Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-04-12
2003-04-01
Ford, John M. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217050, C544S184000, C540S599000
Reexamination Certificate
active
06541472
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to compounds and compositions for preventing and treating virus infections and the diseases associated therewith, particularly those infections and associated diseases caused by viruses in the Flaviviridae family, especially the pestiviruses.
BACKGROUND OF THE INVENTION
The Flaviviridae family of viruses is composed of three genera: pestivirus, flavivirus and hepacivirus (hepatitis C virus).
The pestivirus genus consists of the prototypic member bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, also called hog cholera virus) and border disease virus (BDV) of sheep. Human pestiviruses have not been as extensively characterized as the animal pestiviruses. However, serological surveys indicate considerable pestivirus exposure in humans. Pestivirus infections in man have been implicated in several diseases including, but not likely limited to, congenital brain injury, infantile gastroenteritis and chronic diarrhea in human immunodeficiency virus (HIV) positive patients. M. Giangaspero et al., Arch. Virol. Suppl., 7: 53-62 (1993); M. Giangaspero et al., Int. J. STD. AIDS, 4(5): 300-302 (1993); R. Yolken et al., Lancet, 1(8637): 517-20 (1989); C. R. Wilks et al., Lancet, 1(8629): 107 (1989); M. Giangaspero et al., Lancet, 2: 110 (1988); B. J. Potts et al., Lancet, 1(8539): 972-973 (1987).
Pestivirus infections of domesticated livestock (cattle, pigs, and sheep) cause significant economic losses worldwide. BVDV is ubiquitous and causes 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 are capable of causing an acute fatal disease, with mortality rates of 17% to 32%. BVDV is also able to establish persistent infections in fetuses infected before 150 days of gestation. When born, these persistently infected (PI) animals are immunotolerant to the infecting BVDV strain and remain viremic throughout life. PI animals constitute 1% to 2% of the cattle population in the United States and serve as virus reservoirs and continuous sources for virus spread in herds. PI animals may also succumb to fatal mucosal disease upon superinfection with closely related, but distinct, BVDV virus strains. CSFV, while eradicated from the United States and Canada, causes widespread disease in Europe and elsewhere in the world.
Flaviviruses and hepaciviruses represent important pathogens of man and are also prevalent throughout the world. There are 38 flaviviruses associated with human disease, including the dengue fever viruses, yellow fever virus and Japanese encephalitis virus. Flaviviruses cause a range of acute febrile illnesses and encephalitic and hemorrhagic diseases. Hepaciviruses currently infect approximately 1 of the world population and cause persistent infections leading to chronic liver disease, cirrhosis, hepatocellular carcinoma and liver failure.
Currently, there are no antiviral pharmaceutical drugs to prevent or treat pestivirus or flavivirus infections. For hepacivirus (hepatitis C virus)infections, interferon alfa (IFN) is currently the only approved drug in the United States. While IFN treatment has been reported to improve symptoms in 20% to 40% of patients, the remainder do not respond favorably to IFN treatment. For patients who do respond, a sustained improvement of liver function reportedly is seen in only 10% to 20% of patients; the majority of patients relapse upon cessation of IFN treatment. Thus, while IFN has been shown to have some utility in treating hepatitis C, its effectiveness is limited and its cure rate is low.
