(2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid

Patent metadata

Field	Value
Publication number	US-9433598-B2
Application number	US-201615040481-A
Country	US
Kind code	B2
Filing date	Feb 10, 2016
Priority date	Feb 11, 2015
Publication date	Sep 6, 2016
Grant date	Sep 6, 2016

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 of the structure:

or a pharmaceutically acceptable salt thereof.

2. (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid.

3. A crystalline form of calcium (2S,4R)-5-(5′-chloro-2′-fluoro-[1,1′-biphenyl]-4-yl)-4-(2-ethoxy-2-oxoacetamido)-2-(hydroxymethyl)-2-methylpentanoate.

4. The crystalline form of claim 3 , wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 20 values of 7.18±0.2, 7.38±0.2 and 7.97±0.2.

5. The crystalline form of claim 3 , wherein the crystalline form is characterized by a powder X-ray diffraction pattern comprising diffraction peaks at 20 values of 3.98±0.2, 5.00±0.2, 7.18±0.2, 7.38±0.2, 7.97±0.2, 8.87±0.2, and 10.91±0.2.

6. The crystalline form of claim 5 , wherein the crystalline form is further characterized by having one or more additional difrraction peaks at 20 values selected from 3.47±0.2, 9.99±0.2, 15.74±0.2, 15.98±0.2, and 18.98±0.2.

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 237° C. and about 241° 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 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 process for preparing the compound of claim 1 , the process comprising (a) mixing ethanol and oxalyl chloride to form a solution; (b) reacting (2S,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid benzyl ester with the solution; and (c) combining resulting mixture with palladium on carbon under hydrogen to yield the compound of claim 1 .

23. A process for preparing the compound of claim 1 , the process comprising:
(a) dissolving ethanol in dicloromethane;
(b) adding oxalyl chloride to form a solution and stirring at room temperature;
(c) evaporating solvent from solution;
(d) adding remaining solution to (2S,4R)-4-amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid benzyl ester that is first dissolved in dicloromethane;
(e) adding N,N-diisopropylethylamine and stirring a room temperature;
(f) evaporating solvent to form a solid;
(g) combining solid with palladium 10 wt % on carbon in solvent to form a mixture;
(h) placing mixture under hydrogen with stirring; and
(i) filtering off palladium on carbon and vacuum drying to yield the compound of claim 1 .

24. The process according to claim 23 , wherein the resulting solids in steps (0 and (i) are purified by chromatography.

25. A process for preparing the crystalline form of claim 3 , the process comprising:
(a) dissolving (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid in ethanol and N,N-diisopropylethylamine to form solution A;
(b) dissolving calcium trifluoromethane sulfonate in ethanol to form solution B;
(c) adding dropwise solution B to solution A to form a slurry;
(d) stirring at room temperature; and
(e) isolating the resulting solids to yield the crystalline form.

26. The process according to claim 25 , the process further comprising:
(f) cooling the crystalline form to about 5° C. and adding a cold ethanol:water mixture under vigorous stirring; and
(g) filtering and drying at room temperature to yield crystalline form.

Assignees

• Theravance Biopharma R&D Ip Llc

Inventors

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

Classifications

• 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

• A61P9/12

  Antihypertensives · CPC title

• A61P13/12

  of the kidneys · CPC title

• A61K9/0019 Primary

  Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00) · CPC title