# US 9,428,457 B2 · Neprilysin inhibitors

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- Number: US 9,428,457 B2
- Document ID: US9428457B2
- Status: Granted
- Kind: B2
- Application number: 14/749,949
- Filed: 2015-06-25
- Published: 2015-12-31
- Granted: 2016-08-30
- Earliest claimed: 2013-03-05
- Assignees: Theravance Biopharma R&D IP, LLC
- Applicants: Erik Fenster; Melissa Fleury; Adam D. Hughes
- Inventors: Erik Fenster; Melissa Fleury; Adam D. Hughes
- Web page: https://patentgrep.com/patent/US9428457B2

## CPC

- C07C 243/38: with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
- A61K 31/197: the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205)
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/397: having four-membered rings, e.g. azetidine
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/42: Oxazoles
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/4409: only substituted in position 4, e.g. isoniazid, iproniazid
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 233/56: having carbon atoms of carboxamide groups bound to carbon atoms of carboxyl groups, e.g. oxamides
- C07C 235/12: having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
- C07C 235/20: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 235/34: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 235/74: of a saturated carbon skeleton
- C07C 235/78: the carbon skeleton containing rings
- C07C 235/80: having carbon atoms of carboxamide groups and keto groups bound to the same carbon atom, e.g. acetoacetamides
- C07C 243/24: Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
- C07C 243/32: the carbon skeleton containing rings
- C07C 259/04: without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/08: with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
- C07D 207/09: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 207/12: Oxygen or sulfur atoms
- C07D 207/14: Nitrogen atoms not forming part of a nitro radical
- C07D 207/16: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/22: by oxygen atoms
- C07D 211/38: Halogen atoms or nitro radicals
- C07D 211/42: attached in position 3 or 5
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 211/48: having an acyclic carbon atom attached in position 4
- C07D 211/60: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 211/62: attached in position 4
- C07D 213/56: Amides
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 213/65: attached in position 3 or 5
- C07D 213/75: Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
- C07D 213/86: Hydrazides; Thio or imino analogues thereof
- C07D 213/87: in position 3
- C07D 233/06: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to ring carbon atoms
- C07D 239/36: as doubly bound oxygen atom or as unsubstituted hydroxy radical
- C07D 261/02: not condensed with other rings
- C07D 261/04: having one double bond between ring members or between a ring member and a non-ring member
- C07D 265/30: not condensed with other rings
- C07D 295/32: acylated with carboxylic or carbonic acids, or their nitrogen or sulfur analogues
- C07D 307/68: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 309/08: 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
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 493/10: Spiro-condensed systems
- C07C 2601/08: the ring being saturated
- C07C 2601/16: the ring being unsaturated
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

In one aspect, the invention relates to compounds having the formula: where R1-R5 and X are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and processes and intermediates for preparing such compounds.

## Claims

### Claim 1

A compound selected from:
(a) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-(2-hydroxyacetylamino)-pentanoic acid;
(b) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-(2-methoxyacetylamino)-pentanoic acid;
(c) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-4-(2-ethoxyacetylamino)-2-hydroxy-pentanoic acid;
(d) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-(2-isopropoxyacetylamino pentanoic acid
(e) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-[2-(pyridin-3-yloxy)-acetylamino]-pentanoic acid;
(f) (2R,4R)-4-(2-Benzyloxy-acetylamino)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxy-pentanoic acid;
(g) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-(2-phenoxyacetylamino)-pentanoic acid;
(h) (2R,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-[2-(4-hydroxyphenoxy)-acetylamino]-pentanoic acid;
(i) (2S,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxy-4-[2-(3-methoxyphenoxy)-acetylamino]-pentanoic acid;
(j) (2S,4R)-5-(3′-Chlorobiphenyl-4-yl)-2-hydroxymethyl-4-(2-methoxy-acetylamino)-2-methylpentanoic acid;
(k) (2S,4R)-4-(2-Benzyloxyacetylamino)-5-(3′-chlorobiphenyl-4-yl)-2-hydroxymethyl-2-methyl-pentanoic acid; or
a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 3 (depends on 2)

The pharmaceutical composition of claim 2, further comprising AT1 receptor antagonist.

### Claim 4 (depends on 1)

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