Amino anthracenediones-bis platinum complexes, useful as antitum

Details Amino anthracenediones-bis platinum complexes, useful as antitum Amino anthracenediones-bis platinum complexes, useful as antitum

1990-06-14

1992-09-08

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544 64, 546 10, 552209, 556136, 556137, A01N 5502, A61K 31555

Patent

active

051458489

DESCRIPTION:

BRIEF SUMMARY
This invention concerns new bis-platinum complexes, a method for their preparation and pharmaceutical compositions containing them.
An object of this invention is bis-cis-platinum complexes of formula I: ##STR2## wherein X, X', that can be the same or different, are ligands selected from the group consisting of Cl, Br, OH, CH.sub.3 SOCH.sub.3 .multidot.Cl, CH.sub.3 SOCH.sub.3 .multidot.Br, CH.sub.3 SOCH.sub.3 .multidot.OH or, taken together, from the anion of a linear or cyclic, optionally substituted, dicarboxylic acid; C.sub.1 -C.sub.5 -alcohols, acetonitrile and ethylacetate; ##STR3## wherein each of Rc and Rd, that can be the same or different, are hydrogen or hydroxy; substituted by hydroxy, C.sub.1 --C.sub.3 -alkoxy, C.sub.2 -C.sub.8 -polyalkoxy or sulphonic groups, or it represents a residue of a mono-amino-sugar, in acetalic or linear form of formulae a and b respectively: ##STR4## ` wherein R.sub.1 is hydrogen, C.sub.1 -C.sub.3 -alkyl, hydroxymethyl or aminomethyl group, R.sub.2, R.sub.3 and R.sub.4 are amino, hydroxy or hydrogen with the proviso that at least one of them is hydrogen and only one of R.sub.1, R.sub.2 or R.sub.3 be an amino group, R.sub.5 is hydroxy, C.sub.1 -C.sub.3 -alkoxy or benzlyoxy; when R.sub.5 is hydroxy, the formulae a and b represent the same structure wherein the cyclic hemiacetalic form and the opened aldehydic form are in equilibrium, whereas when R.sub.5 is alkoxy or benzlyoxy, it may be either an .alpha. or a .beta.-oloside; (CH.sub.2 CH.sub.2 O).sub.p OCH.sub.3, (CH.sub.2 CH.sub.2 O).sub.p CH.sub.2 H.sub.5 ; acids.
Pharmaceutically useful salts of compound I are those with inorganic acids, as hydrohalogenidric acids, e.g. hydrochloric, hydrobromic and hydroiodic acids; or with organic acids such as acetic, succinic, tartaric and fumaric acids.
Examples of preferred aminosugars as ligands of the compounds of the invention are: 2-amino-desoxy-D-glucose(D-glucosamine), .alpha.-D-xylo-pyranosylamine, .alpha.-D-lyxo-piranoxylamine, .alpha.-D-manno-pyranosylamine, .alpha.-D-ribo-pyranosylamine, 1-daunosamine, 1-acosamine, 1-ristosamine, 2-amino-2-desoxy-D-galactose (galactosamine, D-chondrosamine), .alpha.-D-arabino-pyranosylamine, 6-amino-6-deoxy-.alpha.-D-glucopyranose, 2-amino-2,6-dideoxy-L-glucose, 3-amino-3-deoxy-D-glucose, 2-amino-2,6-dideoxy-D-glucose, 3-amino-3,6-dideo-D-mannose (mycosamine).
The compounds of the invention are obtained by mixing the solution of an anthracenedione ligand II: ##STR5## either as a free base or as a salt, wherein Ra, Rc, Rd and n have the above meanings, in a suitable solvent, with at least 2 molar equivalents of a platinum complex III quaternary phosphonium salt, X" is an univalent anion, preferably halogen (chlorine, bromine, iodine) and Rb is an alkyl residue of an amine or of an amino sugar as above described, dissolved in a suitable solvent, so giving rise to the formation of the compounds Ia: ##STR6## wherein Solv, X", Ra, Rb, n, A have the above meanings.
Compounds Ia may be optionally reacted with water in suitable medium to obtain compounds Ib: ##STR7## wherein Solv, X", Ra, Rb, n, A are as above defined and X"' is hydroxy; finally, if desired, said compounds Ia, Ib are reacted with dimethylsulphoxide to give other compounds of the invention.
Said compounds may also be treated with alkali, earth-alkali or silver salts of dicarboxylic acids such as malonic or succinic acids, optionally substituted, to give the compounds I wherein X and X', taken together, form the anion of dicarboxylic acid such as malonate, hydroxymalonate, 1,2-cyclohexanedicarboxylate, etc.
When the ligand is a salt, the compounds of the invention are also salts that, if desired, can be converted into neutral complexes by treatment with equimolar quantities of a base.
If desired, neutral complexes of formula I can be converted into the corresponding slats by reaction with stoichiometric quantities of non-toxic pharmaceutically acceptable acids.
Preferred solvents for the preparation of the reagent are water, mono- or polyhydroxylic C.sub.1 -C.sub.4 -alcohols

REFERENCES:
patent: 4732893 (1991-09-01), Pasini et al.
Gibson et al., J. Med. Chem. 1991, 34, 414-420.

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