Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
1998-07-29
2002-09-24
Richter, Johann (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C536S028900
Reexamination Certificate
active
06455506
ABSTRACT:
TECHNICAL FIELD
This invention pertains to the general field of benzimidazole nucleoside analogs and their use as antiviral agents. More particularly, this invention pertains to benzimidazole nucleoside analogs wherein the sugar group is a lyxofuranosyl group and derivatives thereof. The present invention also pertains to methods of making such benzimidazole nucleoside analogs and derivatives, compositions comprising such compounds, the use of such compounds in antiviral treatment.
BACKGROUND
Throughout this application, various references including but not limited to publications, patents, and published patent applications are referred to by an identifying citation.
Members of the herpesvirus family (Herpesviridae) share a common virion architecture. A typical herpesvirion consists of (a) a core containing a linear, double-stranded DNA, (b) an icosahedral capsid, approximately 100-120 nm in diameter, containing 162 capsomeres, (c) an amorphous, sometimes asymmetric material that surrounds the capsid, designated as the tegument, and (d) an envelope containing viral glycoprotein spikes on its surface.
Major examples of human pathogens of the herpesviruses family include herpes simplex viruses (HSV) 1, 2, and cercopithecine herpesvirus 1 (B-virus); varicella-zoster (which causes chickenpox and shingles); Epstein-Barr virus (EBV, which causes mononucleosis); lymphocryptovirus; human herpesvirus 6 (HHV6); human herpesvirus 7 (HHV7) and kaposi-associated herpes virus (KHV); or human herpesvirus 8 (HHV8). Human cytomegalovirus (HCMV), also a human herpes virus, is a leading opportunistic pathogen among immunosuppressed individuals (see Alford, C. A.; Britt, W. J. Cytomegalovirus. In
The Human Herpesviruses.
Roizman, B.; Whitley, R. J.; Lopez, C. (Editors.) Raven Press, New York, 1993 pp. 227-255) and neonates (see Alford, C. A.; Stagno, S.; Pass, R. F.; Brit, W. J. Congenital and Perinatal Cytomegalovirus Infections in Bone Marrow Transplants.
Rev. Infect. Dis.
1990, 12, s793-s804 and Gallant, J. E.; Moore, R. D.; Richman, D. D.; Keruly, J.; Chaisson, R. E. Incidence and Natural History of Cytomegalovirus Disease in Patients with Advanced Immunodeficiency Virus Disease Treated with Zidovudine.
J. Infect. Dis.
1992, 166, 1223-1227).
Animal pathogens include infectious bovine rhinotracheitis virus, bovine mammillitis virus, cercopithecine herpesvirus 1 (B-virus), which are all simplexviruses; pseudorabies virus (PRV, of swine), equine rhinopneumonitis and coital exanthema viruses (varicellaviruses); baboon herpesvirus, pongine (chimpanzee) herpesvirus (lymphocryptovirus); Marek's disease virus (of fowl), turkey herpesvirus; herpesvirus ateles and herpesvirus saimiri (rhadinovirus); among others. For reviews see, Murphy et al., Virus Taxonomy, in Fields et al. (eds.)
Fundamental Virology,
1991, Raven Press, New York, p. 9-36; Watson et al.,
Molecular Biology of the Gene,
Fourth Edition, 1987, Benjamin/Cummings Publ. Co., Menlo Park, Calif., p. 904, 933.
Herpesvirus genomes, which are generally 120 to 230 kb long, encode 50 to 200 different proteins. These include a large array of enzymes involved in nucleic acid metabolism (e.g., thymidine kinase, thymidylate synthetase, dUTPase, ribonucleotide reductase, etc.), and DNA synthesis (e.g., DNA polymerase, helicase, primase).
