FI70414C - FOERFARANDE FOER FRAMSTAELLNING AV NYA 4'-IODDERIVATER AV ANTRACYKLINGLYKOSIDER - Google Patents

Description

7041 4

METHOD FOR THE PREPARATION OF NEW ANTHRACYCLINE GLYCGBIIDI EN 4'-IODINE BODY ANIMALS - FÖRFARANDE FÖR FRAMSTÄLLNING AV NYA 4 'IODODERIVATER AV ANTRACYKLINGLYKOSIDER

The present invention relates to an analogous process for the preparation of an anthracycline and cicoside compound of general formula I for use as a medicament.

Λ O

O OH [I

1 o f f oT

X .V. . .-k X J (I) T Ύ r r

OCH ^ O OH f J O

CH3-7 - o - / · l-r-y I NH2 wherein R is hydrogen or hydroxy-

Both novel glycosides 11a, namely 4'-deoxy-4'-iodidororubicin 11a and 41-deoxy-4'-iodidoxorubicin 11a, have been found to have excellent tumor growth inhibitory activity.

The starting material for the preparation of the compounds is 4 1 -deoxy-4'-iodo-N-1-trifluoroacetyldaunorubicin of the formula II, an intermediate compound described in European Patent Publication No. 81107618.1 (24.9.81).

O OH II

^ ^ ** 0H (II) OCH3 O OH ^

CH3 i-- ° W

| NH-COCF3 2 70414

According to the invention, said compound of formula (II) is subjected to mild alkaline hydrolysis dissolved in acetone. treating it for 3 hours at 0 ° C with 0.1 N aqueous sodium hydroxide to give the free glycoside base (I; R = CH 2), which is finally isolated as the hydrochloride and, if desired, reacted with bromine to give the corresponding 14-bromo derivative, which upon treatment with aqueous sodium formate is converted to 4'-deoxy-4'-iododoxorubicin (I; R = OH), which is also isolated as the hydrochloride.

The novel anthracycline glycosides 11a prepared according to the present invention have a tumor growth inhibitory effect. In particular, 4'-deoxy-4'-iodidoxorubicin11a (I; R = OH) has considerable activity in tumor experiments in mice.

The compounds of the invention may be used in pharmaceutical compositions comprising a therapeutically effective amount of an anthracycline glycoside of formula I and a pharmaceutically acceptable diluent or carrier. Furthermore, the compounds of the invention can be used to treat certain tumors in mammals by administering therapeutically effective amounts of said compounds to those suffering from the tumor.

Next, the invention will be further illustrated by the preparation examples and the biological test results.

Example 1 4'-Deoxy-4'-iodideunorubicin (I; R = H) (X00-0138)

To a solution of 2.0 g of 4'-iodo-N-trifluoroacetyldunoirubicin in 10 ml of acetone was added 80 ml of 0.1 N aqueous sodium hydroxide solution. After incubation for 3 hours at 0 ° C, the pH of the solution was adjusted to 4.5 with 0.1 N aqueous hydrogen chloride and then extracted with chloroform to eliminate aglycones.

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The pH of the aqueous solution was then adjusted to 8.6 and extracted with chloroform.

When the combined extracts were dried over anhydrous sodium sulfate, concentrated to a small volume, acidified (pH 4.5) with 0.1 N methanolic chloroform and allowed to crystallize to give the title compound as the hydrochloride. Yield 1.5 g, m.p. 157 ° C (dec.); FD-MS: 637 (M < + >).

Thin layer chromatographic analysis on silica gel plate (254 (Merck)) using CHCl 3 MeOH 2 O: AcOH (80: 20: 7: 3 t i 1 a v / 1 i 1 a v), δ = 0.72.

Example 2 4'-Deoxy-41-iodidoxorubicin (I; R = OH) (X00-0163)

To a solution of 4'-deoxy-4'-iododununububicin in a mixture of methanol and dioxane according to the method described in U.S. Patent No. 3,803,124, bromine was added to form a 14-bromo derivative which was treated with aqueous sodium formate to give 4'-Deoxy-4'-iodidoxorubicin, which was separated as the hydrochloride. mp. 2300 ° C (dec.); FD-MS: 653 (M < + >).

Thin layer chromatographic analysis on silica gel plates ^ 254 (Merck) using CHCl 3, MeOH / H 2 O / AcOH (80: 20: 7: 3 v / v) R f = 0.5.

Biological activity of X00-O138 and X00-0163

The compounds have been tested for HeLa cells in vitro by comparing daunorubicin in (DNR) and doxorubicin (DX). The results shown in Table 1 show that X00-0163 was more cytotoxic than DX. The tumor growth inhibitory effect was observed in vivo in mice with P388 ascites leukemia. The results obtained are shown in Table 2. Both new derivatives are active against P388-1 leukemia.

