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  Vanadium (iv) metallocene complexes having spermicidal activityUSPTO Application #: 20050192266Title: Vanadium (iv) metallocene complexes having spermicidal activity Abstract: Novel spermicidal compounds which are organometallic cyclopentadienyl metal complexes, particularly vanadium IV complexes, are described including corresponding contraceptive and therapeutic compositions and method for providing contraception and selective killing of testicular germ cells. Included among the vanadium complexes are vanadocene dichloride, vanadocene dibromide, bis (methyl cyclopentadienyl) vanadium dichloride, vanadocene diiodide, vanadocene di-pseudohalides, and others. Most active found was vanadocene diselenocyanate. (end of abstract)
Agent: Merchant & Gould PC - Minneapolis, MN, US Inventors: Osmond D'Cruz, Phalguni Ghosh, Fatih M. Uckun USPTO Applicaton #: 20050192266 - Class: 514184000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Heavy Metal Containing (including Salts) The Patent Description & Claims data below is from USPTO Patent Application 20050192266. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001] This invention relates to metallocene compositions containing vanadium (IV). More particularly, the invention relates to Vanadium (IV) complexed metallocene, having spermicidal activity. BACKGROUND OF THE INVENTION [0002] 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. [0003] Vanadium is a physiologically essential element which can be found in one of 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). [0004] 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 was evaluated for its potential to impact sperm activity. Results of studies with structurally distinct organometallic complexes containing vanadium (IV) surprisingly demonstrated these compounds to be potent spermicidal agents at nano-micromolar concentrations. These compounds have also surprisingly been found to exhibit selective apoptosis-inducing activity against testicular germ cells in vivo. SUMMARY OF THE INVENTION [0005] Organometallic complexes containing vanadium (IV), including vanadocene dichloride (VDC), bis (methylcyclopentadienyl) vanadium dichloride (VMDC), vanadocene dibromide (VDB), vanadocene diiodide (VDI), vanadocene diazide (VDA), vanadocene dicyanide (VDCN), vanadocene dioxycyanate (VDOCN), vanadocene dithiocyanate (VDSCN), vanadocene diselenocyanate (VDSeCN), vanadocene ditriflate (VDT), vanadocene monochloro oxycyanate (VDCO), and vanadocene monochloro acetonitrilo tetrachloro ferrate (VDFE) were found to have spermicidal activity. Specifically, the "vanadocene" complexes elicited potent spermicidal activity at nano-micromolar concentrations with an order of efficacy VDSeCN>VDSCN>VDB>VMDC>VDA>VDC>VDI>VDT>VDFE>VDC- O. In contrast, control metallocene complexes containing titanium, zirconium, molybdenum, and hafnium lacked spermicidal activity. [0006] Accordingly, the present invention includes a contraceptive composition containing a spermicidal effective amount of an organometallic cyclopentadienyl vanadium IV complex and a pharmaceutically acceptable carrier, diluent or vehicle. [0007] Another aspect of the present invention is a method of contraception including the step of contacting sperm with a spermicidal effective amount of an organometallic cyclopentadienyl vanadium IV complex. [0008] Yet another embodiment of the invention utilizes the selective apoptotic-inducing properties of organometallic cyclopentadienyl vanadium IV complexes against testicular germ cells to selectively kill normal testicular germ cells and testicular germ cell tumors. BRIEF DESCRIPTION OF THE DRAWINGS [0009] FIG. 1 shows chemical structures for the various metallocene complexes. [0010] FIG. 2 shows dose-response curves for 5 metallocene dichlorides on human sperm motility. [0011] FIG. 3 shows effects of vanadocene dichloride on sperm motion parameters. [0012] FIG. 4 shows the effect of vanadocene dichloride on sperm acrosomal membrane integrity. [0013] FIG. 5 shows laser scanning confocal fluorescence images of sperm. [0014] FIGS. 6A and 6B show a high-resolution low-voltage SEM of sperm incubated in the absence (FIG. 6A) and presence of 100 .mu.M VDC (FIG. 6B) or 10 .mu.M Ca-Ionophore (FIG. 6C) after 3 hours of treatment (.times.18,000 magnification). [0015] FIG. 7 is a bar graph illustrating the effect of pH on spermicidal activity of VDC. [0016] FIG. 8 is a bar graph illustrating time-course of apoptosis induced by VDC measured by the flow cytometric FITC-Annexin V binding assay. [0017] FIG. 9 are confocal laser scanning microscopy images of apoptotic nuclei in VDC-treated sperm. [0018] FIG. 10 is a bar graph illustrating time-course of sperm labeling by TUNEL method following treatment with VDC. [0019] FIGS. 11A and 11B are graphs showing dose response curves for twelve vanadocene complexes on sperm motility, including VDC, VMDC, VDB, VDI, VDA, and VDCN in FIG. 11A, and VDO, VDSCN, VDSeCN, VDT, VDCO, and VDFe in FIG. 11B. [0020] FIG. 12 is a graph showing dose response for inorganic vanadium compounds, and indicating lack of spermicidal activity by these compounds. Continue reading... Full patent description for Vanadium (iv) metallocene complexes having spermicidal activity Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Vanadium (iv) metallocene complexes having spermicidal activity patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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