SU1181550A3 - Method of producing 4'-subderivatives of anthracyclineglycosides - Google Patents

Abstract

1. A method for producing 4-iodine derivatives of anthracyclyclic ligands of the general formula where R is a hydrogen atom or a hydroxy group, characterized in that 4. for 3 hours at 0 ° C with aqueous 0.1 N sodium hydroxide solution, after which the resulting free glycoside base is either converted to hydrochloride salt or subjected to 00 interaction with bromine and the resulting 14 bromine is treated with an aqueous solution of formate On Atri for the preparation of 4-4 -deoksi -yodoksorubitsiSP on which is also isolated as the hydrochloride salt.

Description

1 The invention relates to a process for the synthesis of new glycosidic anthracycline antibiotics, specifically 4-iodine derivatives of anthracycline glycides of the general formula O, he has been used, where I R-0 H 1 H-COSR 3 where R is a hydrogen atom or an oxy group with antitumor activity. Anthracycline glycosides, daunorubicin and doxorubicin, exhibiting antitumor activity are known. The purpose of the invention is to obtain new derivatives of glycosidic anthrax antibiotics. The goal is achieved according to the method, which states that 4 -deoxy-4-yod-Nt of fluoroacetyldaunorubicin of the formula O OH / -t bH-CGH3 is subjected to soft alkaline hydrolysis in an acetone medium for 3 hours with aqueous 0.1 N sodium hydroxide solution, after which the resulting free glycoside base is either converted to the hydrochloride salt, or reacted with bromine and the resulting 14-bromo derivative is treated with an aqueous solution of sodium formate to obtain 4-deoxy-4-iodoxorubicin, which also vsch Eat as hydrochloride salt. 50 2 Example 1.4 - Deoxy-4-iododunorubicin (1 R H), (X00 - () t38). Handle a solution of 2.0 g of 4.-iodo-N-trifluoroacetyldaunorubicin in 10 ml of acetone with 80 ml of an aqueous solution of 0.1N. NaOH. After 3 hours at 0 ° C, the pH of the solution is adjusted to 4.5 with O, 1N. aqueous HC1 and extracted with chloroform to remove the aglycones. The pH of the aqueous solution is then adjusted to 8.6 and extracted with chloroform. The combined extracts are dried over anhydrous sodium sulfate, concentrated to a small volume, and acidified to pH 4.5 with 0.1 N. methanol solution of HCl for crystallization of the target product in the form of its hydrochloric acid salt. Output 1.5. square 157 ° C (decomp.), FD-MS: 637 (M). those on plates with diatomaceous earths R254 (Merck) using CHCIj: gMeONGN OGASOP 80: 20: 7: 3 (vol.), Pf 0.72. Pr and m-e p 2.4 -Deoxy-4 -; iodoxorubicin (1; R OH), (XOO0163). A solution of 4-deoxy-4-iodo-nunorubicin in a mixture of methanol and dioxane is treated with bromine according to a known method to form its 14-bromo-derivative, which when treated with an aqueous solution of sodium formate gives 4-deoxy-4-iodoxorubicin, which is isolated as an acid salt. . M.p. 230 ° C (decomp.), FD-MS:: 653 (M); TLC on plates with diatomaceous earth (Merck) using sleep 1J: MeOH: HO: .Ason 80:20: 7: 3, Pf 0.5 . The biological activity of the target compounds XOO-0138 and XOO-0163. Compounds were tested against daunorubicin (DNP) and doxorubicin (DXA) against Hela cells in vitro. In tab. Figure 1 shows the effect on the cloning efficacy of Hela cells (processed for 24 hours). From the above data it follows that XOO-0138 is less cytotoxic than DNP, while XOO-0163 is more cytotoxic than BPS. Antitumor activity was assessed in vivo in mice bearing P338 ascitic eukemia. The results are presented in table 2. Experiments were performed on 31 DF or CDF1 mice inoculated in vivo with 1U leukemia cells. Both new derivatives are active against P38B leukemia. Of particular interest is the result obtained in treating mice with tumors with compound XOO-0163: with an optimal non-toxic dose of 15 mg / kg, XOO-U163 cures more than 50% of the mice (6/10), and at a dose of 10 mg / kg it is cured 3 / 10 mice and there was a significantly greater increase in lifespan compared to control (205%). Consequently, the antitumor activity of XOO-0163 is definitely higher than that of DXS, which, when optimized for a 10.0 mg / kg optimal dose of 10 mg / kg, only bites tumors suffering from tumors by chance. Compound XOO-138 was also tested against Gross leukemia (treated on day 1 after tumor inoculation). In tab. Figure 3 presents data on the effects of Gross leukemia, which show that, at the optimal non-toxic dose of 11.8 mg / kg, XOO-0138 exhibits a higher antitumor activity than DNR, and is approximately the same as that of DXS (mouse SEH are injected in vivo 2-10 leukemia cells).

Compound

Daunorubicin

HOO-0138

4 -Deoxy-4-Iodo-daunorubicin

Doxorubicin

HOO-0163

4-Deoxy-4-iodooxorubicin

Dose, (ng / il)%

U

ng / ml

2.57

6.2553

3.1110

15

100O

255

6.2109

25O

12,516

6,270

5.5

25O

6,216

1,591

0.39104

 2.9160 165

Ying

4.4160 185

6.6175, 135

4.4140

6.6155

10185, 75 15

22.5 60

4.4210

in

6.6260

10265

6.6240

10305

15620

22.5: 390.

In vivo treatment on day 1 after tumor inoculation.

Average survival time of treated mice / mean survival time of controls X 100. Evaluation based on the dissect data.

table 2

0/10

0/10, 0/10 0/10 1/10, 0/10 0/10 7/10, 7/10 0/10 0/10

0/10

0/10, 6/10 8/10

10/10

0/10

0/10

0/10

0/10

0/10

0/10

1/10

Table 3

ten

13

16.9

22

11.8

15.4

norubi20 30

40

In vivo treatment on day 1 after tumor inoculation.

1181550

eight

Continued table. 3

0/10

0/10 0/10 0/10 0/10 0/10 1/10 0/10 0/10 0/10

2/10

0/10

4/8, 6/10

0/8, 0/10

77 8/8 0/8

8/8

0/8.

Claims (1)

1 . METHOD FOR PRODUCING 4'-IODINE DERIVATIVES OF ANTHRACYCLINGGLYCOSIDES of the general formula where R is a hydrogen atom or an oxy group, characterized in that 4 ^1. -Deoxy-4 ^1- iodo-Y-trifluoroacetyldaunorubicin of the formula is subjected to mild alkaline hydrolysis in acetone for 3 hours at 0 ° C using 0.1 N aqueous. sodium hydroxide solution, after which the obtained free glycosidic base is either converted into a hydrochloride salt or reacted with bromine and the resulting 14-bromo derivative is treated with an aqueous solution of sodium formate to obtain 4 ¹ -deox. and-4 ¹ -iodoxorubicin, which is also isolated as hydrochloride salt.