working up the extract yielded 12.2 g of an inhomogeneous product which was chromatographed on a column of 200 g of silica gel. First, the chloroform elutes the less polar impurities and then elutes 2.10 g (14%) of the desired base, which crystallizes from benzene and melts at 132-134 ° C. Neutralization with hydrogen chloride gives the hydrochloride which crystallizes from a mixture of acetone and ether and melts at 162 ° C.

The preparation of the starting 2- (phenylthio) benzonitrile is not described in the available literature.

It can be prepared as follows: A mixture of 13.8 g of 2-chlorobenzonitrile, 11.0 g of thiophenol, 13.9 g of potassium carbonate and 100 ml of dimethylformamide is stirred and refluxed for 15 hours under a nitrogen atmosphere. The solvent was evaporated in vacuo, the residue was diluted with water and extracted with benzene. Treatment of the extract and distillation of the residue gave 20.7 g (98%) of the desired nitrile, m.p.

215-220 ° C / 70 Pa, which crystallizes from a mixture of cyclohexane and petroleum ether, m.p. 56.5-58 ° C.

Claims (1)

SUBJECT OF THE INVENTION Amidines and amidoximes series diphenylsulfide of the formula I _(m ol / = \ suboptions .nr (CH _{2) n} C R 'wherein R is hydrogen or OH, r' is NH ₂ , 1-piperidinyl, 4-morpholinyl, 4-methyl-1-piperazinyl or 4- (2-hydroxyethyl) -1-piperazinyl, m is equal to 0 or 1, and also n denotes 0 or 1, and salts thereof.