(2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyloxazole-2-carbonyl)amino]pentanoic acid

Patent metadata

Field	Value
Publication number	US-9533962-B2
Application number	US-201615042391-A
Country	US
Kind code	B2
Filing date	Feb 12, 2016
Priority date	Feb 19, 2015
Publication date	Jan 3, 2017
Grant date	Jan 3, 2017

Abstract

In one aspect, the invention relates to a compound of the structure:

or a pharmaceutically acceptable salt thereof, and a crystalline form of this compound, having neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising this compound; methods of using this compound; and processes for preparing this compound.

First claim

What is claimed is:

1. A compound having the structure:

or a pharmaceutically acceptable salt thereof.

2. (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyl-oxazole-2-carbonyl)amino]pentanoic acid.

3. A crystalline form of (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyl-oxazole-2-carbonyl)amino]pentanoic acid.

4. The crystalline form of claim 3 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 8.48±0.20, 14.19±0.20, 17.03±0.20, 21.15±0.20, and 25.41±0.20.

5. The crystalline form of claim 3 , wherein the crystalline form is characterized by a powder x-ray diffraction pattern comprising diffraction peaks at 2θ values of 7.51±0.20, 8.48±0.20, 14.19±0.20, 17.03±0.20, 17.62±0.20, 17.87±0.20, 20.59±0.20, 21.15±0.20, 21.88±0.20, 24.45±0.20, 24.78±0.20, 25.41±0.20, 25.67±0.20, 27.67±0.20, and 28.22±0.20.

6. The crystalline form of claim 5 , wherein the crystalline form is further characterized by having one or more additional diffraction peaks at 2θ values selected from 16.09±0.20, 18.70±0.20, 19.21±0.20, 19.40±0.20, 21.64±0.20, 22.25±0.20, 26.43±0.20, 28.55±0.20, 30.73±0.20, 31.10±0.20, 32.64±0.20, 33.14±0.20, and 34.46±0.20.

7. The crystalline form of claim 3 , 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 .

8. The crystalline form of claim 3 , 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 165° C. and 169° C.

9. The crystalline form of claim 3 , wherein the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2 .

10. A pharmaceutical composition comprising the compound of claim 1 or the crystalline form of claim 3 and one or more pharmaceutically acceptable carriers.

11. The pharmaceutical composition of claim 10 , wherein the pharmaceutically acceptable carrier is magnesium stearate.

12. A pharmaceutical composition comprising the compound of claim 1 or the crystalline form of claim 3 and an AT 1 receptor antagonist, an angiotensin-converting enzyme inhibitor, a phosphodiesterase (PDE) inhibitor, a renin inhibitor, a diuretic, or combinations thereof, and optionally one or more pharmaceutically acceptable carriers.

13. An oral dosage form comprising the compound of claim 1 or the crystalline form of claim 3 in a capsule, tablet, liquid or suspension.

14. The oral dosage form of claim 13 wherein a release of the compound of claim 1 or the crystalline form of claim 3 in a subject is an immediate, controlled or delayed release.

15. The oral dosage form of claim 13 , wherein the capsule material is gelatin, polysaccharide, chitosan or synthetic polymers.

16. The oral dosage form of claim 13 , wherein the hard capsule comprises gelatin, polysaccharides, or synthetic polymers.

17. The oral dosage form of claim 13 , wherein the capsule comprises hydroxypropyl methylcellulose.

18. An intravenous dosage form comprising the compound of claim 1 or the crystalline form of claim 3 in a buffered solution.

19. A method for treating hypertension, heart failure, or renal disease, the method comprising administering to a patient a therapeutically effective amount of the compound of claim 1 or the crystalline form of claim 3 .

20. A method of treating a renally-impaired subject, the method comprising administering a therapeutically effective amount of the compound of claim 1 or the crystalline form of claim 3 to the subject.

21. The method according to claim 20 , wherein the renally-impaired subject 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 .

22. A method of increasing atrial natriuretic peptide (ANP) or cyclic guanosine monophosphate (cGMP) levels in a subject with hypertension, heart failure, or renal disease, the method comprising administering to a subject a therapeutically effective amount of the compound of claim 1 or the crystalline form of claim 3 .

23. The method according to claim 22 , wherein levels of ANP and cGMP are measured in either urine or plasma or both in a subject.

24. A process for preparing the compound of claim 1 , the process comprising coupling (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester with 2-methyloxazole-2-carboxylic acid to yield the compound of claim 1 .

25. A process for preparing the compound of claim 1 , the process comprising:
(a) combining 2-methyloxazole-2-carboxylic acid and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU) in N,N-dimethylformamide (DMF) and stirring at room temperature;
(b) adding (2R,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester and N,N-diisopropylethylamine and stirring at room temperature;
(c) isolating and then dissolving the resulting solids in dry ethanol and dry tetrahydrofuran;
(d) adding a solution of lithium hydroxide in water; and
(e) isolating the resulting solids to yield the compound of claim 1 .

26. The process according to claim 25 , wherein the resulting solids in steps (c) and (e) are purified by chromatography.

27. A process for preparing the crystalline form of claim 3 , the process comprising:
(a) dissolving (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyloxazole-2-carbonyl)amino]pentanoic acid in ethyl acetate and hexanes to complete dissolution; and
(b) isolating the resulting solids to yield the crystalline form.

28. A process for preparing the crystalline form of claim 3 , the process comprising:
(a) coupling (2R,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxypentanoic acid ethyl ester with sodium 5-methyloxazole-2-carboxylate to yield (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyloxazole-2-carbonyl)amino]pentanoic acid;
(b) treating (2R,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyloxazole-2-carbonyl)amino]pentanoic acid with ethyl acetate and hexanes to complete dissolution; and
(c) isolating the resulting solids to yield the crystalline form.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

• Fleury Melissa
• Hughes Adam D
• Beausoleil Anne-Marie
• Fenster Erik
• Thalladi Venkat R
• Rapta Miroslav

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/04

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

• A61P43/00

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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title