JP2010241750A - Benzofuran derivative having anti-hepatitis c virus effect - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical drug for treating or preventing HCV infection, and a method for using the same. <P>SOLUTION: The pharmaceutical drug for treating or preventing HCV infection comprises a combination of a compound represented by formula (1) (wherein R<SP>1</SP>is a hydrogen atom, acyl group or arylalkoxycarbonyl group; and R<SP>2</SP>and R<SP>3</SP>are each independently a (non)substituted alkyl group, (non)substituted alkenyl group or (non)substituted alkynyl group, or R<SP>2</SP>and R<SP>3</SP>together form a cycloalkyl group) and interferon. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a medicament for treating or preventing HCV infection using a benzofuran derivative and interferon, and use thereof.

  Hepatitis C virus (HCV) infection usually causes chronic hepatitis, often leading to cirrhosis or hepatocellular carcinoma. The number of carriers is now about 3% (~ 170 million) of the world's population. HCV avoids the immune system of the host due to an unclear cause, so persistent infection is often established even when infected with an adult with an advanced immune system, which progresses to chronic hepatitis, cirrhosis, and liver cancer. It is also known that even after excision, there are many patients whose liver cancer recurs due to inflammation that continues in the non-cancerous part.

  At present, combined use of PEGylated interferon (PEG-IFN) and ribavirin (Non-patent Documents 1 and 2) is known as the most effective treatment method for HCV infection. However, the number of patients for whom interferon treatment is effective is limited to about 1/3 of all patients, and interferon response to HCV genotype 1b is particularly low. Therefore, development of an anti-HCV drug that can replace or be used in combination with interferon is desired. Among them, apart from symptomatic treatment that suppresses inflammation with an anti-inflammatory agent, development of a drug that reduces or eradicate HCV in the affected liver is strongly desired.

  HCV is a single-stranded RNA virus belonging to the Flaviviridae family. The RNA genome produces at least 10 viral proteins, including structural and nonstructural (NS) proteins. The former is involved in the formation of HCV particles. The latter plays an important role in HCV genome replication (Non-patent Document 3). In general, NS protein complexes associate with lipid rafts on the Golgi and endoplasmic reticulum membranes where it is accepted that HCV infection occurs (Non-Patent Documents 4 and 5). Thus, when lipid raft aggregates are destroyed, suppression of HCV replication may occur.

  The present inventors have reported that 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran (hereinafter referred to as BO-653) is a low density lipoprotein ( It has been reported that it is effective for arteriosclerosis because it suppresses the oxidation of (LDL) (Non-patent Document 6). In addition, the present inventors have shown that BO-653 and its similar compounds are useful as therapeutic agents for arteriosclerosis because they have antioxidant action and lipid peroxidation inhibitory action, and myocardial infarction, stroke, etc. Useful for the treatment of ischemic organ damage (Patent Documents 1 and 2), useful as an intimal thickening inhibitor and as a restenosis inhibitor after percutaneous coronary angioplasty (PTCA) (Patent Documents) 3, 4), useful as a therapeutic or preventive agent for visceral kidney disease and organ preservative (Patent Documents 5 and 6), useful as a preventive or therapeutic agent for atherosclerosis or xanthomatosis (Patent Documents 7, 8, 9), useful as a drug for reducing the incidence of acute coronary syndrome or reducing symptoms (Patent Document 10), useful as a drug for treating fatty liver or liver disease (Patent Document 11) It indicated.

  However, there has been no disclosure or suggestion that the combined use of BO-653 and its similar compounds and interferon is useful as a preventive and / or therapeutic agent for HCV infection.

JP-A-6-206842 US Pat. No. 5,574,178 JP-A-9-188619 US Pat. No. 6,103,753 Japanese Patent Laid-Open No. 10-72458 US Pat. No. 6,133,279 Japanese Patent Laid-Open No. 11-21238 US Pat. No. 6,156,793 US Pat. No. 6,417,225 WO03 / 018001 WO2005 / 030198

Glue, P. et al., Hepatology, 32, 647-653 (2000) Reddy, K.R. et al., Hepatology, 33, 433-438 (2001) Rosenberg, S., J Mol Biol, 313, 451-464 (2001) Aizaki, H. et al., Virology, 324, 450-461 (2004) Gao, L. et al., J Virol, 78, 3480-3488 (2004) Cynshi O, Kawabe Y, Suzuki T, Takashima Y, Kaise H, Nakamura M, Ohba Y, Kato Y, Tamura K, Hayasaka A, Higashida A, Sakaguchi H, Takeya M, Takahashi K, Inoue K, Noguchi N, Niki E , Kodama T. Antiatherogenic effects of the antioxidant BO-653 in three different animal models.Proc Natl Acad Sci US A. 1998 95: 10123-8

  This invention is made | formed in view of such a condition, The objective is to provide the pharmaceutical for treating or preventing HCV infection which combines a benzofuran derivative and an interferon. Another object of the present invention is to provide a method for treating or preventing HCV infection, which comprises the step of administering a benzofuran derivative and interferon to a subject.

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物およびインターフェロンを組み合わせてなる、ＨＣＶ感染症を治療または予防するための医薬。 Specifically, the present invention includes the following.
[1] The following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined together to form a cycloalkyl group.) A medicament for treatment or prevention.

[2] The medicament according to [1], wherein the medicament for treating or preventing HCV infection is a combination drug.

