Daunomycin analogues, their preparation and use

#This application is related to and incorporates by reference the contents of application Ser. No. 560,105, filed Mar. 19, 1975 in the names of Federico Arcamone, Aurelio Di Marco and Sergio Penco and entitled DAUNOMYCINS, PROCESS FOR THEIR PREPARATION AND USES THEREOF, said application being owned by the unrecorded assignee hereof.

#1. Field of the Invention

#The present invention relates to novel analogues of the known antibiotic daunomycin, processes for their preparation and the use thereof in treating various mammalian tumors.

#The process according to the invention is illustrated by the following preparative example wherein all parts given are by weight unless otherwise indicated.

#1.2 g 4-demethoxydaunomycinone-7-methyl ether (prepared according to the procedure described in C. M. Wong, Canadian Journal of Chemistry, 1971, 49, 2712) were dissolved in 22 ml. of trifluoroacetic acid and left standing overnight at room temperature, after which the solution was evaporated in vacuo to form a residue which was taken up in 50 ml. of acetone to which 10 ml. of 5% aqueous sodium bicarbonate were added. After 30 minutes, the solvent was evaporated off in vacuo, and the resulting residue taken up in chloroform and washed with water. Evaporation of the chloroform left a residue that was chromatographed on silica gel to give 0.475 g. of (+)4-demethoxydaunomycinone, m.p. 152.degree.-155.degree. C. This material produced a single spot at Rf = 0.44 when subjected to thin layer chromatography on silica gel using 80/20 (vol.) chloroform/acetone as eluent.

#0.3 g. of (+)4-demethoxydaunomycinone was dissolved in 75 ml. of anhydrous chloroform, and 0.6 g. of mercuric oxide, 0.15 g. of mercuric bromide and 5 g. of 5 A molecular sieve were added thereto with stirring. After one hour, 0.7 g. of 1-chloro-2,3,6-trideoxy-3-trifluoroacetamido-4-trifluoroacetoxy-.alpha.-L- lyxopyranose was added and the suspension was stirred at room temperature for 16 hours. After filtration, the solution was concentrated in vacuo to form a residue which was then dissolved in 200 ml. of methanol and refluxed for 15 minutes. After evaporation of the methanol, the residue was chromatographed on a silica gel column using, as the elution solvent chloroform:benzene:methanol:100:20:3 (vol.) a first fraction of 0.270 g. of a mixture of the .alpha.-anomers of (-)daunosaminyl(-)4-demethoxydaunomycinone and (-)daunosaminyl (+)4-demethoxydaunomycinone in the form of the N-trifluoroacetyl derivatives (single spot on silica gel plates Rf = 0.34; chloroform:acetone 80:20 (vol.)), and a second fraction of 0.150 g. of a mixture of the .beta.-anomers of (-)daunosaminyl(-)4-demethoxydaunomycinone and (-)daunosaminyl(+)4-demethoxydaunomycinone in the form of the N-trifluoroacetyl derivatives were obtained.