THIOPHENE COMPOUNDS
Polymorph Forms M, H, P, X, and ZA of Compound (1) represented by the following structural formula: are described. A method of preparing polymorph Form M of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes isopropanol, ethyl acetate, n-butyl acetate, methyl acetate, acetone, 2-butanone (methylethylketone (MEK)), or heptane, or a combination thereof at a temperature in a range of 10° C. to 47° C. to form From M of Compound (1). A method of preparing polymorph Form H of Compound (1) includes stirring a solution of Compound (1) at a temperature in a range of 48° C. to 70° C. to form Form H of Compound (1). A method of preparing polymorph Form P of Compound (1) includes stirring a mixture of Compound (1) and a solvent system that includes a solvent selected from the group consisting of dichloromethane and tetrahydrofuran (THF), and a mixture thereof at room temperature to form Form P of Compound (1). A method of preparing polymorph Form X of Compound (1) includes removing ethyl acetate from ethylacetate solvate G of Compound (1). A method of preparing polymorph Form ZA of Compound (1) includes removing n-butyl acetate from n-butyl acetate solvate A of Compound (1).
1 . A polymorphic form of Compound 1 represented by the following structural formula:
wherein the polymorphic form is polymorph Form M, polymorph Form H, polymorph Form P, polymorph Form X, or polymorph Form ZA.
2 . The polymorphic form of claim 1 , wherein the polymorphic form is Polymorph Form M of Compound 1.
3 . The polymorphic form of claim 2 , wherein Polymorph Form M is characterized as having an X-ray powder diffraction pattern with the most intense characteristic peak expressed in 2-theta±0.2 at 19.6; or 19.6, 16.6, 18.1, 9.0, 22.2, and 11.4, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
4 . (canceled)
5 . The polymorphic form of claim 2 , wherein Polymorph Form M is characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 2 ; or as having a solid state C 13 NMR spectrum substantially the same as that shown in FIG. 6 .
6 . The polymorphic form of claim 2 , wherein Polymorph Form M is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 230±2° C.; or having peaks at 177.3, 134.3, 107.4, 56.5, 30.7, and 25.3 in a solid state C 13 nuclear magnetic spectroscopy (NMR) spectrum.
7 . (canceled)
8 . (canceled)
9 . The polymorphic form of claim 1 , wherein the polymorphic form is Polymorph Form H of Compound 1.
10 . The polymorphic form of claim 9 , wherein Polymorph Form H is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at 6.6 and 17.3; or 6.6, 18.7, 8.5, 17.3, 15.8, and 19.4, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation and wherein the peak at 6.6 is the most intense peak.
11 . (canceled)
12 . The polymorphic form of claim 9 , wherein Polymorph Form H is characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 3 ; or as having a solid state C 13 NMR spectrum substantially the same as that shown in FIG. 7 .
13 . The polymorphic form of claim 9 , wherein Polymorph Form H is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 238±2° C.; or having peaks at 162.2, 135.9, 131.1, 109.5, 45.3, and 23.9 in a solid state C 13 nuclear magnetic spectroscopy (NMR) spectrum.
14 . (canceled)
15 . (canceled)
16 . The polymorphic form of claim 1 , wherein the polymorphic form is Polymorph Form P of Compound 1.
17 . The polymorphic form of claim 16 , wherein Polymorph Form P is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at 7.0 and 15.8; or 7.0, 15.8, 9.8, 19.3, 8.5, and 21.9, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation and wherein the peak at 7.0 is the most intense peak.
18 . (canceled)
19 . The polymorphic form of claim 16 , wherein Polymorph Form P is characterized as having X-ray powder diffraction pattern substantially the same as that shown in FIG. 4 ; or as having a solid state C 13 NMR spectrum substantially the same as that shown in FIG.
20 . The polymorphic form of claim 16 , wherein Polymorph Form P is characterized as having an endothermic peak in differential scanning calorimetry (DSC) at 160±2° C.; or having peaks at 161.5, 133.6, 105.8, 44.4, 31.1 and 22.1 in a solid state C 13 nuclear magnetic spectroscopy (NMR) spectrum.
21 . (canceled)
22 . (canceled)
23 . The polymorphic form of claim 1 , wherein the polymorphic form is Polymorph Form X of Compound 1.