[3] The pharmaceutical according to [1], wherein the compound represented by the general formula (1) and interferon are used in combination.

[4] The medicament according to [3], wherein the compound represented by the general formula (1) and interferon are administered simultaneously, sequentially or separately.

[5] A medicine for treating or preventing HCV infection is a kit comprising a pharmaceutical composition containing the compound represented by the general formula (1) and a pharmaceutical composition containing interferon. [3] Alternatively, the medicine according to [4].

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物を有効成分として含有し、インターフェロンと併用することを特徴とする、ＨＣＶ感染症を治療または予防するための医薬。 [6] The following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group) as an active ingredient and used in combination with interferon A medicament for treating or preventing HCV infection characterized by the above.

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物と併用することを特徴とする、ＨＣＶ感染症を治療または予防するための医薬。 [7] Containing interferon as an active ingredient, the following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or HCV infection, characterized in that it is a substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group) A medicine for treating or preventing symptom.

[8] The medicament according to any one of [1] to [7], wherein R ¹ is a hydrogen atom.

[9] The medicament according to any one of [1] to [8], wherein R ² and R ³ are unsubstituted alkyl groups.

[10] The medicament according to [9], wherein the unsubstituted alkyl group is an n-butyl group, an n-pentyl group, an n-hexyl group or an n-heptyl group.

[11] The compound represented by the formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzofuran, 4,6-di -T-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl- Any of [1] to [10], which is 2,3-dihydrobenzofuran or 4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzofuran The medicine according to any one of the above.

[12] The compound represented by the formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, [1] to [11] The medicament according to any one of [11].

[13] The medicament according to any one of [1] to [12], wherein the interferon is a pegylated interferon.

[14] The medicament according to any one of [1] to [13], wherein the HCV infection is hepatitis C, cirrhosis, liver fibrosis, or liver cancer.

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物およびインターフェロンを対象に投与する工程を含む、ＨＣＶ感染症を治療または予防する方法。 [15] The following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group.) A method of treating or preventing HCV infection.

[16] The method of [15], wherein the compound represented by the general formula (1) and interferon are administered simultaneously to a subject.

[17] The method according to [15], wherein the compound represented by the general formula (1) and interferon are separately administered to a subject.

[18] The method according to [15], wherein R ¹ is a hydrogen atom.

[19] The method according to [15], wherein R ² and R ³ are unsubstituted alkyl groups.

[20] The method according to [19], wherein the unsubstituted alkyl group is an n-butyl group, an n-pentyl group, an n-hexyl group, or an n-heptyl group.

[21] The compound represented by the formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzofuran, 4,6-di -T-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl- [15] The method according to [15], which is 2,3-dihydrobenzofuran or 4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzofuran.

[22] The compound represented by formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran; The method described.

[23] The method according to [15], wherein the interferon is a pegylated interferon.

[24] The method according to [15], wherein the HCV infection is hepatitis C, cirrhosis, liver fibrosis, or liver cancer.

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物およびインターフェロンの使用。 [25] The following general formula (1) for producing a medicament for treating or preventing HCV infection:

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group.) And use of an interferon.

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物の使用。 [26] The following general formula (1) for producing a medicament for treating or preventing HCV infection in combination with interferon:

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group.

（式中、Ｒ¹ は、水素原子、アシル基、又はアリールアルコキシカルボニル基であり；Ｒ² 及びＲ³ は、独立して、置換若しくは未置換のアルキル基、置換若しくは未置換のアルケニル基、又は置換若しくは未置換のアルキニル基であるか、又はＲ² とＲ³ とが一緒になってシクロアルキル基を形成してもよい。）で表される化合物と併用してＨＣＶ感染症を治療または予防するための医薬を製造するための、インターフェロンの使用。 [27] The following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined together to form a cycloalkyl group.) Use of interferon for the manufacture of a medicament.

[28] The use according to any one of [25] to [27], wherein R ¹ is a hydrogen atom.

[29] The use according to any one of [25] to [28], wherein R ² and R ³ are unsubstituted alkyl groups.

[30] The use according to [29], wherein the unsubstituted alkyl group is an n-butyl group, an n-pentyl group, an n-hexyl group, or an n-heptyl group.

[31] The compound represented by the formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzofuran, 4,6-di -T-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl- Any of [25] to [30], which is 2,3-dihydrobenzofuran or 4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzofuran Use as described in Crab.

[32] The compound represented by the formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, [25] to [25] [31] The use according to any one of [31].

[33] The use according to any one of [25] to [32], wherein the interferon is a pegylated interferon.

[34] The use according to any one of [25] to [33], wherein the HCV infection is hepatitis C, cirrhosis, liver fibrosis, or liver cancer.

  The present inventors have clarified that HCV replication is synergistically suppressed by using a specific benzofuran derivative represented by the general formula (1) in combination with interferon. For example, a pharmaceutical comprising these two components can be a new drug for treating HCV infection that is safer and more effective.

