Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-29
2002-12-03
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S262100, C514S085000, C514S085000, C514S085000, C514S085000
Reexamination Certificate
active
06489330
ABSTRACT:
This invention relates to treatment of medical conditions associated with infection with human herpesvirus 8 (HHV-8), and to the use of compounds in the preparation of a medicament for use in the treatment of such conditions.
When used herein, ‘treatment’ includes prophylaxis as appropriate.
EP-A-141927 (Beecham Group p.l.c.) discloses penciclovir, the compound of formula (A):
and salts, phosphate esters and acyl derivatives thereof, as antiviral agents. The sodium salt hydrate of penciclovir is disclosed in EP-A-216459 (Beecham Group p.l.c.). Penciclovir and its antiviral activity is also disclosed in Abstract P.V11-5 p.193 of ‘Abstacts of 14th Int. Congress of Microbiology’, Manchester, England Sep. 7-13, 1986 Boyd et. al.).
Orally active bioprecursors of the compound of formula (A) are of formula (B):
and salts and derivatives thereof as defined under formula (A): wherein X is C
1-6
alkoxy, NH
2
or hydrogen. The compounds of formula (B) wherein X is C
1-6
alkoxy or NH
2
are disclosed in EP-A-141927 and the compounds of formula (B) wherein X is hydrogen, disclosed in EP-A-182024 (Beecham Group p.l.c.) are preferred prodrugs. A particularly preferred example of a compound of formula (B) is that wherein X is hydrogen and wherein the two OH groups are in the form of the acetyl derivative, described in Example 2 of EP-A-182024, hereinafter referred to as famciclovir.
The compounds of formulae (A) and (B) and salts and derivatives thereof have been described as potentially effective in the treatment of infections caused by herpesviruses, such as herpes simplex type 1, herpes simplex type 2, varicella-zoster, Epstein-Barr viruses, and cytomegalovirus. Famciclovir, sold in the United Kingdom and the United States of America under the trademark, FAMVIR, is used for treating herpes zoster (shingles).
Human herpesvirus 8 (HHV-8) is a recently discovered member of the family Herpesviridae. The virus is first reported by Chang et al in ‘Science’ Vol 266, Dec. 16th, 1994, p1865 and termed HHV-8 by Schulz et al in ‘Nature’ Vol 373, Jan. 5th, 1995, p17. This virus is described therein as being associated with Kaposi's Sarcoma (KS), the most common neoplasm ocurring in persons with aquired immunodeficiency syndrome (AIDS). Agents previously suspected of causing KS include cytomegalovirus (CMV), hepatitis B virus, human herpesvirus 6, HIV and
Mycoplasma penetrans
. It is possible that HHV-8 is associated with other proliferative diseases, involving various cell types, including endothelial, epithelial, neuronal, pancreatic, myloid cell types, and inflammatory, autoimmune-like, and tissue degenerative diseases such as rheumatoid arthritis, lupus eritematosis and multiple sclerosis. It is also possible that HHV-8 is associated with AIDS related illness. When used herein, the alternative term for HHV-8, which is ‘Kaposis Sarcoma-associated Herpes Virus’, is included.
It has now been discovered that the above compounds have potential activity against HHV-8.
Accordingly, the present invention provides a method of treatment of HHV-8 infection in humans, which method comprises the administration to the human in need of such treatment, an effective amount of a compound of formula (A):
or a bioprecursor, or a pharmaceutically acceptable salt, phosphate ester and/or acyl derivative of either of the foregoing.
The term ‘acyl derivative’ is used herein to include any derivative of the compounds of formula (A) in which one or more acyl groups are present. Such derivatives are included as bioprecursors of the compounds of formula (A) in addition to those derivatives which are per se biologically active.
The compound of formula (A) may be in one of the forms disclosed in EP-A-216459 (Beecham Group p.l.c.).
REFERENCES:
patent: 0141927 (1985-05-01), None
patent: 0182024 (1986-04-01), None
patent: 0216459 (1987-07-01), None
patent: 0 458 363 (1991-11-01), None
patent: WO A 9200742 (1992-01-01), None
Boyd et al, Antiviral Chemistry & Chemotherapy, vol. 4, supplement 1, pp. 3-11, 1993.*
Clarke et al, 113CA:189452 , 1990.*
Black et al., Medical Virology, vol. 3, “Human Herpesvirus 7,” pp. 217-223 (1993).
Clarke et al., Biochimica et Biphysica Acta, 1050, “Epstein-Barr Virus Gene Expression in Interferon-Treated Cells. Implications for the Regulation of Protein Synmthesis and the Antiviral State,” pp. 167-173 (1990).
Feorino et al., Abstract of Poster of the Eighth International Conference on Antiviral Research (ICAR) (1995), “Evaluation of Antiviral Agents Against HHV-6 and HHV-7 in Human Cord Blood Cells”.
Feorino et al., Full Poster of the Eighth International Conference on Antiviral Research (ICAR) (1995), “Evaluation of Antiviral Agents Against HHV-6 and HHV-7 in Human Cord Blood Cells”.
Nicholas, J., Journal of Virology, vol. 70(9), “Determination and Analysis of the Complete Nucleotide Sequence of Human Herpesvirus 7,” pp. 5975-5989 (1996).
Berneman et al., Proc. Natl. Acad. Sci., USA, 89, pp. 10552-10556 (1992).
Frenkel et al., Fields Virology, 3rd. Ed. pp. 20609-20622 (1996).
Harnden et al., vol. 110 Chemical Abstract:173658p, pp. 819 (1989).
Akesson-Johansson et al., Antimicrobial Agents and Chemotherapy, Dec. 1990, vol. 34(12), pp. 2417-2419.
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Agut et al., Institut Pasteur/Elsevier, (1989), 140(3) pp. 219-228.
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Ablashi D. V. et al. In Vivo, vol. 5 (3), 1991, pp. 193-200.
Fields B N et al., Fields Virology, Chapter 71, p. 2221 (1996).
J.B. Black et al., Virus Research 52 (1997) pp. 25-41.
Vere Hodge RA. et al., Antiviral Chemistry and Chemotherapy (1993) 4 Suppl. 1, pp. 13-24.
Earnshaw D.L. et al., Antimicrobial Agents and Chemotherapy (1992) 36, pp. 2747-2757.
Vere Hodge et al., Antimicrobial Agents and Chemotherapy (1989) 33, pp. 223-229.
Boyd et al., Antimicrobial Agents and Chemotherapy (1987) 31, pp. 1238-1242.
Larsson A. et al., Antimicrobial Agents and Chemotherapy (1986) 30. pp. 598-605.
Boyd et al., Antiviral Chem. Chemother, Suppl., 4(1), pp. 3-11 (1993).
Luppi et al., Haematologica, 81(3), pp. 265-281 (1996).
Fields et al., Fields Virology, 3rd Ed., Phila.-NY, p. 2595 (1995).
Esser Klaus Max
Hodge Richard Anthony Vere
Novartis International Pharmaceutical Ltd.
Savitsky Thomas R.
Travers Russell
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