CS254730B1 - 4-Substituted 1- (1- (2- (arylthio) -5-halophenyl) ethyl) piperazines and their salts - Google Patents

Abstract

The solution falls into the field of synthetic drugs. Its subject is antitussive and antimicrobial 4-substituted 1-(1-(2-(arylthio)-5-halophenyl)ethyl)-piperazines of the general formula I in which R denotes a chlorine or bromine atom, R1 and denotes a hydrogen atom or a chlorine atom and R3 denotes methyl, 2-hydroxyethyl, 2-methoxyethyl-phenyl or chlorophenyl, except for the case where R = Cl, R1 = R2 = H and R3 = methyl, as well as their salts with pharmaceutically acceptable inorganic or organic acids. The substances according to the invention are prepared by substitution reactions of the corresponding 1-(2- -(arylthio)-5-halophenyl)ethyl chlorides with N-monosubstituted piperazines, in which the N-substituent is methyl, 2-hydroxyethyl, 2-methoxyethyl, phenyl or chlorophenyl. Preferred salts are hydrochlorides and maleates.

Description

The invention relates to 4-substituted 1- (1- (2- (arylthio) -5-halophenyl) ethyl) piperazines of formula I

ch ₃

Wherein R is chlorine or bromine, R and R are hydrogen or chlorine and o

R is methyl, 2-hydroxyethyl, 2-methoxyethyl, phenyl or chlorophenyl, except where R = Cl, R = R = H and R = methyl, and salts thereof with pharmaceutically acceptable inorganic or organic acids.

The literature (Rajšner M. et al., Collect. Czech. Chem. Commun. 43, 1276, 1978) describes 1- (1- (2- (phenylthio) -5-chlorophenyl) ethyl) -4-methylpiperazine for which locally anesthetic, spasmolytic and relatively weak antimicrobial activity in vitro were reported. It has now been found that the compounds of the invention defined by formula I exhibit antitussive activity, in part antireserpine, centrally depressant and diuretic, and in many cases intense antimicrobial activity in vitro. Thus, the compounds of formula I are useful as antitussives (anti-cough agents) and as chemotherapeutics against certain infectious diseases.

Preferred compounds of the invention are: 1- (1- (2- (phenylthio) -5-chlorophenyl) ethyl) -4- (2-hydroxyethyl) piperazine (bis (hydrogen maleate)) (Ia; I, R = Cl, R ² = R ² = H, R ² = CH ² Cl 2 OH); 1- (1- (2- (phenylthio) -5-chlorophenyl) ethyl) -4-phenylpiperazine (hydrochloride) (Ib; I, R = Cl,

R ² = R ² = H, R ² = CgHjj); 1- (1- (2- (phenylthio) -5-chlorophenyl) ethyl) -4- (3-chlorophenyl) piperazine (hydrochloride) (Ic; I, R = Cl, R ² = R ² = H, R ² = 3-chlorophenyl); l- (l- (2-chlorophenylthio) -5-chlorophenyl) ethyl) -4-methylpiperazine (bis (hydrogen maleate)) (Id ;, I, R = Cl, R ² = 2-C1,

R ² = H, R ² = CH); 1- (1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl) -4- (2-hydroxyethyl) piperazine (bis (hydrogen maleate)) (le, I, R = Cl, R ² = 2-C1 R ² = H, R ² = 2-hydroxyethyl); 1- (1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl) -4-phenylpiperazine) dihydrochloride) (If; I, R = Cl, R ² = = 2-Cl, R ² = H, R ² = CgHg); 1- (1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethyl) -4-methylpiperazine (bis (hydrogen maleate)) (Ig, I, R = Cl, R ² = 4-C1, ^R2 = H R ² = CH ² ; 1- (1- (2- (4-chlorophenyl 1 2 ^J thio) -5-chlorophenyl) ethyl) -4-phenylpiperazine) hydrochloride) (H, I, R = Cl, R = 4-C1, R = H, O

R = C (Hg); 1- (1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethyl) -4- (3-chlorophenyl) piperazine (hydrochloride) (where i: R = Cl, R ² = 4-C1, ² R = H, R ² = 3-chlorophenyl); 1- (1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl) -4-methylpiperazine (bis (hydrogen maleate)) (monohydrate) (1j;

