Crystalline salts of a plasma kallikrein inhibitor
View Patent ↗Disclosed are crystalline salts of Compound I, methods of preparing them, and related pharmaceutical preparations thereof. Also disclosed are methods of treatment using the crystalline salts of the invention.
1. A crystalline salt of Compound I,
wherein the salt is a bis(hydrochloride) salt.
2. The crystalline salt of claim 1 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ±0.2°) of 5.3, 9.0, and 22.0.
3. The crystalline salt of claim 1 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.3, 9.0, and 22.0.
4. The crystalline salt of claim 2 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ±0.2°) of 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3.
5. The crystalline salt of claim 3 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.3, 9.0, 19.8, 21.2, 22.0, and 23.3.
6. The crystalline salt of claim 4 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ±0.2°) of 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3.
7. The crystalline salt of claim 5 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.3, 9.0, 14.3, 16.2, 19.8, 21.2, 22.0, 23.3, 24.6, and 30.3.
8. The crystalline salt of claim 1 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ±0.2°) of 5.28, 8.96, and 22.01.
9. The crystalline salt of claim 1 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.28, 8.96, and 22.01.
10. The crystalline salt of claim 8 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ±0.2°) of 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31.
11. The crystalline salt of claim 9 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.28, 8.96, 19.79, 21.16, 22.01, and 23.31.
12. The crystalline salt of claim 10 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ±0.2°) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.
13. The crystalline salt of claim 11 , having characteristic peaks in the X-ray powder diffraction (XRPD) pattern at values of two theta (° 2θ) of 5.28, 8.96, 14.27, 16.18, 19.79, 21.16, 22.01, 23.31, 24.64, and 30.31.
14. The crystalline salt of claim 1 , having an XRPD pattern substantially similar to that shown in FIG. 1 .
15. The crystalline salt of claim 1 , wherein the crystalline salt has a thermogravimetric-infrared spectrum substantially as shown in FIG. 2 .
16. A pharmaceutical composition comprising the crystalline salt of claim 1 ; and one or more pharmaceutically acceptable carriers.
17. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is formulated for parenteral administration.
18. The pharmaceutical composition of claim 16 , wherein the pharmaceutical composition is formulated for oral administration.
19. A method of treating or preventing a disease or condition characterized by aberrant plasma kallikrein activity, comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline salt of claim 1 .
20. The method of claim 19 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is selected from the group consisting of stroke, inflammation, reperfusion injury, acute myocardial infarction, deep vein thrombosis, post fibrinolytic treatment condition, angina, edema, angioedema, hereditary angioedema, sepsis, arthritis, hemorrhage, blood loss during cardiopulmonary bypass, inflammatory bowel disease, diabetes mellitus, retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, proliferative retinopathy, neuropathy, hypertension, brain edema, increased albumin excretion, macroalbuminuria, and nephropathy.
21. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is angioedema.
22. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is hereditary angioedema.
23. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is stroke.
24. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is reperfusion injury.
25. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is acute myocardial infarction.
26. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is hemorrhage.
27. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is blood loss during cardiopulmonary bypass.
28. The method of claim 20 , wherein the disease or condition characterized by aberrant plasma kallikrein activity is selected from the group consisting of retinopathy, diabetic retinopathy, diabetic macular edema, diabetic macular degeneration, age-related macular edema, age-related macular degeneration, and proliferative retinopathy.