THIOPHENE COMPOUNDS
A co-crystal of Compound (1) includes Compound (1) and a co-crystal former selected from the group consisting of urea, nicotinamide, and isonicotinamide, wherein Compound (1) is characterized by the following structural formula: A pharmaceutical composition includes such a co-crystal of Compound (1) and at least one pharmaceutically acceptable carrier or excipient.
1 . A co-crystal comprising Compound (1) and a co-crystal former selected from the group consisting of urea, nicotinamide, and isonicotinamide, wherein Compound (1) is represented by the following structural formula:
2 . The co-crystal of claim 1 , wherein the co-crystal former is urea.
3 . The co-crystal of claim 2 , characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 18.4, 12.1, 15.6, 20.1, 10.8, and 11.7, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
4 . The co-crystal of claim 2 , wherein the X-ray powder diffraction pattern includes characteristic peaks expressed in 2-theta±0.2 at the following positions with relative intensities in parentheses: 18.4 (100.0%), 12.1 (69.1%), 15.6 (65.0%), 20.1 (52.6%), 10.8 (46.5%), and 11.7 (44.1%).
5 . The co-crystal of claim 2 , characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 190±2° C.
6 . The co-crystal of claim 2 , characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 1 .
7 . The co-crystal of claim 1 , wherein the co-crystal former is nicotinamide.
8 . The co-crystal of claim 7 , characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 21.7 and 15.5, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
9 . The co-crystal of claim 8 , characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 21.7, 10.2, 18.9, 17.8, 22.9, and 15.5, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
10 . The co-crystal of claim 9 , wherein the X-ray powder diffraction pattern includes characteristic peaks expressed in 2-theta±0.2 at the following positions with relative intensities in parentheses: 21.7 (100.0%), 10.2 (54.8%), 18.9 (53.2%), 17.8 (50.4%), 22.9 (44.6%), and 15.5 (42.5%).
11 . The co-crystal of claim 7 , characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 2 .
12 . The co-crystal of claim 1 , wherein the co-crystal former is isonicotinamide.
13 . The co-crystal of claim 12 , characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 21.7 and 11.6, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
14 . The co-crystal of claim 13 , characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 21.7, 10.2, 17.8, 22.9, 18.9, and 11.6, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
15 . The co-crystal of claim 14 , wherein the X-ray powder diffraction pattern includes characteristic peaks expressed in 2-theta±0.2 at the following positions with relative intensities in parentheses: 21.7 (100.0%), 10.2 (63.6%), 17.8 (32.8%), 22.9 (28.9%), 18.9 (27.8%), and 11.6 (23.8%).
16 . The co-crystal of claim 12 , characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 3 .
17 . A pharmaceutical composition comprising a co-crystal of any one of claims 1 - 16 and at least one pharmaceutically acceptable carrier or excipient.
18 . A method of inhibiting or reducing the activity of HCV polymerase in a biological in vitro sample, comprising administering to the sample an effective amount of a co-crystal according to any one of claims 1 - 16 .
19 . A method of treating a HCV infection in a subject, comprising administering to the subject a therapeutically effective amount of a co-crystal according to any one of claims 1 - 16 .
20 . A method of inhibiting or reducing the activity of HCV polymerase in a subject, comprising administering to the subject a therapeutically effective amount of a co-crystal according to any one of claims 1 - 16 .
21 . The method of claim 19 or 20 , further comprising co-administering one or more additional therapeutic agents to the subject.
22 . The method of claim 21 , wherein the additional therapeutic agents include an anti-HCV drug.
23 . The method of claim 22 , wherein the anti-HCV drug is an HCV protease inhibitor.
24 . The method of claim 23 , wherein the HCV protease inhibitor is an HCV NS3 inhibitor.
25 . The method of claim 21 , wherein the anti-HCV drug is an HCV NS5A inhibitor.
26 . The method of any one of claims 21 - 25 , wherein an interferon and/or ribavirin is co-administered.
27 . The method of claim 26 , wherein the interferon is a pegylated interferon.
28 . The method of claim 27 , wherein the pegylated interferon is a pegylated interferon-alpha.
29 . The method of claim 27 , wherein the pegylated interferon is pegylated interferon-alpha 2a or pegylated interferon-alpha 2b.
30 . The method of any one of claims 18 - 29 , wherein the HCV is genotype 1.
31 . The method of any one of claims 18 - 29 , wherein the HCV is genotype 1a or genotype 1b.
32 . A method of preparing a co-crystal comprising Compound (1) and a co-crystal former selected from the group consisting of urea, nicotinamide, isonicotinamide, wherein Compound (1) is represented by the following structural formula:
comprising the step of:
stirring a mixture of Compound 1 and the co-crystal former to form the co-crystal.
33 . The method of claim 32 , wherein the co-crystal former is urea.
34 . The method of claim 33 , wherein the mixture of Compound 1 and the co-crystal former is stirred in a solvent system that includes dichloromethane and/or acetonitrile.
35 . The method of claim 32 , wherein the co-crystal former is nicotinamide.
36 . The method of claim 35 , wherein the solvent system includes acetonitrile.
37 . The method of claim 32 , wherein the co-crystal former is isonicotinamide.
38 . The method of claim 37 , wherein the solvent system includes acetonitrile.