SU1007338A1 - Derivatives of 2-( -chloroethylthio)-3-chloro-3-( - -choloroethylthio-4-chloro-4-methylcyclohexyl)-propanic acid displaying antitumoral activity - Google Patents

Abstract

Derivatives of 2-p-chloroethylthio) 3-HLOR-3-

Description

This invention relates to a method.

obtaining new derivatives of 2- (| 3 chloroethylthio) -3 chloro-3- (3 - | -chloroethylthio-chloro-methylcyclohexyl) -propanoic acid of formula I

ClCH2CHiS-r CHCl-CH | CH CHiCl) -COX.

. sns-yi -.

 C1. where X is OH, NHCgI5, or OCHN3, which have antitumor activity and can be used in medicine.

Known compounds from the class of sulfides, which are the closest structural analogs of the compounds of formula I, for example, alkylthiochloropropic acid derivatives of the general formula R RiCCl-CH (SCHgCHjrCl) -COX, where R, is H, 0%; 2 - CH ,, CgHyj X - OH,, NHCfiH COOCiHs-, have insufficiently high antitumor activity (inhibition of tumor growth 3-57%).

The aim of the invention is to expand the arsenal of anticancer

means.

Compounds of formula I are prepared

O9 O9 00 by reaction of the corresponding 3-C-methylcychexene-3-yl) -acrylic acid derivative with -chloroethyl with ulphene chloride in dichloromethane at room temperature. The yield of the target products is 97.2%,

PRI me R 1. 0.01 mol - (k methylcyclohexene-3-yl) acrylic acid, obtained by condensation of malonic acid with α-methylcyclohexene-3-aldehyde, is dissolved in kQ ml of dichloromethane and added dropwise at room temperature 0.02 mol of chloroethylsulfene chloride in 10 ml of chlorochloride. The reaction mixture is left for 1 h at room temperature. After completion of the reaction (disappearance of the characteristic color of sulfene chloride), the solvent is evaporated in vacuo at room temperature. 4.16 g (97%.) Of 2- (ethylthio) -3-chloro-3 (3-p-chloroethylthio-chloro-methylcyclohexyl) -propanoic acid is obtained. Found ,,: C 39.40; H 5.30. Z Calculated,%: C 39.27; H 5.18 "PRI me R.,., Anilide 2- (B-chloro ethylthio) -3 chloro-3 (C - 3 chloroethylthio-chloro-4-methylcyclohexyl) -propanoic acid is obtained from .anilide 3 ( h-me or il-cloxene-3-yl-acrylic acid as in Example 1 as an oil, which, when dried, becomes a powder. Yield 7.2 g (93.5%) o Found D. C A7.61; H 5.16; S 12, A3; C1 27.50. C.-tf-iH Cl mS. Calculated: C 47.72; H 5.40; S 12.75; C1 28.17 „PMR spectrum, ppm , 53 (СНС1) 5.73 (CH.j), chemical shifts of CHS protons are overlapped by chemical shifts of chloroethylthio groups. PRI me R 3 o Methyl ester 2- (A chloro-ethylthio) -3-chloropty-3 (3/3 chlorostilthio - -chloro-methylcyclohexyl) -propanoic acid is obtained from 3 ((-methylcyclohexen-3 -yl) -acrylic acid, analogously to the example in the form of oil. Yield 5, f g (9b, 6). Found: C 43 , 06; H 5.21; S 15.55; C1 32.49., Calculated D: C, 40.74; H 5.47; S 14.50; C1 32.06. PMR spectrum, m-.d. : 1.13 (CHCl3), 3.77 (OCH) 1.75 (SIZ), chemically shifts of protons CHS overlap with chemical shifts of protons chpor ethylthio groups Offered productions chloroethylthiolchloropropanoic acid, specifically 2 - ((L-chloroethylthio) -3-chloro-3- (3 | P) -chloroethylthio-chloro-methylcyclohexyl) propanoic acid, its anilyl and methyl ether, in the experiment on rats show antitumor activity. The toxicity of the compounds was determined in experiments on intact outbred female rats weighing 100-120 g. The compounds are insoluble in water and administered intraperitoneally suspended in vegetable oil. The antitumor activity of the new compounds was determined in rats with a vaccinated Walker carcinosarcoma, sarcoma 5, M-1 sarcoma, Pliss lymphosarcoma, and PC-1 alveolar cancer of the liver. A total of BOO rat was used. In order to vaccinate a tumor, each rat was injected at 0.5 cm 3 of a 20% suspension of tumor cells in a physiological solution. Treatment was started days after vaccination and continued daily / for 10 days. The effect of the drug was judged by the weight of the tumor at the end of the experiment. The results of biological tests are shown in the table. Experimental data show that the acid of formula I has a higher toxicity when administered in single doses, as well as its lower anilide. With respect to Walker's carcinosarcoma, all compounds of formula I exhibit almost the same activity (inhibition of tumor growth 97.9, E%, 001) o In relation to sarcoma 5, the acid of formula I was more active. On the PC-1 grafted it was equally active anilide and methyl ester and the acid itself are less active; they are formulas I. All compounds reliably reduce the number of leukocytes. Thus, the novel compounds have high antitumor activity and can be used to treat experimental tumors.

