Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-21
2003-11-25
Padmanabhan, Sreeni (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S256000, C514S269000, C514S272000, C514S467000, C514S461000
Reexamination Certificate
active
06653318
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pyrimidine nucleoside compounds and their use to treat viral infections of Varicella Zoster Virus, Epstein Barr Virus and Kaposi's Sarcoma virus, also known as HV-8 and related complications of these viral infections. In another aspect of the present invention, the use of one or more nucleoside compound to increase the rentention or the metabolic/catabolic half-life of 5-fluorouracil (FU) in cancer patients is also described.
BACKGROUND OF THE INVENTION
As human bacterial infections have become more manageable and treatable through the use of increasingly available antibiotic agents, viral infections have remained a more difficult and less treatable target. Emphasis in finding agents to treat viral infections has remained a high priority. Problematic virus is Varicella zoster virus, Epstein Barr virus and Kaposi's Sarcoma virus.
Varicella zoster virus (VZV), a member of the herpes virus family, is a main causative agent for a primary infection (varicella and chickenpox) as well as a recurrent disease (zoster and shingles). Snoeck, et al., “Chemotherapy of varicella-zoster virus-infections.”
Intl. J. Antimicrob. Agents
1994, 4, 211-226. The course of varicella is generally benign in immunocompetent patients, however, in immunocompromised patients, particularly patients suffering from the acquired immune deficiency syndrome (AIDS), transplant recipients, and cancer patients, VZV infections can be life-threatening. Snoeck, et al. “Current pharmacological approaches to the therapy of varicella zoster virus infections. A guide to treatment.”,
Drugs
1999, 57, 187-206; and Lee, P. J. and Annunziato, P. “Current management of herpes zoster.”
Infections in Medicine
1998, 15, 709-713.
The current treatment for patients infected with VZV and for immunocompetent patients at risk, such as pregnant women or premature infants, is based on acyclovir (ACV). See, Whitley, R. J. “Therapeutic approaches to varicella-zoster virus infections.”
J. Infect. Dis
. 1992, 166, Suppl. 1: 51-57; Shepp, et al. “Treatment of varicella-zoster virus in severely immunocompromised patients: a randomized comparison of acyclovir and vidarabine.”
New Engl. J. Med
. 1986, 314, 208-212; Whitley, et al. “Disseminated herpes zoster in the immunocompromised host: a comparative trial of acyclovir and vidarabine.”
J. Infect. Dis
. 1992, 165, 450-455. However, the efficacy and low oral bioavailability of ACV (De Miranda and Blum, “Pharmacokinetics of acyclovir after intravenous and oral administration.”
J. Antimicrob. Chemother
. 1983, 12, Suppl. B: 29-37), as well as the emergence of drug-resistant virus strains (See, Pahwa, et al. “Continuous varicella-zoster infection associated with acyclovir resistance in a child with AIDS”
J. Am. Med. Assoc
. 1988, 260, 2879-2882; Linnemann, et al. “Emergence of acyclovir-resistant varicella zoster virus in an AIDS patient on prolonged acyclovir therapy.”
AIDS
1990, 4, 577-579; Jacobson, et al. “Acyclovir-resistant varicella zoster virus infection afetr chronic acyclovir therapy in patients with the acquired immunodeficiency syndrome (AIDS).”
Ann. Intern. Med
. 1990, 112, 187-191), have stimulated the development of new compounds for the treatment of VZV infection.
Among the efforts to develop new compounds, (E)-5-(2-bromovinyl)uracil (BVU) analogues, such as (E)-5-(2-bromovinyl)-2′-deoxyuridine (BVDU) and 1-&bgr;-
D
-arabinofuranosyl-(E)-5-(2-bromovinyl)uracil (BVaraU), have been found to exhibit potent anti-VZV activity. See, for example, De Clercq, et al. “(E)-5-(2-Bromovinyl)-2′-deoxyuridine: a potent and selective anti-herpes agent.”
Proc. Natl. Acad. Sci. USA
1979, 76, 2947-2951 and Machida, et al., “Antiherpes-viral and anticellular effects of 1-&bgr;-
D
-arabinofuranosyl-E-5-(2-halogenovinyl)uracils.
Antimicrob. Agents Chemother
. 1981, 20, 47-52. However, metabolic stability of BVDU by pyrimidine nucleoside phosphorylase and, recently, drug interaction of BVaraU with anticancer agent 5-FU, which resulted in death of several patients with cancer and herpes zoster, have been potential drawbacks and limit their use. Desgranges, et al.,
Biochem. Pharmacol
. 1983, 32, 3583; David, S., “Deaths bring clinical trials under scrutiny in Japan.”
