SU1306471A3 - Method for producing derivatives of diphenylsulfide - Google Patents

Abstract

The invention relates to a class of diphenylsulfide derivatives, in particular, the preparation of substances of the general formula (1) p-X-CbH4-8-C (, H4-p-C, where X is hydrogen, chlorine, or methyl; R - -C (0 ) SNgCN C (0) (0) CH3Jj RI is hydrogen or lower alkyl that has a hypolipedymic effect (HD), in particular the ability to reduce the amount of cholesterols and triglycerides in the blood, and can be used to treat atherosclerosis. of HG events, new derivatives of diphenylsulfide have been obtained.The reactions are subjected to compounds of the general formula (II) nX-CfeH4SC6H4-n-Rz + CH, C (0) SH, where R, -C (0) (0) OR2; Rj has the indicated values, in an organic solvent — ethanol, benzene, diethyl ether, chloroform, acetone, ethyl acetate or dimethylformamide, at a temperature of (-10) - (+ 50) C for 0.5–24 h of Compound ( I) low toxicity — LDjp 1000 mg / kg. Reduction of cholesterol and triglyceride in blood (%) and increase in liver mass (%) of compound (I) dp is 24.1; 14.2; 3.0 against 10.6; 12.4 and 2.3 for 2-acetyl-3- (4-phenoxybenzosh1) propionic acid (structural analog) and 1.1; 41.9 and 34.2 (dp hlofibrata). 2 tab. CO 05 "

Description

11306471

This invention relates to a process for the preparation of new diphenyl sulfide derivatives of the general formula

/ -L. xCOOV S - (O) - COCH2CH

SSSH

e

where X is hydrogen, chlorine or methyl;

R is hydrogen or lower apical, which have the ability to reduce the amount of lipids, such as cholesterol and triglycerides, in the blood and can therefore be used in medicine.

The aim of the invention is to develop a method for producing new derivatives of diphenylsulfide, which have an increased ability to reduce the amount of cholesterol in the blood;

Example 1. A. In 100 ml of dichloromethane, 5.58 g of diphenyl sulfide and 2.99 g of mapein anhydride are dissolved.

Example 2. A, To a solution of 8.53 3- (4-phenylthiobenzoyl) acrylic acid in 50 ml of dimethylformamide, 4.54 g of dimethyl sulfate and 2.50 g of potassium carbonate are added. The resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the resulting mixture was extracted with diethyl ether. The organic layer was washed alternately with water, saturated sodium bicarbonate solution, water, and dried over magnesium sulfate. Diethyl ether was removed from the solution by evaporation, and the residue was recrystallized from a mixture of hexane and dichloromethane to obtain 6.80 g of methyl 3- (4-phenyl-thiobenzoyl) acrylate, mp 85-86.5

B. To a solution of 2.98 g (10.0 mmol of methyl 3- (4-phenylthiobenzoyl) acrylate in 30 ml of DIET1-SHOVE ester, 0.8 ml (11.2 mmol) of thioacetic acid is added. The resulting mixture is stirred

15

, - at room temperature during read. To the resulting solution 5

5.97 g of anhydrous aluminum chloride is gradually added, after which stirring is continued at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure and poured into a mixture of 5 ml of concentrated hydrochloric acid and 100 g of ice, and the mixture obtained is extracted ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate, and then ethyl acetate is evaporated under reduced pressure. The residue is crystallized from a mixture of hexane and ethyl acetate to obtain 6.56 g of 3- (4-phenylthiobenzoyl) 40 acrylic acid, m.p. 157-159 0. B. To a solution of 2.84 g (10.0 mmol) of 3- (4-phenylthiobenzoyl) -acrylic acid in 30 ml of chloroform, 0.8 np (11.2 mmol) of thioacetic acid are added. . The resulting mixture is stirred for 5 hours at room temperature. Chloroform is removed from the mixture by evaporation under reduced pressure, and the residue is purified on a chromatographic silica gel column (eluent hexane: ethyl acetate), and then recrystallized from a mixture of hexane and ethyl acetate to obtain 3.24 g (90%)

The reaction solution was washed alternately with water, with an aqueous saturated sodium bicarbonate solution, water, and dried over magnesium sulfate. The diethyl ether was removed from the solution by evaporation, and the residue was purified in a chromatographic silica gel column (eluent: hexane: DIETHYL ester) to obtain 3.73 g (99.7%) of methyl 2-acetylthio-3- (4 -phenylthiobenzoyl) propane 35 onata in the form of oil.

IR (СНС1з),

m cop

 : 1735 (puff ether, thioe | fir), 1680 (ketone).