The anti-HCV effect by the combined use of BO-653 and PEG-IN in a chimeric mouse having a human liver infected with HCR (genotype 1b), specifically, the level of HCV RNA in the serum of the chimeric mouse It is a graph to show. In the graph, ● represents the BO-653 administration group, Δ represents the PEG-IFN administration group, ○ represents the BO-653 + PEG-IFN combination group, and □ represents the non-administration group. This shows the effect on the liver damage by the combined use of BO-653 and PEG-IN in chimeric mice with human liver infected with HCR (genotype 1b), specifically human albumin in the serum of chimeric mice It is a graph which shows a density | concentration. In the bar graph, the right-down diagonal line graph shows the result one day before administration, the white bar graph shows the result one day after administration, the left-down diagonal line graph shows the result 7 or 8 days after administration, and the black bar graph shows the result 14 days after administration. It is a graph which shows the anti- HCV action of BO-653 by the luciferase assay method and WST-8 assay method using HCV replicon holding cells. The left scale on the Y-axis shows luciferase activity (%) by the luciferase assay, the right scale on the Y-axis shows cell viability (%) by the WST-8 assay, and ○ in the graph shows luciferase activity , ● indicates cell viability.

  In the present invention, “hepatitis C virus (HCV)” means all viruses capable of causing hepatitis C. Examples of HCV subtypes include those based on genotype differences and those based on serogroup differences. Examples of the genotype include 1a, 1b, 2a, 2b, 3a, 3b, 4, 5 and 6. In the present invention, preferred genotypes are 1a and 1b, and more preferred genotype is 1b. It is done. The serogroup is a serological grouping based on an antigen-antibody reaction, and specific examples thereof include serogroup 1, serogroup 2, and a serogroup that does not fall into any of the above two groups. Further, genotypes 1a and 1b can correspond to serogroup 1, and genotypes 2a and 2b can correspond to serogroup 2, respectively.

  In the present invention, “HCV infection” means all the symptoms caused by infection of the HCV living body (including monkeys such as humans and chimpanzees). Specific examples include hepatitis C, cirrhosis, Examples include liver fibrosis and liver cancer. Hepatitis C can be classified into chronic hepatitis, acute hepatitis, fulminant hepatitis and the like, and viremia in each of these hepatitis is also included in HCV infection. Whether or not the living body has an HCV infection is determined by, for example, measuring the amount of HCV antibody in serum, detecting the core antigen of HCV in serum, detecting RNA of HCV in serum, and combinations thereof Can do.

  In the present invention, the “medicament for treating or preventing HCV infection comprising a combination of the compound represented by the general formula (1) and interferon” refers to the compound represented by the general formula (1) and the interferon. Any combination of pharmaceuticals may be used for simultaneous, separate or sequential administration in the treatment or prevention of HCV infection. The medicament of the present invention may contain the compound represented by the general formula (1) and interferon in the same pharmaceutical composition (that is, it may be a compounding agent), and the general formula (1) The compound represented and the interferon may be contained in separate pharmaceutical compositions. In addition, the compounding ratio of the compound represented by the general formula (1) in the combination drug and the interferon may be set to a certain ratio in advance, or may be changed to an arbitrary ratio at the time of administration depending on the severity of symptoms or judgment of a doctor. You can also The medicament of the present invention may be a kit comprising a pharmaceutical composition containing the compound represented by the general formula (1) and a pharmaceutical composition containing interferon.

Here, in the above-mentioned “medicament for treating or preventing HCV infection in combination”, when the compound represented by the general formula (1) and interferon are contained in separate pharmaceutical compositions, The dosage forms of the two separate preparations may be the same or different. For example, either or both may be a parenteral preparation, an injection, an infusion, or an intravenous infusion.
In order to treat or prevent HCV infection, which is a combination of the above-described pharmaceuticals used in the treatment or prevention of HCV infection as described above and further combined with one or more preparations. "Medicine".

  The present invention also relates to a medicament for treating or preventing HCV infection characterized by being used in combination with interferon, which contains a compound represented by the general formula (1) as an active ingredient. When the pharmaceutical agent is used in combination with interferon, it may be administered simultaneously with interferon, or the pharmaceutical agent may be administered before or after administration of interferon.

  The present invention also relates to a medicament for treating or preventing HCV infection, characterized by being used in combination with a compound represented by the general formula (1) containing interferon as an active ingredient. When interferon is used in combination with this drug, it may be administered simultaneously with this drug, or interferon may be administered before or after administration of this drug.

R ¹ of the compound of the general formula (1) used in the present invention is a hydrogen atom, an acyl group or an arylalkoxycarbonyl group. Preferred acyl groups are acyl groups having 1 to 10 carbon atoms, examples of which include formyl, acetyl, propionyl, and benzoyl groups. Preferred arylalkyloxycarbonyl groups are arylalkyloxycarbonyl groups having from 7 to 11 carbon atoms, examples of which include benzyloxycarbonyl and naphthylmethyloxycarbonyl groups.

R ¹ is preferably a hydrogen atom and an acyl group, more preferably a hydrogen atom and an acetyl group, and particularly preferably a hydrogen atom.

R ² and R ³ of the compound of the general formula (1) are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group.

  Preferred alkyl groups are linear or branched alkyl groups having 1 to 20 carbon atoms, examples of which are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, sec-pentyl, t-pentyl, neopentyl, n-hexyl, isohexyl, ethylbutyl, n-heptyl, isoheptyl, ethylpentyl, n-octyl, ethylhexyl, propylpentyl, nonyl, decyl, Pentadecyl and stearyl groups are included. More preferably, it is a linear or branched alkyl group having 1 to 10 carbon atoms, and particularly preferably a linear alkyl group having 3 to 8 carbon atoms.

