CRYSTALLINE FORMS OF 8-(2-FLUOROBENZYL)-6-(3-(TRIFLUOROMETHYL)-1H-1,2,4-TRIAZOL-5-YL)IMIDAZO[1,2-a]PYRAZINE AS sGC STIMULATORS
The present disclosure relates to crystalline forms of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine, depicted below as a compound of Formula (I): which are useful as a stimulator of soluble guanylate cyclase (sGC). The present disclosure also provides pharmaceutically acceptable compositions comprising the crystalline forms and methods of using said compositions in the treatment of various disorders.
1 . A crystalline form of 8-(2-fluorobenzyl)-6-(3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)imidazo[1,2-a]pyrazine, wherein:
(1) the crystalline form is crystalline form Form B characterized by (i) at least three x-ray powder diffraction peaks at 2θ angles selected from 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°; (ii) at least four x-ray powder diffraction peaks at 2θ angles selected from 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°; (iii) x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°; (iv) x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°; (v) a DSC pattern that is substantially the same DSC pattern shown in FIG. 6 ; or (vi) a TGA pattern that is substantially the same TGA pattern shown in FIG. 7 ;
(2) the crystalline form is Crystalline Hydrate 1 characterized by (i) at least three x-ray powder diffraction peaks at 2θ angles selected from 11.50, 15.2°, 17.0°, 17.7°, and 18.3°; (ii) at least four x-ray powder diffraction peaks at 2θ angles selected from 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°; (iii) x-ray powder diffraction peaks at 2θ angles 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°; (iv) x-ray powder diffraction peaks at 2θ angles 11.5°, 13.5°, 15.2°, 17.0°, 17.7°, 18.3°, 19.1°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4°; (v) a DSC pattern that is substantially the same DSC pattern shown in FIG. 9 ; or (vi) a TGA pattern that is substantially the same TGA pattern shown in FIG. 10 ; or
(3) the crystalline form is Crystalline Hydrate 3 characterized by (i) at least three x-ray powder diffraction peaks at 2θ angles selected from 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°; (ii) at least four x-ray powder diffraction peaks at 2θ angles selected from 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°; (iii) x-ray powder diffraction peaks at 2θ angles 10.3°, 12.10, 13.5°, 16.9°, and 24.4°; (iv) x-ray powder diffraction peaks at 2θ angles 10.3°, 12.1°, 13.5°, 15.9°, 16.9°, 17.6°, 22.0°, 22.9°, 24.4°, and 28.9°; (v) a DSC pattern that is substantially the same DSC pattern shown in FIG. 15 ; or (vi) a TGA pattern that is substantially the same TGA pattern shown in FIG. 16 .
2 .- 10 . (canceled)
11 . The crystalline Form B of claim 1 , wherein the crystalline form is characterized by at least three x-ray powder diffraction peaks at 2θ angles selected from 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°.
12 . The crystalline Form B of claim 1 , wherein the crystalline form is characterized by at least four x-ray powder diffraction peaks at 2θ angles selected from 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°.
13 . The crystalline Form B of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 17.2°, and 21.0°.
14 . The crystalline Form B of claim 1 , wherein the crystalline form is characterized by x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
15 . The crystalline Form B of claim 11 , wherein the peaks have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.
16 . The crystalline Form B of claim 11 , wherein the crystalline form has a DSC pattern that is substantially the same DSC pattern shown in FIG. 6 .
17 . The crystalline Form B of claim 11 , wherein the crystalline form has a TGA pattern that is substantially the same TGA pattern shown in FIG. 7 .
18 . (canceled)
19 . The crystalline form of claim 1 , wherein the crystalline form is Crystalline Hydrate 1, wherein the crystalline form is characterized by (i) at least three x-ray powder diffraction peaks at 2θ angles selected from 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°; (ii) at least four x-ray powder diffraction peaks at 2θ angles selected from 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°; (iii) x-ray powder diffraction peaks at 2θ angles 11.5°, 15.2°, 17.0°, 17.7°, and 18.3°; (iv) at least six, at least seven, at least eight, at least nine, or at least ten diffraction peaks at 2θ angles selected from 11.5°, 13.5°, 15.2°, 17.0°, 17.7°, 18.3°, 19.1°, 22.1°, 23.1°, 23.3°, 24.2°, 24.9°, and 29.4°; (v) a DSC pattern that is substantially the same DSC pattern shown in FIG. 9 ; or (vi) a TGA pattern that is substantially the same TGA pattern shown in FIG. 10 .
20 .- 34 . (canceled)
35 . The crystalline form of claim 1 , wherein the crystalline form is Crystalline Hydrate 3, wherein the crystalline form is characterized by (ii at least three x-ray powder diffraction peaks at 2θ angles selected from 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°; (ii) at least four x-ray powder diffraction peaks at 2θ angles selected from 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°; (iii) x-ray powder diffraction peaks at 2θ angles 10.3°, 12.1°, 13.5°, 16.9°, and 24.4°; (iv) at least six, at least seven, at least eight, or at least nine x-ray powder diffraction peaks at 2θ angles 10.3°, 12.1°, 13.5°, 15.9°, 16.9°, 17.6°, 22.0°, 22.9°, 24.4°, and 28.9°; (v) a DSC pattern that is substantially the same DSC pattern shown in FIG. 15 ; or (vi) a TGA pattern that is substantially the same TGA pattern shown in FIG. 16 .
36 .- 41 . (canceled)
42 . A pharmaceutical composition comprising the crystalline form B of claim 1 ; and a pharmaceutically acceptable carrier or diluent.
43 . A method of treating a CNS disorder in a patient in need thereof, comprising the step of administering to said patient the crystalline form of claim 1 .
44 . The crystalline Form B of claim 13 , wherein the crystalline form is characterized by at least six x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
45 . The crystalline Form B of claim 13 , wherein the crystalline form is characterized by at least seven x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
46 . The crystalline Form B of claim 13 , wherein the crystalline form is characterized by at least eight x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
47 . The crystalline Form B of claim 13 , wherein the crystalline form is characterized by at least nine x-ray powder diffraction peaks at 2θ angles 8.9°, 12.2°, 13.6°, 14.5°, 15.7°, 17.2°, 17.7°, 21.0°, 22.7°, 23.9°, 25.0°, 26.7°, and 27.6°.
48 . The crystalline Form B of claim 14 , wherein the peaks have a relative intensity of at least 10%, of at least 15%, of at least 20%, or of at least 25%.