JPS58189196A - 4-demethoxy-13-dihydrodaunorubicin and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an anthracycline glycoside thread antitumor antibiotic, a method for producing the same, and a pharmaceutical composition containing the same.

The present invention provides 4-demethoxy-13-dihydrodaunorubicin having the formula and pharmaceutically acceptable pictorial addition salts thereof.

Compounds according to the invention are described in U.S. Pat. No. 4,046,878.
It can be prepared by reduction of the y functional group of 4-demethoxydaunorubicin, which is a compound described in the specification *. 4 due to excess sodium plow hydride
Treatment of -demethoxydaunorubicin/ gives 4-demethoxy-16-dihydrodaunorubicin in high yield. Sodium chloride can be added to an aqueous solution of 4-demethoxydaunorubicin at a temperature of pH 10. Reduction is very rapid. After removal of excess reducing agent, the crude product extracted from the aqueous phase with an organic extract is prepared by chromatographic treatment and preferably one of its salts. It can be isolated as Riege sulfate.

This method is within the scope of this invention.

Additionally, the present invention provides a pharmaceutical composition comprising 4-demethoxy-16-cyhydrodaunorubicin or a pharmaceutically acceptable salt thereof together with a diluent or carrier.

The invention is illustrated by the following examples.

Example 4 - Preparation of demethoxy-16-dihydrodaunorubicin 0.87 ml of 4-demethoxydaunorubicin in 250 ml of water
The pH of the 5f solution was adjusted with a 0.1N aqueous solution of sodium hydroxide.
Adjust to 10 and then add 0.09S' of sodium hydride.
Process with. After 8-10 minutes, the solution was stirred and the temperature was reduced to 0.
Distill into 250 mg of 2N aqueous hydrochloric acid.

Then, the solution heated to pH 8.5 is repeatedly extracted with ethyl acetate. The combined extracts are evaporated to dryness under vacuum.

Methylene dichloride/methanol/water (volume ratio 100:20:2) using the residue dissolved in methylene nitride as eluent
prepared by chromatography on a column of silica gel using The 7-lactone containing the title compound is collected and evaporated to a small volume.

A precipitate is obtained by adding a stoichiometric amount of 0.1N methanolic chloride and excess diethyl ether to the solution. The product is collected, quenched with ether and dried under vacuum. The title compound [15V is preferred. Melting point 159-1
60° (decomposition). FD-M8: m/z (M”). Kiesel gel plate (Msrck ■ F254) Soil TLC'
Common thread (chloroform/methanol/vinegar removal/water (volume ratio 8:2:0.7:α3)): Rf O, 26
゜The biological oiliness of the compound of the present invention is as follows.

[Oil-based in sample recording tube]

Cytotoxicity (Colony inhibition test 1 for \shi cells) vh
``J jLed, Chem, J IMl 8 Thread 7
[Performed on Hesi cells by the method described in J3 Sada (1975). Exponentially growing cells (2 days after polarization) were treated with taunorhiscine, 4-demethoxydaunorubicin, and 4-demethoxy-15-dihydrotaunorhisine. . After 24 hours of exposure to the drug, they are fk, +t+, trypsinized and plated (200 cells/plate). On day 6, count 50 and subtract the colonies containing the above cells. The dosage to produce 50 fetuses is calculated based on the dosage-response curve. The data are shown in Table 1.

Table 1 Daunorubicin 25 612.5
52 116.292 12.5 10 6.2 37 5.55.1
73 15 126 3.1 45 t56 10(1 [In vivo viscosity] Activity against ascites white suppression disease P388 Experiments were carried out in CDI-1 mice in which 106 leukemia cells per mouse were intraperitoneally implanted. Treatment was performed intralimbally on day 1.

Daunorubicin 4.4 180
0/106.6 168 2/1
00.75 155 3/10 Hisin α22 160 0/10 [J, 33
170 0/10o,s
Activity against 170 3/10 Cross Shirobai Disease Experiments were carried out in C3H mice that were intravenously inoculated with 2×10' leukemia cells per mouse.

Treatment was performed intravenously on day 1.

Daunorubicin 10 150
0/1015 183 0/102
2.5 255 0/102.5
255 0/105.5 266
0/10t26 250 0/10
t9 258 0/10 Activity experiment for advanced mammalian mice 2X10 1! The experiment was performed on CBH mice inoculated with Rin cells.

VS Exhibition 6476 1.2 2029 42 [1,833743 1,2120165 (Note) (a) When Gu Yan was very clear, Tadaba was used and treated once a week for four times.

2 Growth Patent Applicant: Firmitalia Calguchi Elba Societa Bel Azzio

Claims (1)

Claims: An anthracycline glycoside having the following: and a pharmaceutically acceptable acid addition salt thereof. 2) A known solution of 4-demethoxydaunorubicin in a water bath solution and at room temperature with excess sodium monohydrate from 8 to 1
0 min, the alkaline reaction mixture was poured into α2N aqueous hydrochloric acid to adjust the p)l to 8.5, and the reduction product was extracted with an organic solvent (and then extracted with methylene dichloride/dichloride as eluent). Methanol/water (volume 1 ratio 100:20:2)
F as the free base by chromatography on a silica gel column using a mixture of
A patented process for producing icrin glycosides, characterized in that the desired product is finally isolated as a salt by treatment with the chemical fjkh negative of 01N methanol 8Z hydrogen chloride. 6) The range m of the ribs that are combined with the 6-note carrier
1 '554 A pharmaceutical composition comprising an anthracycline glycoside. 4) P! P688 leukemia, cross leukemia and mammalian cancer comprising administering to a host affected by +88 leukemia, cross leukemia and mammalian cancer a therapeutically effective one of the anthracycline glycosides according to claim 1. How to prevent the growth of lumps in mammals.