  Preferred alkenyl groups are straight or branched alkenyl groups having 2 to 20 carbon atoms, examples of which include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, isohexenyl. , Ethylbutenyl, heptenyl, isoheptenyl, ethylpentenyl, octenyl, nonenyl, decenyl, and pentadecenyl groups. More preferably, it is a linear or branched alkenyl group having 2 to 10 carbon atoms, and particularly preferably a linear alkenyl group having 3 to 8 carbon atoms.

  Preferred alkynyl groups are linear or branched alkynyl groups having 2 to 20, preferably 2 to 10 carbon atoms, with linear alkynyl groups having 3 to 8 carbon atoms being particularly preferred. Examples include alkynyl groups corresponding to the examples given for alkenyl groups.

R ² and R ³ together may form a cycloalkyl group having 5 to 10 carbon atoms. Examples of preferred cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl.

Examples of substituents that can be present when R ² and R ³ are alkyl, alkenyl, or alkynyl groups include halogen, lower alkoxy, hydroxy, amino, nitro, and trifluoromethyl groups.

Preferred R ² and R ³ are linear unsubstituted alkyl groups having 3 to 8 carbon atoms, and both R ² and R ³ are an n-butyl group, an n-pentyl group, and an n-hexyl group. Or the case where it is n-heptyl group is especially preferable. Most preferably, both R ² and R ³ are n-pentyl groups.

Preferred compounds of formula (1) include:
4,6-di-tert-butyl-5-hydroxy-2,2-dimethyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-diethyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-propyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-isopropyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-s-butyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-t-butyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-t-pentyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-isopentyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-neopentyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-octyl-2,3-dihydrobenzofuran;
4,6-di-t-butyl-5-hydroxy-2,2-di-n-nonyl-2,3-dihydrobenzofuran; and 4,6-di-t-butyl-5-hydroxy-2,2- Di-n-decyl-2,3-dihydrobenzofuran is mentioned.

Particularly preferred compounds of the formula (1) include 4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzofuran, 4,6-di-t- Butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl-2,3 -Dihydrobenzofuran, and 4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzofuran, and 4,6-dihydrobenzofuran represented by the following formula: Most preferred is di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran (BO-653).

  The compound represented by the formula (1) used in the present invention is disclosed in, for example, JP-A-6-206842, US Pat. No. 5,574,178, WO02 / 06263, as described in WO2005 / 030198, In addition to the corresponding EP 1304328A, Tamura K, Kato Y, Ishikawa A, Kato Y, Himori M, Yoshida M, Takashima Y, Suzuki T, Kawabe Y, Cynshi O, Kodama T, Niki E, Shimizu M. Design and synthesis of 4,6-di-tert-butyl-2,3-dihydro-5-benzofuranols as a novel series of antiatherogenic antioxidants. J Med Chem. 2003 46: 3083-93 and the like.

  In the present invention, “interferon” is a generic term for proteins or glycoproteins having an antiviral action induced from animal cells by viruses, double-stranded RNA, lectins and the like. In addition to antiviral action, it has cell growth inhibitory action and immunomodulatory action. It is classified into several types according to production cells, specific receptor binding ability, and bio-physicochemical properties. The main types include α, β, and γ. In addition, the existence of IFNω and IFNτ Are known. Furthermore, interferon α is known to have 20 or more subtypes. At present, various genetically modified preparations such as PEGylated and consensus interferon are being developed and marketed as well as natural forms.

  The interferon in the present invention may be any of the above types, but is preferably α or γ. In addition, the interferon in the present invention is a natural type, an artificially mutated genetically modified type, or a naturally occurring mutant as long as the ability to suppress HCV proliferation is enhanced in combination with the compound represented by the general formula (1) , A fusion protein, or a fragment thereof. The interferon of the present invention may be PEG (polyethylene glycol) (PEG-IFN). PEGylation of interferon can be performed by methods known to those skilled in the art (Japanese Patent No. 2980569). Examples of the PEGylated interferon include peginterferon-α-2a (Pegasys (registered trademark)) and peginterferon α-2b (pegintron (registered trademark)). PEG-IFN used in Example 1 of the present application refers to pegylated interferon-α-2a. Furthermore, the interferon of the present invention may be interferon bound to albumin. Examples of interferon bound to albumin include albuinterferon α-2b (albuferon (registered trademark)).

  There is no particular limitation on the origin of the interferon in the present invention, and it can be derived from, for example, human, chimpanzee, orangutan, dog, horse, sheep, goat, donkey, pig, cat, mouse, guinea pig, rat, rabbit and the like. Not limited to these, other mammals can be derived. Preferably it is human-derived interferon.

  The amino acid sequence of human interferon α or γ is known. For example, if it is interferon α, the amino acid sequence described in GenBank: NM_024013 can be used, and if it is interferon γ, the amino acid sequence described in GenBank: NM_000619 can be used. Can do. The amino acid sequence of interferon α is shown in SEQ ID NO: 1, the nucleotide sequence is shown in SEQ ID NO: 2, the amino acid sequence of interferon γ is shown in SEQ ID NO: 3, and the nucleotide sequence of the same γ is shown in SEQ ID NO: 4. The interferon can be prepared by methods well known to those skilled in the art. For example, mRNA is prepared from human-derived interferon-producing cells by a well-known means to prepare a cDNA library, and all or one of the base sequences described in SEQ ID NO: 2 or SEQ ID NO: 4 is prepared from the cDNA library. It can be prepared by selecting a cDNA that hybridizes with a probe comprising a partial base sequence under stringent conditions, expressing the cDNA using an appropriate host / vector system, and purifying the resulting protein. The host / vector system may be used from the examples of host / vector systems that can be used in the production of antibodies described below. Alternatively, a primer is designed based on the nucleotide sequence set forth in SEQ ID NO: 2 or SEQ ID NO: 4, RT-PCR is performed using the above primer using mRNA prepared from human-derived interferon-producing cells as a template, The obtained cDNA can also be expressed and prepared.