In herpesviruses, the linear genome is characterized by repeated sequences, which vary in number, length and arrangement between the various classes of herpesvirus. In Epstein-Barr virus, for example, the ends of the genome have a large number of short (500-base pair) repetitions of the identical sequence as well as an internal sequence consisting of half a dozen repeats of a 3-kb sequence. In herpes simplex virus 1 and 2 and HCMV, portions of sequences from both termini are repeated in an inverted orientation and juxtaposed internally, dividing the genomes into two components, each of which consists of unique sequences flanked by inverted repeats. In this instance, both components (a long, L, arm and a short, S, arm) can invert relative to each other. DNA extracted from virions or infected cells consists of four equimolar populations differing in the relative orientation of the two components. For reviews see, Watson et al., 1987, p. 935; Roizman, Herpesviridae: A Brief Introduction, in Fields et al. (eds.)
Fundamental Virology,
1991, Raven Press, New York, p. 841-847; Roizman et al., Herpes Simplex Viruses and Their Replication, in Fields et al. (eds.)
Fundamental Virology,
1991, Raven Press, New York, p. 849-895.
To initiate infection, the virus attaches to receptors on a host cell. Fusion of the viral envelope with the plasma membrane rapidly follows initial attachment. The de-enveloped capsid is then transported to the nuclear pores, where DNA is released into the nucleus and rapidly circularizes. In the next steps, the transcription and translation of the herpes genes are tightly regulated. Three classes of genes are known, called &agr;, &bgr; and &ggr; (or immediate early, early and late). Expression of the &agr; genes is required to induce &bgr; gene expression; expression of &bgr; genes both induces &ggr; genes and shuts off &agr; genes; and expression of &ggr; genes turns off &bgr; genes. Thus, there are three distinct waves of herpesvirus gene expression during replication. Interestingly, the process seems to be circular in that at least one virion protein (a &ggr; gene product) is required to induce a gene expression soon after infection. This product enters with the virion and so helps to start the cycle. For reviews see, Watson et al., 1987, p. 935-936; Roizman et al., Herpes Simplex Viruses and Their Replication, in Fields et al. (eds.)
Fundamental Virology,
1991, Raven Press, New York, p. 849-895.
Some herpesviruses such as HSV-1 and HSV-2 have a wide host-cell range, multiply efficiently and rapidly destroy infected cells. Others (e.g. EBV, HHV6) have a narrow host-cell range or, in the case of HCMV, replicate slowly. For reviews see, Roizman et al., Herpes Simplex Viruses and Their Replication, in Fields et al. (eds.)
Fundamental Virology,
1991, Raven Press, New York, p. 849-895.
Herpesviruses replicate in the cell nucleus, wherein the nucleolus is displaced, disaggregated and then fragmented, and host chromosomes are marginated, which may lead to chromosome breakage. Host protein synthesis declines very rapidly (for most herpesviruses but not HCMV), host ribosomal RNA synthesis is reduced, and glycosylation of host proteins ceases. Production of progeny is invariably accompanied by the irreversible destruction of the infected cell. For reviews see, Roizman et al., Herpes Simplex Viruses and Their Replication, in Fields et al. (eds.)
Fundamental Virology,
1991, Raven Press, New York, p. 849-895.
A variety of disease symptoms and a complex clinical course are caused by herpesviruses. In the case of a first infection in an adult human, the symptoms may be very severe. Herpesviruses can cause recurrent infections, and the disability associated with these recurrences is a significant health problem. The most frequent manifestations of recurrent herpetic disease states were disclosed to involve the orofacial and genital regions and recurrent herpetic keratitis was characterized as a leading cause of blindness in the United States. Herpetic genital infections with a high incidence of subsequent recurrent episodes were noted as being recognized more frequently and being associated with significant morbidity. Cohen et al., U.S. Pat. No. 4,709,011, issued Nov. 24, 1987.
In studies on the molecular basis of disease induced by HSV, the endpoint of the research objective—the disease—may be synonymous with the destruction of the central nervous system (CNS). To disseminate to a target organ, however, the virus may first multiply at peripheral sites. In experimental systems, neurovirulence, the model of the disease producing the phenotype of HSV, is the consequence of (i) peripheral multiplication; (ii) invasion of the CNS; (iii) growth in the CNS. Virulence loci have been ascribed to sev
Drach John C.
Townsend Leroy B.
Birch & Stewart Kolasch & Birch, LLP
Crane Lawrence
Richter Johann
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