Compounds having anti-hepatitis C virus effect

Details Compounds having anti-hepatitis C virus effect Compounds having anti-hepatitis C virus effect

2003-02-27

2004-10-26

Powers, Fiona T. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S256000, C514S342000, C514S369000, C514S389000, C544S333000, C544S405000, C546S269700, C548S183000, C548S316100

Reexamination Certificate

active

06809101

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a treating agent against hepatitis C, in detail an anti-hepatitis C virus agent, a nucleic acid polymerase inhibitor, and a RNA-dependent RNA polymerase inhibitor.
BACKGROUND ART
It is supposed that there are one to two hundred million people infected with hepatitis C virus (hereafter called as HCV) worldwide, and over 1.5 million people infected with HCV in Japan. Approximately 50% of them become chronic hepatitis, and approximately 20% thereof become liver cirrhosis or hepatocellular carcinoma after 30 years or more of the infection. In Japan, twenty and several thousand people die every year due to hepatocellular carcinoma caused by HCV infection. At present, interferon &agr; is used widely as a treating agent against hepatitis C, however, percentage of successful treatment is only 20% to 30% and its side effect is strong. It is expected to develop a more useful and more safety treating agent.
The anti-HCV agents are targeted on protease, RNA helicase, RNA-dependent RNA polymerase, and the like, and as the RNA-dependent RNA polymerase inhibitor known are cerulenin, gliotoxin, and dioxobutyric acid ((1) Antiviral Res., 41, 65 (1999), (2) Antiviral Ther., 3 (Suppl 3), 99 (1998), (3) WO00/06529).
On the other hand, as an acylthiazolidinedione derivative similar to a compound of the present invention, a compound wherein the acyl group is a substituted benzoyl group is described in (1) Strukt. Mekh. Deistviya Fiziol. Aktiv. Veschestv (1972) 92-92, (2) Khim. Geterotsikl. Soedin. (1972), (11), 1492-1495. However, in these references a concrete medical use is not described. Furthermore, a compound wherein the acyl group is a substituted heteroarylcarbonyl group is not; described therein at all.
DISCLOSURE OF INVENTION
The development of a treating agent against hepatitis C, especially an HCV RNA-dependent RNA polymerase inhibitor, is expected.
It is found that an acylthiazolidinedione derivative and the like have an HCV RNA-dependent RNA polymerase inhibitory effect.
That is, the present invention relates to:
(1) A treating agent against hepatitis C virus which contains as an active ingredient a compound of the formula (I), a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof:
wherein R
1
is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R
2
and R
3
taken together with the adjacent carbon atom form an optionally substituted heterocyclic group having one or more of oxo and/or thioxo,
(2) A treating agent against hepatitis C virus as described in (1) wherein R
1
is optionally substituted heteroaryl or optionally substituted aryl; R
2
and R
3
taken together with the adjacent carbon atom form a group of the formula (A):
wherein A
1
and A
3
are each independently oxygen atom or sulfur atom; A
2
and A
4
are each independently —O—, —S—, or —NR
4
— wherein R
4
is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl,
(3) A treating agent against hepatitis C virus as described in (2) wherein A
1
is oxygen atom; A
2
is —NH—; A
1
and A
4
are sulfur atom,
(4) A compound of the formula (II):
wherein R
1
is optionally substituted carbocyclic group or optionally substituted heterocyclic group; A
1
and A
3
are each independently oxygen atom or sulfur atom; A
2
is —NR
4
— wherein R
4
is hydrogen, optionally substituted alkyl, optionally substituted acyl, optionally substituted aryl, or optionally substituted aralkyl, provided that when R
1
is optionally substituted aryl, R
4
is hydrogen or optionally substituted alkyl; A
4
is —S—; and provided that the following compounds are excluded wherein A
1
is oxygen atom, A
2
is —NEt-, A
3
is sulfur atom, and R
1
is 4-bromophenyl, 4-n-butoxycarbonylphenyl, 4-methoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3-methylphenyl, 4-methylphenyl, 4-chlorophenyl or phenyl; A
1
is oxygen atom, A
2
is —NH—, A
3
is sulfur atom, and R
1
is 2-thiocarboxyphenyl or 2-carboxyphenyl; and A
1
is oxygen atom, A
2
is —NH—, A
1
is oxygen atom, and R
1
is 2-carboxyphenyl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(5) A compound of (4) wherein R
1
is optionally substituted heteroaryl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(6) A compound of (4) wherein R
1
is non-substituted heteroaryl or heteroaryl substituted with alkyl, alkoxy, hydroxy, halogen, trityl, alkoxyalkoxy, cyanoallylalkoxy, cyanoalkoxy, hydroxyalkyl, cyanoalkyl, carboxy or alkoxycarbonyl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(7) A compound of (5) or (6) wherein R
1
is optionally substituted 5-membered heteroaryl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(8) A compound of (5) or (6) wherein R
1
is optionally substituted furyl, optionally substituted t-hienyl, optionally substituted pyrrolyl, optionally substituted imidazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted triazolyl, optionally substituted oxadiazolyl, optionally substituted tetrazolyl, optionally substituted pyridyl, optionally substituted benzofuryl, optionally substituted pyrimidinyl, optionally substituted pyrazinyl, or optionally substitutec(thiazolyl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(9) A compound of (4) wherein R
1
is optionally substituted aryl;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(10) A compound of any one of (4) to (9) wherein A
2
is —NH—;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(11) A compound of any one of (4) to (10) wherein A
1
is oxygen atom; A
3
is sulfur atom;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(12) A compound of any one of (4) to (9) wherein A
1
is oxygen atom; A
2
is —NH—; A
3
is sulfur atom; A
4
is —S—;
a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(13) A pharmaceutical composition which contains as an active ingredient a compound of any one of (4) to (12), a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof,
(14) A pharmaceutical composition of (13) as a treating agent against hepatitis C,
(15) A pharmaceutical composition of (13) as an anti-hepatitis C virus agent,
(16) A pharmaceutical composition of (13) as a nucleic acid polymerase inhibitor,
(17) A pharmaceutical composition of (13) as a RNA-dependent RNA polymerase inhibitor,
(18) A method of treating hepatitis C comprising administration of a treating agent against hepatitis C of (1),
(19) Use of a compound of (1) for the preparation of a treating agent against hepatitis C,
The present invention has found that a compound of the formula (I), a tautomer, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof:
wherein R
1
is an optionally substituted carbocyclic group or an optionally substituted heterocyclic group; R
2
and R
3
taken together with the adjacent carbon atom form an optionally substituted heterocyclic group having one or more of oxo and/or thioxo; exhibits an inhibitory effect against nucleic acid polymerase, in detail an inhibitory effect against RNA-dependent RNA polymerase, and inhibits the increase of HCV, whereby to provide a treating agent against HCV containing these compounds or the like.
A characteristic of the compounds used in the present invention is that the group represented by R
1
, and an optionally substituted heterocyclic group having one or more of oxo and/or thioxo which is formed by R
2
and R
3
taken together with the adjacent carbon atom are substituted on a group of the formula:
Especially, as a compound of the formula (1) the following cases are preferred.
wherein R
1
is optionally substituted heteroaryl or optionally substituted aryl,
wherein R
1
is optionally substituted heteroaryl,
wherein R
1
is non-substituted heteroaryl or hete

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