  Those skilled in the art can appropriately select the stringent hybridization conditions. For example, in hybridization solution containing 25% formamide, 50% formamide under more severe conditions, 4 × SSC, 50 mM Hepes pH 7.0, 10 × Denhardt's solution, 20 μg / ml denatured salmon sperm DNA at 42 ° C. After overnight prehybridization, a labeled probe is added and hybridization is performed by incubating overnight at 42 ° C. The cleaning solution and temperature conditions in the subsequent cleaning are about “1 × SSC, 0.1% SDS, 37 ° C.”, and more severe conditions are about “0.5 × SSC, 0.1% SDS, 42 ° C.”. Can be carried out at about “0.2 × SSC, 0.1% SDS, 65 ° C.”. Thus, isolation of a polynucleotide having high homology with the probe sequence can be expected as the conditions for washing for hybridization become more severe. However, combinations of the above SSC, SDS, and temperature conditions are exemplary, and those skilled in the art will recognize the above or other factors that determine the stringency of hybridization (eg, probe concentration, probe length, hybridization reaction). It is possible to achieve the same stringency as above by appropriately combining the time and the like.

  A polypeptide encoded by a polynucleotide isolated using such a hybridization technique usually has high homology in amino acid sequence with the polypeptide identified by the present inventors. High homology means at least 40% or more, preferably 60% or more, more preferably 80% or more, more preferably 90% or more, more preferably at least 95% or more, and more preferably at least 97% or more (for example, 98% or more). To 99%) sequence homology. The identity of the amino acid sequence is determined, for example, by the algorithm BLAST by Karlin and Altschul (Proc. Natl. Acad. Sci. USA 87: 2264-2268, 1990, Proc. Natl. Acad. Sci. USA 90: 5873-5877, 1993). Can be determined by. Based on this algorithm, a program called BLASTX has been developed (Altschul et al. J. Mol. Biol. 215: 403-410, 1990). When the amino acid sequence is analyzed by BLASTX, the parameters are set to score = 50 and wordlength = 3, for example. When using BLAST and Gapped BLAST programs, the default parameters of each program are used. Specific techniques for these analysis methods are known (http://www.ncbi.nlm.nih.gov.).

  In addition to the interferon having the above sequence, a polypeptide similar to the interferon having the above sequence is preferably used in the present invention as long as the ability to suppress HCV proliferation is enhanced in combination with the compound represented by the general formula (1). Can do. As such a polypeptide, a polypeptide comprising an amino acid sequence in which one or more amino acids are deleted, substituted, added, and / or inserted in the amino acid sequence described in SEQ ID NO: 1, wherein the general formula (1) A polypeptide having a high HCV growth inhibitory ability in combination with a compound represented by the following: an amino acid sequence in which one or more amino acids are deleted, substituted, added or / and inserted in the amino acid sequence set forth in SEQ ID NO: 3 A polypeptide having a high HCV growth inhibitory ability in combination with the compound represented by the general formula (1), a base sequence that hybridizes with the base sequence described in SEQ ID NO: 2 under stringent conditions A polypeptide comprising the amino acid sequence encoded by HCV, and having high HCV growth inhibition in combination with the compound represented by the general formula (1) A polypeptide comprising an amino acid sequence encoded by a base sequence that hybridizes with a base sequence described in SEQ ID NO: 4 under stringent conditions, and a compound represented by the general formula (1): Mention may be made of polypeptides having a high ability to suppress HCV proliferation when used in combination.

Such polypeptides can be prepared by methods well known to those skilled in the art. For example, it can be prepared by selecting and expressing a clone that hybridizes from a cDNA library prepared from interferon-producing cells using all or part of the nucleotide sequence of SEQ ID NO: 2 or 4 as a probe. it can. Alternatively, by subjecting the base sequence described in SEQ ID NO: 2 or 4 to a gene modification method well known to those skilled in the art, such as a mutation introduction method by PCR and a cassette mutation method, by introducing mutations site-specifically or randomly, Can be prepared. Alternatively, a sequence in which a mutation is introduced into the base sequence described in SEQ ID NO: 2 or 4 can be synthesized by a commercially available nucleic acid synthesizer.
Ribavirin may be further combined with a medicament for treating or preventing HCV infection, which is a combination of the compound represented by the general formula (1) of the present invention and interferon.

  In the present specification, the term “treatment” means that administration of the drug of the present invention to a subject eliminates or reduces HCV, suppresses further spread of HCV, and reduces symptoms caused by HCV infection. Meaning and specific examples include elimination of HCV, calming of hepatitis, and prevention and reduction of progression from hepatitis to cirrhosis, liver fibrosis and liver cancer. In addition, the description of “prevention” means that it is administered to a subject before HCV infection, thereby preventing HCV infection or suppressing proliferation.

