New piperazine compound and use thereof as a hcv polymerase inhibitor   

Abstract: wherein each symbol is as defined in the specification, or a pharmaceutically acceptable salt thereof, or a solvate thereof and an anti-HCV agent and an HCV polymerase inhibitor containing this compound. The compound of the present invention shows an anti-HCV activity based on the HCV polymerase inhibitory activity, and useful as an agent for the prophylaxis or treatment of hepatitis C. The present invention relates to a compound represented by the following formula [I]

TECHNICAL FIELD

The present invention relates to a novel piperazine compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is useful as a therapeutic agent for hepatitis C. The present invention relates to an anti-HCV agent, which contains a piperazine compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, which is effective for the prophylaxis or treatment of hepatitis C and which shows anti-hepatitis C virus (HCV) activity, particularly anti-HCV activity based on an RNA-dependent RNA polymerase inhibitory activity.

BACKGROUND ART

In 1989, a main causative virus of non-A non-B posttransfusion hepatitis was found and named hepatitis C virus (HCV). Since then, several types of hepatitis viruses have been found besides type A, type B and type C, wherein hepatitis caused by HCV is called hepatitis C.

The patients infected with HCV are considered to involve several percent of the world population, and the infection with HCV characteristically becomes chronic.

HCV is an envelope RNA virus, wherein the genome is a single strand plus-strand RNA, and belongs to the genus Hepacivirus of Flavivirus. Of the same hepatitis viruses, for example, hepatitis B virus (HBV), which is a DNA virus, is eliminated by the immune system and the infection with this virus ends in an acute infection except for neonates and infants having yet immature immunological competence. In contrast, HCV somehow avoids the immune system of the host due to an unknown mechanism. Once infected with this virus, even an adult having a mature immune system frequently develops persistent infection.

When chronic hepatitis is associated with the persistent infection with HCV, it advances to cirrhosis or liver cancer in a high rate. Enucleation of tumor by operation does not help much, because the patient often develops recurrent liver cancer due to the sequela inflammation in non-cancerous parts. In addition, there is a report on the involvement of HCV infection in dermatosis such as chronic urticaria, lichen planus, cryoglobulinemic purpura and the like.

Thus, an effective therapeutic method of hepatitis C is desired. Apart from the symptomatic therapy to suppress inflammation with an anti-inflammatory agent, the development of a therapeutic agent that reduces HCV to a low level free from inflammation and that eradicates HCV has been strongly demanded.

At present, a treatment with interferon is the only effective method known for the eradication of HCV. However, interferon can eradicate the virus only in about one-third of the patient population. For the rest of the patients, it has no effect or provides only a temporary effect. In recent years, polyethylene glycolated interferon has been put to practical use, and enhanced effects and reduced side effects have been achieved. However, complete response rate still remains at a low level, and therefore, an anti-HCV drug to be used in the place of or concurrently with interferon is awaited in great expectation.

In recent years, Ribavirin (1-β-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) has become commercially available as a therapeutic agent for hepatitis C, which is to be used concurrently with interferon. It enhances the efficacy of interferon but only to a low efficacy rate, and a different novel therapeutic agent for hepatitis C is desired.

Also, an attempt has been made to potentiate the immunocompetence of the patient with an interferon agonist, an interleukin-12 agonist and the like, thereby to eradicate the virus, but an effective pharmaceutical agent has not been found yet.

In addition, the inhibition of HCV growth, wherein HCV-specific protein is targeted, has been drawing attention these days.

The gene of HCV encodes a protein such as serine protease, RNA helicase, RNA-dependent RNA polymerase and the like. These proteins function as a specific protein essential for the growth of HCV.

One of the specific proteins, RNA-dependent RNA polymerase (hereinafter to be also briefly referred to as an HCV polymerase), is an enzyme essential for the growth of the virus. The gene replication of HCV having a plus-strand RNA gene is considered to involve synthesis of a complementary minus-strand RNA by the use of the plus-strand RNA as a template and using the obtained minus-strand RNA as a template, amplifying the plus-strand RNA. The portion called NS5B of a protein precursor, that HCV codes for, has been found to show an RNA-dependent RNA polymerase activity, and is considered to play a central role in the HCV gene replication.

Therefore, an HCV polymerase inhibitor can be a target in the development of an anti-HCV drug, and the development thereof is eagerly awaited. However, an effective HCV polymerase inhibitor has not been developed yet, like in other attempts to develop an anti-HCV drug based on other action mechanisms. As the situation stands, no pharmaceutical agent can treat hepatitis C satisfactorily.

The following describes known compounds comparatively similar to the present invention.

WO2004/73599 (page 33, Table 1) discloses the following compound a and the like as anti-HCV agents (see patent document 1).

However, the compound of the present invention is not disclosed in the specification, and any description suggestive thereof is not found.

As references disclosing compounds other than for anti-HCV agents, which are comparatively similar to the compound of the present invention, the following can be mentioned.

WO2004/71390 (page 33, line 8) discloses the following compound b and the like as compounds usable for the treatment of dysmenorrhea and the like (see patent document 2).

WO2004/31182 (page 25, line 4) discloses the following compound c and the like as compounds usable for the treatment of infertility (see patent document 3).

WO2000/39119 (page 42, Example 28L) discloses the following compound d and the like as compounds usable for inhibiting abnormal growth of cells (see patent document 4).

U.S. Pat. No. 5,880,128 (columns 67-68, Example 24) discloses the following compound e and the like as compounds usable for inhibiting abnormal growth of cells (see patent document 5).

