CRYSTALLINE FORMS OF A FARNESOID X RECEPTOR AGONIST
Described herein is the farnesoid X receptor agonist, 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate, including crystalline forms and pharmaceutically acceptable salts, solvates, and formulations thereof.
1 .- 2 . (canceled)
3 . A crystalline form of 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate that is Form 1 having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.4° 2-Theta, 8.4° 2-Theta, 14.6° 2-Theta, 15.4° 2-Theta, 16.8° 2-Theta, 17.0° 2-Theta, 17.3° 2-Theta, 17.6° 2-Theta, 18.9° 2-Theta, and 19.3° 2-Theta
(f).
4 .- 7 . (canceled)
8 . The crystalline form of claim 3 , wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 213° C.
9 .- 12 . (canceled)
13 . A crystalline form of 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate that is Form 2 having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 8.5° 2-Theta, 12.8° 2-Theta, 13.4° 2-Theta, 16.2° 2-Theta, 17.0° 2-Theta 18.8° 2-Theta, 19.5° 2-Theta, and 20.5° 2-Theta
(f).
14 .- 17 . (canceled)
18 . The crystalline form of claim 13 , wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 212° C.
19 .- 24 . (canceled)
25 . A crystalline form of 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate that is Form 3 having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 7.5° 2-Theta, 15.1° 2-Theta, 16.6° 2-Theta, 16.9° 2-Theta, 17.2° 2-Theta, 17.5° 2-Theta, and 18.7° 2-Theta
(f).
26 .- 29 . (canceled)
30 . The crystalline form of claim 25 , wherein the crystalline form has a DSC thermogram with an endotherm having an onset at about 214° C.
31 .- 34 . (canceled)
35 . A crystalline form of 4-((4-(1-(tert-butyl)-1H-pyrazol-4-yl)pyridin-2-yl)((4-(4-methoxy-3-methylphenyl) bicyclo[2.2.2]octan-1-yl)methyl) carbamoyl)cyclohexyl 3-hydroxyazetidine-trans-1-carboxylate that is Form 4 having an X-ray powder diffraction (XRPD) pattern with characteristic peaks at 5.4° 2-Theta, 8.9° 2-Theta, 9.9° 2-Theta, 14.8° 2-Theta, 15.9° 2-Theta, 16.2° 2-Theta, 16.8° 2-Theta, 17.5° 2-Theta, 18.5° 2-Theta, and 20.1° 2-Theta
(f).
36 .- 39 . (canceled)
40 . The crystalline form of claim 35 , wherein the crystalline form has a DSC thermogram a first endotherm having an onset at about 164° C. and a second endotherm having an onset at about 209° C.
41 .- 43 . (canceled)
44 . A pharmaceutical composition comprising the crystalline form of claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients.
45 .- 64 . (canceled)
65 . A method of treating a gastrointestinal disease or condition in a mammal, comprising administering to the mammal the crystalline form of claim 25 , or a pharmaceutically acceptable salt or solvate thereof.
66 . The method of claim 65 , wherein the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, post-surgical inflammation, gastric carcinogenesis, graft versus host disease or any combination thereof.
67 . The method of claim 65 , wherein the gastrointestinal disease or condition is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), unsubtyped IBS (IBS-U), or bile acid diarrhea (BAD).
68 .- 69 . (canceled)
70 . A pharmaceutical composition comprising the crystalline form of claim 35 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one inactive ingredient selected from pharmaceutically acceptable carriers, diluents, and excipients.
71 . A method of treating a gastrointestinal disease or condition in a mammal, comprising administering to the mammal the crystalline form of claim 35 , or a pharmaceutically acceptable salt or solvate thereof.
72 . The method of claim 71 , wherein the gastrointestinal disease or condition is necrotizing enterocolitis, gastritis, ulcerative colitis, Crohn's disease, inflammatory bowel disease, irritable bowel syndrome, gastroenteritis, radiation induced enteritis, pseudomembranous colitis, chemotherapy induced enteritis, gastro-esophageal reflux disease (GERD), peptic ulcer, non-ulcer dyspepsia (NUD), celiac disease, intestinal celiac disease, post-surgical inflammation, gastric carcinogenesis, graft versus host disease or any combination thereof.
73 . The method of claim 71 , wherein the gastrointestinal disease or condition is irritable bowel syndrome with diarrhea (IBS-D), irritable bowel syndrome with constipation (IBS-C), mixed IBS (IBS-M), unsubtyped IBS (IBS-U), or bile acid diarrhea (BAD).
74 . A method of treating ulcerative colitis or Crohn's disease in a mammal, comprising administering to the mammal the crystalline form of claim 3 , or a pharmaceutically acceptable salt or solvate thereof.
75 . A method of treating ulcerative colitis or Crohn's disease in a mammal, comprising administering to the mammal the crystalline form of claim 13 , or a pharmaceutically acceptable salt or solvate thereof.