Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-10-19
2002-09-24
Lambkin, Deborah C. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S422000, C514S397000, C514S365000, C514S374000, C548S532000, C548S533000, C548S518000, C548S314700, C548S205000, C548S236000, C548S237000
Reexamination Certificate
active
06455571
ABSTRACT:
TECHNICAL FIELD
The present invention relates to novel compounds, compositions and methods for inhibiting neuraminidase, especially influenza neuraminidase. The invention also contemplates a composition and methods for preventing and treating an influenza infection and processes for making such compounds and synthetic intermediates employed in these processes.
BACKGROUND OF THE INVENTION
Many disease-causing microorganisms possess a neuraminidase (also known as sialidase) which is involved in the replication process of the microorganism. In particular, viruses of the orthomyxovirus and paramyxovirus groups possess a neuraminidase. Diseases associated with paramyxoviruses include RSV (respiratory syncytial virus-related diseases), pneumonia and bronchiolitis (associated with paramyxovirus type 3) and laryngotracheobronchitis (associated with paramyxovirus type 1). Some of the more important disease-causing microorganisms in man and/or animals which possess a neuraminidase include Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae, Arthrobacter sialophilus, influenza virus, parainfluenza virus, mumps virus, Newcastle diseane virus, fowl plague virus, equine influenza virus and Sendai virus.
Morality due to influenza is a serious problem throughout the world. The disease is devastating to man, lower mammals and some birds. Although vaccines containing attenuated influenza virus are available, those vaccines only provide immunological protection toward a few influenza strains and are less effective in otherwise immunologically compromised populations such as the elderly, young children, and in those who suffer from chronic respiratory illness. The productivity loss from absence due to sickness from influenza virus infection has been estimated to be more than $1 billion per year.
There are two major strains of influenza virus (designated A and B). Currently, there are only a few pharmaceutical products approved for treating influenza. These include amantadine and rimantadine, which are active only against the A strain of influenza viruses, and ribavirin, which suffers from dose-limiting toxicity. Mutant virus which is resistant to amantadine and rimantadine emerges quickly during treatment with these agents.
Very recently the first influenza neuraminidase inhibitor, zanamivir, was approved. However, it can only be administered by inhalation. Therefore, there is a continuing need for improved agents for treatment and/or prevention of influenza infection.
Neuraminidase is one of two major viral proteins which protrude from the envelope of influenza virus. During the release of progeny virus from infected cells, neuraminidase cleaves terminal sialic acid residues from glycoproteins, glycolipids and oligosaccharides on the cell surface. Inhibition of neuraminidase enzymatic activity leads to aggregation of progeny virus at the surface. Such virus is incapable of infecting new cells, and viral replication is therefore retarded or blocked. X-ray crystallographic studies and sequence alignments have shown that the residues which directly contact the sialic acid portion of the substrate are strictly conserved in the neuraminidase from all A and B influenza strains. Thus, a compound which binds to the sialic acid binding region of the neuraminidase active site will block the replication of both the A and B strains of influenza virus. Compounds which are influenza neuraminidase inhibitors will be useful for the prevention of influenza infection and will be useful for the treatment of influenza infection.
The following references disclose neuraminic acid derivatives with the disclosed utility listed after each reference:
L. Von ltzstein, et al., European Patent Application No. EP539204, published Apr. 28, 1993 (antiviral agent);
T. Honda, et al., European Patent Application No. EP823428, published Feb. 11, 1998 (sialidase inhibitor; influenza treatment);
T. Honda, et al., International Patent Application No. WO98/06712, published Feb. 19, 1998 (sialidase inhibitor; influenza remedy);
L. Von Itzstein, et al., International Patent Application No. WO95/20583, published Aug. 3, 1995 (viral neuraminidase inhibitor; influenza treatment);
P. Smith, International Patent Application No. WO95/18800, published Jul. 13, 1995 (viral neuraminidase inhibitor);
P. Colman, et al., International Patent Application No. WO92/06691, published Apr. 30, 1992 (viral neuraminidase inhibitor);
L. Von Itzstein, et al., U.S. Pat. No. 5,648,379, issued Jul. 15, 1997 (influenza treatment);
P. Reece, et al., International Patent Application No. WO97/32214, published Sep.4, 1997 (bind to influenza virus neuraminidase active site); and
