Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-01
2001-01-23
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S309000, C544S310000, C544S311000, C544S312000, C544S314000, C544S299000, C544S300000, C544S301000, C544S302000
Reexamination Certificate
active
06177437
ABSTRACT:
FIELD OF THE INVENTION
The invention relates generally to inhibitors of Herpes Simplex virus uracil-DNA glycosylase (UDG). More particularly, the invention relates to methods of inhibiting the activity of UDG in animals. Still more particularly, the invention relates to novel 6-aromatic substituted uracil compounds, therapeutic compositions thereof, and methods of treating Herpes Simplex virus Type I and Type II recurrent infections and Herpes simplex encephalitis in humans using the compounds and/or therapeutic compositions. All patents, published patent applications and other references disclosed herein are hereby expressly incorporated, in their entirety, by reference.
BACKGROUND OF THE INVENTION
Herpes Simplex virus Type 1 (HSV1), Herpes Simplex virus Type 2 (HSV2). Varcella-Zoster virus (VZV), and Epstein Barr virus (EBV) infections in humans are characterized by episodes of epithelial eruptions involving active virus production alternating with periods without clinical symptoms, i.e., in which the virus is in a latent state. In the case of the herpes virus VZV, the initial acute infection is known as chicken pox, and reactivation from the subsequent latent infection is manifested as the disease shingles. Animal models of the latent state show that at some defined period following inoculation with virus, conventional homogenization techniques are unable to detect free virus, but that the presence of the vital genome can be demonstrated by explanation rescue (cocultivation) techniques (Price, 1985).
In the mouse latency model for HSV1, viral genomes can be detected in sensory ganglia, most abundantly in trigeminal ganglia. The stimuli that cause virus to travel to neural cell bodies, the form of the viral genome present in the cells, and the molecular events that occur during reactivation of the virus are not known.
Herpes simplex virus (HSV), following a primary lytic infection in peripheral mucocutaneous tissues, enters nerve terminals and establishes lifelong latent infections in sensory nerve ganglia (Focher et al., 1993). During latency, no infectious virus is detectable, but such virus can “reactivate” causing recurrent disease at the original site of infection. Typically for HSV1 diseases, latent infection of the trigeminal ganglia is associated with herpes keratitis and infection of cervical ganglia with herpes labialis, whereas for HSV2, latent infections of sacral ganglia are associated with genital infections. Several reviews summarize the understanding of the mechanisms underlying herpes virus latency (Savva et al., 1995; Wildy et al., 1982; Stevens et al., 1987).
Maintenance of the latent state may be mediated by both viral and cellular (host) functions, and may last for the life of the host. Reactivation of the virus may be caused by various environmental, immunological and pharmacological stimuli, and involves replication of the virus genome, centrifugal travel of viral DNA or virus particles through the sensory nerve to the original site of infection, and re-establishment of clinical disease. The morbidity of recurrent herpes virus infections has prompted numerous studies related to treatment or prevention.
Recurrent Herpes simplex infections are significant medical problems. Up to one half of latently infected individuals may have one or more episodes of clinical disease per year. Recurrences are especially serious in immunocompromised patients and with virus strains that are drug resistant. It has even been suggested that herpes viruses are co-factors for HIV disease (Griffiths, 1995). Some AIDS patients experience breakthrough of herpes virus disease even on high dose acyclovir (Youle et al., 1994). Recurrent herpes labialis affects 20-45% of the U.S. population, and about 25% of those have 3 or more recurrences per year (Overall, 1979). Herpes keratitis is the leading cause of blindness in the U.S., and recurrence of this disease in immunocompromised patients has become increasingly associated with morbidity (Schwab, 1988). Recurrent genital herpes is both a medical and a social problem, and, although continuous antiviral treatment is effective, asymptomatic viral shedding can still occur (Bowman et al., 1990).
It is believed that, at present, acyclovir will reduce recurrences in genital infections, but in fact only about 20% of those infected remain recurrence free. In addition, most studies indicate that acyclovir does not prevent viral shedding. Thus, prevention of both recurrent disease and transmissibility to others are important goals in antiviral drug design.
Herpes encephalitis, primarily associated with HSV1, is a disease with high morbidity. Untreated, the mortality rate approaches 90%, and, although acyclovir and araA are effective in reducing mortality, the prognosis for severe cases and the elderly is poor (Jeffries et al., 1995). Antiviral nucleosides may be less effective in encephalitis because of the lack of the activating enzyme, thymidine kinase, in nerve cells.
Development of antiherpetic drugs has focused on targeting inhibitors against the various enzymes encoded by the herpes viruses. Among virus-specific enzymes, the viral DNA polymerase has been an important target for nucleoside analogs such as acyclovir, bromovinyldeoxyuridine and DHPG.
Currently available antiviral drugs such as arabinosyladenine, acyclovir, and phosphonoacetic acid are effective in the treatment of acute HSV infections, but less so in preventing recurrent infections. For example, recurrent herpes labialis and herpes encephalitis in children and older adults are generally resistant to standard antiviral drugs. Acyclovir prevented in vitro reactivation of HSV1 from latently infected trigeminal ganglia of mice only with continuous presence of the drug, as also found for arabinosyladenine and phosphonoacetic acid (Price, 1985). In human patients, the frequency of HSV recurrences following acyclovir treatment were not different than before treatment (Roizman et al., 1987), and it has been suggested that recurrences are longer and more severe in AIDS patients than in immunocompetent patients (Ho, 1992).
HSV1 and HSV2 are known to encode a thymidine kinase (“TK”) enzyme in addition to the viral DNA polymerase. The viral DNA polymerase is known to catalyze the replication of the viral genome, although the role(s) of the viral TKs are not well understood. It is thought that herpes virus TK expression is required for the establishment or reactivation of virus from its latent state, particularly in tissues such as peripheral nerve ganglia where host TK expression and DNA synthesis are absent (Price, 1985). Inhibitors of HSV1- and HSV2-TK, and their use for treating recurrent Herpes virus infections are described in U.S. Pat. No. 5,646,155.
Recent results have suggested similar roles for the HSV1-specific uracil DNA glycosylase (UDG) (Jacobson et al., 1989). It is now hypothesized that Herpes Simplex virus Type 1 uracil-DNA glycosylase (HSV-1 UDG or “UDG”) is an important enzyme for efficient viral reactivation (Overall, 1979). UDG contributes to post-replicative DNA repair by removal of uracil residues from DNA, resulting either from cytosine deamination or dUTP incorporation, by cleavage of the N-glycosidic bond linking the base to the deoxyribose phosphate backbone. Recent evidence suggests that the viral UDG is required both for virus reactivation from latency and for efficient replication in nerve tissue (Schwab, 1988). The continuous spontaneous deamination of cytosine coupled with the lack of cellular UDG in neurons (Bowman, 1990) are consistent with a requirement for the virus-encoded enzyme in the reactivation and replication of HSV in nerve cells.
OBJECTS OF THE INVENTION
Therefore, it is an object of the invention to provide inhibitors of Herpes Simplex virus uracil-DNA glycosylase (UDG).
It is another object of the invention to provide therapeutic compositions for treatment of recurrent Herpes Simplex infections and herpes simplex encephalitis.
It is yet another object of the invention to provide a method for treating/preventing Herpes Simplex virus recurre
Ford John M.
Lahive & Cockfield LLP
Lauro, Esq. Peter C.
University of Massachusetts Medical Center
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