R = Cl, R ² = 3-C1, ^R2 = 4-C1, R ² = CH); 1- (1- (2- (3.4-dichlorophenylthio) -5-chlorophenyl) ethyl) ^J .12

-4- (2-hydroxyethyl) piperazine (bis (hydrogen maleate)) (Ik; I, R = Cl, R = 3-Cl, R = 4-Cl,

R ² = 2-hydroxyethyl); 1- (1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl) -4- (2-methoxyethyl) 12 3 piperazine (bis (hydrogen maleate)) (II; I, R = Cl, R = 3-Cl, R = 4-Cl, R = 2-methoxyethyl);

1- (1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl) -4-phenylpiperazine (dihydrochloride) (Im;

I, R = Cl, i? ² = 3-Cl, R ² = 4-Cl, R ² = C, H); 1- (1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) oo 12 ethyl) -4- (3-chlorophenyl) piperazine (dihydrochloride) (In; I, R Cl, R = 3-Cl, R = 4-C1

R ² = 3-chlorophenyl); 1- (1- (2- (2.5-dichlorophenylthio) -5-chlorophenyl) ethyl) -4-methylpiperazine (bis (hydrogen maleate)) (Ιο; I, R = Cl, R ² = 2-C1, ² R -5-C 1, R ² = CH 2); 1- (1- (2- (2,5-dichlorophenylthio) -5-chlorophenyl) ethyl) -4- (2-hydroxyethyl) piperazine (bis (hydrogen maleate)) (Ip;

I, R = Cl, R ² = 2-C1, ^R2 = 5-C1, ^R2 = 2-hydroxyethyl); 1- (1- (2- (2,5-dichlorophenylthio) -51)

(chlorophenyl) ethyl) -4- (3-chlorophenyl) piperazine hydrochloride (Iq; I, R = Cl, R = 2-Cl, R = 5-Cl, R ² = 3-chlorophenyl); 1- (1- (2- (phenylthio) -5-bromophenyl) ethyl) -4-methylpiperazine (bis (hydro

3 (maleate)) (Ir 1, R = Br, R = R = H, R = CH 2).

The names of these substances are no longer used, but for shortness they are referred to as Ia to Ir.

The pharmacological properties of some of the compounds of the invention, as found in animal tests, and their antimicrobial effects in in vitro tests are now listed:

Acute toxicities were determined in mice? They are shown the median lethal dose LD _5Q mg / kg and further a method of administration of substances (intravenous and oral = iv - after): Ia, 60 iv? Ib, > 2500, po; Ic,> 2500, po; Id, 60, iv; Ie, 30, iv; If, 2500, po; Ig, 80, iv *, Ih,> 2500, po; II, 2500, po; Ij, 87.5, iv; Ik, 125, iv; II, 100, iv; Im,> 2500, po; lo, 75-100, iv; Ip, 2000, po; Ir, 363, following in these IV tests, mice died of convulsions within 5 min; sublethal doses induce excitation, convulsions, then sedation; toxic symptoms disappear within 15 to 30 minutes after administration.

Antitussive effect in rats; oral doses in mg / kg are reported that reduce the frequency of coughing attacks to about 50% compared to control; cough was induced by inhalation of an aerosol solution of citric acid: Ia, 60; Ib, 300; Ic, 300; Id, 60; 1, 75; Ik,

125

Central depressant effect manifested by potentiation of thiopental sleep in mice; are given i.v. doses in mg / kg prolonging the sleep duration to 200% (as compared to control): 1, 5 to 10; The antireserpine effect in rats, inhibiting gastric ulceration after reserpine, shows Ir at an oral dose of 50 mg / kg. Ip shows a diuretic effect in mice; at an oral dose of 100 mg / kg, it increases diuresis by 100%, which is comparable to the effect of hydrochlorothiazide.