NMR (CDCl1), M.D.: 2.36 (3N, s) 3.49 (1H, d.ds, 6 Hz); 3.65 (1H, dd.d., 8 Hz); 3.74 (3N, p.), 4.72 (1H, dd.d., 6 Hz); 7.21 (W, d., Hz), 7.40-7.52 (5H, m.); 7.79 (2H, Hz).

Example 3. A. In a similar manner to Example 2A, using 5.55 g of diethylsulphate instead of dimethyl sulfate, 7.77 g of ethyl 3- (4-phenylthiobenzoyl acrylate) are obtained, mp 74-75 C.

B. Analogously to Example 2B, using 3.12 g (10 mmol) ethyl-3- (4-phenylthiobenzoyl) acrylate instead of methyl 3- (4-phenylb; nzoyl) acrylate, I get 3.46 g (89%) ethyl -2-acetylthio-3- (42-acetylthio-3- (4-phenylthiobenzoyl) pro 55 Felylthiobenzoyl) propionate, so pl.

pionic acid, so pl. 116.5-118.5 C, Calculated,%: C 59.98; H 4.47,

 ig it

Found,%: C 59.76; H 4.54.

71.5-72 ,.

Calculated,%: C, 61.82; H 5.19.

CjflH 00482

Found, f ,: C 61.81; H 5.25.

Example 2. A, To a solution of 8.53 g of 3- (4-phenylthiobenzoyl) acrylic acid in 50 ml of dimethylformamide, 4.54 g of dimethyl sulfate and 2.50 g of potassium carbonate are added. The resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and the resulting mixture was extracted with diethyl ether. The organic layer is washed alternately with water, saturated sodium bicarbonate aqueous solution, water, and dried over magnesium sulfate. Diethyl ether was removed from the solution by evaporation, and the residue was recrystallized from a mixture of hexane and dichloromethane to obtain 6.80 g of methyl 3- (4-phenyl-thiobenzoyl) acrylate, mp, 85-86.5 ° C.

B. To a solution of 2.98 g (10.0 mmol) of methyl 3- (4-phenylthiobenzoyl) acrylate in 30 ml of DIET1-SHOVE ester, 0.8 ml (11.2 mmol) of thioacetic acid is added. The mixture is stirred

five

at room temperature for 5

The reaction solution was washed alternately with water, with an aqueous saturated sodium bicarbonate solution, water, and dried over magnesium sulfate. Diethyl ether is removed from the solution of 40 40 45 50

the residue is purified on a silica gel chromatography column (eluant: hexane: DIETHYL ester) to obtain 3.73 g (99.7%) of methyl 2-acetylthio-3- (4-phenylthiobenzoyl) propyne 35 as in oils.

IR (СНС1з),

m cop

 : 1735 (ester, thioe | fir), 1680 (ketone).

NMR (CDCl1), MH: 2.36 (3N, p.); 3.49 (1H, dd.d., 6 Hz); 3.65 (1H, dd.d., 8 Hz); 3.74 (3N, p.), 4.72 (1H, dd.d., 6 Hz); 7.21 (W, d., Hz), 7.40-7.52 (5H, m.); 7.79 (2H, Hz).

Example 3. A. In analogy to Example 2A, using 5.55 g of diethyl sulfate instead of dimethyl sulfate, 7.77 g of ethyl 3- (4-phenylthiobenzoyl) acrylate are obtained, m.p. 74-75 C.

B. Analogously to Example 2B, using 3.12 g (10 mmol) ethyl 3- (4-phenylthiobenzoyl) acrylate instead of methyl 3- (4-phenylb; nzoyl) acrylate, obtain 3.46 g (89%) ethyl -2-acetylthio-3- (4F eiylthiobenzoyl) propionate, so pl.

71.5-72 ,.

Calculated,%: C, 61.82; H 5.19.

CjflH 00482

Found, f ,: C 61.81; H 5.25.

An example. A. Analogously to Example 1A, using 6.00 g of para-methyl diphenyl sulfide and instead of diphenyl sulfide, 3.30 g (4-methylphenylthio) benzoyl acrylic acid is obtained in the form of an amorphous solid.

IR (n),, cm-: 1700 (carboxylic acid); 1665 (ketone).

NMR (CDClI), MD: 2, A (3N, p.); 6.86 (1H, d, Hz); 7.18 (2H, d, Hz); 7.26 (2H, d, Hz); 7.45 (2H, d, Hz); 7.86 (2H, d, J 9 Hz); 7.93 (1H, d., Hz).

