FI89496C - FREQUENCY FARING FOR 4-DEMETOXY-4-AMINOANTRACYKLINER - Google Patents

Description

89496

This invention relates to a process for the preparation of pharmacologically effective anthracycline glycosides, and pharmaceutically acceptable acid addition salts thereof.

The invention relates to a process for the preparation of anthracycline glycosides of the general formula (I). OH nh2 where R | means a hydrogen atom, or pharmaceutically acceptable addition salts thereof. Preferred salts are the hydrochloride salts.

- Glycosides of the formula (I), i.e. 4-Demethoxy-4-amino-daunorubicins, and pharmaceutically acceptable addition salts thereof, are prepared by a process wherein: 4-demethoxy-4-N-trifluoroacetamido-daunomycinone of formula (II) is an oil. )

Cf 3 COO 0 Oil 0 '| (reacted with 1-halo-N, O-ditrifluoroacetyl-daunoamine of formula (III)

Ha) Γ n ,, C0CF3 (III)

Ococf3 wherein Hal represents a halogen atom, preferably chlorine, and the product thus obtained is deprotected to give an anthracycline glycoside of formula (I) wherein R1 is hydrogen, and said Glycoside of formula (I) is converted, if desired, into a pharmaceutically acceptable salt thereof.

The condensation of 4-demethoxy-4-N-trifluoroacetamido-daunomycinone (II) and the protected halogen sugar (III) can be performed in the presence of silver triflate. The method described in US-A-4107423 can be used to give (7S, 9S) -O-trifluoroacetyl-protected derivatives of α-glycosides. 4-Demethoxy-4-N-trifluoroacetamido-daunomycinone can be dissolved in anhydrous methylene chloride by the reaction at 5-10 ° C. The N-trifluoroacetyl protecting groups can be removed by mild alkali treatment.

Preferably, the anthracycline glycoside of formula (I), li 3 89496 wherein R 1 is hydrogen, is isolated as its hydrochloride.

The preparation of a daunomycinone derivative of formula (II) and protected derivatives thereof in which the 4-arino group is protected is described in Patent Application No. 881792, from which this application is partitioned.

The invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or diluent and an anthracycline glycoside of formula (I) or a pharmaceutically acceptable salt thereof prepared as described above.

Conventional formulations, carriers and diluents may be used. Compositions for administration to a patient contain a therapeutically effective amount of a Gly coside. Thus, a therapeutically effective amount of a glycoside can be administered to a human in a conventional manner.

Glycosides are anti-tumor agents. The compound of formula (I), i. 4-demethoxy-4-amino-daunorubicin activity is tested by comparing its in vitro cytotoxicity of daunorubicin (DNR) against the human colon rauhassyöpäsoluissa that are sensitive (LoVo) or resistant (LoVo / DX) of daunorubicin-bicine. The results are shown in Table 1: 4 89496 TABLE 1: Colon inhibition test A hour after treatment.

Compound LoVo LoVo / DX

I050 (μg / ml) ID50 (μg / ml) I 0.7 99 ONR 50.3 1805

The U \ vivo activity of compounds (I) and DNR against diffuse Gross-1 leukemia was also determined. The results are; shown in Table 2.

l · 5 89496 TABLE 2: Processing i.v. + 1h

Compound mg / kg T / C% TOX

DNR 10 133 0/10 15 167 0/10 22.5 200 1/10 I 1.6 183 0/10 1.9 192 0/10 2.29 200 1/10 Mean of the treated mice. lifetime 'T / C% = - x 100. ·, Mean of controls. lifetime • ’· TOX = poisoning deaths f> 89496

The following example illustrates the invention.

EXAMPLE 1 4-Demethoxy-4-amino-daunorubicin (I) 0.08 g of 4-demethoxy-4-N-trifluoroacetamido-daunomycinone prepared as described in Example 6 of application 881792 was dissolved in anhydrous roethylene chloride and the solution was frozen at 5-10 °. C. A solution of 0.024 g of 1-chloro-N, O-ditrifluoroacetyl-daunosamine was prepared according to the method described in Cancer Chemotherapy Reports, Part 3, Vol. 6, No. 2, p.