Antimicrobial activity in in vitro assays; minimum µg / ml inhibitory concentrations are given if they do not exceed 25 µg / ml: Streptococcus beta-haemolyticus, Id 10, Ie 25, Ig 5, I 5, Ik 5, II 25, lo 5, Ir 6.2; Streptococcus faecalis, Id, 12.5; Ig 12.5, 10p, 10k, 10p, 10p; Staphylococcus pyogenes aureus, Id 10, Ie 25, Ig 5, I 5, Ik 10, II 25, lo 5,

Ip 10; Trichophyton mentagrophytes, Id 25, Ie 25, Ig 25, Ii 12.5, Ik 12.5, II 25, lo 12.5, Ip 12.5.

Compounds of the invention of formula I may be prepared by substitution reactions of 1- (2- (arylthip) -5-halophenyl) ethyl chlorides of formula II,

ch ₃

Wherein R, R and R are the same as in Formula I, with the 1-substituted piperazines of formula III, (III) o

in which R is also the same as in formula I. Of the starting materials of formula II only 1- (2- (phenylthio) -5-chlorophenyl) ethyl chloride is known (Rajner M. et al., cited); the preparation of others is described in the examples. All of the compounds of formula (II) used are oily liquids, distilling even under vacuum with partial decomposition; they were therefore mostly used raw and without characterization. Of the compounds of Formula III, 1-methylpiperazine and 1- (2-hydroxyethyl) piperazine are commercially available; others were prepared according to the literature: 1- (2-methoxyethyl) piperazine (Polivka Z. et al., Collect. Czech. Chem. Commun. 48, 2,395, 1983), 1-phenylpiperazine (Vejdelek ZJ et al., Collect. Chem. Commun. 40, 1 204 (1975), 1- (3-chlorophenyl) piperazine (Pollard CB, Wicker TJ, Jr., J. Am. Chem. Soc. 76, 1853, 195).

Preferably, two modifications can be used for said substitution reactions. In the case of hydrophilic piperazines with aliphatic N-substituents, the chloro derivatives II and amines III, which are used in a four-fold excess, are heated to reflux for 7 h in a small amount of chloroform as reaction medium. The excess monosubstituted piperazine is then removed by washing with water and the desired crude bases converted to the maleate which is purified by crystallization. In the case of considerably hydrophobic aryl piperazines, according to a second modification, the chloro derivatives II are reacted with equimolar quanta of amines III in dimethylformamide at 120 to 130 ° C in the presence of anhydrous potassium carbonate.

The crude bases obtained by the isolation process are converted to the hydrochlorides by shaking between dilute hydrochloric acid and benzene. Their high hydrophobicity is demonstrated by the fact that the hydrochlorides are not transferred to the aqueous phase, but rather to the benzene, from where they are obtained by evaporation and crystallization.

All of the compounds described herein are novel. Their identity was assured by analyzes and spectral methods. In the case of end products, the spectra were measured for free bases (crystalline or oily) which were liberated from the respective purified salts by alkalization and isolated by ether extraction. In the cases mentioned above, the preparation processes are merely illustrative of the preparation possibilities of the substances according to the invention? they are not intended to exhaustively describe all possible methods of preparation.

Example 1, Compound Ia

A mixture of 5.7 g of 1- (2- (phenylthio) -5-chlorophenyl) ethyl chloride, 13.0 g of 1- (2-hydroxyethyl) piperazine and 15 ml of chloroform is stirred and refluxed for 6 hours. After cooling, it is diluted with 120 ml of benzene and washed four times with 25 ml of water. The benzene layer was dried and evaporated under reduced pressure. The oily residue (7.4 g, 98%) was dissolved in 40 mL of absolute ethanol and a solution of 4.64 g of maleic acid in 15 mL of ethanol was added while warm. Slow addition of 120 ml of ether induces crystallization of the bis (hydrogen maleate) product. After standing until the next day is it aspirated and dried under vacuum? 8.6 g (70%) of a melting point of 135 DEG-137 DEG C. are obtained.

Crystallization from 2-propanol gave a constant melting pure product, m.p. Mp 134-136 ° C. Decomposition of a sample of this salt with aqueous ammonia and extraction with ether gives a crystalline base Ia which melts in pure state at 72-76 ° C (benzene-hexane).