B. Analogously to Example 1B, using 2.98 g (10.0 mmol) (4-methylphenylthio) benzoyl acrylic acid instead of 3- (4-phenylthiobenzoyl) acrylic acid, 1.93 g (52%) of 2-acetylthio -3-4- (4-methylphenylthio) benzoyl propionic acid, m.p. 127-129 C.

Calculated,%: C 60.94; H 4.84,

C) if0 2Found,%: C 60.67; H 5.04.

Example5. A. Analogously to Example 1A, using 6.62 g of para-chlorophenylsulphide instead of diphenylsulphide, 6.97 g of (4-chlorophenylthio) benzoyl acrylic acid are obtained, m.p. 164-165 C.

B. Analogously to Example 1B, using 3.19 g (10.0 mmol) of 3-C4- (4-chloro-luta) are suspended in 30 ml of ethanol, 1.2 ml (16.8 mmol) of thio-acetic acid are added, the mixture stirred at room temperature for 3 hours and left overnight. Ethanol is evaporated under reduced pressure, the residue is purified by column chromatography on silica gel (eluent mixture of hexane and chloroform) and recrystallized from a mixture of hexane and ethyl acetate to give 3.20 g (89%) of 2-acetylthio-3- (4-phenylthiobenzoyl) propionic acid.

Example 9. Procedures 15 of Example 8 are repeated, using 30 m of benzene instead of ethanol as solvent and stirring at 30 for 10 h. 2.98 g are obtained (83 2-acetylthio-3- (4-phenylthiobenzoyl) 20 propionic acid.

Example 10. 2.84 g (10.0 mmol of 3- (4-phenylthiobenzosh1) acrylic acid is dissolved in 10 MP dimethyl form of the amide, 1.0 mm (14.0 mmol of 25 thioacetic acid) is added and the mixture is stirred for 30 minutes Water is added to the solution and extracted with ethyl acetate. The organic layer is washed with water and dried over magnesium sulfate 30. The ethyl acetate is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (eluant mixture of hexane and chloroform) and recrystallized phenylthio) benzoyl acrylic acid

instead of 3- (4-Fensh1Tiobenzoyl) acrylic 35, it is called from ethyl acetate with the resulting acid; -3.67 g (93%) is obtained by the use of 3.31 g (92%) of 2-acetylthio-3- (4-acetylthio-3- 4- (4-chlorophenylthio) benzoyl propionic acid, mp 111-.

Calculated. %: C 54.75; H 3.83.

C ,, H, C104.

Found,%: C 54.95; H 4.01.

EXAMPLE 6 The procedure of Example 1B was repeated. Using 30 ml of ethyl acetate instead of chloroform as a solvent with stirring at 50 ° C for 2 hours, 3.18 g (88%) of 2-acetylthio-3- ( 4-phenyl 1Tiobenzoyl) propionic acid.

Example 7. The procedure of Example 1B is repeated, using 30 ml of acetone instead of chloroform as a solvent with stirring at 10 ° C for 7 hours. 3.38 g (94%) of 2-acetylthio-3- (4- phenylthiobenzoyl) propionic acid.

Example 8. 2.84 g (10.0 mmol) of 3- (4-phenylthiobenzoyl) acrylic cisphenylthiobenzoyl) propionic acid The tests for biological activity are carried out in the following manner.

40

Experiment 1. Five week old male Wister rats (weight 120 + 6 g) are kept for a week at constant temperature and humidity (

 5 rats in each group). Ethyl 2- (4-chlorophenoxy-2-methyl propionate) chlorofibrate is used as a reference drug. As test compounds, suspensions of the formulas of the proposed formula and comparative preparation in a 5% solution of gum arabic are used. Each of the test compounds is administered orally to rats of each group in daily doses of lOO mg / kg as an active ingredient for three days. Similarly, 5 g of a solution of gum arabic alone is administered orally to the rats of the control group. After the introduction of me.

3064714

Lots are suspended in 30 ml of ethanol, 1.2 ml (16.8 mmol) of thioacetic acid are added, the mixture is stirred at room temperature for 3 hours and left overnight. Ethanol is evaporated under reduced pressure, the residue is purified by column chromatography on silica gel (eluent mixture of hexane and chloroform) and recrystallized from o-hexane and ethyl acetate to give 3.20 g (89%) of 2-acetylthio-3- ( 4-phenylthiobenzoyl) propionic acid.

Example 9. Procedure 15 of Example 8 is repeated, using 30 ml of benzene instead of ethanol as solvent and stirring for 10 hours. 2.98 g (83%) of 2-acetylthio-3- (4-phenylthiobenzoyl) are obtained 20 propionic acid.

