Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heavy metal containing doai
Reexamination Certificate
2000-02-16
2002-01-08
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heavy metal containing doai
C514S310000
Reexamination Certificate
active
06337348
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions containing oxy-vanadium (IV). More particularly, the invention relates to oxy-vanadium (IV) containing complexes having spermicidal activity.
BACKGROUND OF THE INVENTION
The known spermicidal agents, nonoxynol-9 and gramicidin, exert their effects via a detergent-like ability to damage the sperm plasma membrane, perturb its conformation and destroy its semi-permeable nature thereby impairing the sperm motility and egg fertilizing functions (Wilborn, et al.,
Fertil Steril
1983; 39:717-719; Bourinbaiar, et al.,
Life Sci
1994; 54:PL 5-9). Because of their non-specific membrane disruptive properties, such vaginal spermicides have been shown to damage the cervicovaginal epithelium, as well, which may lead to a lower degree of protection from sexually transmitted diseases (Niruthisard, et al.,
Sex Transm Dis
1991; 18:176-179). A novel vaginal contraceptive preferably does not function with the non-specific membrane toxicity mediated by detergent-type action of the currently available vaginal contraceptives.
Vanadium is a physiologically essential element which can be found in one to five (I to V) oxidation states. Several inorganic salts containing vanadium with oxidation state +4 (IV) have been shown to function as modulators of cellular redox potential and to exert pleiotropic effects in multiple biological systems by catalyzing the generation of reactive oxygen intermediates. See, for example, Shi, et al.,
Ann Clin Lab Sci
1996; 26:390-49; Byczkowski, et al.,
Bull Environ Contam Toxicol
1988; 41:696-703; Younes, et al.,
Toxicology
1991; 66:63-74, and Sakurai, et al.,
Biochem Biophys Res Commun
1995; 206:133-137. Reactive oxygen intermediates have been reported to affect sperm motility by a combination of peroxidation of membrane lipids and proteins (Aitken, et al.,
Biol Reprod
1989; 40:183-197; Jones, et al.,
Fertil Steril
1979; 31:531-537). Peroxidative damage to the sperm plasma membrane is an important pathophysiological mechanism in the onset of male infertility (Aitken, et al.,
BioEssays
1994; 16:259-267). It has also been shown that superoxide radicals generated by the action of xanthine oxidase exert a direct, suppressive effect on many aspects of sperm function (Aitken, et al.,
J. Reprod. Fertil.
1993; 97:441-450). Sperm are thought to be particularly susceptible to oxidative stress by virtue of their high content of unsaturated fatty acids and their relative paucity of cytoplasmic enzymes for scavenging the reactive oxygen intermediates that initiate lipid peroxidation (Alvarez, et al.,
J Androl
1987; 8:338-348).
There is a need for new spermicidal compounds for contraceptive purposes. The ability of vanadium (IV) containing organometallic complexes to catalyze the generation of reactive oxygen species and the spermicidal activity of these agents was described in copending patent application U.S. Ser. No. 09/008,898, which is hereby incorporated by reference for all purposes.
Metallocene complexes containing vanadium (IV) as the central metal ion within the tetrahedral bis(cyclopentadienyl) [Cp
2
] metal complex (vanadocene) have potent spermicidal activity against human sperm (
Biol Reprod
58:1516,1998;
Molec Hum
Reprod 4:683, 1998). The spermicidal activity was dependent on vanadium (IV) as the central metal ion within the Cp
2
-metal complex, but the various diacido groups and bidentate ligands coordinated to the Cp
2
-vanadium (IV) moiety also significantly modulated the spermicidal potency.
SUMMARY OF THE INVENTION
Organometallic complexes containing oxovanadium (IV) (VO) have now been found to have potent, concentration-dependent spermicidal activity at micromolar concentrations. Preferred oxovanadium complexes of the invention are complexes having at least one bidentate ligand. Suitable bidentate ligands include N,N′; N,O; and O,O′ bidentate ligands.
The spermicidal activity of oxovanadium (IV) complexes was found to be irreversible, since the treated sperm underwent apoptosis, as determined by the flow cytometric quantitation of mitochondrial membrane potential, surface Annexin V binding assay, and in situ DNA nick-end labeling of sperm nuclei. The percentages of apoptotic sperm quantitated by these flow cytometric assays correlated well with the spermicidal potency of oxovanadium (IV) complexes. These results provide unprecedented evidence that the spermicidal and apoptosis-inducing properties of diverse oxovanadium (IV) complexes is due to vanadium (IV) as the central metal ion within the oxovanadium (IV) complex. The oxovanadium (IV) complexes typically included at least one bidentate ligand within the complex. Suitable bidentate ligands include N,N′; N,O; and O,O′ bidentate ligands. Examples of suitable bidentate ligands include bipyridyl, bridged bipyridyl and acetophenone ligands modulating the spermicidal potency. One example of a bridged bipyridyl includes phenanthroline. These novel oxovanadium (IV) complexes, and particularly the bromo-hydroxyacetophenone complex [OV(Br,OH-acph)
2
], are useful as contraceptive agents.
Accordingly, the present invention includes spermicidal oxovanadium complexes, as well as contraceptive compositions containing a spermicidal effective amount of an oxovanadium IV complex and a pharmaceutically acceptable carrier, diluent or vehicle. The spermicidal compounds of the invention include organometallic oxovanadium (IV) complexes. Preferably, the oxovanadium (IV) is complexed with at least one bidentate ligand.
One suitable embodiment of the invention having a bidentate ligand wherein the bidenate ligand is a bipyridyl has the general formula I, shown below:
where R and R
1
are the same or different and are independently selected from: H, lower alkyl, halogen, lower alkoxy, halogenated alkyl, cyano, carboalkoxy (e.g. C
2
-C
6
) and nitro; X and X
1
are the same or different and are independently selected from: monodenate and bidentate ligands; and n is 0 or 1.
Another suitable embodiment of the invention having a bidentate ligand wherein the bidentate ligand is a bridged bipyridyl has the general formulae IV, shown below:
where R
2
and R
3
are the same or different and are selected from H, lower alkyl, halogen, lower alkoxy, halogenated alkyl, cyano, carboalkoxy (e.g. C
2
-C
6
) and nitro; X
2
and X
3
, are the same or different and are selected from monodentate and bidentate ligands; Z is selected from O, CH
2
, CH
2
—CH
2
, and CH═CH; and n is 0 or 1.
Another suitable embodiment of the invention having a bidentate ligand wherein the bidentate ligand is a bridged bipyridyl, and the bridged bipyridyl is phenanthroline, has the general formula II, shown below:
where R
4
, R
5
and R
6
are the same or different and are independently selected from: H, lower alkyl, halogen, lower alkoxy, halogenated alkyl, cyano, carboalkoxy (e.g. C
2
-C
6
) and nitro; X
4
and X
5
are the same or different and independently selected from: monodentate and bidentate ligands; and n is 0 or 1.
Another suitable embodiment of the invention having a bidentate ligand wherein the bidentate ligand is an O,O′ bidentate ligand, and the complex has the general formulae III, is shown below:
where R
7
and R
9
are the same or different and are independently selected from: H, lower alkyl, lower alkoxy, and halogenated alkyl; R
8
is selected from H, lower alkyl, halo, lower alkoxy, and halogenated alkyl; Y and Y
1
are the same or different and independently selected from the group consisting of: monodentate and bidentate ligands; and n is 0 to 1.
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D'Cruz Osmond
Dong Wanhong
Uckun Faith M.
Hartley Michael G.
Merchant & Gould
Parker Hughes Institute
Willis Michael A.
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