Example 2, Ib

A mixture of 1- (2- (phenylthio) -5-chlorophenyl) ethyl chloride (7.10 g), dimethylformamide (10 ml), 1-phenylpiperazine (4.05 g) and potassium carbonate (3.5 g) was stirred and heated at 100 to 100 h for 3 h. 110 ° C and then for a further 3 hours at 125-130 ° C. After cooling, the mixture is diluted with 100 ml of benzene, washed with water to remove inorganic salts, and shaken twice with 50 ml of 2.5M-HCl.

After separation, 6.2 g (56%) of the hydrochloride of the desired compound precipitated from the benzene layer overnight in the refrigerator. 163 DEG-164 DEG C. (ethanol). As in the previous case, crystalline base Ib is released, which crystallizes from a mixture of benzene and hexane and melts at 87-91 ° C.

Example 3, Ic

As above, 7.1 g of 1- (2- (phenylthio) -5-chlorophenyl) ethyl chloride are reacted with 4.9 g of 1- (3-chlorophenyl) piperazine in 10 ml of dimethylformamide in the presence of 3.5 g of potassium carbonate . Analogous work-up by crystallization from benzene solution gave 7.7 g (64%) of crude Ic hydrochloride which was purified by crystallization from 2-propanol, m.p.

153-155 ° C. The loose base is oily.

Example 4, Id

Analogously to Example 1, 6.34 g of 1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 8.0 g of 1-methylpiperazine in 10 ml of chloroform. 7.4 g (97%) of crude oily base Id are obtained, which is converted to crystalline bis (hydrogen maleate) (9.3 g, 76%) by neutralization with maleic acid in acetone / ethanol / ether (9.3 g, 76%), m.p. 141 DEG-143.5 DEG C. (2-propanol). The loose base is oily.

The starting material 1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl chloride is a novel substance (not described in the literature) which is obtained, for example, as follows:

To a stirred solution of 25 g of 2- (2-chlorophenylthio) -5-chloroacetophenone (Protiva M. et al .; Collect. Czech. Chem. Commun. 51, 156, 1986) in 100 ml of ethanol is slowly added at 60 ° C. 3.8 g of sodium borohydride are added in portions and the mixture is refluxed for 1.5 h. The ethanol is evaporated, the residue is diluted with 100 ml of water and the resulting suspension is heated to 100 ° C for several minutes. After cooling, the product was extracted with benzene and the extract was worked up to give 24.8 g (98%) of crude 1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethanol, m.p. Mp 82-85 ° C. Crystallization from a mixture of cyclohexane and petroleum ether gave the pure material, melting at 84-85.5 ° C.

A solution of 10.1 g of thionyl chloride in 20 ml of benzene is added dropwise to the solution of 23.8 g of the preceding alcohol in 50 ml of benzene with stirring at 40 ° C over 30 minutes. The mixture was refluxed for 2 hours and then freed from the volatiles by complete evaporation in vacuo. The residual oil (24.2 g, 95%) is crude 1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl chloride which is used for further work without further purification and without characterization.

Example 5, Compound Ie

As in the previous case, 6.34 g of crude 1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl chloride were reacted with 13.0 g of 1- (2-hydroxyethyl) plperazine in 10 ml of chloroform. Analogous work-up gave 8.0 g (95%) of the crude base which was converted to crystalline bis (hydrogen maleate) by neutralization with maleic acid in 2-propanol and diluting the solution with ether; 10.2 g (79%), mp 134-135 ° C (2-propanol-ether). The base, released in the same manner as in the example, is crystalline and retains 1 molecule of water, so that even after crystallization from a mixture of benzene and petroleum ether, it appears as a monohydrate (shown analytically by ⁴ H NMR), mp 90-92 ° C.

Example 6, If

Similar to Example 2, a reaction of 6.34 g of crude 1- (2- (2-chlorophenylthio) -5-chlorophenyl) ethyl chloride with 3.2 g of 1-phenylpiperazine in 8 ml of dimethylformamide is carried out in the presence of

3.5 g of potassium carbonate. Upon processing, crystalline hydrochloride is precipitated by shaking the benzene solution of the crude base with dilute hydrochloric acid;

7.6 g (79%), m.p. 207-207.5 ° C (ethanol-ether). The loose base is oily.

