SU534063A1 - Derivatives of ( )-chloro- ( )-choloroethyl butyric acid displaying antitumoral activity, and method of producing same - Google Patents

Abstract

1. Derivatives of (J (^) - chloro- (jf (^) - chloroethylthiomethyl) • acid of the general FORMULA CH. (R, l-CH (R,) - CH, -COil3'here R < - C1, SCH; ^ CHj, C]; R ^ - ССНгСН ^ С!, С1; R ^ - ОН, NljCeiir, NHCgH4COOC2H5, ШСНССООЮСНгС ^ Нд, having antitumor activity u and with the fact that the corresponding derivative of vinylacetic acid is reacted with chloroethylsulfonic chloride e in tetrachloromethane medium, followed by holding the reaction mixture for 10-15 h at 0-5''c and isolating the desired product of the indicated formula, where R ^ is C1 , and Rg "SCH ^ CHg ^ Cl, or boiling over Lednov in anhydrous nitromethane ™ for apportionment of the compounds of the above formula wherein RI -. SCHgCH ^ Cl, R ^ - C ^ Clos

Description

The invention relates to a derivative of th (y) -chloro-y (/ i) -chloroethylthiobutyric acid of the formula I, not described in literature.

 CKg - COR,

where R, - Cl, SCHgCIIgCl;

R is SCH CHiCl, Cl;

R, is OH, NHCgH, NHCgUg-COOCgHg.,

NHCHCCOO CHgCgllg., Which have biological activity and can be used as antitumor agents. Known carboxyl derivatives of mustard gas, namely about (A) chloro- / 3 (about)

Chloroethylthiocarboxylic derivatives show insufficiently high antitumor activity.

