4-substituted anthracyclinones and anthracycline glycosides and

Details 4-substituted anthracyclinones and anthracycline glycosides and 4-substituted anthracyclinones and anthracycline glycosides and

1991-04-25

1996-12-24

Killos, Paul J.

Organic compounds -- part of the class 532-570 series

Organic compounds

Polycyclo ring system containing anthracene configured ring...

552208, C07H 1524

Patent

active

055874959

DESCRIPTION:

BRIEF SUMMARY
This application is a 35 USC 371 of PCT/EP89/0/266 filed Oct. 24, 1989.
The present invention relates to anthracyclinone intermediates and to anthracycline glycosides obtainable therefrom.
According to the present invention, there are provided 4-substituted anthracyclinones of formula (I): ##STR3## wherein R represents a straight or branched alkyl, alkenyl or alkynyl group of up to 16 carbon atoms, preferably of up to 4 carbon atoms, optionally substituted by (a) an aryl group which is unsubstituted or substituted by an inert group such as alkyl, alkoxy or nitro; (b) an alkoxy group; (c) a trialkylsilyl group; (d) an ester group or (e) an amido group.
The anthracyclinones of formula (I) are intermediates in the preparation of antitumor anthracycline glycosides. Accordingly the present invention further provides anthracycline glycosides having the formula (IX): ##STR4## wherein R is as defined above and R.sub.1 is a hydrogen atom or a hydroxy group; and their pharmaceutically acceptable salts. Preferred acid addition salts are the hydrochloride salts.
The anthracyclinones of formula (I) and anthracycline glycosides of formula (IX) have a carbon-carbon bond at position C-4. In the definition of radical R, an aryl group is preferably phenyl. Alkyl and alkoxy groups are typically C.sub.1 -C.sub.4 alkyl and C.sub.1 -C.sub.4 alkoxy groups respectively. The ester group (d) is typically a (C.sub.1 -C.sub.4 alkoxy) carbonyl group. The amido group (e) is typically carbamoyl. The alkyl, alkenyl or alkynyl group may be substituted at one or more carbon(s) in the chain by a said group (a) to (e).
Preferred groups which R may represent are vinyl (ethenyl), allyl (propenyl, e.g. 2'-propenyl) trimethylsilylethynyl, trimethylsilylvinyl, phenylethynyl or an alkoxycarbonylvinyl group such as 2'-methoxycarbonylvinyl. The substituents are preferably attached to the 2'-carbon atom of the vinyl or ethynyl group and to the 3'-carbon atom of an allyl group.
Preferred compounds of formula (I) are selected from 4-demethoxy-4-ethenyl-daunomycinone, 4-demethoxy-4'-(2'-methoxycarbonyl)-ethenyl-daunomycinone, 4-demethoxy-4-trimethylsilylethynyl-daunomycinone and 4-demethoxy-4-(2'-propenyl)-daunomycinone. Preferred compounds of formula (IX) are 4-demethoxy-4-ethenyl-daunomycin and its hydrochloride.
The compounds of general formula (I) are obtained from 4-sulfonyl anthracyclinones of formula (II): ##STR5## wherein R' represents an alkyl group having from 1 to 10 carbon atoms optionally substituted by one or more halogen atoms or an aryl group optionally substituted by halogen, alkyl, alkoxy or nitro. Preferred groups which R' may represent are trifluoromethyl, 4-fluorophenyl and 4-tolyl. A carbon atom or chain is introduced at position C-4 under mild conditions to give compounds of formula (I) otherwise accessible only by total chemical synthesis. Moreover it is noteworthy that none of the remaining functional groups is affected by the reaction and the stereochemistry at C-7 and C-9 is completely preserved.
Accordingly, the present invention provides a process for the preparation of a 4-substituted anthracyclinone of formula (I), which process comprises reacting a 4-demethyl-4-sulfonyl-13-dioxolanyl daunomycinone of formula (II) with: optionally substituted by a said group (a) to (e), or vary from 0 to 4 but n is not 0, and Y may be a halogen atom or a straight or branched alkyl group having 1 to 6 carbon atoms, in the presence of a catalytic amount of a compound of formula (IV) (hereunder referred to as catalyst): or different, each represent an anion such as Cl.sup.- or CH.sub.3 COO.sup.- or a neutral molecule as a solvent molecule, a mono- or a di-phosphine, a phosphite or a diamine, and p and q may vary from 0 to 4, to obtain a compound of formula (VI): ##STR6## wherein R is as defined above; and removing the 13-oxo protecting group by acid hydrolysis.
In the compound of formula (IV), preferred transition metal atoms which M' may represent are palladium or nickel. Preferred groups which L and/or L' may represent are chelating diphosp

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