Crystalline 2-amino-2-(hydroxymethyl)propane-1,3-diol salt of 4-(4-(1-isopropyl-7-OXO-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypryridin-2-YL)benzoic acid
The invention provides the tris salt of 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid as a crystalline anhydrous or tri-hydrate; as well as polymorphs, pharmaceutical compositions, dosage forms, and the use thereof in treating diseases, conditions or disorders modulated by the inhibition of an acetyl-CoA carboxylase (ACC) enzyme(s) in an animal.
1. A crystalline 2-amino-2-(hydroxymethyl)propane-1,3-diol salt of 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-1′-carbonyl)-6-methoxypyridin-2-yl)benzoic acid, wherein the crystalline salt is a trihydrate crystalline salt.
2. The crystalline salt of claim 1 , wherein the ratio of 4-(4-(1-isopropyl-7-oxo-1,4,6,7-tetrahydrospiro[indazole-5,4′-piperidine]-t-carbonyl)-6-methoxypyridin-2-yl)benzoic acid and the salt is 1:1.
3. The trihydrate crystalline salt of claim 1 , wherein said trihydrate crystalline salt has a PXRD pattern comprising peaks at diffraction angles of 8.4, 9.0, and 10.5 2θ, ±0.2° 2θ.
4. The trihydrate crystalline salt of claim 3 , wherein said trihydrate crystalline salt has a Raman spectrum comprising peak shifts at 1507, 1557, and 1610 cm −1 , ±2 cm −1 .
5. The trihydrate crystalline salt of claim 4 , wherein said trihydrate crystalline salt has a 13 C ssNMR spectrum comprising chemical shifts at 19.2, 149.5, and 163.8 ppm, ±0.2 ppm.
6. The trihydrate crystalline salt of claim 1 , wherein said trihydrate crystalline salt has an analytical parameter selected from the group consisting of
a PXRD pattern comprising peaks at diffraction angles of 8.4 and 9.0 2θ, ±0.2° 2θ,
a Raman spectrum comprising peak shifts at 1557 and 1610 cm −1 , ±2 cm −1 , and
a 13 C ssNMR spectrum comprising at least one chemical shift at 19.2, 149.5, or 163.8 ppm, ±0.2 ppm.
7. The trihydrate crystalline salt of claim 1 , wherein said trihydrate crystalline salt has an analytical parameter selected from the group consisting of a PXRD pattern comprising peaks at diffraction angles of 8.4 and 9.0 2θ, ±0.2° 2θ, and a Raman spectrum comprising at least one peak shift at 1507, 1557, or 1610 cm −1 , ±2 cm −1 .
8. The trihydrate crystalline salt of claim 1 , wherein said trihydrate crystalline salt has an analytical parameter selected from the group consisting of a PXRD pattern comprising peaks at diffraction angles of 8.4 and 9.0 2θ, ±0.2° 2θ, and a 13 C ssNMR spectrum comprising at least one chemical shift at 19.2, 149.5, or 163.8 ppm, ±0.2 ppm.
9. The trihydrate crystalline salt of claim 1 , where said trihydrate crystalline salt is substantially pure.
10. A pharmaceutical composition comprising the crystalline salt of claim 1 in a therapeutically effective amount with a pharmaceutically acceptable carrier.
11. A method of treating a disease selected from nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and type 2 diabetes (T2D) in a mammal, the method comprising administering to the mammal a therapeutically effective amount of the crystalline salt of claim 1 .