Nature
1994, 369, 697 and Watabe, et al., “Lethal drug interactions of the new antiviral, sorivudine, with anticancer prodrugs of 5-fluorouracil.”
Yakugaku Zasshi
1997, 117, 910-921. Efforts to address these problems have led to several interesting nucleosides, such as 4′-thio-BVDU and the carbocyclic analog carba BvdU. Dyson, et al. “The synthesis and antiviral activity of some 4′-thio-2′-deoxy nucleoside anlogues.”
J. Med. Chem
. 1991, 34, 2782-2786 and Herdewijn, et al., “Synthesis and antiviral activity of the carbocyclic analogues of (E)-5-(2-halovinyl)-2′-deoxyuridines and (E)-5-(2-halovinyl)-2′-deoxycytidines.”
J. Med. Chem
. 1985, 28, 550-555. However, the carba derivatives perform very poorly in vivo although they are resistant to degradation and in cell cultures have antiviral activities comparable to those of the parent compounds. Spadari, et al., “5-Iodo-2′-deoxy-
L
-uridine and (E)-5-(2-bromovinyl)-2′-deoxy-
L
-uridine: selective phosphorylation by herpes simplex virus type 1 thymidine kinase, antiherpetic activity, and cytotoxicity studies.”
Mol. Pharmacol
. 1995, 47, 1231-1238.
L-&bgr;-BVOddU was originally discovered by Krzystof, et al. to have inhibitory activity against HSV-1 replication. Although this compound is known, the potential usage for the treatment of VZV has not been reported. See Krzystof, et al.,
Bioorganic and Medical Chemistry Letter
. Vol 4 (22):2667-2672.
Epstein-Barr virus (EBV) is an important human pathogen, related to herpes simplex virus (HSV). Elliot Kieff,
Virology
, Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et al. Epstein-Barr Virus and Its Replication. Chapter 74. Pp 2343-2396 and Alan B. Rickinson and Elliot Kieff, Ibid. Chapter 75, pp. 2397-2446. EBV is a lymphotrophic member of the genus Lumphocryptovirus, and belongs to the sub-family gammaherpesvirinae. Another new member of human virus also belonging to this family is Kaposi's sarcoma-associated herpes virus (KSHV/HHV8). Chang, et al.,
Science
, 266:1865-1869 (1994); Cesarman, et al.,
N. Eng. J. Med
., 332:1186-1191 (1995); Soulier, et al.,
Blood
, 86:1276-1280 (1995). There are two sub-types of EBV identified and their genomes are nearly identical, but there is no clear relationship between EBV associated diseases and EBV sub-types. Abdul-Hamid, et al.,
Virology
, 190: 168-175 (1992) and Sample, et al.,
J. Virol
., 64:4084-4092 (1990). The lytic EBV genome is a linear, double-stranded, 172 Kbp DNA composed of 60 mol % guanine and cytosine. The genome has been sequenced and it was found to be capable of encoding a number of virus specified proteins, which include several enzymes involved in virus DNA synthesis during lytic infection of EBV. In vitro, EBV infection is generally limited to B-lymphocytes, although epithelial cells can also be infected. Sixbey, et al.,
Nature
, 306:480-483 (1983). In humans, the virus genome can be detected in B-lymphocytes and T-lymphocytes as well as epithelial cells. The EBV genome replicates lytically in the linear form and can also be latent as supercoiled circular DNA. The expression of the EBV genome in lytic infected cells is very different from latent infected cells. EBV specified DNA plymerase, Dnase and dThd kinase are only expressed in cells upon lytic DNA replication. Cell culture studies indicated the essential role of EBV specified DNA polymerase for EBV DNA replication during lytic infection, but not for the maintenance of supercoiled EBV DNA in latent infected cells. A unique set of EBV proteins including EBVNA 1 and sometimes, EBNA LP, 2, 3A, 3B, 3C, LMP 1 as well as LMP2 is expressed in latent infected or transformed cells. Elliot Kieff,
Virology
, Third Edition, Edited by B. N. Fields, D. M. Knipe, P. M. Howley, et
Chai Yongseok
Cheng Yung-Chi
Chu Chung K.
Li Ling
Coleman Henry D.
Coleman Sudol Sapone P.C.
Jiang S.
Padmanabhan Sreeni
Yale University
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