Crystalline(2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-bipheny]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid and uses thereof

Patent metadata

Field	Value
Publication number	US-10472335-B2
Application number	US-201816125991-A
Country	US
Kind code	B2
Filing date	Sep 10, 2018
Priority date	Mar 8, 2016
Publication date	Nov 12, 2019
Grant date	Nov 12, 2019

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 for treating hypertension, heart failure, or renal disease in a patient in need thereof, the method comprising administering a crystalline free acid form of (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (Compound I′) to the patient.

2. The method of claim 1 , wherein the hypertension is primary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, or hypertension with renal artery stenosis.

3. The method of claim 1 , wherein the renal disease is diabetic nephropathy, chronic kidney disease, proteinuria, acute kidney injury, nephrotic syndrome, focal segmental glomerulosclerosis or polycystic kidney disease.

4. A method of treating hypertension, heart failure, or renal disease in a renally-impaired patient, the method comprising administering a therapeutically effective amount of a crystalline free acid form of (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl ]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (Compound I′) to the patient.

5. The method of claim 4 , 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 .

6. A method of increasing atrial natriuretic peptide (ANP) or cyclic guanosine monophosphate (cGMP) levels in a human for at least 24 hours, the method comprising administering to the human an ANP or cGMP-increasing amount of a crystalline free acid form of (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-2-(ethoxymethyl)-4-(3-hydroxyisoxazole-5-carboxamido)-2-methylpentanoic acid (Compound I′).

7. The method of claim 6 , wherein levels of ANP and cGMP are measured in either urine or plasma or both in the human.

8. The method of claim 1 , 4 or 6 , wherein Compound I′ is administered parenterally.

9. The method of claim 1 , 4 or 6 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.51±0.20, 11.62±0.20, 13.05±0.20, 15.07±0.20, and 23.28±0.20.

10. The method of claim 1 , 4 or 6 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 6.51±0.20, 11.62±0.20, 13.05±0.20, 15.07±0.20, 17.12±0.20, 23.28±0.20, and 26.19±0.20.

11. The method of claim 1 , 4 , or 6 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising one or more diffraction peaks at 2θ values selected from 6.51±0.20, 11.62±0.20, 13.05±0.20, 15.07±0.20, 15.72±0.20, 17.12±0.20, 20.79±0.20, 21.10±0.20, 23.28±0.20, 24.48±0.20, 25.81±0.20, and 26.19±0.20.

12. The method of claim 1 , 4 or 6 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern in which the peak positions are substantially in accordance with the peak positions of the pattern shown in FIG. 1 .

13. The method of claim 1 , 4 or 6 , wherein the crystalline form is characterized by a differential scanning calorimetry trace recorded at a heating rate of 10° C. per minute which shows a maximum in endothermic heat flow at a temperature between about 214° C. and about 218° C.

14. The method of claim 1 , 4 or 6 , wherein the crystalline form is characterized by a different scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .

15. The method of claim 1 , 4 or 6 , wherein Compound I′ is administered once-daily.

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/04

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P13/12

  of the kidneys · CPC title