Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Patent
1985-10-03
1989-07-25
Lee, Mary C.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
514 63, 514501, 514492, 514503, 514505, A61K 31295
Patent
active
048514306
DESCRIPTION:
BRIEF SUMMARY
Metallicenium compounds are formed by chemical or electrochemical one-electron oxidation of metallocenes; see Wilkinson et al., J. Am. Chem. Soc., Volume 74, page 2125 (1952) and Rosenblum, "Chemistry of the Iron Group Metallocenes", Wiley, N.Y. (1965). They are salt-like substances, some of which are hydrophilic or even water-soluble. In these compounds, the cyclopentadienyl ring is linked to the central metal atom by a hapto-5-bond.
It has now been found that metallicenium compounds have a chemotherapeutic action, and in particular display cytostatic properties.
The invention relates to metallicenium salts of the general formula I R'.sub.y)].sub.a.sup.m+ [A].sub.b.sup.n- (I) H.sub.5-y R'.sub.y denote cyclopendadienyl rings which, independently of one another, can be unsubstituted (x and y=0) or mono-, di-, tri-, tetra- or penta-substituted (x and y=1, 2, 3, 4 or 5), and in which R and R' independently of one another represent identical or different substituents and denote alkyl, cycloalkyl, hydroxyalkyl, aminoalkyl, halogenoalkyl, alkenyl, aryl, aralkyl, ferrocenyl, ferrocenylium, ferrocenylalkyl, acyl, halogenyl, trialkylsilyl, tricycloalkylsilyl, triarylsilyl, triaralkylsilyl or carboxyl, ester, amide or hydrazide groups, or R and R' together form an alkylene bridge with 2 to 4 bridge atoms; a, b, m and n are integers, and m has the value 1 or 2, n has the value 1, 2 or 3 and a.times.m=b.times.n; and A is a complexating or very bulky anion which stabilizes the metallicenium cation; and solvates of these salts, for use as medicaments, in particular their use as cytostatics in combating tumors susceptible thereto.
A preferred group of compounds used according to the invention comprises the ferricenium and cobalticenium compounds (M=Fe or Co), which are available inexpensively; for the same reason, unsubstituted compounds (x and y=0) are preferred.
If R or R' is alkyl, hydroxyalkyl, aminoalkyl, halogenoalkyl or halogenyl, x or y preferably has the value 1, 2, 3, 4 or 5. If R or R' is cycloalkyl, alkenyl, aryl, aralkyl, ferrocenyl, ferrocenylium, ferrocenylalkyl, acyl, trialkylsilyl, tricycloalkylsilyl, triarylsilyl or triaralkylsilyl or a carboxyl, ester, amide or hydrazide group, x or y preferably has the value 1 or 2.
"Alkyl" is understood as meaning straight-chain or branched alkyl radicals with 1 to 10, preferably 1 to 6 and in particular 1 to 4, carbon atoms. Specific examples are methyl, ethyl, isopropyl, n-butyl, tert.-butyl, 2-ethylhexyl and n-decyl.
"Cycloalkyl" is understood as meaning cycloaliphatic radicals with 3 to 8, preferably 3 to 6 and in particular 6, carbon atoms. Specific examples are cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl and cyclooctyl.
"Alkenyl" is understood as meaning unsaturated radicals with 2 to 10, preferably 2 to 6 and in particular 2 to 4, carbon atoms. Vinyl is a specific example.
"Aryl" is understood as meaning aromatic and fused aromatic radicals with 6 to 18, preferably 6 to 14 and in particular 6 to 10, carbon atoms. Phenyl is a specific example.
"Halogen" is understood as meaning fluorine, chlorine, bromine and iodine, fluorine, chlorine and bromine being preferred.
"Acyl" is understood as meaning aliphatic or aromatic acyl radicals with up to 12, preferably up to 7 and in particular up to 4, carbon atoms. Specific examples are acetyl, propionyl and benzoyl.
The hydroxyalkyl, aminoalkyl, halogenoalkyl, alkylene, aralkyl, ferrocenylalkyl, trialkylsilyl, tricycloalkylsilyl, triarylsilyl and triaralkylsilyl substituents are preferably derived from the alkyl, cycloalkyl, aryl or halogen radicals mentioned. The ester groups are preferably alkylester groups with 1 to 4 carbon atoms in the alkyl radical.
Preferred examples of the anion A are anionic complexes of the type [M'X.sub.4 ].sup.n- (n=1 or 2) or [M'X.sub.6 ].sup.n- (n=1, 2 or 3), in which M'=B, Bi, Co, Fe, Ga, Hg, Ru o Sb and X=F, Cl, Br or phenyl. Of these, BF.sub.4.sup.-, B.phi..sub.4.sup.-, FeCl.sub.4.sup.-, FeBr.sub.4.sup.-, BiCl.sub.4.sup.-, GaCl.sub.4.sup.-, PF.sub.6.sup.- and RuCl.sub.4.sup.- are pa
REFERENCES:
patent: 4608387 (1986-08-01), Kopf et al.
Castagnola et al., J. of Organometallic Chem., vol. 60, pp. C17, 18 (1973).
Nesmeyanov et al., Chem. Ber., vol. 93, p. 2729 (1960).
Akaroni et al., J. of Organomettalic Chem., vol. 22, p. 179 (1970).
Aly et al., Chem. Commun., p. 404 (1965).
Kopf Hartmut
Kopf-Maier Petra
Neuse Eberhard W.
Dentz Bernard I.
Lee Mary C.
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