Ruthenium(III) complexes as antineoplastic agents

Details Ruthenium(III) complexes as antineoplastic agents Ruthenium(III) complexes as antineoplastic agents

1991-12-13

1995-04-25

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

546 4, 549 3, A61K 3141, A61K 31535, C07F 1500

Patent

active

054098939

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to octahedric ruthenium(III) complexes, to a process for their preparation and to pharmaceutical compositions containing them.
After the discovery of the antineoplastic properties of cis-diamino dichloro-platinum(II) (cisplatin), the interest for metal organic complexes as potential anti-tumor agents increased (see for instance M. J. Cleare et al., "Antitumor properties of metal complexes"; Sigel H. (ed.) "Metal ions in biological system (Vol. II ) metal complexes as anticancer agents". M.Dekker, Inc. Basel, N.Y. (pages 1-56)
Cisplatin is now widely used in anti-tumor mono-or polychemotherapy (see for example A. W. Prestayko et
al., Cisplatin: current status and new developments, Acad. Press Inc., New York, 1980), and similarly to several anti-tumor agents its spectrum of action covers some kinds of tumor (testis, ovary, bladder, head-neck). Other tumors, such as disseminated lungs or breast tumors or the colon-rectal tumor are not sensitive to treatment with this compound (see for example Osieka R. et al., Klin. Wochenschr. 57, 1249 (1979).
The search of new metal-organic complexes is aimed at the development of new compounds (containing Pt and/or other transition elements) endowed with a wider spectrum of activity and lower toxicity than known anti-tumor agents. The use of ruthenium as an alternative to platinum was first suggested by L. J. Anghileri et al., (Krebsforsch. 83, 213, 1975) with studies on "Ruthenium Rot" or ruthenium polycations provided with anti-tumor activity. The anti-tumor activity of Ruthenium(II) or (III) complexes has been already disclosed by T. Giraldi et al., (Cancer Res. 37, 2662, 1977); M. J. Clarke (Acs. Symp. Ser. 149, 157, 1980).
The synthesis of Ru(II) anionic complexes with 5-membered heterocycles, such as imidazole and pyrazole was described by F. Kralik (Collec. Czecho. Chem Comm., 26, 1298, 1961); S. A. Zaichi (Transition Metalchemie, Vol. 4, No. 2, Verlag Chemie, pag. 133-136) prepared imidazole complexes and subsequently Ru(II) and Ru(III) complexes were synthetized by J. Levis (J. Chem. Soc. (A) 366-370, 1967).
The anti-tumor activity of some of these complexes has been studied; particular attention was paid to imidazolium bis-imidazole-tetrachloro ruthenate(III) (ICR) whose activity was studied in classic experimental tumors such as P388 leukemia and/or B16 melanoma (B. K. Keppler et al., J. Cancer Res. Oncol., 111, 166 (1986) and against an autoctone colon-rectal tumor induced by acetoxymethyl methylnitrosamine (F. T. Garzon et al., Cancer Chemoter. Pharmacol., 19, 347, 1987). Neutral complexes of Ru(III) of formula B.sub.3 RuX.sub.3 wherein B is a basic heterocycle (mono or polycyclic) containing one or more nitrogen atoms and X is chlorine or bromine, having anti-tumor activity are described in WO 86/00804 as well as co-precipitates thereof with polyvinylpyrrolidone of MW=1700, suited to overcome their poor water solubility, allowing the preparation of aqueous solutions useful for administration to animals.
Trans complexes of Ru (II), a namely trans-Ru(II)-tetrakisdimethylsulphoxide, are reported by G. Mestroni et al. (Italian Pat. Appln. 20180 A/87) as endowed, at equitoxic dosages, with a cytotoxic activity at least 10 times higher than that of the above cited complexes cis-Ru(II)-tetrakis-dimethylsulphoxide (T. Giraldi et al., above cited).
We have found that the contemporary presence of sulphoxide and basic nitrogen ligands in the apex positions of the octahedric neutral and anionic ruthenium (III) complexes produces compounds endowed with considerable anti-tumour activity.
The complexes of the invention have the following formula (I): ##STR1## wherein R.sub.1 and R.sub.2, which are the same or different, are C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 cycloalkyl-(C.sub.1 -C.sub.6)-alkyl, phenyl, aryl-(C.sub.1 -C.sub.6)-alkyl, a 5- or 6-membered heterocyclic group containing at least one oxygen or nitrogen atom, a heterocyclyl-(C.sub.1 -C.sub.6)-alkyl group wherein the heterocycle residue is as above d

REFERENCES:
patent: 3557143 (1971-01-01), Suh et al.
patent: 3576012 (1971-04-01), Matlack
Sarma et al. Polyhedron, 7, No. 18, pp. 1727-1735, 1988.
Metal Complexes in Cancer Therapy, "The Development of Tumor-Inhibiting Ruthenium Dimethylsulfoxide Complexes", pp. 161-187, 1993.

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