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

Patent metadata

Field	Value
Publication number	US-12351561-B2
Application number	US-202418442885-A
Country	US
Kind code	B2
Filing date	Feb 15, 2024
Priority date	Mar 8, 2016
Publication date	Jul 8, 2025
Grant date	Jul 8, 2025

Abstract

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.

First claim

What is claimed is:

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 fract

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Hughes Adam D
• Fleury Melissa
• Rapta Miroslav
• Thalladi Venkat R
• Baldwin R Michael
• Bourdet David L

Classifications

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/415

  1,2-Diazoles · CPC title

• A61K9/4816

  Wall or shell material · CPC title

• A61K9/0053

  Mouth and digestive tract, i.e. intraoral and peroral administration · CPC title