SUMMARY OF THE INVENTION
In accordance with one aspect, the present invention provides a compound and composition for preventing and treating pestivirus infection and for preventing and treating diseases associated with pestivirus infection in mammalian hosts. The compounds of the invention have the following structure:
in which A represents a substituent selected from the group consisting of:
(a) NR
1
R
2
wherein R
1
and R
2
are radicals independently selected from the group consisting of H, straight or branched chain alkyl groups (C
1
-C
6
), substituted or unsubstituted aryl groups, substituted or unsubstituted aralkyl groups in which the alkyl group is C
1
-C
6
, alkoxy groups (C
1
-C
6
), acyl groups (C
1
-C
7
), substituted or unsubstituted carbalkoxy groups (C
1
-C
8
alkoxy), or R
1
and R
2
, together with the nitrogen atom to which they are attached, represent a substituted or unsubstituted heterocyclic ring selected from the group consisting of benzopyridazine, indole, benzotriazole, hexamethyleneimine, imidazole, isoxazole, morpholine, phthalimide, piperidine, piperazine and pyrrolidine;
(b) a substituted or unsubstituted heterocyclic group selected from the group consisting of pyridine, benzimidazole, benzodioxane, benzofurazan, indole, benzothiophene, coumarin, furan, hexamethyleneimine, isoxazole, oxadiazole, piperazine, piperidine, pyridine, pyrimidine, pyrrolidine, quinoline, quinuclidene, tetrahydropyran and thiazole;
(c) a substituted or unsubstituted phenyl group; and
(d) OR
3
, wherein R
3
represents a radical selected from the group consisting of H, a straight or branched chain alkyl (C
1
-C
6
) group, a substituted or unsubstituted phenyl group a substituted or unsubstituted phenylalkyl group wherein the alkyl group is C
1
-C
6
, or a substituted or unsubstituted tetrahydropyran; Q represents a linking moiety selected from the group consisting of —[(A′)
n
—(CO)]
p
—, —S—, —(SO)—, —(SO
2
)— or a valence bond, A′ being —NR
a
— or —O— and R
a
being H or alkyl (C
1
-C
6
); R
b
, R
c
and R
d
independently represent H, alkyl (C
1
-C
4
), substituted or unsubstituted phenyl or COOR, R being hydrogen or alkyl (C
1
-C
6
); m is an integer from 0 to 6; n and p independently represent 0 or 1; and q and r are independently integers from 0 to 4; said phenyl, aryl, aralkyl, carbalkoxy and heterocyclic substituents and the W, X, Y and Z substituents being selected from the group consisting of H, alkyl (C
1
-C
6
), substituted or unsubstituted aryl (C
6
-C
15
), substituted or unsubstituted aralkyl (C
7
-C
15
), halogen, CF
3
, CN, O-alkyl (C
1
-C
6
), acyloxy (C
1
-C
6
acyl), S-alkyl (C
1
-C
6
), SO-alkyl (C
1
-C
6
), SO
2
-alkyl (C
1
-C
6
), NH
2
SO
2
, NO
2
, NH
2
, NHR′, NR′R″, alkyl COOR′, COOR′, alkyl CONR′R″, CONR′R″,
R′ and R″ being independently selected from the group consisting of hydrogen or alkyl (C
1
-C
6
), and the isomers and pharmaceutically acceptable salts of said compound.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention can be conveniently prepared from known starting materials according to the general synthetic scheme illustrated below. Specific embodiments of anti-pestivirus compounds within the scope of the invention are exemplified below.
In the general synthetic scheme, thiosemicarbazide is reacted with isatin to form 5H-1,2,4-triazino[5,6-b]indole-3(2H)-thione. This product is alkylated with an appropriate halo-derivative to provide the sulfur-substituent desired in the final product.
R
var
signifies any of the various sulfur substituents mentioned above with reference to the compounds of Formula I.
In vitro studies have been performed demonstrating the usefulness of compounds described herein as antiviral agents against pestiviruses. Antiviral activity was measured on the basis of activity against bovine viral diarrhea virus (BVDV) in a cell culture assay. The specificity of antiviral activity toward pestiviruses was also demonstrated in cell culture. Animal safety and bioavailability studies were also performed. The biological studies of the antiviral activity of the compounds of the invention are also described in the examples that follow.
Compounds with particular utility, including isomeric forms, have the formula:
in which R
1
and R
2
are the sam
Nitz Theodore J.
Pevear Daniel C.
Seipel Martin
Dann Dorfman Herrell and Skillman, P.C.
Ford John M.
ViroPharma Incorporated
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