P. Reece, et al., International Patent Application No. WO98/21243, published May 23, 1998 (anti-influenza agent).
The following references disclose sialic acid derivatives with the disclosed utility listed after each reference:
Y. Ohira, et al., International Patent Application No. WO98/11083, published Mar. 19, 1998 (antiviral agent);
Y. Ohira, European Patent Application No. EP882721, published Dec. 9, 1998 (antiviral agent); and
B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibrio cholerae neuraminidase inhibitor).
The following references disclose benzene derivatives, cyclohexane derivatives or cyclohexene derivatives with the disclosed utility listed after each reference:
Y. Babu, et al., U.S. Pat. No. 5,602,277, issued Feb. 11, 1997 (neuraminidase inhibitors);
M. Luo, et al., U.S. Pat. No. 5,453,533, issued Sep. 26, 1995 (influenza neuraminidase inhibitor; influenza treatment);
Y. Babu, et al., International Patent Application No. WO96/30329, published Oct. 3,1996 (neuraminidase inhibitor; viral infection treatment);
N. Bischofberger, et al., U.S. Pat. No. 5,763,483, issued Jun. 9, 1998 (neuraminidase inhibitor);
C. Kim, et al., International Patent Application No. WO99/31047, published Jun. 24, 1999 (neuraminidase inhibitor, influenza treatment);
V. Atigadda, et al., J. Med. Chem. 42 2332-2343 (1999) (influenza neuraminidase inhibitor); and
K. Kent, et al., International Patent Application No. 98/07685, published Feb. 26, 1998 (intermediates for the preparation of neuraminidase inhibitors).
C. Kim, et al., International Patent Application No. WO98/17647, published Apr. 30, 1998 discloses piperidine derivatives that are useful as neuraminidase inhibitors.
N. Bischofberger, et al., International Patent Application No. WO96/26933, published Sep. 6, 1996 and N. Bischofberger, et al., International Patent Application No. WO99/141 85, published Mar. 25, 1999 disclose various substituted 6-membered ring compounds that are useful as neuraminidase inhibitors.
The following references disclose dihydropyran derivatives that are useful as viral neuraminidase inhibitors:
D. Andrews, et al., International Patent Application No. WO97/06157, published Feb. 20, 1997 and U.S. Pat. No. 5,919,819, issued Jul. 6, 1999; and
P. Cherry, et al., International Patent Application No. WO96/36628, published Nov. 21, 1996.
C. Kim, et al., U.S. Pat. No. 5,512,596, issued Apr. 30, 1996 discloses 6-membered aromatic ring derivatives that are useful as neuraminidase inhibitors.
G. Diana, et al., International Patent Application No. WO98/03487, published Jan. 29, 1998 discloses substituted pyridazines that are useful for treatment of influenza.
B. Horenstein, et al., International Patent Application No. WO99/06369, published Feb. 11, 1999 discloses piperazine derivatives that are useful as neuraminidase inhibitors.
The following references disclose substituted cyclopentanes that are useful as neuraminidase inhibitors and treatments for influenza:
Y. Babu, et al., International Patent Application No. WO97/47194, published Dec. 18, 1997; and
Y. Babu, et al., International Patent Application No. WO99/33781, published Jul. 8, 1999.
L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990) discloses pyrrolidine analogs of neuraminic acid that are useful as Vibrio cholerae sialidase inhibitors.
W. Brouillette, et al., International Patent Application No. WO99/14191, published Mar. 25, 199
Bayrakdarian Malken
Chen Hui-Ju
Chen Yuanwei
Degoey David A.
Flosi William J.
Abbott Laboratories
Donner B. Gregory
Lambkin Deborah C.
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