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-11230536-B2
Application number	US-202016928206-A
Country	US
Kind code	B2
Filing date	Jul 14, 2020
Priority date	Mar 8, 2016
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

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 composition comprising a crystalline form of a compound or salt of Formula (I):

2. The composition of claim 1 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising peaks at 6.51±0.2 and 15.07±0.2 degrees 2θ.

3. The composition of claim 1 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising peaks at 11.62±0.2, 13.05±0.2, and 23.28±0.2 degrees 2θ.

4. The composition of claim 2 , wherein the powder x-ray diffraction pattern further comprises at least one peak selected from 11.62±0.2, 13.05±0.2, and 23.28±0.2 degrees 2θ.

5. The composition of claim 2 , wherein the powder x-ray diffraction pattern further comprises peaks at 11.62±0.2, 13.05±0.2, and 23.28±0.2 degrees 2θ.

6. The composition of claim 2 , wherein the powder x-ray diffraction pattern further comprises at least one peak selected from 15.72±0.2, 17.12±0.2, 18.77±0.2, 19.63±0.2, 20.79±0.2, and 24.48±0.2 degrees 2θ.

7. The composition of claim 2 , wherein the powder x-ray diffraction pattern further comprises peaks at 15.72±0.2, 17.12±0.2, 18.77±0.2, 19.63±0.2, 20.79±0.2, and 24.48±0.2 degrees 2θ.

8. The composition of claim 5 , wherein the powder x-ray diffraction pattern further comprises peaks at 15.72±0.2, 17.12±0.2, 18.77±0.2, 19.63±0.2, 20.79±0.2, and 24.48±0.2 degrees 2θ.

9. The composition of claim 1 , wherein the crystalline form is characterized by a differential scanning calorimetry thermogram comprising an endotherm in the range of about 214 to 218° C.

10. The composition of claim 5 , wherein the crystalline form is further characterized by a differential scanning calorimetry thermogram comprising an endotherm in the range of about 214 to 218° C.

11. The composition of claim 8 , wherein the crystalline form is further characterized by a differential scanning calorimetry thermogram comprising an endotherm in the range of about 214 to 218° C.

12. The composition of claim 1 , wherein the crystalline form is non-solvated.

13. The composition of claim 1 , wherein the compound of Formula (I) is a free acid.

14. A pharmaceutical composition comprising the composition of claim 1 and a pharmaceutically acceptable carrier.

15. A pharmaceutical composition comprising the composition of claim 2 and a pharmaceutically acceptable carrier.

16. A pharmaceutical composition comprising the composition of claim 10 and a pharmaceutically acceptable carrier.

17. The pharmaceutical composition of claim 16 , wherein the pharmaceutically acceptable carrier is magnesium stearate.

18. An oral dosage form comprising the composition of claim 1 .

19. An oral dosage form comprising the composition of claim 2 .

20. An oral dosage form comprising the composition of claim 10 .

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Hughes Adam D
• Fleury Melissa
• Rapta Miroslav
• Thalladi Venkat R

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61K31/42 Primary

  Oxazoles · CPC title

• C07D261/18 Primary

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title