Organic compounds -- part of the class 532-570 series – Organic compounds – Tetracyclo naphthacene configured ring system having at...
Patent
1991-01-25
1993-06-08
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Tetracyclo naphthacene configured ring system having at...
536 64, 552202, 552206, 552207, C07C 5000
Patent
active
052181308
DESCRIPTION:
BRIEF SUMMARY
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 hydrogen atom or a straight or branched alkyl, alkenyl or alkynyl group of up to 10 carbon atoms, preferably of up to 4 carbon atoms. Preferred compounds are:
Compounds of formula (I) are key intermediates for the preparation of antitumor 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. Preferred compounds are:
The present invention also provides a process for the preparation of a 4-substituted anthracyclinone of formula (I) above, which process comprises carbonylating 4-demethyl-4-sulfonyl-13-dioxolanyl daunomycinone of formula (II): ##STR5## wherein R' represents an alkyl group of 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, with carbon monoxide in the presence of a nucleophile R-OH wherein R is as defined above, an organic or inorganic base and as catalyst a compound of formula (III): or different, each represent an anion or a neutral molecule and n and m may vary from 0 to 4, to obtain a compound of formula (V): ##STR6## wherein R is as defined above; and removing the 13-oxo protecting group by acid hydrolysis.
The invention additionally provides a process for the preparation of an anthracycline glycoside of formula (IX) or a pharmaceutically acceptable salt thereof, which process comprises:
(i) reacting a 4-substituted anthracyclinone of formula (I) with a halosugar of formula (X): ##STR7## wherein Hal represents a halogen atom, the 3"-amino group is protected or unprotected and the 4"-hydroxy group is protected or unprotected; and, if present, removing the or each protecting group from the product thus-obtained such as to obtain an anthracycline glycoside of formula (IX) wherein R.sub.1 is a hydrogen atom;
(ii) if desired, converting the said glycoside of formula (IX) thus obtained into a pharmaceutically acceptable salt thereof;
(iii) if desired, brominating the said glycoside of formula (II) or pharmaceutically acceptable salt thereof and hydrolysing the 14-bromo derivative thus obtained so as to form the corresponding glycoside of formula (IX) wherein R.sub.1 is a hydroxy group; and
(iv) if desired, converting the said glycoside of formula (IX) wherein R.sub.1 is hydroxy into a pharmaceutically acceptable salt thereof.
Compounds of formula (I) are obtained from 4-sulfonylanthracyclinones of formula (II) ##STR8## wherein R' represents an alkyl group having from 1 to 10 carbon atoms; a halo or polyhalo such alkyl group, for example a perfluoroalkyl group; or an aryl group such as a phenyl group optionally substituted by at least one, for example from one to three, halogen atom(s) or alkyl, alkoxy or nitro group(s). The halogen atom may be chloro or fluoro. The alkyl and alkoxy groups may contain from 1 to 10, for example from 1 to 4, carbon atoms. Preferred groups which R' may represent are trifluoromethansulfonyl, 4-fluorophenyl and 4-tolyl.
Compounds of formula (II) can be prepared from naturally occurring daunomycinone (IV) as described in European Applications Nos. 89301282.3 and 89303418.1. ##STR9##
More specifically, a compound of formula (II) can be prepared from (+) daunomycinone of formula (IV) (Scheme 1 below). This can be prepared by a suitable hydrolysis of daunorubicin, in its turn obtained by fermentation as described in U.S. Pat. No. 4,012,284. The daunomycinone is demethylated by treatment with AlCl.sub.3 in an inert organic solvent such as nitrobenzene at the reflux temperature to give 4-demethyldaunomycinone, which is called also carminomycinone (VI). Such a process is descr
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Cabri Walter
De Bernardinis Silvia
Francalanci Franco
Penco Sergio
Brown Johnnie R.
Farmitalia Carlo Erba S r l
Peselev Elli
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