  In the present invention, the combined use of the compound represented by the general formula (1) and interferon refers to administration or use of the compound represented by the general formula (1) and interferon (hereinafter simply referred to as “administration”). It is not limited by the order of administration or the administration interval. Moreover, you may implement as a kit which combined the compound of this invention and interferon. Furthermore, when the compound represented by the general formula (1) and interferon are used in combination, it is possible to reduce the respective doses as desired, as compared with the case where any one is used alone.

  The order of administration of the compound represented by general formula (1) and interferon is as follows: administration of interferon after administration of the compound, simultaneous administration of compound represented by general formula (1) and interferon, and administration of general formula (1 ) May be administered in any order.

  When the compound represented by general formula (1) and interferon are administered separately, the administration interval between the compound represented by general formula (1) and interferon is not particularly limited, and factors such as the administration route and dosage form are taken into consideration. Can be set. An example of the administration interval is usually 0 to 168 hours, preferably 0 to 72 hours, more preferably 0 to 24 hours, more preferably 0 to 12 hours. It is.

The administration interval of interferon is not limited, but is usually once a day to once a month, and preferably once a week. In addition, the administration interval of the compound represented by the general formula (1) is not limited, but is usually once a day to once in February, preferably once a day to 1 month. Once.
In addition, when the compound represented by the general formula (1) and interferon are administered separately, the administration method and the number of administrations per day may be the same or different. Furthermore, the weight ratio of the compound represented by the general formula (1) and interferon is not particularly limited.

  The compound represented by the general formula (1) can be used in medicine as it is or as a pharmacologically acceptable salt thereof. The salt is not particularly limited as long as it is pharmacologically acceptable, and examples thereof include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid; acetic acid, tartaric acid, lactic acid, citric acid. Salts with organic acids such as acid, fumaric acid, maleic acid, succinic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, toluene sulfonic acid, naphthalene sulfonic acid and camphor sulfonic acid; alkali such as sodium, potassium and calcium Examples thereof include salts with metals or alkaline earth metals.

  The compound represented by the general formula (1) or the pharmacologically acceptable salt may include a solvent addition form (solvate) and a crystal form (multi-system).

  The amount of the active ingredient compound contained in the medicament is not particularly limited and is appropriately selected within a wide range, and is, for example, 0.1 to 99.5% by weight, preferably 0.5 to 90% by weight.

  A compound represented by the general formula (1) or a pharmacologically acceptable salt, and / or interferon as an active ingredient according to a conventional method, an excipient, a binder, a disintegrant, a lubricant, a flavoring agent, It can be formulated using known adjuvants that can be usually used in the pharmaceutical formulation technical field, such as solubilizing agents, suspension agents, and coating agents. In molding into tablets, conventionally known carriers can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone; dry starch, sodium alginate, agar powder, laminaran powder , Disintegrating agents such as sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, monoglyceride stearate, starch, lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; quaternary Ann Absorption promoters such as nium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid; purified talc, stearate, boric acid powder, polyethylene glycol, etc. Examples of such abundant agents can be given.

  Furthermore, the tablets can be made into tablets with ordinary coatings, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets. In molding into the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc; Examples include binders such as tragacanth powder, gelatin and ethanol; disintegrants such as laminaran agar. In molding into the form of suppository, conventionally known carriers can be widely used as carriers, such as polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like. it can. When prepared as injections, the solutions and suspensions are preferably sterilized and isotonic with blood, and when formed into these solutions, emulsions and suspensions, this is used as a diluent. Any of those commonly used in the field can be used, and examples thereof include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and a normal solubilizer, buffer, soothing agent, etc. May be added. Furthermore, a coloring agent, a preservative, a fragrance | flavor, a flavoring agent, a sweetening agent, etc. and other pharmaceuticals can also be contained as needed.

  The above medicament is preferably administered in a dosage unit form, and is administered orally, intra-tissue (subcutaneous, intramuscular, intravenous, etc.), local (transdermal etc.) or rectally. Can do. It will be appreciated that the medicament is administered in a dosage form suitable for these administration methods.

  When a compound represented by the general formula (1) or a pharmacologically acceptable salt thereof and an interferon are administered as a pharmaceutical, the dosage depends on the patient's condition such as age and weight, administration route, nature of the disease and the like. It is desirable to adjust in consideration of the degree and the like. Usually, for humans, the amount of the active ingredient of the present invention is 0.001 to 2000 mg per day as the amount of the active ingredient of the present invention. In some cases, a dose lower than the above range may be sufficient, and conversely, a dose exceeding the above range may be required. When administering a large amount, it is desirable to divide the dose into several times a day.

  The oral administration can be performed in solid, powder or liquid dosage units, for example, powders, powders, tablets, dragees, capsules, drops, sublingual agents, other dosage forms, and the like. .

  The intra-tissue administration can be performed, for example, by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection such as a solution or suspension. These are compounds that are represented by the general formula (1) or a pharmacologically acceptable salt thereof, and / or a certain amount of interferon that is suitable for injection purposes such as an aqueous or oily medium. It is produced by suspending or dissolving in a toxic liquid carrier and then sterilizing the suspension or solution.

  The above-mentioned topical administration (transdermal administration etc.) can be performed by using forms of external preparations such as liquids, creams, powders, pastes, gels, ointments and the like. These include a compound represented by the general formula (1) or a pharmacologically acceptable salt thereof, and / or a certain amount of interferon, a fragrance, a colorant, a filler, Manufactured by combining with one or more of surfactants, humectants, emollients, gelling agents, carriers, preservatives, stabilizers and the like.

