Viral polymerase inhibitors

Details Viral polymerase inhibitors Viral polymerase inhibitors

2001-11-27

2002-11-12

Aulakh, C. S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C546S118000, C514S894000

Reexamination Certificate

active

06479508

ABSTRACT:

TECHNICAL FIELD OF THE INVENTION
The invention relates to inhibitors of RNA dependent RNA polymerases, particularly those viral polymerases within the Flaviviridae family, and more particularly the NS5B polymerase of HCV.
BACKGROUND OF THE INVENTION
About 30,000 new cases of hepatitis C virus (HCV) infection are estimated to occur in the United States each year (Kolykhalov, A. A.; Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000;
J. Virol.
74: 2046-2051*). HCV is not easily cleared by the hosts' immunological defences; as many as 85% of the people infected with HCV become chronically infected. Many of these persistent infections result in chronic liver disease, including cirrhosis and hepatocellular carcinoma (Hoofnagle, J. H.; 1997;
Hepatology
26: 15S-20S*). There are an estimated 170 million HCV carriers world-wide, and HCV-associated end-stage liver disease is now one of the leading cause of liver transplantation. In the United States alone, hepatitis C is responsible for 8,000 to 10,000 deaths annually. Without effective intervention, the number is expected to triple in the next 10 to 20 years. There is no vaccine to prevent HCV infection. Prolonged treatment of chronically infected patients with interferon or interferon and ribavirin is the only currently approved therapy, but it achieves a sustained response in fewer than 50% of cases (Lindsay, K. L.; 1997;
Hepatology
26: 71S-77S*, and Reichard, O.; Schvarcz, R.; Weiland, O.; 1997
Hepatology
26: 108S-111S*). HCV belongs to the family Flaviviridae, genus hepacivirus, which comprises three general of small enveloped positive-strand RNA viruses (Rice, C. M.; 1996;
“Flaviviridae:
the viruses and their replication”; pp. 931-960 in
Fields Virology
; Fields, B. N.; Knipe, D. M.; Howley, P. M. (eds.); Lippincott-Raven Publishers, Philadelphia Pa. *). The 9.6 kb genome of HCV consists of a long open reading frame (ORF) flanked by 5′ and 3′ non-translated regions (NTR's). The HCV 5′ NTR is 341 nucleotides in length and functions as an internal ribosome entry site for cap-independent translation initiation (Lemon, S. H.; Honda, M.; 1997;
Semin. Virol.
8: 274-288*). The HCV polyprotein is cleaved co- and post-translationally into at least 10 individual polypeptides (Reed, K. E.; Rice, C. M.; 2000;
Curr. Top. Microbiol. Immunol.
242: 55-84*). The structural proteins result from signal peptidases in the N-terminal portion of the polyprotein. Two viral proteases mediate downstream cleavages to produce non-structural (NS) proteins that function as components of the HCV RNA replicase. The NS2-3 protease spans the C-terminal half of the NS2 and the N-terminal one-third of NS3 and catalyses cis cleavage of the NS2/3 site. The same portion of NS3 also encodes the catalytic domain of the NS3-4A serine protease that cleaves at four downstream sites. The C-terminal two-thirds of NS3 is highly conserved amongst HCV isolates, with RNA-binding, RNA-stimulated NTPase, and RNA unwinding activities. Although NS4B and the NS5A phosphoprotein are also likely components of the replicase, their specific roles are unknown. The C-terminal polyprotein cleavage product, NS5B, is the elongation subunit of the HCV replicase possessing RNA-dependent RNA polymerase (RdRp) activity (Behrens, S. E.; Tomei, L.; DeFrancesco, R.; 1996;
EMBO J.
15: 12-22*; and Lohmann, V.; Körner, F.; Herian, U.; Bartenschlager, R.; 1997;
J. Virol.
71: 8416-8428*). It has been recently demonstrated that mutations destroying NS5B activity abolish infectivity of RNA in a chimp model (Kolykhalov, A. A.; Mihalik, K.; Feinstone, S. M.; Rice, C. M.; 2000;
J. Virol.
74: 2046-2051*).
* incorporated herein by reference