Example 10. 2.84 g (10.0 mmol) of 3- (4-phenylthiobenzos1) acrylic acid is dissolved in 10 MP of dimethylformamide, 1.0 mm (14.0 mmol) of 25 thioacetic acid are added and the mixture is stirred at for 30 minutes Water is added to the solution and extracted with ethyl acetate. The organic layer is washed with water and dried 30 on magnesium sulfate. The ethyl acetate is evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (eluent mixture of hexane and chloroform) and recrystallization of 3.31 g (92%) of 2-acetylthio-3- (4phenylthiobenzoyl) propionic acid. The tests for biological activity are carried out in the following manner.

0

Experiment 1. Five week old male Wister rats (weight 120 + 6 g) are kept for a week at constant temperature and humidity (

 5 rats in each group). Ethyl 2- (4-chlorophenoxy-2-methyl propionate) chlorofibrate is used as a reference drug. As test compounds, suspensions of the coQ of the proposed formula and comparative preparation in a 5% solution of gum arabic are used. Each of the test compounds is administered orally to rats of each group in daily doses of lOO mg / kg as an active ingredient for three days. Similarly, 5 g of a solution of gum arabic alone is administered orally to the rats of the control group. After the introduction of mex5

513064716

TOBoro compounds in rats are not allowed to eat a suspension of the tested compounds at 18 h and are anesthetized with diethyl ether — 0.2% CMC-Na aqueous solution

Blood is taken from the inguinal artery and inguinal vein, and the serum lipid volume is determined with the aid of the autoangent.

At the same time, the liver is removed and its relative weight (relative to body weight) is determined.

in the amount of 100 mg / kg per day. A 0.2% aqueous solution of CMC-Na is orally administered to royal animals. After the end of the course, the rats are not allowed to eat for 24 hours and then lulled in diethyl ether. Blood is collected through the inguinal artery and inguinal vein.

In tab. 1 shows the characteristics;) determine the volume of lipid in serum with

tics of decreasing blood lipids in blood (as a percentage of the difference in lipid concentration between the dose group and the control group) and characteristics of an increase in liver weight (similarly as the percentage of the relative weight of the liver) due to the administration of the proposed compound 1. and a comparative drug.

Table

value, Significance at 0.1% level

authenticity

Experiment 2, Acute Toxicity Test.

Eight-week-old male JCR mice (body weight 28-32 g, 8 mice per group) were orally administered a suspension of the compound of Example 1 in a 5% gum arabic solution, observed 7 days after the administration, and then counted LDgQ, LDjg, for the compound of Example 1, it is greater than 1000 mg / kg.

Experiment 3 (comparative). Used in the experiments, 8-week-old male Wister rats weighing 170 1 for 7 days receive food rich in cholesterol containing cholesterol 1 and sodium choleate 0.5%. During this time, they are orally administered

suspension of the tested compounds in a 0.2% aqueous solution of CMC-Na

in the amount of 100 mg / kg per day. A 0.2% aqueous solution of CMC-Na was orally administered to the control animals. After completing the course, the rats were not allowed to eat for 24 hours and then euthanized with diethyl ether. Blood is collected through the inguinal artery and the inguinal vein and

ff

using an automatic analyzer. At the same time, the liver is removed and its relative weight (relative to the weight of the animal) is determined.

In tab. 2 shows data on the reduction in blood lipid (percentage of lipid concentration in blood of rats treated with the drug and control animals), 20 as well as the degree of increase in liver weight (similar percentage of relative difference in liver weight)

table 2

Note. Compound 2-acetylthio-3- (4-phenylthiobenzosh1) propionic acid, Compound B 2-acet1Tio-3- (4-phenoxybenzoyl) propionic acid, Compound C 2-aceto1-thio-3-4- (4-chlorophenoxy) benzoyl propionic acid, compounds B and C, of known analogous structure);

compound D chlorofibrate - known.

From tab. 2 that the compounds according to the invention sharply reduce the cholesterol content in comparison with the known compounds in experiments with rats with a high cholesterol content.

Claims (1)

Invention Formula The method of obtaining diphenylsulfide derivatives of the general formula where X is hydrogen, chlorine or methyl; R is hydrogen or lower alkyl, characterized in that the compound of the general formula OU-SOSN SHSOOV 13064718 where X and R have the indicated meanings, are reacted with thioacetic acid in an organic solvent, such as ethanol, benzene, diethyl ether, chloroform, acetone, ethyl acetate or dimethylformamide, at a temperature of (-U) - () C in for 0.5-24 hours