  The above-mentioned rectal administration is carried out by using a compound represented by the general formula (1) or a pharmacologically acceptable salt thereof, and / or a certain amount of interferon, for example, higher esters such as palmitic acid myristyl ester, polyethylene It can be carried out using a suppository mixed in a low melting point solid consisting of glycol, cocoa butter, a mixture thereof and the like.

The administration can be performed, for example, by using a liquid dosage unit form for subcutaneous, intramuscular or intravenous injection such as a solution or suspension. These compounds are suitable for injection purposes such as aqueous or oily medium, for example, a compound represented by the general formula (1) or a pharmacologically acceptable salt thereof and / or an interferon. It is produced by suspending or dissolving in a non-toxic liquid carrier and then sterilizing the suspension or solution.
In addition, all prior art documents cited in the present specification are incorporated herein by reference.

  Hereinafter, one embodiment of the present invention will be described more specifically with reference to examples.

[Example 1] Anti-HCV effect of BO-653 and PEG-IFN in chimeric mice infected with HCV

  Using chimeric mice with human liver infected with HCR6 (genotype 1b), 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydro The inhibitory ability of benzofuran (BO-653) was examined. The purchased chimeric mouse (Phoenix Bio Inc., Hiroshima, Japan) was used.

  Specifically, according to Table 1, BO-653 and / or PEG-IFN (Chugai, Tokyo, Japan) is administered to mice infected with HCV genotype 1b (HCR6, accession number AY045702) by oral administration or subcutaneous injection. Blood was collected.

[Table 1] Administration schedule to chimeric mice infected with HCV genotype 1b

  In Table 1, B, I, and BO indicate that each operation was performed as necessary, and that the administration of the reagent started from the 0th day. PEG-IFN was injected at 30 μg / kg. The amount of BO-653 administered orally was 2000 mg / kg (BO).

  Next, total RNA was purified from 1 μl of serum collected from the chimeric mice using the AGPC method. HCV RNA was quantified by real-time PCR by methods known to those skilled in the art (Takeuchi, T. et al. Gasteroenterology, 116, 636-642 (1999)).

As a result, in the group administered with 20 times the amount of PEG-IFN (30 μg / kg / twice a week) used in clinical treatment, 8 days after administration from before administration (1.3 × 10 ⁷ copies / ml serum) The amount was reduced to about 1/30 (4.6 × 10 ⁵ copies / ml serum) and 14 days after administration to about 1/45 (2.8 × 10 ⁵ copies / ml serum). On the other hand, in the BO-653 single administration group, no significant decrease in the amount of HCV RNA was observed, but in the combination treatment group with PEG-IFN, about 1/30 amount (3.1 × 10 ⁵⁾ was observed 8 days after administration. 14 days after administration, the amount decreased to about 1/180 (5.4 × 10 ⁴ copies / ml serum) (FIG. 1).

  At the same time, we monitored the human albumin (h-Alb) concentration. Human albumin concentration was measured in 2 μl of serum using Alb-II kit (Eiken Chemical, Tokyo, Japan) according to the manufacturer's instructions. No significant decrease was observed in any of the administration groups (FIG. 2).

  From these results, in HCV-infected chimeric mice, BO-653 alone did not significantly reduce the amount of virus. A significant decrease in viral load was observed compared to (* p <0.05). In addition, no significant liver damage was observed in any of the administration groups.

[Example 2] HCV replicon replication inhibitory action of BO-653 On the day before the start of the experiment, HCV replicon-retaining cells Huh7 # 3-1 containing a luciferase gene were added to a 96-well white multiwell plate (for luciferase) and a 96-well multiwell plate (toxicity). 4500 / well for each (for testing). At this time, DMEM GlutaMaxI (DMEM5) medium containing 5% FCS was used. About 20 hours after the next day, BO-653 diluted with DMEM5 was added to each well so that the final concentrations were 0.2, 0.5, 1, 4, 12, 37, 111, 333, and 1000 micromolar. After 72 hours at 37 ° C. with 5% CO ₂ , luciferase assay and cytotoxicity test using WST-8 were performed. The thing which does not add BO-653 was set as the negative control.

Luciferase assay
Steady-Glo Lucifease Assay Buffer ^™ and Substrate ^™ (Promega, cat # E2520) were returned to room temperature. Buffer was added to Substrate and mixed well.
The plate was removed from the incubator, and after 30 minutes or more, it was pipetted 3 to 4 times by adding 100 microliters per well with a multichannel pipette. After standing for 5 minutes or longer, the activity was measured by the EnVision ™ 2103 Multilabel Reader, and the activity was determined from the amount of chemiluminescence. The IC ₅₀ (50% inhibitory concentration) of BO-653 was 34 micromolar.

WST-8 assay
Cytotoxicity was evaluated using Cell Counting Kit-8 (DOJINDO Laboratories, cat # 341-08001). The cultured plate was removed from the incubator and the medium was discarded. To this, 110 μL of Cell Counting Kit-8 diluted 11-fold with PBS was added per well and incubated at 37 ° C. for 60 minutes. After incubation, the plate was taken out and shaken for 10 seconds with a plate shaker. The absorbance of the plate was measured with an EnVision ™ 2103 Multilabel Reader (measuring wavelength: 450 nm, control wavelength: 590 nm), and the wells without BO-653 were taken as 100% to determine the cytotoxicity of each drug. No cytotoxicity of BO-653 was observed (IC ₅₀ > 1000 micromolar).

