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