# US 9,433,598 B2 · (2S,4R)-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-4-(ethoxyoxalylamino)-2-hydroxymethyl-2-methylpentanoic acid

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- Number: US 9,433,598 B2
- Document ID: US9433598B2
- Status: Granted
- Kind: B2
- Application number: 15/040,481
- Filed: 2016-02-10
- Published: 2016-08-11
- Granted: 2016-09-06
- Earliest claimed: 2015-02-11
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Theravance Biopharma R&D IP, LLC
- Inventors: Adam D. Hughes; Erik Fenster; Melissa Fleury; Anne-Marie Beausoleil; Venkat R. Thalladi; Jerry Nzerem; Miroslav Rapta
- Web page: https://patentgrep.com/patent/US9433598B2

## CPC

- C07C 235/74: of a saturated carbon skeleton
- A61K 9/0019: {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)}
- A61K 9/0075: {for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles}
- A61K 9/0078: {for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions}
- A61K 9/008: {comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]}
- A61K 9/0095: {Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches (A61K9/0007 takes precedence; eatable gels or foams A61K9/0056; oral mucosa adhesive forms A61K9/006)}
- A61K 9/10: Dispersions; Emulsions
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2059: {Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin}
- A61K 9/4858: {Organic compounds}
- A61K 9/4866: {Organic macromolecular compounds}
- A61K 31/216: of acids having aromatic rings, e.g. benactizyne, clofibrate
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 13/12: of the kidneys
- C07C 233/56: having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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
- 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 compound of the structure:
or a pharmaceutically acceptable salt thereof.

### Claim 2

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

### Claim 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.

### Claim 4 (depends on 3)

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.

### Claim 5 (depends on 3)

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.

### Claim 6 (depends on 5)

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.

### Claim 7 (depends on 3)

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.

### Claim 8 (depends on 3)

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.

### Claim 9 (depends on 3)

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.

### Claim 10 (depends on 1, 3)

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

### Claim 11 (depends on 10)

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

### Claim 12 (depends on 1, 3)

A pharmaceutical composition comprising the compound of claim 1 or the crystalline form of claim 3 and an AT1 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.

### Claim 13 (depends on 1, 3)

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

### Claim 14 (depends on 1, 3, 13)

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.

### Claim 15 (depends on 13)

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

### Claim 16 (depends on 13)

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

### Claim 17 (depends on 13)

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

### Claim 18 (depends on 1, 3)

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

### Claim 19 (depends on 1, 3)

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.

### Claim 20 (depends on 1, 3)

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.

### Claim 21 (depends on 20)

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 m2 and 15 mL/min/1.73 m2.

### Claim 22 (depends on 1)

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.

### Claim 23 (depends on 1)

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.

### Claim 24 (depends on 23)

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

### Claim 25 (depends on 3)

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.

### Claim 26 (depends on 25)

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.