Example 7, Ig

Analogously to Example 1, 6.34 g of 1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 10.0 g of 1-methylpiperazine in 20 ml of chloroform. After evaporation of the chloroform, the crude product is partitioned between 120 ml of benzene and 200 ml of water. The base is then extracted from the benzene solution into excess dilute hydrochloric acid, the aqueous layer is again liberated with aqueous ammonia and isolated by extraction with benzene; 3.6 g (47%) of an oily liquid. Neutralization with maleic acid in ethanol and addition of ether gave 4.6 g of crystalline bls (hydrogen maleate), m.p. 154.5-155.5 ° C (ethanol).

The starting material 1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethyl chloride used is a novel substance not yet described in the literature. It can be prepared, for example, by the following procedure:

Similar to Example 4, a reduction of 23.0 g of 2- (4-chlorophenylthio) -5-chloroacetophenone (Bartl V. et al., Collect. Czech. Chem. Commun. 48, 1173 (1983)) is carried out by 3. 1.0 g of sodium borohydride in 100 ml of ethanol. 22.7 g (99%) of crude and oily 1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethanol are obtained which is distilled at 187 ° C / 0.1 mbar.

Conversion of this material (20.5 g) to the desired 1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethyl chloride is also carried out similarly as described in Example 4, i.e. with 8.3 g of thionyl chloride in 60 ml of benzene. The crude product is obtained in theoretical yield (21.9 g) and is used further in the crude state. For characterization, the sample can be distilled under vacuum, b.p. 171 ° C / 80 Pa; however, partial decomposition takes place.

Example 8, Compound Ih

Similar to Example 2, 6.34 g of 1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethylene chloride was reacted with 3.24 g of 1-phenylpiperazine in 10 ml of dimethylformamide in the presence of 3.0 g of potassium carbonate. The monohydrochloride of the desired product is obtained again by crystallization from a benzene solution; 6.4 g (67%), m.p. 202-205.5 ° C (ethanol). The base released from this salt is crystalline and melts at 142-146 ° C (benzene-petroleum ether).

Example 9, compound II

Similar to Example 2, 6.9 g of 1- (2- (4-chlorophenylthio) -5-chlorophenyl) ethylene chloride are reacted with 4.3 g of 1- (3-chlorophenyl) piperazine in 10 ml of formamide in the presence of 3.5 g. g of potassium carbonate. After analogous work-up, the monohydrochloride is recovered from the benzene solution; 7.0 g (62%), m.p. 175 DEG-177.5 DEG C. (2-propanol ether). The liberated base is crystalline and melts at 133-136 ° C (benzene-petroleum ether).

Example 10, compound 1j

Similar to Example 1, 6.4 g of 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethylene chloride are reacted with 10.0 g of 1-methylpiperazine in 10 ml of chloroform. 7.6 g (90%) of a crude oily base are obtained which, by neutralization with maleic acid in ethanol, gives 6.7 g of crystalline bis (hydrogen maleate) which crystallizes from aqueous acetone as the monohydrate, m.p. Mp 146-147.5 ° C.

The starting material 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl chloride used is a novel substance not previously described in the literature. It can be obtained, for example, by the following procedure:

A stirred mixture of 37.8 g of 2,5-dichloroacetophenone (Rajsner M. et al., Cited), 39.4 g of 3,4-dichlorothiophenol (Red I et al., Collect. Czech. Chem. Commun. 41, 881, 1976), 47 g of potassium carbonate and 1.0 g of copper catalyst are heated to 150-155 ° C. After cooling to 80 ° C, the mixture was diluted with 150 ml of benzene, the inorganic salts were removed by filtration and washed with benzene, and the filtrate was evaporated. The solid residue is crystallized from 700 ml of methanol. 51.1 g (77%) of 2- (3,4-dichlorophenylthio) -5-chloroacetophenone, m.p. 104.5-106 ° C (methanol).

The obtained ketone (49.0 g) is reduced with 7.0 g of sodium borohydride in 200 ml of boiling ethanol similarly as described for the analogous example in Example 4. 44.0 g (89%) of crude oily 1- ( 2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethanol boiling at 205 ° C / 1.1 kPa.