123, in diethyl ether, and a solution of 0.150 g of silver trifluoromethanesulfonate in methylene dichloride was added simultaneously and rapidly with stirring. After 5 minutes, 0.070 g of silver trifluoromethanesulfonate was added and after 5 minutes the reaction was quenched with collidine. The mixture was filtered, washed with saturated aqueous sodium hydrogen carbonate solution and water, dried and concentrated in vacuo.

The residue was chromatographed on a silica gel column eluting with methylene chloride to give 4-demethoxy-4-N-trifluoroacetamido-N-trifluoroacetyl-daunorubicin (I). 1 HNMR (200 MHz, CDCl 3): 13.76 (s, 1H, 6-OH); 13.41 (s, 1H, 11-OH); 7.69 (dd, J = 1.2, 7.5 Hz, 1H, 1-H); 7.49 (dd, J = 7.5, 8.3 Hz, 1H, 2-H); 6.97 (dd, J = 1.2, 8.3 Hz, 1H, 3-H); 6.80 (broad signal, 2H, NH 2); 6.64 (d, J = 8.9 Hz, 1H, NHCOCF 3); 5.50 (d, J = 3.9 Hz, 1H, 1'-H)? 5.26 (dd, J = 1.8, 3.7 Hz, 1H, 7H); 4.3-4.2 (m, 3H, 9-OH, 5'-H, 3'-H); 3.65 (m, 4'H); 3.26 (dd, J = 1.5, 19.0 Hz, 1H, 10-Heq); 2.95 (d, J = 19.0 Hz, 1H, 10-Hax); 2.41 (s, 3H, COCH}); 2.30 (ddd, J = 1.5, 1.8, 15.6 Hz, 1H, 8Heq); 2.16 (dd, J = 3.7, 15.6 Hz, 1H, 8-Hax); 2.0-1.6 (m, 2H, 2'-CH 2); 1.30 (d, J = 6.6 Hz, 3H, 5'-CH 3).

I: 7 89496

The compound was dissolved in 10 ml of assetone and treated with 30 ml of 0.1 N aqueous sodium hydroxide at 0 ° C for 3 hours. 0.1 N aqueous hydrochloric acid was then added to the solution to adjust the pH to 4.5, and the aglycone was removed by extraction with methylene chloride.

The aqueous solution was then adjusted to pH 8.6 and extracted with methylene chloride, dried over anhydrous sodium sulfate, concentrated to a small volume and acidified to pH 4.5 with 0.1 N methanolic hydrochloric acid to give the title compound as its hydrochloride.

TLC on silica gel plate F254 (Merck) eluting with methylene chloride / methanol / acetic acid / water (80/20/7/3, vol.) Rf = 0.63; FD-MS / m / z 512 [M < + >].

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Claims (3)

0 OH 0 NH 0 OH 1 2 0 OH NH 2 (I) wherein R 1 represents a hydrogen atom, or a pharmaceutically acceptable acid addition salt thereof, characterized in that 4-demethoxy-4-N-trifluoroacetamido-daunomycinone of formula (II) OH (n) is reacted with 1-halo-N, O-ditrifluoroacetyl-daunosamine of formula (III) 9 69496 Hal CM3y ^ \ 0 ^ I ^ HCOCF ^^ OCOCF3 (III) wherein Hal is halogen, preferably chlorine, and the product thus obtained is deprotected to produce an anthracycline glycoside of formula (I), and the resulting glycoside of formula (I) is converted, if desired, into a pharmaceutically acceptable salt thereof. formeln (I) 0 OH 0 N, i2 0 OH ^ (I) OH nh2 där R, betyder en väteatom, eller för framställning av dess pharmaceutic godtagbara syrra-additionssalt, kän n -netecknat därav, att. daunomycinone with formula (il) o is q (H) CFjCONH o OH 0'H in the form of 1-halo-N, O-ditrifluoroacetyl-daunoamine with formula (III) Hai (III) 0COCF3 to which halogen, halogenated chlorine, och from I. I. 89496 is a product of a compound group for the preparation of anthracyclic glycosides of formula (I), and of the glycosides of formula (I), which are self-contained, for use in the manufacture of pharmaceutical products.