The above results are shown in FIG. From this result, it was confirmed that the compound of the general formula (1) was useful as a therapeutic or prophylactic agent for HCV infection even when used alone (single agent).
[Table 2]

[Reference Example 1] Inhibition of HCV replicon replication by Met-BO In Example 2 above, instead of using BO-653, 4,6-dioxylase described in Free Radical Research, 2006; 40 (1): 21-30 HCV replicon replication inhibitory action was examined using -t-butyl-5-methoxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran (Met-BO).
That is, HCV replicon-carrying cells Huh7 # 3-1 containing the luciferase gene on the day before the start of the experiment were plated at 4500 cells / well in each of a 96-well white multiwell plate (for luciferase) and a 96-well multiwell plate (for toxicity test). It was. At this time, DMEM GlutaMaxI (DMEM5) medium containing 5% FCS was used. About 20 hours after the next day, Met-BO diluted with DMEM5 was added to each well so that the final concentration was 0.2, 0.5, 1, 4, 12, 37, 111, 333, and 1000 micromolar. After 72 hours at 37 ° C. with 5% CO ₂ , luciferase assay and cytotoxicity test using WST-8 were performed. The thing which does not add Met-BO was made into the negative control.

Luciferase assay
Steady-Glo Lucifease Assay Buffer ^™ and Substrate ^™ (Promega, cat # E2520) were returned to room temperature. Buffer was added to Substrate and mixed well.
The plate was removed from the incubator, and after 30 minutes or more, it was pipetted 3 to 4 times by adding 100 microliters per well with a multichannel pipette. After standing for 5 minutes or longer, the activity was measured by the EnVision ™ 2103 Multilabel Reader, and the activity was determined from the amount of chemiluminescence. The IC ₅₀ (50% inhibitory concentration) of Met-BO was 60 micromolar.

WST-8 assay
Cytotoxicity was evaluated using Cell Counting Kit-8 (DOJINDO Laboratories, cat # 341-08001). The cultured plate was removed from the incubator and the medium was discarded. To this, 110 μL of Cell Counting Kit-8 diluted 11-fold with PBS was added per well and incubated at 37 ° C. for 60 minutes. After incubation, the plate was taken out and shaken for 10 seconds with a plate shaker. The absorbance of the plate was measured with an EnVision ™ 2103 Multilabel Reader (measurement wavelength: 450 nm, control wavelength: 590 nm), and the cytotoxicity of each drug was determined with the well containing no Met-BO as 100%. Met-BO cytotoxicity was not observed (IC ₅₀ > 1000 micromolar).
The results are shown in Table 3. From this result, it was confirmed that Met-BO is useful as a therapeutic or prophylactic agent for HCV infection.
[Table 3]

  The present invention provides medicaments and methods for the prevention and / or treatment of HCV infection.

Claims (14)

The following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined together to form a cycloalkyl group.) A medicament for treatment or prevention.   The medicament according to claim 1, wherein the medicament for treating or preventing HCV infection is a combination drug.   The pharmaceutical according to claim 1, wherein the compound represented by the general formula (1) and interferon are used in combination.   The pharmaceutical according to claim 3, wherein the compound represented by the general formula (1) and the interferon are administered simultaneously, sequentially or separately.   The medicine for treating or preventing HCV infection is a kit comprising a pharmaceutical composition containing the compound represented by the general formula (1) and a pharmaceutical composition containing interferon. The pharmaceutical described. The following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or A substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group) as an active ingredient and used in combination with interferon A medicament for treating or preventing HCV infection characterized by the above. Containing interferon as an active ingredient, the following general formula (1):

Wherein R ¹ is a hydrogen atom, an acyl group, or an arylalkoxycarbonyl group; R ² and R ³ are independently a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, or HCV infection, characterized in that it is a substituted or unsubstituted alkynyl group, or R ² and R ³ may be combined to form a cycloalkyl group) A medicine for treating or preventing symptom. The pharmaceutical according to any one of claims 1 to 7, wherein R ¹ is a hydrogen atom. The pharmaceutical according to any one of claims 1 to 8, wherein R ² and R ³ are unsubstituted alkyl groups.   The medicament according to claim 9, wherein the unsubstituted alkyl group is an n-butyl group, an n-pentyl group, an n-hexyl group or an n-heptyl group.   The compound represented by the formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-butyl-2,3-dihydrobenzofuran, 4,6-di-t- Butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran, 4,6-di-t-butyl-5-hydroxy-2,2-di-n-hexyl-2,3 The pharmaceutical according to any one of claims 1 to 10, which is -dihydrobenzofuran or 4,6-di-t-butyl-5-hydroxy-2,2-di-n-heptyl-2,3-dihydrobenzofuran. .   The compound represented by formula (1) is 4,6-di-t-butyl-5-hydroxy-2,2-di-n-pentyl-2,3-dihydrobenzofuran. A medicament according to any one of the above.   The medicament according to any one of claims 1 to 12, wherein the interferon is a pegylated interferon.   The medicament according to any one of claims 1 to 13, wherein the HCV infection is hepatitis C, cirrhosis, liver fibrosis, or liver cancer.

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