Metal complexes having an antineoplastic action and medicaments

Details Metal complexes having an antineoplastic action and medicaments Metal complexes having an antineoplastic action and medicaments

1982-05-21

1989-02-14

Goldberg, Jerome D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heavy metal containing doai

514492, 424 78, 424 80, 548402, 549206, A61K 3132, A61K 3128, A61K 3174, A61K 3179

Patent

active

048046817

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The invention relates to metal complexes having an antineoplastic action and to medicaments containing these complexes.


BACKGROUND

A medicament which contains the complex compound cis-diamminedichloroplatinum(II) has recently been marketed as a chemotherapeutic agent against cancer. This compound, known by the International Nonproprietary Name (INN) of cisplatin has proved to be an extremly potent antitumor agent, especially in the treatment of testicular tumors, and also, for example, of ovarian tumors and of oat-cell carcinomas. The disadvantage of cis-platin is its relatively high toxicity. Its nephrotoxicity and its action leading to lasting damage to hearing are particularly serious. Renal damage and damage to hearing are found with considerable frequency after administration of only a single therapeutic dose. Besides the nephrotoxic and hematotoxic action, the long-lasting severe nausea and the retching associated therewith are, above all, also extremely unpleasant for the patient. Numerous other platinum complexes (German Offenlegungsschrift No. 2,445,418, German Offenlegungsschrift No. 2,837,237, German Offenlegungsschrift No. 2,626,559 and German Offenlegungsschrift No. 2,539,179) and complex compounds of other transition metals have recently been proposed as agents having a cytostatic action. In German Offenlegungsschrift No. 2,801,355, a brown amorphous complex which is obtained by reacting ascorbic acid with a titanium(III) compound and a copper(II) compound (in a molar ratio of 36:1:6) is said to have curative and prophylactic actions against, inter alia, leukemia. It has been reported that titanocene dichloride, zirconocene dichloride and hafnocene dichloride have an inhibiting action on ascitic Ehrlich tumors in mice [P. Kopf-Maier, B. Hesse and H. Kopf, J. Cancer Res. Clin. Onco., 96, 43 (1980)]. Dialkyl- tin-dihalide phenanthroline complexes and bipyridyl complexes have been said to have inhibiting actions on P388 leukemia in mice (A. J. Crowe and P. J. Smith, Chemistry and Industry, page 200, Mar. 1, 1980).


BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 compare the invention to Cisplatin and controls with regard to median survival time in experiments on two cancer models.


THE INVENTION

Surprisingly, it has now been found that complexes of formula I being monosubstituted or polysubstituted (independently) by fluorine, chlorine, bromine, nitro, C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 -alkoxy or trifluoromethyl]; hydrogen; fluorine when M denotes zirconium or hafnium; number 1 and 1 or 0; less toxic than cisplatin. Accordingly, compared with cisplatin, these compounds have a significantly greater therapeutic range. They are useful as chemotherapeutic agents with few side effects for the treatment of tumors, e.g. ovarian tumors, and testicular tumors. Accordingly the compounds are useful for alleviation of pain and suffering in connection with cancer therapy, remission, alleviation of symptoms and extension of life expectancy.
The complexes are alternatively represented by the following formulae:


__________________________________________________________________________ (A) [H.sub.3 C--CO--CR.sup.3 --CO--CH.sub.3 ].sub.2 SnX.sub.2 (N) [H.sub.3 C--CO--CR.sup.3 --CO--R.sup.4 ].sub.3 ZrX.degree. (B) [H.sub.3 C--CO--CR.sup.3 --CO--R.sup.4 ].sub.2 SnX.sub.2 (O) [R.sup.4 --CH.sub.2 --CO--CR.sup.3 --CO--R.sup.2 ].sub.3 ZrX.degree. (C) [R.sup.4 --CH.sub.2 --CO--CR.sup.3 --CO--R.sup.2 ].sub.2 SnX.sub.2 (P) [R.sup.4 --CO--CR.sup.3 --CO--R.sup.2 ].sub.3 ZrX.degree. (D) [R.sup.4 --CO--CR.sup.3 --CO--R.sup.2 ].sub.2 SnX.sub.2 (Q) [H.sub.3 C--CO--CR.sup.3 --CO--CH.sub.3 ].sub.2 HfX.degree..sub.2 (E) [H.sub.3 C--CO--CR.sup.3 --CO--CH.sub.3 ].sub.2 TiX.sub.2 (R) [H.sub.3 C--CO--CR.sup.3 --CO--R.sup.4 ].sub.2 HfX.degree..sub.2 (F) [H.sub.3 C--CO--CR.sup.3 --CO--R.sup.4 ].sub.2 TiX.sub.2 (S) [R.sup.4 --CH.sub.2 --CO--CR.sup.3 --CO--R.sup.2 ].sub.2 HfX.degree..sub.2 (G) [R.sup.4 --CH.sub.2

REFERENCES:
Chemical Abstracts 97:150723e (1982).
Chemical Abstracts 98:11155d (1983).
Feld et al., The Organic Chemistry of Titahiom, Washington Butterworths, 1965, p. 60.

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