WO1999/37304 discloses the following compound f and the like as factor Xa inhibitors, and application to viral infections is exemplarily shown (see patent document 6).

WO2001/07436 discloses the following compound g and the like as factor Xa inhibitors, and application to viral infections is exemplarily shown (see patent document 7).

WO2005/86898 (page 95, Example 9) and US2005/234033 (page 37, Example 9) disclose the following compound h and the like as therapeutic agents for proliferative diseases (see patent document 8 and patent document 9).

WO2000/53596 (page 42, in Table 2) discloses the following compound i and the like as compounds having activity for the central nervous system and activity for inflammatory diseases and allergic diseases (see patent document 10).

WO1998/37079 (page 138, lines 19-20) discloses the following compound j and the like as therapeutic agents for the diseases caused by abnormal nitric oxide production, such as multiple sclerosis and the like (see patent document 11).

JP2001-294572 (page 297, Example 349) discloses the following compound k and the like as compounds having an antithrombotic effect (see patent document 12).

EP1104754 (Example A-33) and EP1031563 (Example 33) disclose the following compound l and the like as compounds having an antithrombotic effect (see patent document 3 and patent document 14).

As compounds other than for a pharmaceutical use, which are comparatively similar to the compound of the present invention, the following can be mentioned.

WO2001/54504 (FIG. 55) discloses the following compound m and the like as anthelmintics (see patent document 15).

Other document (Tetrahedron Letters, 39, 1295-98, 1998; page 1297, Table II) discloses the following compound n and the like, and its synthetic method is described (see non-patent document 1).

However, none of these references discloses the compound of the present invention, not to mention use of the compounds of these references as anti-HCV agents or description suggestive thereof. [patent document 1] WO2004/73599 (page 33, Table 1) [patent document 2] WO2004/71390 (page 33, line 8) [patent document 3] WO2004/31182 (page 25, line 4) [patent document 4] WO2000/39119 (page 42, Example 28L) [patent document 5] U.S. Pat. No. 5,880,128 (columns 67-68, Example 24) [patent document 6] WO1999/37304 [patent document 7] WO2001/07436 [patent document 8] WO2005/86898 (page 95, Example 9) [patent document 9] US2005/234033 (page 37, Example 9) [patent document 10] WO2000/53596 (page 42, in Table 2) [patent document 11] WO1998/37079 (page 138, lines 19-20) [patent document 12] JP2001-294572 (page 297, Example 349) [patent document 13] EP1104754 (Example A-33) [patent document 14] EP1031563 (Example 33) [patent document 15] WO2001/54504 (FIG. 55) [non-patent document 1] Tetrahedron Letters, Vol. 39, pages 1295-98, 1998 (page 1297, Table II)

DISCLOSURE OF THE INVENTION

Based on the findings from the preceding studies, it has been elucidated that a pharmaceutical agent having an anti-HCV activity is effective for the prophylaxis and treatment of hepatitis C, and particularly an anti-HCV agent having an inhibitory activity on RNA-dependent RNA polymerase of HCV can be a prophylactic and therapeutic agent effective against hepatitis C and a prophylactic and therapeutic agent for the disease caused by hepatitis C.

Accordingly, the present invention provides a pharmaceutical agent having an anti-HCV activity, particularly a pharmaceutical agent having an RNA-dependent RNA polymerase inhibitory activity.

The present inventors have made an in-depth study of compounds having an anti-HCV activity, particularly RNA-dependent RNA polymerase inhibitory activity, and completed the present invention.

More particularly, the present invention provides the following.

[1] An anti-HCV agent comprising, as an active ingredient, a compound represented by the following formula [I] or a pharmaceutically acceptable salt thereof, or a solvate thereof:

wherein ring A is a C3-12 carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), n is an integer of 1 to 6, ring B is a C3-12 carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and

a hydrogen atom,

—CO— (CH2)a—NH—R7, —CO— (CH2)b—NHCOR8, —CO—(CH2)c—NHCOOR9 (wherein R1 to R9 and R11 are the same or different and each is a hydrogen atom or a C1-10 alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, and a, b and c are the same or different and each is an integer of 1 to 4),

a C1-10 alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, or

wherein X is a bond, C1-4 alkylene, —CO—(CH2)p—, —CONR10—(CH2)q—, —CO—(CH2)r—O—(CH2)s—, —CO—(CH2)t—NH—(CH2)u—, —CO—(CH2)v—CONH—(CH2)w—, or

ring C is a C3-12 carbon ring group optionally substituted by 1 to 5 substituents selected from the following group A, or a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group A (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), R10 is a hydrogen atom, or a C1-10 alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, p, q, r, s, u, v and w are the same or different and each is 0 or an integer of 1 to 4, and t is an integer of 1 to 4, group A: halogen atom, nitro group, cyano group,

(wherein Ra1 to Ra20 are the same or different and each is a hydrogen atom, a C1-10 alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C3-12 carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), or a C6-12 aryl-C1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the following group C), a C1-10 alkyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C2-10 alkynyl group optionally substituted by 1 to 5 substituents selected from the following group B, a C3-12 carbon ring group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclic group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclic group has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), a C6-12 aryl-C1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, a heterocyclyl-C1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the following group C (wherein the heterocyclyl moiety has, besides carbon atom, 1 to 6 hetero atoms selected from nitrogen atom, oxygen atom and sulfur atom), and a C3-10 cycloalkyl-C1-4 alkyl group optionally substituted by 1 to 5 substituents selected from the following group C, group B:

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