Anti-tumor platinum complexes

Details Anti-tumor platinum complexes Anti-tumor platinum complexes

1994-02-22

1995-04-11

Dees, Jose G.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

556137, C07F 1500, A61K 3128

Patent

active

054058694

DESCRIPTION:

BRIEF SUMMARY
The present invention refers to platinum(II) complexes of formula (1) (HCl).sub.n.sbsb.l (ROH).sub.m ( 1) branched C.sub.1 -C.sub.6 alkylamine, cyclopentylamine, a cyclic amine such as cyclopropylamine or cyclohexylamine; or the two a groups form a linear or cyclic C.sub.2-8 -alkyl-1,2 or 1,3-diamine;
The linear or branched C.sub.1-5 alkylamine is preferably isopropylamine, propylamine or n-pentylamine; the linear or branched C.sub.1-3 dialkylamine is preferably diisopropylamine.
Examples of linear C.sub.2-8 -alkyl-1,2- or 1,3-diamine include 1,2-ethylenediamine, (R, S, racemic or meso)-butane-1,2-diamine, 1,3-propylenediamine; examples of cyclic diamine comprise R, S, racemic or meso cyclopentane-1,2-diamine; R, S, (racemic or meso) cyclohexane-1,2-diamine; 1,1-bis-aminomethyl-cyclopentane; 1; 1-bisaminomethylcyclohexane.
When m is 1, the compounds (1) are solvates with water or alcohols.
When n.sub.1 is 1, the compounds (1) are addition salts. Particularly preferred compounds are: cis-diamino-chloro-(4-amino)benzoate-platinum(II), cis-diamino-chloro-(4-a mino)benzoate-platinum(II) hydrochloride, (1A) aquo-cis-diamino-chloro-(4-amino)benzoate-platinum(II), (1B) cis-diamino-chloro-(4-amino)benzoate-platinum(II) mono methanol solvate, (1C).
The compounds of formula (1) are prepared by a process comprising: ##STR1## wherein a.sub.m is a defined above, with at least one molar equivalent of p-aminobenzoic acid in the form of free acid or of carboxylate salt with a mono or bivalent metal, preferably alkali, alkaline-earth metal or silver, in a suitable hydroxylated solvent;
Preferred solvents are water, C.sub.1-3 alcohols or mixtures thereof. Water solutions or suspensions of reagents are particularly preferred.
It is particularly preferred the use of lithium p-aminobenzoate which is more easily handled and less toxic than the silver or barium salts.
The reaction may be carried out by mixing water solutions of the reagents or adding a dichloroplatinum(II) of formula (2) as finely subdivided solid to a water solution of p-aminobenzoic acid in form of free acids or its salts. The mixture is stirred for a period ranging from some hours to some days, at temperature from the room temperature to the reflux temperature.
Preferred temperatures are comprised from 50.degree. to 80.degree. C. for a period from 1 and 24 hours.
At least one molar equivalent of p-aminobenzoic acid or of its salt is used per mole of platinum complex (2); the use of an excess amount increases the reaction rate.
The purification of compounds (1) may be carried out by precipitation as hydrochloride salts by dilution of an aqueous solution with concentrated hydrochloric acid; or by silica gel column chromatography or by repeated crystallizations from an alcoholic solvents, e.g. methanol.
The dichloro platinum complexes (2) are commercially available or they are known or they may be prepared by known methods.
The compounds (1), particularly in the salified form, are characterized by a good or very good water solubility (e.g.: 1A 7 mg/ml; 1C>3 mg/ml), and the solutions in water or in HCl 0.01N have a remarkable stability (12-24 hours at least at room temperature). The compounds (1) have a low toxicity; for example the LD.sub.50 for 1B and 1C is higher than 240 mg/kg was surprisingly higher than 1200 mg/kg for 1A. The low toxicity is combined with a low or irrelevant nephrotoxicity as shown by the BUN value of 36.+-.8 mg/100 ml, after a cumulative dose of 1200 mg/kg of compound 1A, and measured at the 8.sup.th day after the end of the treatment.
The evaluation of the cytotoxic activities of the compounds (1) was carried out "in vitro" measuring, according to known methods, the inhibition of the colony formation, the cell viability (Trypan blu) and the incorporation of tritiated thymidine in tumoral and normal cells.
For instance, compound 1A cis-diamino-chloro-(4-amino)benzoate-platinum(II) hydrochloride inhibits the "in vitro" growth of leukemia cells P388, K562 and Jurkat (ID.sub.50 measured by incorporation of tritiated thymidine at 48 hours o

REFERENCES:
Craciunescu et al., Eur. J. Med. Chem.-Chim. Ther., vol. 19, No. 4, pp. 353-357 (1984).
Patent Abstract of Japan, vol. 13, No. 145, C583, abstract of JP 63-303987 (1988).

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