Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-07-06
2004-06-29
Webman, Edward J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S230200
Reexamination Certificate
active
06756368
ABSTRACT:
Throughout this application, various publications are referenced by author, date and citation. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
BACKGROUND OF THE INVENTION
Viral infection is the cause of a number of human and animal diseases throughout the world. Considerable effort has been focused on developing treatments for preventing infection and reducing virus pathogenesis.
Infection by the alphaherpesviruses herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) result in a variety of viral diseases which are distributed worldwide including oral and genital epithelial lesions, encephalitis and ocular keratitis (15, 16, 20, 87, 91). Among these, herpetic ocular infection is the leading infectious cause of blindness in developed countries (45, 52, 53, 87). In immunocompetent and immunocompromised patients herpesvirus infections are among the most frequent causes of virus disease (74, 84, 92). Herpesvirus infections are characterized by their ability to establish latency and reactivate from the latent state (76). Consequently, both primary and recrudescent infections in immunocompromised patients are life-threatening (74, 84, 92).
Several medications exist which are approved for use in the treatment of herpesvirus infections, e.g. aciclovir (“ACV”), penciclovir, valaciclovir, and famciclovir. Derivatives of these are being developed and/or undergoing clinical trials (2, 5, 17). In general these drugs are nucleoside analogs and thus their primary target is virus DNA synthesis (27, 32). A majority of these pharmaceuticals are activated by the HSV protein thymidine kinase (“tk”). Although many of these drugs and their prodrugs target an aspect(s) of the herpes life cycle, they are also proving to be mutagenic or otherwise cytotoxic. In addition, many drug resistant strains are appearing with increasing frequency (13, 14, 17, 29, 30, 51, 66, 77). It is not surprising that these strains have been found to be resistant to the most commonly used of these treatments, ACV. Resistance appears to arise from either altered activation of the drug via aberrant tk expression or substrate specificity (18, 28) or by mutations in other enzymatic processes such as DNA polymerase activity (13, 14, 44, 66, 77). Therefore, new drugs need to be developed which target other aspects of the virus life cycle in order to find treatments which are most effective against the existing drug-resistant strains as well as all the known herpes viruses.
U.S. Pat. No. 5,756,491 relates to antiviral cobalt-organic compounds which are also known as the CTC series of compounds. The disclosures of U.S. Pat. No. 5,756,491, as well as U.S. Pat. No. 5,049,557 referred to therein, in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein.
The CTC series of cobalt containing compounds possess anti-inflammatory (93) and anti-viral activity (3, 22, 25, 88). Several CTC complexes have moderate activity in vitro and in vivo against HSV-1 and 2, varicella-zoster virus (VZV), cytomegalovirus and Epstein-Barr virus (3, 22, 25, 88). Previous studies show that CTC-96, structure of which is shown in
FIG. 1
, a derivative of CTC-23 (3, 22, 25, 88, 93), is the least cytotoxic and most effective of the CTC compounds against HSV-1 and 2 (3, 22). CTC-96 is also effective in inhibiting HSV-1 production in tissue culture (3). In the rabbit eye model, CTC-96 is able to reduce the corneal surface level of HSV-1 and facilitate the recovery from dendritic keratitis (3, 22). It has been suggested that the anti-inflammatory properties of the CTC complexes may aid in recovery from ocular disease (3). Although the anti-herpetic activity of the CTC series has been known for many years, neither the mechanism by which it acts nor the stage of the virus life cycle at which CTC-96 exerts its inhibitory action on HSV-1 has been elucidated.
SUMMARY OF THE INVENTION
The subject invention provides a method of preventing the infection of a cell by a virus comprising contacting the cell with a compound having the structure:
wherein L=L′=2-methylimidazole.
The subject invention also provides a method of treating a cell infected by a virus comprising contacting the cell with a compound having the structure:
wherein L=L′=2-methylimidazole.
More particularly, the inventive method is useful against either an enveloped viruses or a non-enveloped virus.
In a preferred embodiment, the inventive method is useful against an enveloped virus selected from the group consisting of varicella-zoster virus, vesicular stomatitis virus, and influenza virus.
In another preferred embodiment, the inventive method is useful against a non-enveloped virus selected from the group consisting of poliovirus and adenovirus.
REFERENCES:
patent: 5049557 (1991-09-01), Dori et al.
patent: 5756491 (1998-05-01), Dori
patent: 6008190 (1999-12-01), Meade et al.
Dunkel et al., (1991) “Ctc 23 Efficacy in Vitro and on Hsv-1-induced Ocular Epithelial and Stromal Disease in the Rabbit”Antivir. Res. Supp. 1: 135 (Exhibit 11).
Louie and Meade., (1998) “A Cobalt Complex That Selectively Disrupts the Structure and Function of Zinc Fingers”,Proc. Natl. Acad. Sci. USA. 95: 6663-6668 (Exhibit 12).
Ostrow et al., (1994) Topical Ctc-96 Accelerates Wart Growth in Rabbits Infected with Cottontail Rabbit Papillomavirus.Antivir. Res. 24: 27-35 (Exhibit 13).
Pope et al., (1998) The Anti-herpes Simplex Virus Activity of N-docosanol Includes Inhibition of the Viral Entry Process.Antivir. Res. 40: 85-94 (Exhibit 14).
Reusser, P., (1998) Current Concepts and Challenges in the Prevention and Treatment of Viral Infections in Immonocompromised Cancer Patients.Support Care Cancer, 6: 39-45 (Exhibit 15).
Vogt et al., (1992) “Antiviral Activity of a Series of Cobalt Containing Complexes Against Herpesvirus Infection in Vitro and in Vivo”Antivir. Res. 17: 114 (Exhibit 16).
Wood, M. J., (1996) “Antivirals in the Context of Hiv Disease”J. Antimicrob. Chemother. 37: 97-112 (Exhibit 17).
Wooley et al., (1992) “The influence of Superoxide Scavenging Compound Ctc 23 on Type Ii Collagen-induce Arthritis in Mice”Agents Actions35: 273-279 (Exhibit 18).
Aguilar, et al. (1999) The Polysulfonated Compound Suramin Blocks Adsorption and Lateral Diffusion of Herpes Simplex Virus Type-1 in Vero Cells.Virology258: 141-151. (Exhibit 4).
Alrabiah and Sacks. (1996) New Antiherpesvirus Agents: Their Targets and Therapeutic Potential.Drugs, 52: 17-32 (Exhibit 5).
Asbell et al., (1998) Efficacy of Cobalt Chelates in the Rabbit Eye Model for Epithelial Herpetic Keratitis.Cornea, 17: 550-557 (Exhibit 6).
Balfour, H. H, (1999) “Antiviral Drugs”N. Engl. J. Med. 340: 1255-1268 (Exhibit 7).
Blum et al., (1998) “Isolation of a Myoglobin Molten Globule by Selective Cobalt (iii)-induced Unfolding”,Proc. Natl. Acad. Sci. USA. 95: 6659-6662 (Exhibit 8).
Bourne et al., (1997) Evaluation of the Antiviral Activity of an Organometallic Compound in the Guinea Pig Model of Genital Herpes.Antiviral Research, 34: A81 (Exhibit 9).
Devin et al., (1993) Efficacy of Ctc Topical Therapy During Hsv-1-induced Epithelial and Stromal Keratitis in the Rabbit.Invest. Opthal. Vis. Sci. 34: 1348 (Exhibit 10).
Lium Erik K.
Schwartz Jennifer A.
Silverstein Saul J.
Cooper & Dunham LLP
The Trustees of Columbia University in the City of New York
Webman Edward J.
White John P.
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