The development of new and specific anti-HCV treatments is a high priority, and virus-specific functions essential for replication are the most attractive targets for drug development. The absence of RNA dependent RNA polymerases in mammals, and the fact that this enzyme appears to be essential to viral replication, would suggest that the NS5B polymerase is an ideal target for anti-HCV therapeutics.
WO 00/06529 reports inhibitors of NS5B which are &agr;, &ggr;-diketoacids.
WO 00/13708, WO 00/10573, and WO 00/18231 report inhibitors of NS5B proposed for treatment of HCV.
SUMMARY OF THE INVENTION
The present invention reduces the difficulties and disadvantages of the prior art by providing a novel class of compounds useful for the treatment and prevention of hepatitis C virus (HCV) infection. The aforesaid compounds have been found to inhibit an RNA dependent RNA polymerase encoded by HCV.
In a first aspect, the invention provides a compound of formula I:
wherein:
X is CH or N;
Y is O or S;
Z is OH, NH
2
, NMeR
3
, NHR
3
; OR
3
or 5- or 6-membered heterocycle, having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from:
COOH and —O-(C
6-10
)aryl-(C
2-6
)alkenyl-COOH;
A is N, COR
7
or CR
5
, wherein R
5
is H, halogen, or (C
1-6
) alkyl and R
7
is H or (C
1-6
alkyl), with the proviso that X and A are not both N;
R
6
is H, halogen, (C
1-6
alkyl) or OR
7
, wherein R
7
is H or (C
1-6
alkyl);
R
1
is selected from the group consisting of 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N, and S, phenyl, phenyl(C
1-3
)alkyl, (C
2-6
)alkenyl, phenyl(C
2-6
)alkenyl, (C
3-6
)cycloalkyl, (C
1-6
)alkyl, CF
3
, 9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S,
wherein said heterocycle, phenyl, phenyl(C
2-6
)alkenyl and phenyl(C
1-3
)alkyl), alkenyl , cycloalkyl, (C
1-6
)alkyl, and heterobicycle are all optionally substituted with from 1 to 4 substituents selected from: OH, halogen, CF
3
, amino, cyano, phenyl(C
1-4
)alkoxy, COOH, —OCH
2
CONHCH
2
Ph, (C
1-4
)alkyl, —OCH
2
CONH(CH
2
)
2-3
N(CH
3
)
2
, (C
1-4
)alkoxy, —OCH
2
CO-(morpholino), pyrrolidinyl, carboxy(C
2-4
)alkenyl, phenoxy, —NH(C
2-4
)acyl, —O(CH
2
)
m
OH, m being an integer from 2 to 4, SO
3
, and NO
2
;
R
2
is selected from (C
1-6
)alkyl, (C
3-7
)cycloalkyl, (C
3-7
)cycloalkyl(C
1-3
)alkyl, (C
6-10
)bicycloalkyl, norbornane, phenyl, and pyridyl, all of which is optionally substituted with from 1 to 4 substituents selected from
halogen, (C
1-6
)alkyl, —CH
2
OH, O-benzyl and OH;
R
3
is selected from H, (C
1-6
)alkyl, (C
3-6
)cycloalkyl, (C
3-6
)cycloalkyl(C
1-6
)alkyl, (C
6-10
)aryl, (C
6-10
)aryl(C
1-6
)alkyl, (C
2-6
)alkenyl, (C
3-6
)cycloalkyl(C
2-6
)alkenyl, (C
6-10
)aryl(C
2-6
)alkenyl, N{(C
1-6
)alkyl}
2
, NHCOO(C
1-6
)alkyl(C
6-10
)aryl, NHCO(C
6-10
)aryl, (C
1-6
)alkyl-5- or 10-atom heterocycle, having 1 to 4 heteroatoms selected from O, N and S, and 5- or 10-atom heterocycle having 1 to 4 heteroatoms selected from O, N and S;
wherein said alkyl, cycloalkyl, aryl, alkenyl and heterocycle are all optionally substituted with from 1 to 4 substituents selected from: OH, COOH, COO(C
1-6
)alkyl, (C
1-6
)alkyl, (C
1-6
)alkyl-hydroxy, phenyl, benzyloxy, halogen, (C
2-4
)alkenyl, (C
2-4
)alkenyl-(C
1-6
)alkyl-COOH, and carboxy(C
2-4
)alkenyl, 5- or 6-membered heterocycle having 1 to 4 heteroatoms selected from O, N and S, said heterocycle being optionally substituted with from 1 to 4 substituents selected from:
(C
1-6
alkyl), CF
3
, OH, (CH
2
)
p
COOH, COOH, NHCH(C
1-6
alkyl)
2
, NHCO(C
1-6
alkyl), NH
2
, NH(C
1-6
alkyl), and N(C
1-6
alkyl)
2
, wherein p is an integer from 1 to 4;
9- or 10-membered heterobicycle having 1 to 4 heteroatoms selected from O, N and S, said heterobicycle being optionally substituted with from 1 to 4 substituents selected from:
halogen, OPO
3
H, sulfonamido, SO
3
H, SO
2
CH
3
, —CONH
2
, —COCH
3
, (C
1-3
)alkyl, (C
2-4
alkenyl)COOH, tetrazolyl, COOH, —CONH
2
, OH, NO
2
, NH
2
, —O(CH
2
)
p
COOH, hydantoin, benzoyleneurea, triazolyl, (C
1-4
)alkoxy, cyano, azido, —O—(C
1-6
)alkyl COOH, —O—(C
1-6
)alkyl COO-(C
1-6
)alkyl, —NHCOCOOH, —NHCOCONHOH, —NHCOCONH
2
, —NHCOCONHCH
3
, —NHCO(C
1-6
)alkyl-COOH, —NHCOCONH(C
1-6
)alkyl-COOH, —NHCO(C
3-7
)cycloalkyl-COOH, —NHCONH(C
6-10
)aryl-COOH, —NHCONH(C
6-

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