Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1993-05-12
1996-04-23
Peselev, Elli
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 174, 536 185, 536 186, C07H 1524
Patent
active
055104690
DESCRIPTION:
BRIEF SUMMARY
The invention relates to a new anthracycline glycosides, to processes for their preparation and to pharmaceutical compositions containing them.
A new class of anthracycline glycoside antibiotics in which the 3'-nitrogen atom of the sugar moiety is enclosed in a 4-morpholino ring bearing a hydroxy or acyloxy substituent at position C-2 have now been found. The present invention therefore provides an anthracycline glycoside of formula 1. ##STR2## wherein R.sub.1 is hydrogen or a methoxy group; R.sub.2 is hydrogen or hydroxy; both R.sub.3 and R.sub.4 represent hydrogen or one of R.sub.3 and R.sub.4 is hydroxy and the other of R.sub.3 and R.sub.4 represents hydrogen; R.sub.5 represents hydrogen atom or an acyl residue --COX in which X is a C.sub.1 -C.sub.8 linear or branched alkyl, an aryl an aryl, (lower alkyl), or a 5- or 6- membered heteroaromatic group; or a pharmaceutically acceptable salt thereof.
In particular X may be a linear or branched alkyl group containing from 1 to 6 carbon atoms, for example 1 to 4 carbon atoms. X may in particular be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or tert-butyl.
Alternatively X may be an aryl group such as a phenyl or naphthyl group, unsubstituted or substituted by 1 to 3 substituents each of which may independently be a linear or branched alkyl or alkoxy group of from 1 to 6 carbon atoms for example from 1 to 3 carbon atoms, a halogen atom or a nitro group.
If X represents an aryl (lower alkyl) group then the alkyl group may be linear or branched alkyl group and may contain up to 6, for example up to 4 carbon atoms as above. The aryl group may be as defined above, and may be substituted or unsubstituted. For example R.sub.5 may be benzyl or phenethyl.
If X represents a heteroaromatic group then it may contain one, two or three heteroatoms selected from nitrogen, oxygen and sulphur. The heteroaromatic group may be unsubstituted or substituted as defined above for an aryl group, and may for example be a pyrrole, indole, isoindole, pyrazole, imidazole, pyridine, quinoline, isoquinoline, pyridazine, pyrimidine, pyrazine, furan, isoxazole oxazole or thiophene. In particular X may be a pyrrole, indole, pyridine, quinoline, isoquinoline or furan.
Particularly preferred salts of the compounds of the present invention are pharmaceutically acceptable addition salts such as hydrochlorides.
Particularly preferred compounds of formula I include:
(1a) 3'-deamino-3'-(2-benzoyl-4-morpholinyl)doxorubicin (R.sub.1 .dbd.OCH.sub.3, R.sub.2 .dbd.R.sub.3 .dbd.OH, R.sub.4 .dbd.H, R.sub.5 .dbd.COC.sub.6 H.sub.5), and its hydrochloride, and
(1b) 3'-deamino-3'-(2-hydroxy-4-morpholinyl)doxorubicin (R.sub.1 .dbd.OCH.sub.3, R.sub.2 .dbd.R.sub.3 .dbd.OH, R.sub.4 .dbd.H, R.sub.5 .dbd.H).
The compounds of formula 1 may be prepared by the formation of a substituted morpholinyl ring at C-3' on the sugar moiety of the anthracyclines through a reductive alkylation, based on using a dialdehyde of the general formula 2, ##STR3## wherein R.sub.5 has the same meaning as above reported with the proviso that R.sub.5 does not represent hydrogen.
The compounds of formula 1 in which R.sub.5 is hydrogen may be prepared by hydrolysis of the corresponding acyloxy derivatives.
Accordingly, the present invention provides a process for the preparation of an anthracycline glycoside of formula 1 as above defined or a pharmaceutically acceptable salt thereof, which process comprises
(i) reacting an anthracycline of general formula 3, ##STR4## wherein R.sub.1, R.sub.2, R.sub.3 and R.sub.4 have the same meaning as above defined, or a salt thereof, with an aldehyde of formula 2 in the presence of a reducing agent such as an alkali metal cyanoborohydride and, if desired, converting the compound of formula 1 thus obtained into a pharmaceutically acceptable salt or;
(ii) deacylating a compound of formula 1 wherein R.sub.5 represents an acyl group --COX as defined above, or a salt thereof, to provide a corresponding compound of formula 1 wherein R.sub.5 represents hydrogen and, if desired, converting the compoun
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Bargiotti Alberto
Faiardi Daniela
Suarato Antonino
Farmitalia Carlo Erbq S.r.l.
Peselev Elli
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