Carminomycin derivatives, their preparation and use

N-acyl derivatives of the known antitumor antibiotic carminomycin, particularly N-trifluoroacetyl carminomycin, have a much lower toxicity than carminomycin.

BACKGROUND OF THE INVENTION 
1. Field of the Invention 
The invention relates to antitumor anthracycline antibiotics and more 
particularly, to N-acyl derivatives of the known antitumor antibiotic 
carminomycin. 
2. The Prior Art 
It is well known that carminomycin is a natural anthracycline antibiotic 
which displays antitumor activity in humans and animals (G. F. Gause, M. 
G. Brazhnikova and V. A. Shorin, Cancer Chemother. Rep., Part 1, 58, 255 
(1974)). Unfortunately, the therapeutic usefulness of carminomycin is 
severely restricted because of its high toxicity. Moreover, carminomycin 
can be obtained in only limited amounts from natural sources and no 
practical syntheses for carminomycin are known; although a total synthesis 
of the aglycone has been reported in the literature (Kende et al, J. Am. 
Chem. Soc. 98, 1967 (1976)). 
SUMMARY OF THE INVENTION 
The present invention relates to carminomycin derivatives and to a 
synthetic process for the manufacture of carminomycin and its derivatives 
which are provided by the invention. 
The present invention provides, in one aspect thereof, N-acyl derivatives 
of carminomycin of the formula I: 
##STR1## 
wherein R is an acyl group selected from the group consisting of acetyl, 
mono, di and trichloroacetyl, trifluoroacetyl, benzoyl and substituted 
benzoyl. Presently, the most preferred such compound is the 
trifluoroacetyl derivative. 
According to the invention, the compounds of formula I [wherein R, in 
addition to being as defined above, may also be hydrogen--in which case, 
the compound is the known antibiotic carminomycin], are prepared from 
daunomycinone (II), according to scheme I (below), with particular 
emphasis on the new N-acyl derivatives of carminomycin. As shown in scheme 
I, daunomycinone (II) is demethylated with a Lewis acid such as aluminum 
trichloride, or tribromide, to form the aglycone of carminomycin (III). 
The latter is then condensed with a 
2,3,6-trideoxy-3-acylamido-4-O-acyl-.alpha.-L-lyxopyranosyl chloride to 
yield compound (IV), wherein the acyl groups are R, as defined above. 
A mild hydrolysis of (IV) in methanol containing triethylamine leads to the 
N-acyl derivatives of carminomycin (I; R=the acyl groups as specified 
above, preferably, trifluoroacetyl). When R is trifluoroacetyl, the 
compound (I) in turn can be transformed into carminomycin itself (I; R=H) 
by treatment with an aqueous alkaline base. 
##STR2## 
In yet another aspect, the invention provides a method of treating certain 
mammalian tumors using the new N-acyl derivatives of carminomycin. These 
new N-acyl derivatives of carminomycin are endowed with antitumor activity 
in mammals and are much less toxic than the parent compound, carminomycin. 
In particular, N-trifluoroacetylcarminomycin, because of its very low 
toxicity, can be administered at very high doses which results in a more 
effective antitumor activity than carminomycin itself.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
The following examples are given to more clearly describe the invention. 
Unless otherwise specified, all parts given are by weight. 
EXAMPLE 1 
4-Demethoxy-4-hydroxydaunomycinone (III) 
To a refluxed solution of 10 g. of daunomycinone (II) in 1 liter of 
dichloromethane, 30 g. of aluminum trichloride were added over a two hour 
period with stirring. After an additional 4 hour period, the reaction 
mixture was cooled and poured into ice water containing 150 g. of oxalic 
acid. The organic layer was separated, washed with water and concentrated 
in vacuo to yield 6 g. of crystalline 4-demethoxy-4-hydroxy-daunomycinone 
(III), which were collected by filtration. 
EXAMPLE 2 
N-trifluoroacetylcarminomycin (I; R=CF.sub.3 CO--) 
To a solution of 1 g. of 4-demethoxy-4-hydroxydaunomycinone (III) and 0.850 
g. of 
2,3,6-trideoxy-3-trifluoroacetamido-4-O-trifluoroacetyl-.alpha.-L-lyxopyra 
nosyl chloride in a 1:1 mixture of dimethyl formamide and dichloromethane, 
a solution of 0.570 g. of silver trifluoromethanesulfonate in 15 ml. of 
anhydrous diethyl ether was added dropwise at room temperature. After 1 
hour of stirring, the reaction mixture was diluted with dichloromethane, 
washed with an aqueous solution of NaHCO.sub.3 and finally with water. The 
solvent was removed in vacuo and the residue taken up in chloroform. The 
insoluble starting material was removed by filtration, and the filtrate 
was evaporated to a residue which was then dissolved in methanol 
containing a trace of triethylamine. The resulting solution was left to 
stand for 2 hours at room temperature. Removal of the solvent in vacuo and 
purification of the residue by column chromatography (silica gel; 
chloroform/acetone 95:5, v/v) afforded 0.370 g. of N-trifluoroacetyl 
carminomycin I; R=CF.sub.3 CO--). 
EXAMPLE 3 
Carminomycin hydrochloride (I; R=H) 
0.5 grams of N-trifluoroacetyl carminomycin (I; R=CF.sub.3 CO--) was 
dissolved in 0.15 N NaOH and left standing for 2 hours at room 
temperature. After acidification with oxalic acid and neutralization with 
aqueous NaHCO.sub.3, the free base with extracted with dichloromethane 
which was washed with water. The solvent was removed in vacuo and the 
resulting residue was dissolved in dry dichloromethane and treated with 1 
equivalent of HCl in methanol. The solution was then concentrated in vacuo 
and diethyl ether was added to precipitate 0.300 g. of carminomycin 
hydrochloride (I; R=H), which was found to be identical to an authentic 
sample. 
Biological Activity 
The activity of N-trifluoroacetyl carminomycin (I; R=CF.sub.3 CO--) on 
P.sub.388 lymphocytic leukemia in CDF.sub.1 male mice (tumor inoculum 
10.sup.6 cells i.p.) in comparison with daunorubicin, doxorubicin and 
carminomycin was determined. Treatment i.p. was effected on days 5, 9 and 
13 after inoculation.sup.(a) 
Table 1 
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Dose mg./kg. 
T/C.sup.(b) 
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Daunorubicin 8 126 
4 115 
2 122 
1 117 
0.5 108 
Doxorubicin 8 185 
4 141 
2 126 
1 122 
0.5 106 
N-trifluoroacetyl- 
25 123 
carminomycin 12.5 104 
6.25 106 
3.1 106 
1.56 98 
Carminomycin 25 0 
12.5 91 
6.25 0 
3.13 129 
1.56 130 
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.sup.(a) Data obtained under auspices of National Cancer Institute. 
.sup.(b) Median survival time expressed as percent of untreated controls. 
The results of another series of experiments, under the same conditions as 
in Table 1, are reported in Table 2. 
Table 2 
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Dose mg./kg. 
T/C.sup.(b) 
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Daunorubicin 32 96 
16 123 
8 132 
4 126 
2 123 
Doxorubicin 16 92 
8 191 
4 189 
2 145 
1 110 
N-trifluoroacetyl- 
200 215 
carminomycin 100 118 
50 145 
25 118 
12.5 96 
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Variations and modifications can, of course, be made without departing from 
the spirit and scope of the invention.