Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-09-24
2001-11-13
Travers, Russell (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S444000, C514S445000, C424S085400
Reexamination Certificate
active
06316492
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for preventing and treating viral infections and the diseases associated therewith, particularly those viral infections and associated diseases caused by viruses within the Flaviviridae family.
BACKGROUND OF THE INVENTION
The Flaviviridae family consists of three genera and several viruses that are currently unassigned to specific genera. The hepacivirus genus includes the hepatitis C virus (HCV). Viruses such as GB virus-A and GB virus-A-like agents, GB virus-D and GBV-C or hepatitis G virus, while at present not formally classified within the hepacivirus genus, are closely related to HCV and represent unassigned members of the Flaviviridae family. Also within the Flaviviridae is the pestivirus genus, which includes bovine viral diarrhea viruses (BVDV), border disease viruses and classical swine fever virus, and the flavivirus genus, with viruses such as dengue, yellow fever, Japanese encephalitis and tick-borne encephalitis viruses.
Viruses within this family cause significant disease in human and animal populations. HCV is a major cause of human hepatitis globally. The World Health Organization estimates that 170 million people worldwide are presently infected with the virus. Most infections become persistent and about 60% of cases develop chronic liver disease. Chronic HCV infection can lead to development of cirrhosis, hepatocellular carcinoma and liver failure.
Interferon and interferon in combination with ribavirin are used in the U.S. for hepatitis due to HCV. These treatments are associated with improved serum enzyme response in some patients. The remainder are non-responsive to treatment. For responders, a sustained clinical improvement is seen in only a small percentage of patients; the majority of patients relapse upon cessation of treatment. Thus, the effectiveness of therapy for chronic hepatitis C is variable and its cure rate remains low. Moreover, therapy is often associated with considerable adverse effects.
Pestivirus infections of domesticated livestock cause significant economic losses worldwide. Pestiviruses cause a range of clinical manifestations including abortion, teratogenesis, respiratory problems, chronic wasting disease, immune system dysfunction and predisposition to secondary viral and bacterial infections. Certain BVDV strains cause an acute fatal disease. BVDV can also establish persistent infected (PI) animals remain viremic throughout life and serve as continuous virus reservoirs. PI animals often succumb to fatal mucosal disease.
Flaviviruses are important pathogens of man and are also prevalent throughout the world. There are at least 38 flaviviruses associated with human disease, including the dengue fever viruses, yellow fever virus and Japanese encephalititis virus. Flaviviruses cause a range of acute febrile illnesses and encephalitic and hemorrhagic diseases.
Currently, there are no antiviral pharmaceuticals to prevent or treat pestivirus or flavivirus infections.
New therapies and preventatives are clearly needed for infections and diseases caused by viruses of Flaviviridae family.
In considering approaches to the diagnosis, control, prevention and treatment of infections and associated diseases caused by viruses, it is often desirable to identify virus-specific functions that may be exploited in such approaches. In particular, enzymatic activities of virus-encoded polypeptides are quite useful. These virus-specified components are often essential for virus replication and may be suitable targets for antiviral drug discovery strategies.
One such target that plays a central role in the life cycle of many RNA viruses is the virus-encoded RNA-dependent RNA polymerase (RdRp) protein. Regarding viruses of the Flaviviridae, this protein is termed NS5B in the case of the hepaciviruses and pestiviruses, and NS5 in the case of the flaviviruses (collectively referred to as NS5). RdRp proteins are a key component of the virus replicase complex, enabling the virus to replicate its RNA genome and produce progeny viruses. The RdRp of RNA viruses is an attractive target for antiviral drug development.
SUMMARY OF THE INVENTION
In accordance with the present invention, there is provided a method for treating viral infection and diseases asscoiated with such infection in a living host having such infection, by administering to such host a therapeutically effective amount of a compound, or a precursor thereof, having the following formula:
wherein W represents O, S, or N(R
a
), R
a
being hydrogen or an alkyl group of 1-5 carbon atoms; X, Y and Z may be the same or different and each represents hydrogen or a substituent selected from the group consisting of halogen, nitro, carboxy, hydroxy, alkyl of 1-5 carbon atoms, trifluoromethyl, alkoxy, acyloxy, cyano, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, carbalkoxy, thio, alkylthio, alkylsufinyl and alkylsulfonyl;
R
1
represents a radical selected from those consisting of an unsubstituted or substituted heterocyclic group, an unsubstituted or substituted bicyclic ring moiety, an unsubstituted or substituted phenyl (C
6
H
5
) group, an unsubstituted or substituted biphenyl (C
6
H
5
-C
5
H
4
) group, an unsubstituted or substituted &ohgr;-phenylalkenyl (C
6
H
5
(CH═CH)
n
) group, n being an integer from 1 to 5, such as phenylethenyl, an unsubstituted or substituted &ohgr;-phenylalkynyl (C
6
H
5
(C≡C)
p
) group, p being an integer from 1 to 5, or an unsubstituted or substituted alkyl group of 1-5 carbon atoms which may be straight or branched chain, said heterocyclic group being selected from those consisting of furan, thiophene, oxazole, oxadiazole, pyridine, pyrimidine, pyrazole, triazole, pyridazine, 1,3-oxathiolane, thiazole, thiadiazole, imidazole, pyrrole, tetrazole and triazine, said bicyclic ring moiety being selected from those consisting of benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, benzoxazole, benzopyrrole (indole), isoindole, benzpyrazole, quinoline, isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, 1,2,3-benzotriazole, benzothiazole, benzimidazole, 1,2,3-benzotriazine and 1,2,4-benzotriazine, the heterocyclic group and bicyclic ring moiety substituents being selected from those consisting of alkyl of 1-5 carbon atoms, halogen, alkoxy, hydroxy, nitro, or an unsubstituted or substituted phenyl group;
the phenyl group substituents, the biphenyl group substituents, the &ohgr;-phenylalkenyl group substituents and the &ohgr;-phenylalkynyl group substituents being at least one selected from those consisting of halogen, nitro, carboxy, hydroxy, alkyl of 1-5 carbon atoms, trifluoromethyl, alkoxy, acyloxy, cyano, amino, alkylamino, dialkylamino, sulfonamido, carboxamido, carbalkoxy, thio, alkylthio, alkylsulfinyl and alkylsulfonyl; the alkyl group substituents being at least one selected from those consisting of carboxy, hydroxy, alkoxy, amino, alkylamino, dialkylamino, thio or alkylthio, and the isomers and pharmaceutically acceptable salts of said compound.
In the compounds of formula I, above, the substituents of the heterocyclic group, the bicyclic ring moiety, the phenyl group, the biphenyl group, etc. may also be perhaloalkyl, dihaloalkyl, monohaloalkyl, and the heterocyclic group and the bicyclic ring moieties may also be substituted with carboxy, carbalkoxy, sulfo, sulfonate (i.e., sulfonic acid esters) thio, alkylthio, alkylsulfinyl or alkylsulfonyl substituents.
The above compounds may also be used for prevention of viral infections and disease associated with such infection in a susceptible host by administering to the host a prophylactically effective amount of the above-described compound or precursor thereof.
DETAILED DESCRIPTION OF THE INVENTION
The compounds used in the method of the invention can be conveniently prepared from known starting materials according to the general synthetic scheme illustrated below.
Preparations of specific anti-hepacivirus compounds which may be used in the practice of this invention are exemplified below.
In carrying out the above general synthetic
Bailey Thomas R.
Young Dorothy C.
Travers Russell
ViroPharma Incorporated
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