Crystalline (2S,4R)-5-(5'-chloro-2'-fluoro-[1,1'-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof
In one aspect, the invention relates to a crystalline form of the structure: or a pharmaceutically acceptable salt thereof, having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising this crystalline form; methods of using this crystalline form and its soluble form (I); and processes for preparing soluble (I) and crystalline (I′) forms.
1. A method of inhibiting neprilysin activity in a renally-impaired patient in need thereof, the method comprising administering to the renally-impaired patient Compound I having the structure:
or a pharmaceutically acceptable salt thereof, wherein Compound I is administered orally once-daily at a dose of 10 mg to 600 mg.
2. The method of claim 1 , wherein the renally-impaired patient has an estimated glomerular filtration rate of between 60 mL/min/1.73 m 2 and 15 mL/min/1.73 m 2 .
3. The method of claim 2 , wherein the renally-impaired patient has severe kidney disease.
4. The method of claim 3 , wherein renal excretion of Compound I in the renally-impaired patient is approximately<5% of the administered dose of Compound I over 24 hours.
5. The method of claim 3 , wherein renal excretion of Compound I in the renally-impaired patient is approximately<2% of the administered dose of Compound I over 24 hours.
6. The method of claim 3 , wherein renal excretion of Compound I in the renally-impaired patient is approximately<1% of the administered dose of Compound I over 24 hours.
7. The method of claim 1 , wherein the renally-impaired patient suffers from heart failure.
8. The method of claim 1 , wherein the renally-impaired patient suffers from heart failure with preserved ejection fraction.
9. The method of claim 1 , wherein the renally-impaired patient suffers from heart failure with reduced ejection fraction.
10. The method of claim 1 , wherein the renally-impaired patient suffers from chronic kidney disease.
11. The method of claim 1 , wherein the renally-impaired patient suffers from diabetic nephropathy.
12. The method of claim 1 , wherein the renally-impaired patient suffers from portal hypertension.
13. The method of claim 1 , wherein Compound I is administered in the form of a pharmaceutical composition.
14. The method of claim 13 , wherein the pharmaceutical composition is an oral dosage form.
15. A method of inhibiting neprilysin activity in a renally-impaired patient in need thereof, the method comprising administering to the renally-impaired patient a crystalline free acid form of a compound having the structure:
16. The method of claim 15 , wherein Compound I′ is administered orally once-daily.
17. The method of claim 15 , wherein Compound I′ is administered at a dose of 10 mg to 600 mg.
18. The method of claim 17 , wherein the renally-impaired patient has an estimated glomerular filtration rate of between 60 mL/min/1.73 m 2 and 15 mL/min/1.73 m 2 .
19. The method of claim 18 , wherein the renally-impaired patient has severe kidney disease.
20. The method of claim 19 , wherein renal excretion of Compound I′ in the renally-impaired patient is approximately<5% of the administered dose of Compound I′ over 24 hours.
21. The method of claim 19 , wherein renal excretion of Compound I′ in the renally-impaired patient is approximately<2% of the administered dose of Compound I′ over 24 hours.
22. The method of claim 19 , wherein renal excretion of Compound I′ in the renally-impaired patient is approximately<1% of the administered dose of Compound I′ over 24 hours.
23. The method of claim 15 , wherein the renally-impaired patient suffers from heart failure.
24. The method of claim 15 , wherein the renally-impaired patient suffers from heart failure with preserved ejection fraction.
25. The method of claim 15 , wherein the renally-impaired patient suffers from heart failure with reduced ejection fraction.
26. The method of claim 15 , wherein the renally-impaired patient suffers from chronic kidney disease.
27. The method of claim 15 , wherein the renally-impaired patient suffers from diabetic nephropathy.
28. The method of claim 15 , wherein the renally-impaired patient suffers from portal hypertension.
29. The method of claim 15 , wherein Compound I′ is administered in the form of a pharmaceutical composition.
30. The method of claim 29 , wherein the pharmaceutical composition is an oral dosage form.
31. A method of treating heart failure in a renally-impaired patient, the method comprising administering a therapeutically effective amount of Compound I having the structure:
or a pharmaceutically acceptable salt thereof, to the renally-impaired patient once-daily.
32. The method of claim 31 , wherein the renally-impaired patient has chronic kidney disease with an estimated glomerular filtration rate (eGFR) between 60 mL/min/1.73 m 2 and 15 mL/min/1.73 m 2 .
33. The method of claim 31 , wherein the therapeutically effective amount is 10 mg to 600 mg.
34. The method of claim 31 , wherein the therapeutically effective amount is 10 mg, 50 mg, 100 mg, or 200 mg.
35. The method of claim 31 , wherein Compound I is orally administered.
36. The method of claim 31 , wherein the heart failure is chronic heart failure.
37. The method of claim 31 , wherein the heart failure is acute heart failure.
38. The method of claim 31 , wherein the heart failure is heart failure with reduced ejection fraction.
39. The method of claim 31 , wherein Compound I is administered in the form of a pharmaceutical composition.
40. The method of claim 39 , wherein the pharmaceutical composition is an oral dosage form.
41. A method of treating heart failure in a renally-impaired patient, the method comprising administering a therapeutically effective amount of a crystalline free acid form of a compound having the structure:
to the renally-impaired patient once-daily.
42. The method of claim 41 , wherein the renally-impaired patient has chronic kidney disease with an estimated glomerular filtration rate (eGFR) between 60 mL/min/1.73 m 2 and 15 mL/min/1.73 m 2 .
43. The method of claim 41 , wherein the therapeutically effective amount is 10 mg to 600 mg.
44. The method of claim 41 , wherein the therapeutically effective amount is 10 mg, 50 mg, 100 mg, or 200 mg.
45. The method of claim 41 , wherein Compound I′ is orally administered.
46. The method of claim 41 , wherein the heart failure is chronic heart failure.
47. The method of claim 41 , wherein the heart failure is acute heart failure.
48. The method of claim 41 , wherein the heart failure is heart failure with reduced ejection fraction.
49. The method of claim 41 , wherein Compound I′ is administered in the form of a pharmaceutical composition.
50. The method of claim 49 , wherein the pharmaceutical composition is an oral dosage form.
51. The method of claim 31 , wherein the heart failure is heart failure with preserved ejection fraction.
52. The method of claim 51 , wherein the renally-impaired patient has chronic kidney disease with an estimated glomerular filtration rate (eGFR) between 60 mL/min/1.73 m 2 and 15 mL/min/1.73 m 2 .
53. The method of claim 51 , wherein the renally-impaired patient suffers from chronic kidney disease.
54. The method of claim 31 , wherein the renally-impaired patient is 65 to 80 years old.
55. The method of claim 39 , wherein the pharmaceutical composition is an intravenous dosage form.
56. The method of claim 31 , further comprising administering an AT 1 receptor antagonist.
57. The method of claim 31 , further comprising administering an aldosterone synthase inhibitor.
58. The method of claim 31 , further comprising administering a phosphodiesterase inhibitor.
59. The method of claim 31 , further comprising administering a mineralocorticoid-receptor antagonist.
60. The method of claim 31 , further comprising administering a soluble guanylate cyclase stimulator.
61. The method of claim 31 , further comprising administering a renin inhibitor.
62. The method of claim 31 , comprising administering Compound I for 14 days.
63. The method of claim 34 , comprising administering Compound I for 14 days.