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Of particular interest is the result obtained by treating tumor mice with X00-0L63. The optimal, non-toxic dose of 15 mg / kg of X00-0163 improved more than 50% of the mice (6/10) and 10 mg / kg improved 3/10 of the mice and significantly increased survival compared to controls (205%). Thus, the tumor growth inhibitory effect of X00-0163 is significantly better than that of DX, which, at an optimal, non-toxic dose of 10 mg / kg, improves tumor mice only occasionally.

Compound X00-138 was also tested for Gross-1 eukemia (treatment one day after tumor inoculation).

The results shown in Table 3 show that the optimal, non-toxic dose of 11.8 mg / kg of X00-0138 is superior to DNR and similar to DX in its tumor growth inhibitory effect.

Table 1. Effect of clonauturnis on HeLa cells

Compound Dose% ID_ 5o (ng / ml) (ng / ml)

Daunorubicin .12.5 7 7 6.25 53 3.1 110 XOO-0138 100 0 15 4'-deoxy-41-iododununubicin 25 5 6.2 109

Doxorubicin 25 08 12.5 16 6.2 70 X00-0163 25 0 5.5 4'-deoxy-4'-iodidoxo-6.2 16 rubicin 1.5 91 0.39 104 a Processing time 24 hours 5 7041 4

Table 2. Effect P 3 88 against ascites leukemia a compound Dose * 3 T / Cc LTSd Toxicity e (mgA-g)% dead

Daunorubicin 2.9 160, 165 0 / 10.0 / 10 0 / 10.0 / 10 4.4 160, 185 0 / 10.0 / 10 1 / 10.0 / 10 6.6 175, 135 0 / 10.0. / 10 7 / 10.7 / 10 X0 0-0138 4.4 140 0/10 0/10 6.6 155 1/10 0/10 10 185, 75 0 / 10.0 / 10 0 / 10.6 / 10 15 70 0/10 8/10 22.5 60 0/10 10/10

Doxorubicin 4.4 210 0/10 0/10 6.6 260 0/10 0/10 10 265 1/10 0/10 X00-0163 6.6 240 0/10 0/10 10 305 3/10 0/10 15> 620 6/10 0/10 22.5 390 3/10 1/10 a The experiments were performed on BDF1 or CDF 1 mice inoculated with 10 leukemia cells ip k Treatment i.p. days after tumor transplantation

Q

Mean survival time of treated mice / mean survival time of controls x 100 'd Long-term survival (> 60 days) 6

Estimated based on autoptic observations 6,70414

Table 3. Effect against Gross leukemia a

Compound Dose b T / Cc LTSd Toxicity (ragAg)% dead

Daunorubisi ini 15 191 0/8 0/8 22.5 158 0/8. 4/8

Doxorubicin 7.7 150 0/10 0/10 10 175 0/10 0/10 13 200 0/10 0/10 16.9 233 0/10 0/10 22 266 0A0 1/10 X00-0138 11.8 208 0/10 0/10 15.4 208 0/10 2/10 41-iodideunoru- 20 175.117 0 / 8.0 / 10 4 / 8.6 / 10 bisin 30 100 0/8 8/8 40 92 0/8 8/8 a C3H mice were injected iv 2 x 106 leukemia cells b Treatment i.v. one day after tumor inoculation c, d, e cf. Table 2

Claims (2)

7 7041 4 CLAIM Analogous process for the preparation of an anthracycline glycoside compound of general formula I for use as a medicament 0 9H ff il t U / C-CH F 'C'l' 'Of' "'OH I I OCH O OH; 3. U> CH3 ·, - o (· ^ 2 'wherein R is hydrogen or a hydroxy group, characterized in that the 4 * -deoxy-4'-iodo-N-trifluoroacetyldaunorubicin of the formula II is gr? -, C-CH0 OO TY ^ OCH O OH 6 .-- 1 (II) CH3 —.- O '·' "1 ^ NK-COCF3 dissolved in acetone is subjected to a slight alkaline hydrolysis by treatment for 3 hours at 0 ° C with sodium hydroxide 0, 1 N aqueous solution to give the free glycoside base (I; R = H), which is finally isolated as the hydrochloride and, if desired, reacted with bromine to form the corresponding 14-bromo derivative, which upon treatment with aqueous sodium formate is converted to 4'-deoxy-41-iododoxorubicin (1; R = OH), which is also isolated as the hydrochloride.