# US 7,410,979 B2 · Synergistically effective combinations of dihaloacetamide compounds and interferon or ribavirin against HCV infections

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- Number: US 7,410,979 B2
- Document ID: US7410979B2
- Status: Granted
- Kind: B2
- Application number: 10/993,212
- Filed: 2004-11-19
- Published: 2005-06-16
- Granted: 2008-08-12
- Earliest claimed: 2003-11-19
- Assignees: Rigel Pharmaceuticals, Inc.
- Inventors: Henry Lu
- Web page: https://patentgrep.com/patent/US7410979B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/42: Oxazoles
- A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom
- A61K 38/21: Interferons {[IFN]}
- A61K 38/212: {IFN-alpha}
- A61K 38/215: {IFN-beta}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates to anti-HCV dihaloacetamide compounds in synergistic combination with an interferon and/or ribavirin and pharmaceutical compositions thereof for inhibition of the replication of HCV virus. The present invention also relates to the use of the compositions to inhibit HCV replication and/or proliferation and to treat or prevent HCV infections.

## Claims

### Claim 1

A method of treating an HCV infection comprising adjunctively administering to a subject a synergistically effective amount of a combination comprising an anti-HCV dihaloacetamide compound with an interferon and/or a ribavirin.

### Claim 2 (depends on 1)

The method of claim 1 in which the interferon is an alpha-interferon.

### Claim 3 (depends on 2)

The method of claim 2 in which the alpha interferon is IFNα-1a or IFNα-1b.

### Claim 4 (depends on 1)

The method of claim 1 in which the interferon is interferon alpha-n1 (INS).

### Claim 5 (depends on 1)

The method of claim 1 in which the interferon is β-interferon or an ω-interferon.

### Claim 6 (depends on 1)

The method of claim 1 in which the interferon comprises a pegylated interferon.

### Claim 7 (depends on 6)

The method of claim 6 in which the pegylated interferon is pegylated interferon-2b, pegylated interferon-2a or a combination thereof.

### Claim 8 (depends on 1)

The method of claim 1 in which the ribavirin has the structure 1-β-D-ribofuranosyl-1,2,4-triazole.

### Claim 9 (depends on 1)

The method of claim 1 in which the combination includes both the interferon and the ribavirin.

### Claim 10 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The method of any one of claims 1-9 in which the anti-HCV dihaloacetamide compound is compound I:

### Claim 11 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The method of any one of claims 1-9 in which the anti-HCV dihaloacetamide compound is compound II:

### Claim 12 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9)

The method of any one of claims 1-9 in which the anti-HCV dihaloacetamide compound is a mixture of compound I:
and compound II:

### Claim 13 (depends on 1)

The method of claim 1 in which the anti-HCV dihaloacetamide compound, interferon and/or ribavirin are administered simultaneously.

### Claim 14 (depends on 1)

The method of claim 1 in which the anti-HCV dihaloacetamide compound, interferon and/or ribavirin are administered sequentially in any order.

### Claim 15

A method of inhibiting HCV replication comprising contacting an HCV virion with a synergistically effective combination comprising an anti-HCV dihaloacetamide compound, an interferon and/or a ribavirin.

### Claim 16 (depends on 1)

The method of claim 1 wherein the anti-HCV dihaloacetamide compound is of the following structural formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein:
R2 and R6 are independently selected from the group consisting of hydrogen, halo, C1-C15 alkyl, substituted C1-C15 alkyl, C1-C15 alkylthio, substituted C1-C15 alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl-C1-C15 alkyloxycarbonyl, substituted aryl-C1-C15 alkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, carbamoyl, substituted carbamoyl, halo-C1-C15 alkyl, sulfamoyl, substituted sulfamoyl, and silyl ethers, provided that at least one of R2 and R6 is other than hydrogen;
R3 and R5 are independently selected from the group consisting of hydrogen, halo, C1-C15 alkyl, substituted C1-C15 alkyl, C1-C15 alkylthio, substituted C1-C15 alkylthio, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl-C1-C15 alkyloxycarbonyl, substituted aryl-C1-C15 alkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, carbamoyl, substituted carbamoyl, halo-C1-C15 alkyl, sulfamoyl, and substituted sulfamoyl;
R4 is selected from the group consisting of hydrogen, halo, C1-C15 alkyl, substituted C1-C15 alkyl, C1-C15 alkylthio, substituted C1-C15 alkylthio, carbamoyl, substituted carbamoyl, alkoxy, substituted alkoxy, alkoxycarbonyl, substituted alkoxycarbonyl, aryl-C1-C15 alkyloxycarbonyl, substituted aryl-C1-C15 alkyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, di-C1-C15 alkylamino, substituted di-C1-C15 alkylamino, halo-C1-C15 alkylamino, sulfamoyl, and substituted sulfamoyl;
R8, R9, and R14 are independently selected from the group consisting of hydrogen, halo, and fluoro;
R11 is hydrogen, or C1-C15 alkyl; and
R12 is selected from the group consisting of substituted C1-C15 alkyl, halo-C1-C15 alkyl, cycloheteroalkyl, and substituted cycloheteroalkyl.