Conversion of the obtained alcohol (44.0 g) to the desired 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl chloride was carried out similarly as described in Example 4, i.e. by reaction with 16.1 g of thionyl chloride in boiling benzene. The crude product was obtained in the theoretical amount (46.5 g) and was used for the substitution reactions.

Example 11, Ik

As in Example 1, 6.4 g of 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethylene chloride are reacted with 9.7 g of 1- (2-hydroxyethyl) piperazine in 11 ml of chloroform. 8.2 g (92%) of the desired crude base are obtained, which is neutralized with maleic acid in ethanol and added

Ί ether was converted to 9.6 g of crystalline bis (hydrogen maleate), m.p. 135-135.5 ° C (acetone-ether). The loose base is oily.

Example 12, Compound II

As in Example 1, 6.4 g of 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 2.8 g of 1- (2-methoxyethyl) piperazine in 6.0 ml of chloroform. 8.1 g (88%) of a crude oily base are obtained, which is neutralized with maleic acid in ethanol, and 5.4 g of bis (hydrogen maleate), m.p. M.p. 148-149 ° C (ethanol-ether). The loose base is oily.

Example 13, Im

As in Example 2, 6.4 g of 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 3.2 g of 1-phenylpiperazine in 8 ml of dimethylformamide in the presence of 3.5 g of potassium carbonate. The product dihydrochloride is again obtained by crystallization from a benzene solution; 5.7 g (51%), m.p. Mp 167-169 ° C (ethanol-ether). The liberated base crystallizes from cyclohexane and melts at 143-146 ° C.

Example 14, In

As in Example 2, 6.4 g of 1- (2- (3,4-dichlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 3.5 g of 1- (3-chlorophenyl) piperazine in 12 ml of dimethylformamide in the presence of 5, 5 g of potassium carbonate. The hydrochloride does not crystallize from the benzene solution. Therefore, the benzene was evaporated and the residue (9.6 g) was dissolved in 50 ml of ethanol and 4.2 g (36%) of crystalline dihydrochloride precipitated by addition of dilute ethereal hydrogen chloride solution. 145-147 ° C (ethanol-ether). The liberated base crystallizes from a mixture of benzene and petroleum ether and melts at 120-124 ° C.

Example 15 Io

As in Example 1, 5.4 g of 1- (2- (2,5-dichlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 7.5 g of 1-methylpiperazine in 11 ml of chloroform. Work-up gave 6.7 g of crude oily base which, by neutralization with maleic acid in ethanol and addition of ether, yielded 5.2 g of crystalline bis (hydrogen maleate), m.p. 153 DEG-154.5 DEG C. (acetone-ether). The loose base is oily.

The starting material 1- (2- (2,5-dichlorophenylthio) -5-chlorophenyl) ethyl chloride used is a novel substance not yet described in the literature. They are prepared, for example, by the following procedure:

Reaction of 28.4 g of 2,5-dichloroacetophenone with 29.6 g of 2,5-dichlorothiophenol (shingle K. et al., Collect. Czech. Chem. Commun. 38, 3 321, 1973) in the presence of 35 g of potassium carbonate and 0.6 g of copper, prepared in analogy to Example 10, gives 18.5 g (37%) of 2- (2,5-dichlorophenylthio) -5-chloroacetophenone, m.p. 131.5 - 132.5 ° C (2-butanone).

The obtained ketone (22.5 g) was reduced with 4.0 g of sodium borohydride in 100 ml of ethanol at 50 ° C (see Example 4). The dark solution obtained was stirred at 50-60 ° C for 1 h and refluxed for 3.5 h. After evaporation of the ethanol, the residue is partitioned between 130 ml of water and 100 ml of benzene. The organic phase is dried and evaporated; the residue (20.7 g) was crystallized from a mixture of 20 ml of cyclohexane and 40 ml of petroleum ether. 17.6 g (60%) of 1- (2- (2,5-dichlorophenylthio) -5-chlorophenyl) ethanol, m.p. 77.5 to 80 ° C.

