Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-11-03
2003-05-20
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...
C514S262100, C514S241000, C514S245000, C514S246000, C514S385000, C514S393000
Reexamination Certificate
active
06566365
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a method for the treatment or prevention Flaviviridae viral infection using nucleoside analogues.
BACKGROUND OF THE INVENTION
Hepatitis is a disease occurring throughout the world. It is generally of viral nature, although there are other causes known. Viral hepatitis is by far the most common form of hepatitis. Nearly 750,000 Americans are affected by hepatitis each year, and out of those, more than 150,000 are infected with the hepatitis C virus (HCV).
HCV is a positive-stranded RNA virus belonging to the Flaviviridae family and has closest relationship to the pestiviruses that include hog cholera virus and bovine viral diarrhea virus (BVDV). HCV is believed to replicate through the production of a complementary negative-strand RNA template. Due to the lack of efficient culture replication system for the virus, HCV particles were isolated from pooled human plasma and shown, by electron microscopy, to have a diameter of about 50-60 nm. The HCV genome is a single-stranded, positive-sense RNA of about 9,600 bp coding 30 for a polyprotein of 3009-3030 amino-acids, which is cleaved, post-translationally by cellular and two viral proteinases into mature viral proteins (core, E1, E2, p7, NS2, NS3, NS4A, NS4B, NS5A, NS5B). It is believed that the structural proteins, E1 and E2, the major glycoproteins are embedded into a viral lipid envelop and form stable heterodimers. The structural core protein interacts with the viral RNA genome to form the nucleocapsid. The genes or regions designated NS2 to NS5 code for nonstructural proteins some of which have enzymatic functions involved in virus replication and protein processing including a polymerase, protease and helicase.
The main sources of contamination with HCV is blood. The magnitude of the HCV infection as a health problem is illustrated by the prevalence among high-risk groups. For example, 60% to 90% of hemophiliacs and more than 80% of intravenous drug abusers in western countries are chronically infected with HCV. For intravenous drug abusers, the prevalence varies from about 28% to 70% depending on the population studied. The proportion of new HCV infections associated with post-transfusion has been markedly reduced lately due to advances in diagnostic tools used to screen blood donors.
The treatment currently available for HCV infection is interferon (IFN), ribavirin, and a combinaison of the two (REBETRON). However, according to different clinical studies, only 70% of treated patients normalize alanine aminotransferase (ALT) levels in the serum and after discontinuation of IFN, 35% to 45% of these responders relapse. In general, only 20% to 25% of patients have long-term responses to IFN. On the other hand, pilot studies suggest that combination treatment with IFN plus Ribavirin (RIBA) results in sustained response in the majority of patients. Different genotypes of HCV respond differently to IFN therapy, genotype 1b is more resistant to IFN therapy than type 2 and 3.
There is therefore a great need for the development of therapeutic agent for treating or preventing Flaviviridae viral infection.
SUMMARY OF THE INVENTION
The present invention provides a method for treating or preventing a Flaviviridea viral infection in a host comprising administering a therapeutically effective amount of at least one compound selected from:
or a pharmaceutically acceptable salts thereof, wherein:
R is H, —NR
2
R
3
or OR
4
wherein
R
2
is H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
cycloalkyl;
R
3
is H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl;
R
4
is H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl; and
Z is H, OR
4′
, or —NR
2′
R
3′
wherein:
R
2′
is H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
3-8
cycloalkyl,
R
3′
is H, C
1-6
alkyl, C
2-6
alkenyl, or C
2-6
alkynyl;
R
4′
is H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl; and and;
Y is N or C—X;
X is chosen from of H, halogen, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, CN, CF
3
, N
3
, NO
2
, C
6-10
aryl, C
6-10
heteroaryl and CORb wherein Rb is chosen from of H, OH, SH, C
1-6
alkyl, C
1-6
aminoalkyl, C
1-6
alkoxy and C
1-6
thioalkyl;
and Ra is chosen from of H, monophosphate, diphosphate, triphosphate, carbonyl substituted with a C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl, C
6-10
aryl, and
wherein each Rc are independently chosen from H, C
1-6
alkyl, C
2-6
alkenyl, C
2-6
alkynyl and an hydroxy protecting group,
wherein said nucleoside is present in the form of the (−) enantiomer, the (+) enantiomer or mixtures thereof, including racemic mixtures.
The present invention provides a method for treating a Flaviviridea viral infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a method for preventing a Flaviviridea viral infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
The present invention provides a method for reducing the biological activity of a Flaviviridea viral infection in a host comprising administering a therapeutically effective amount of at least one compound as described in the present application.
In another aspect, there is provided a pharmaceutical formulation comprising the compound of the invention in combination with a pharmaceutically acceptable carrier or excipient.
Still another aspect, there is provided a method for treating or preventing a Flaviviridea viral infection in a host comprising administering to the subject a combination comprising at least one compound according to formula I or formula II and at least one further therapeutic agent.
In another aspect of the invention is the use of a compound according to formula I, for the preparation of a medicament for treating or preventing a viral infections in a host.
In another aspect of the invention is the use of a compound according to formula II, for the preparation of a medicament for treating or preventing a viral infection in a host.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the viral infection is chosen from Flaviviridea viral infections.
In one embodiment, the Flaviviridea viral infection is chosen from of Hepatitis C virus(HCV), bovine viral diarrhea virus(BVDV), hog cholera and yellow fever.
In an other embodiment, the Flaviviridea viral infection is Hepatitis C.
In one embodiment, there is also provided a method for inhibiting or reducing the activity of viral polymerase in a host, when compared to a standard comprising administering a therapeutically effective amount of a compound having the formula I.
In one embodiment, there is also provided a method for inhibiting or reducing the activity of viral polymerase in a host, when compared to a standard, comprising administering a therapeutically effective amount of a compound having the formula II.
In one embodiment, there is also provided a method for inhibiting the activity of viral polymerase in a host, when compared to a standard comprising administering a therapeutically effective amount of a compound having the formula I.
In one embodiment, there is also provided a method for inhibiting the activity of viral polymerase in a host, when compared to a standard, comprising administering a therapeutically effective amount of a compound having the formula II.
In one embodiment, there is also provided a method for reducing the activity of viral polymerase in a host, when compared to a standard comprising administering a therapeutically effective amount of a compound having the formula I.
In one embodiment, there is also provided a method for reducing the activity of viral polymerase in a host, when compared to a standard, comprising administering a therapeutically effective amount of a compound having the formula II.
In another embodiment, the viral polymerase is HCV polymerase.
In one embodiment, the compounds and methods of the present invention comprise those wherein the following
Bio-Chem Pharma Inc.
Jiang Shaojia A.
Millen White Zelano & Branigan P.C.
Padmanabhan Sreeni
LandOfFree
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