.Note. MTD - maximum tolerated dose.

Claims (5)

The invention relates to a method for producing new derivatives 2-q 3 * chloroethylthio) -3 ^_ chloro-3 (3-β-chloroethylthio- ¹ / -chloro-4 * methylcyclohexyl) propanoic acid of the formula I ClCH ₂ CHiS- <VCHCl-CH (8CH ₂ CH _g C1) -COX. CHjJxJ 'Cl. where X is OH, NHCglIg or 0CH ₃ , which have antitumor activity and can be found using in medicine. Known compounds from the sulfide class, which are the closest structural analogues of compounds of the formula I, for example, derivatives of alkylthiochloropropanoic acid of the general formula R ^ RgCCl-CHiSCH ^ on ^ Cl) -COX, where R ^ - H, GHC; R ^ ~ CH ₉ , C ^ Well) X is OH, 0C ₂ H ₅ , NHCeH4.COOC2.H5 ·, region I. give insufficiently high antitumor activity (inhibition of tumor growth 357%) · The aim of the invention is to expand the arsenal of antitumor agents. Compounds of formula I are prepared by reacting the corresponding derivative of 3 “(4 ^f- methylcyclohexene 3 ^/ -yl) -acrylic acid with β-chloro-tsulfonyl chloride in dichloromethane at room temperature. The yield of target products 93.5 - 97.2%. Example 1. 0.01 mol 3 “(4 ^; methylcyclohexene-Z ¹ -yl) acrylic> acids obtained by condensation of malonic acid with 4-methylcyclohexene-3'-aldehyde are dissolved in 40 ml of dichloromethane and 0.02 mol of {5-chloroethylsulfene SU, 1007338 chloride in 10 ml of dichloromethane are added dropwise at room temperature. The reaction mixture is left for 16 hours at room temperature. ”At the end of the reaction (the characteristic color of sulfene chloride disappears), the solvent is evaporated in vacuo at room temperature. 4.16 g (97.2%) of 2 - (^ - chloroethylthio) -3-chloro-3 ”(3’-p-chloroethylthio- 4-Chloro-4'-methylcyclohexyl) propanoic acid. Found,%: C 39.40; H, 5.30. C ή CI4 0 ₂ S 2 » Calculated,%: C 39.27; And 5.18 " PRI me R. 2 ... 2- (β-Chloroethylthio) -3-chloro-3 ^- (3 ^g -β-chloroethylthio) 4'-chloro-4'-methylcyclohexyl) -propanoic acid anilide is obtained from 3 ~ (4 -me ~) anilide ilcyclohexen-3'-yl) -acrylic acid analogously to example 1 in the form of oil, which when dried turns into a powder. Exit 7.2 g (93.5%) " Found,%: C 47.61; H 5.16; 5 12.43; C1 27.50. C.? PH27C] NOS, Calculated,%: C 47.72; H 5.40; S 12.75; C1 28.17 " PMR spectrum, ppm 4.53 (СНС1) 1.73 (С1Ц), chemical shifts of CHS protons are overlapped by chemical shifts of protons of chloroethylthio groups.