Conversion of the obtained alcohol (16.5 g) to the desired 1- (2- (2,5-dichlorophenylthio) -5-chlorophenyl) ethyl chloride with 5.9 g of thionyl chloride in 40 ml of benzene is carried out in a similar manner as described for an analogous case. in Example 4. The crude oily product was obtained in a theoretical yield (17.2 g) and was used in this state as it decomposed upon vacuum distillation.

Example 16, Compound Ip

Analogously to Example 1, 5.4 g of 1- <2- (2,5-dichlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 9.7 g of 1- (2-hydroxyethyl) piperazine in 11 ml of chloroform. 6.6 g (98%) of crude oil base were obtained, which was converted to crystalline bis (hydrogen maleate) (8.1 g), m.p. 130 DEG-132 DEG C. (acetone). The loose base is oily.

Example 17, compound Iq

Analogously to Example 2, 4.6 g of 1- (2- (2,57-dichlorophenylthio) -5-chlorophenyl) ethyl chloride are reacted with 2.7 g of 1- (3-chlorophenyl) piperazine in 12 ml of dimethylformamide in the presence of 3.0 g of potassium carbonate. The hydrochloride is recovered from the benzene solution after shaking with dilute hydrochloric acid; after crystallization from a mixture of 2-propanol, acetone and ether, 3.1 g (40%), m.p. Mp 170-172 ° C.

Example 18, Ir

Analogously to Example 1, 5.6 g of 1- (2- (phenylthio) -5-bromophenyl) ethyl chloride are reacted with 8.0 g of 1-methylpiperazine in 8 ml of chloroform. 6.2 g (98%) of a crude oily base were obtained, which was converted to 8.4 g of crystalline bis (hydrogen maleate), by neutralization with maleic acid in ethanol, m.p. 157 DEG-158 DEG C. (ethanol-ether). The loose base is oily.

Default used! 1- (2- (phenylthio) -5-bromophenyl) ethyl chloride is a novel substance not yet described in the literature. It can be prepared, for example, by the following procedure:

A mixture of 30.0 g of 2,5-dibromoacetophenone (Polivka Z. et al., Collect. Czech, Chem. Commun.

49, 86, 1984), 12.5 g of thiophenol, 23.5 g of potassium carbonate and 0.4 g of copper are stirred for 10 min at room temperature, then heated at 100 ° C for 1 h without stirring, cooled to 50 ° C and diluted with 140 mL of benzene. The inorganic salts are filtered off and washed with benzene. The filtrate was washed with 50 ml of 10% sodium bicarbonate solution and water, dried and evaporated. Crystallization from 20 ml of hexane yielded 12.2 g of an off-homogeneous product which had to be crystallized from a mixture of 10 ml of cyclohexane and 13 ml of hexane. 8.4 g (26%) of 2- (phenylthio) -5-bromoacetophenone are obtained, m.p. 65.5 - 66.5 ° C (hexane).

The reduction of 8.4 g of the obtained ketone with 1.2 g of sodium borohydride in 40 ml of ethanol is carried out similarly as in the previous cases. 6.8 g (81%) of crude 1- (2- (phenylthio) -5-bromophenyl) ethanol are obtained. Distillation yielded 5.1 g of homogeneous product, b.p. 164-166 ° C / 66 Pa.

The conversion to the desired 1- (2- (phenylthio) -5-bromophenyl) ethyl chloride is carried out as before: from 5.1 g of alcohol and 2.2 g of thionyl chloride in 16 ml of benzene, the theoretical yield (5.6 g) is obtained. a crude chloro derivative which is used for the substitution reaction without purification and characterization.

Severography, n. P., MOST

Price 2,40 Kčs

Claims (1)

4-substituted 1f (1- (2- (arylthio) -5-halophenyl) ethyl) piperazines of formula I CH ₃ Wherein R is a chlorine or bromine atom, R and R are a hydrogen atom or a chlorine atom; R is methyl, 2-hydroxyethyl, 2-methoxyethyl; phenyl or chlorophenyl, except where R = Cl, R = R = H and R = methyl, and their salts with pharmaceutically acceptable inorganic or organic acids.