It is known to react alkylene sulfides with dialkylamidosulfenyl chlorides in an organic solvent medium, for example carbon tetrachloride, to produce dialkylamido-2-chloroalkyldisulfides. Use the appropriate p1e-derivatives of vinyl acetic acid and chloroethylsulfenyl chlorides and carry out the process in carbon tetrachloride, followed by holding the reaction mixture for 10-15 hours at 3. allows you to get the proposed connection. Formulas I, where R | -C1 Rg - .f., F ,, - OH, is obtained by mixing, while cooling, solutions of vinyl acetic acid in carbon tetrachloride with chloroethylsulfene chloride in tetrachloromethane followed by isolation of the target product. A chloro-chloroethylthiobutyric acid is obtained. In order to obtain -chloroethylthio-th, chlorofluoric acid Jf-chloro-chlorine. ethylthiobutyric acid is boiled in water and nitromethane, followed by isolation of the desired product. Mustard derivatives of the formula I, where Rj- - G1, R ,,. - SCUTCH2, С1, Кз - NHCgH, is obtained by mixing at a scientific research institute solutions of vinyl acetic anilide solutions in methylene tetrachloride followed by isolation of the target product. Anilide is obtained. -Chloro-chloroethylthiobutyric acid. For the preparation of the anilide Y-chloroethyl thio-B-chloro-malic acid, anilide X-hg.mt-A-chloroethylthiobutyric acid | t in anhydrous nitromethane. Derivatives, mustard gas of the formula I, gd, zb, PSTEs are obtained by mixing a solution of anesthetic vinyl acetic acid in carbon tetrachloride with chlorostilsulfenyl chloride 8 carbon tetrachloride. Anesthesia zid is obtained in -chloro / a-chloro-, lthiobutyric acid. To obtain N-phenylalanine 5-chloroethylthio (3-chlorobasic acid), a solution of N-phenylalanine vinylacetic acid is mixed. acids in carbon tetrachloride with chloroethylsulfene chloride in carbon tetrachloride. . Try on | 1 (/) - Chloro- | (|) chloroethylthiobutyric acid. To a solution of 2, g (0.0.3 g-mol) of vinyl acetic acid. In 30 ml of tetra chloromethane, 3.93 g (0, PZ g-mol) of chloroethyl sulfene chloride in 20 ml of carbon tetrachloride are added dropwise; at 3 C, at the end of the reaction (the disappearance of the characteristic color of sulfenchloride) the solvent is evaporated in vacuo and recrystallized} G chlor-Bchloroethylthiobutyric acid from a mixture of ether and petroleum ether, m.p. 51-53 ° C, Yield Y5%. Found ,,: With 33.37; H A, 68. , Calculated,%: C 33.21; H 4.65 "For the preparation of T-chloroethylthio-Dchloromethyl acid 1, OR g (0, PP5 g mol) I-chloro - () - chloroethylthio-. the aqueous acid is boiled for 4.5 hours in 30 ml of anhydrous nitroethane, the solvent is evaporated. The residue is recrystallized from absolute hexane, Tspl. . Output 5P% “1Fixed: C 33.50; H.4,88 „GgHioCl O S, -. Calculated,%: C 33.21; H 4.65 “PRI mpe R 2o Anilide () -chloro (Y) -chloroethylthiobutyric acid. To a solution, 83 g (0.03 g-mol) of vinyl acetic anilide in 5 ml of carbon tetrachloride at -3.0 ° C, 3.93 g (0.03 g-mol) of chloroethylsulfene chloride in 20 ml of carbon tetrachloride are added and kept 13 hours with and at the end of the reaction (the disappearance of the characteristic color of sulfenchloride) the solvent is evaporated in vacuum. After recrystallization from absolute ether tpl, 81-YAZ C. Yield 90%, Found: C 49.60; 11 5.12; N 5, OP C, .2H, g-Cl.; NOS. Calculated: C 49.31; H 5.24; N, 4.79 ° To obtain anilide) p-chloroethylthio-chloromethanic acid 1.46 g (p.005 p-mol) of anilide- -chloro-3chloroethylthioic acid is boiled for 5 s in 30 ml of anhydrous nitromethane. The solvent is evaporated. The residue is recrystallized from absolute ether, Topl. , Yield 50%. Found,%: C 49.60; H 5.12; N 4.84, C, 2.H fg-ClgNOS. Calculated,%: C 49.31; H 5.24; M 4.79. Froze Anesthetic-chlorine-ethylthiobutyric acid. To a solution of 6.99 g (0.03 g-mol) of vinyl acetic anesthetic in 30 ml of carbon tetrachloride at 3.degree. C., 3.93 g (0.03 g-mol) of chloroethylsulfene chloride in 20 ml of carbon tetrachloride are added; hours at 3 ° C and at the end of the reaction (the disappearance of the characteristic color of sulfenyl chloride) the solvent is evaporated in vacuo. After recrystallization from absolute ether so pl. 101-102 ° C, Yield R5%. ., 5 The structure of the obtained substance is confirmed by the data of elemental analysis. Example 4, N-Leiylalanine-chloroethylthio-6-chloro-butyric acid To a solution of 6.99 g (0.03 g-mol) of N-phenylalanine vinyl acetic acid in 30 ml of carbon tetrachloride are added dropwise at -30 ° C. m 3.93 g (Ojh3 g-mol) of chloroethylsulfenyl chloride. The reaction mixture is left for 13 hours at 3 ° C. At the end of the reaction (disappearance of the characteristic color of sulfenchloride), the solvent is evaporated in vacuo. The product is recrystallized from a mixture of ether and petroleum, th ether, t „pl, 11-11. Yield 50%, 3 Found: C 49.52; H 5.41; N 3.70 „C | 5H qCl2NO, R, Calculated: С 49.60 - Н 5.25; N 3.85, Carboxyl derivatives of mustard gas in an experiment on rats show a distinct antitumor activity ™. The results of studies of biological activity are given in Ta11. The characteristics of similar and semi-bonded compounds are listed in Table 2. As can be seen from the data of Table 1 and Table 2, the inhibition of tumor growth with known compounds reaches only 3–37% proposed by .1–9B, 5%.

53A063

Continued table. 2

he (Cl) (Cg.H p CH (1) CO-L-Va 1-OH

550 300

ClCUjCHCCHj) (SCHjCH CDCOOCjH

10,050

(SCHjCH CDCH CHCCHj COOC Hy

25 15

L 27

43

40

10 6

31 59

24 29

4.2 1.8