# US 9,872,855 B2 · (2R,4R)-5-(5′-Chloro-2′-fluorobiphenyl-4-yl)-2-hydroxy-4-[(5-methyloxazole-2-carbonyl)amino]pentanoic acid

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- Number: US 9,872,855 B2
- Document ID: US9872855B2
- Status: Granted
- Kind: B2
- Application number: 15/357,269
- Filed: 2016-11-21
- Published: 2017-07-13
- Granted: 2018-01-23
- Earliest claimed: 2015-02-19
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Theravance Biopharma R&D IP, LLC
- Inventors: Melissa Fleury; Adam D. Hughes; Anne-Marie Beausoleil; Erik Fenster; Venkat R. Thalladi; Miroslav Rapta
- Web page: https://patentgrep.com/patent/US9872855B2

## CPC

- A61K 31/421: 1,3-Oxazoles, e.g. pemoline, trimethadione
- A61K 9/4816: {Wall or shell material}
- A61K 9/4825: {Proteins, e.g. gelatin (gelatin capsule shells with substantial amounts of other macromolecular substances A61K9/4816)}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 263/34: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C30B 7/14: the crystallising materials being formed by chemical reactions in the solution
- C30B 29/54: Organic compounds
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C30B: SINGLE-CRYSTAL GROWTH (by using ultra-high pressure, e.g. for the formation of diamonds, B01J3/06); UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL (zone-refining of metals or alloys C22B); PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE (casting of metals, casting of other substances by the same processes or devices B22D; working of plastics B29; modifying the physical structure of metals or alloys C21D, C22F); SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE (for producing semiconductor devices or parts thereof H10); APPARATUS THEREFOR
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## 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.

## Claims

### Claim 1

A pharmaceutical composition comprising a compound of the following structure:
or a pharmaceutically acceptable salt thereof, and an AT1 receptor antagonist or a pharmaceutically acceptable salt thereof;
wherein the AT1 receptor antagonist is selected from the group consisting of abitesartan, azilsartan, azilsartan medoxomil, benzyllosartan, candesartan, candesartan cilexetil, elisartan, embusartan, enoltasosartan, eprosartan, EXP3174, fonsartan, forasartan, glycyllosartan, irbesartan, isoteoline, losartan, medoxomil, milfasartan, olmesartan, olmesartan medoxomil, opomisartan, pratosartan, ripisartan, saprisartan, saralasin, sarmesin, TAK-591, tasosartan, telmisartan, valsartan, and zolasartan; and
wherein the compound is optionally in a crystalline form.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the AT1 receptor antagonist is selected from the group consisting of azilsartan medoxomil, candesartan cilexetil, eprosartan, irbesartan, losartan, olmesartan medoxomil, saprisartan, tasosartan, telmisartan, and valsartan.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt of the AT1 receptor antagonist is selected from the group consisting of candesartan cilexetil, eprosartan mesylate, losartan potassium salt, and olmesartan medoxomil.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, 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.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, 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.

### Claim 6 (depends on 5)

The pharmaceutical composition 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.

### Claim 7 (depends on 1)

The pharmaceutical composition of claim 1, 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.

### Claim 8 (depends on 1)

The pharmaceutical composition of claim 1, 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.

### Claim 9 (depends on 1)

The pharmaceutical composition of claim 1, wherein the crystalline form is characterized by a differential scanning calorimetry trace substantially in accordance with that shown in FIG. 2.