24 . The polymorphic form of claim 23 , wherein Polymorph Form X is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at 7.5 and 12.1; or 7.5, 12.1, 13.0, 13.8, 16.2, and 19.7, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
25 . (canceled)
26 . (canceled)
27 . The polymorphic form of claim 1 , wherein the polymorphic form is Polymorph Form ZA of Compound 1.
28 . The polymorphic form of claim 27 , wherein Polymorph Form ZA is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at 5.2 and 10.2; or 0.2, 10.2, 16.5, 18.6, 19.8, and 20.3, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
29 . (canceled)
30 . (canceled)
31 . (canceled)
32 . A pharmaceutical composition comprising Form M, H, P, X and ZA of Compound 1, or an amorphous form of Compound 1, wherein Compound 1 is represented by the following structural formula:
and
at least one pharmaceutically acceptable carrier or excipient.
33 - 38 . (canceled)
39 . 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 polymorph form of Compound 1 according to claim 1 .
40 . A method of treating a HCV infection in a subject, comprising administering to the subject a therapeutically effective amount of a polymorph form of Compound 1 according to claim 1 .
41 . 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 polymorph form of Compound 1 according to claim 1 .
42 - 53 . (canceled)
54 . A method of preparing Form M of Compound (1) represented by the following structural formula:
comprising stirring a mixture of Compound (1) and a solvent system that includes isopropanol, ethyl acetate, n-butyl acetate, methyl acetate, acetone, 2-butanone, or heptane, or a combination thereof at a temperature in a range of 10° C. to 47° C. to form From M of Compound (1).
55 . The method of claim 54 , wherein the solvent system includes: isopropanol; ethyl acetate; n-butyl acetate; a mixture of n-butyl acetate and acetone; a mixture of n-butyl acetate and methyl acetate; acetone; 2-butanone; a mixture of n-butyl acetate and heptane; a mixture of acetone and heptane; or a mixture of ethyl acetate and heptane.
56 . The method of claim 55 , wherein Compound (1) in:
i) isopropanol is stirred at a temperature in a range of 10° C. to 47° C.;
ii) ethyl acetate is stirred at a temperature in a range of 45° C. to 47° C.;
iii) n-butyl acetate at a temperature in a range of 35° C. to 47° C.;
iv) a mixture of n-butyl acetate and acetone at a temperature in a range of 30° C. to 47° C.;
v) a mixture of n-butyl acetate and methyl acetate at a temperature in a range of 25° C. to 47° C.;
vi) acetone at a temperature in a range of 20° C. to 47° C.;
vii) 2-butanone at a temperature in a range of 30° C. to 47° C.;
viii) a mixture of n-butyl acetate and heptane at a temperature in a range of 25° C. to 47° C.;
ix) a mixture of acetone and heptane at a temperature in a range of 25° C. to 47° C.; or
x) a mixture of ethyl acetate and heptane at a temperature in a range of 25° C. to 47° C.,
to form Form M of Compound (1).
57 . A method of preparing Form H of Compound (1) represented by the following structural formula:
Comprising stirring a solution of Compound (1) at a temperature in a range of 48° C. to 70° C. to form Form H of Compound (1).
58 . (canceled)
59 . (canceled)
60 . A method of preparing Form P of Compound (1) represented by the following structural formula:
comprising:
stirring a mixture of Compound (1) and a solvent system that include a solvent selected from the group consisting of dichloromethane, tetrahydrofuran (THF), and a mixture thereof at room temperature to form Form P of Compound (1).
61 . A method of preparing Form X of Compound (1) represented by the following structural formula:
comprising removing ethyl acetate from ethylacetate solvate G of Compound (1), wherein ethylacetate solvate G of Compound (1) is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 7.5 and 12.1, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.
62 . A method of preparing Form ZA of Compound (1) represented by the following structural formula:
comprising removing n-butyl acetate from n-butyl acetate solvate A of Compound (1), wherein
n-butyl acetate solvate A of Compound (1) is characterized as having an X-ray powder diffraction pattern with characteristic peaks expressed in 2-theta±0.2 at the following positions: 9.7 and 16.5, wherein the X-ray powder diffraction pattern is obtained at room temperature using Cu K alpha radiation.