# US 2014/0194426 A1 · Dual-acting oxazole antihypertensive agents

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- Number: US 2014/0194426 A1
- Document ID: US20140194426A1
- Status: Published application
- Kind: A1
- Application number: 14/062,004
- Filed: 2013-10-24
- Published: 2014-07-10
- Earliest claimed: 2009-07-22
- Assignees: Theravance, Inc.
- Inventors: Paul R. Fatheree; Ryan Hudson; Robert Murray McKinnell
- Web page: https://patentgrep.com/patent/US20140194426A1

## CPC

- 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
- A61K 31/421: 1,3-Oxazoles, e.g. pemoline, trimethadione
- A61K 31/422: not condensed and containing further heterocyclic rings
- A61K 31/4245: Oxadiazoles
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/497: containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/12: Antihypertensives
- C07D 263/38: attached in position 2
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

## Abstract

In one aspect, the invention relates to compounds having the formula: wherein: Ar, Z, R3, R4 and R5 are as defined in the specification, or a pharmaceutically acceptable salt thereof. These compounds have AT1 receptor antagonist activity and neprilysin inhibition activity. In another aspect, the invention relates to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

## Claims

### Claim 1

A compound of formula I:
where: Z is:
where the amide portion of the compound of formula I is on the carbon atom between the oxygen ring atom and the nitrogen ring atom and the R3 moiety is on the carbon ring atom adjacent to the oxygen ring atom;
Ar is selected from:
R1 is selected from —COOR, —SO2NHC(O)R1a, tetrazolyl,
where R1a is —C1-6alkyl, —C0-6alkylene-OR, —C3-7cycloalkyl, —C0-5alkylene-NRR, pyridyl, isoxazolyl, methylisoxazolyl, pyrrolidinyl, morpholinyl, and phenyl optionally substituted with halo; where each R is independently selected from H and —C1-6alkyl;
a is 0, 1, or 2; R2 is F;
R3 is selected from —C2-5alkyl and —O—C1-5alkyl;
R4 is selected from —CH2—SR4a, —CH2—N(OH)C(O)H, —CH(R4b)C(O)NH(OH), and —CH(R4b)COOR4c; where R4a is H or —C(O)—C1-6alkyl; R4b is H or —OH; and R4a is H or —C1-6alkyl; and
R5 is selected from —C1-6alkyl, —CH2-furanyl, —CH2-thiophenyl, benzyl, and benzyl substituted with one or more halo, —CH3, or —CF3 groups;
where each ring in Ar is optionally substituted with 1 to 3 substituents independently selected from —OH, —C1-6alkyl, —C2-4alkenyl, —C2-4alkynyl, —CN, halo, —O—C1-6alkyl, —S—C1-6alkyl, —S(O)—C1-6alkyl, —S(O)2—C1-4alkyl, -phenyl, —NO2, —NH2, —NH—C1-6alkyl and —N(C1-6alkyl)2, wherein each alkyl, alkenyl and alkynyl is optionally substituted with 1 to 5 fluoro atoms;
or a pharmaceutically acceptable salt thereof.

### Claim 2

(canceled)

### Claim 3 (depends on 1)

The compound of claim 1, where Ar is:

### Claim 4 (depends on 1)

The compound of claim 1, where R1 is —SO2NHC(O)CH3, —SO2NHC(O)CH2CH3, —SO2NHC(O)OCH3, —SO2NHC(O)OCH2CH3, —SO2NHC(O)CH2OCH3, —SO2NHC(O)CH2OH, —SO2NHC(O)CH(CH3)OH, —SO2NHC(O)C(CH3)2OH, —SO2NHC(O)CH2OCH3, —SO2NHC(O)(CH2)2OCH3, —SO2NHC(O)-cyclopropyl, —SO2NHC(O)NH(CH3), —SO2NHC(O)N(CH3)2, —SO2NHC(O)NH(CH2CH3), —SO2NHC(O)C(CH3)2NH2, —SO2NHC(O)-2-pyridyl, —SO2NHC(O)-4-pyridyl, —SO2NHC(O)-5-isoxazolyl, —SO2NHC(O)-3-isoxazolyl-5-methyl, —SO2NHC(O)-1-pyrrolidyl, —SO2NHC(O)-4-morpholinyl, —SO2NHC(O)phenyl, —SO2NHC(O)-2-fluorophenyl, 1H-tetrazol-5-yl,

### Claim 5 (depends on 1)

The compound of claim 1, where R3 is propyl, ethyl, butyl, or ethoxy.

### Claim 6 (depends on 1)

The compound of claim 1, where R4 is —CH2SH, —CH2N(OH)C(O)H, —CH2C(O)NH(OH), —CH(OH)C(O)NH(OH), —CH(OH)COOH, or —CH2COOH.

### Claim 7 (depends on 1)

The compound of claim 1, where R4 is —CH2—S—C(O)CH3, —CH(OH)COOCH3, or —CH2COOCH3.

### Claim 8 (depends on 1)

The compound of claim 1, where R5 is i-butyl, —CH2-furan-2-yl, —CH2-thiophen-3-yl, benzyl, 2-bromobenzyl, 2-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-methylbenzyl, or 2-trifluoromethylbenzyl.

### Claim 9 (depends on 1)

The compound of claim 1,
wherein: Ar is:
R1 is —SO2NHC(O)CH3, —SO2NHC(O)CH2CH3, —SO2NHC(O)OCH3, —SO2NHC(O)OCH2CH3, —SO2NHC(O)CH2OCH3, —SO2NHC(O)CH2OH, —SO2NHC(O)CH(CH3)OH, —SO2NHC(O)C(CH3)2OH, —SO2NHC(O)CH2OCH3, —SO2NHC(O)(CH2)2OCH3, —SO2NHC(O)-cyclopropyl, —SO2NHC(O)NH(CH3), —SO2NHC(O)N(CH3)2, —SO2NHC(O)NH(CH2CH3), —SO2NHC(O)C(CH3)2NH2, —SO2NHC(O)-2-pyridyl, —SO2NHC(O)-4-pyridyl, —SO2NHC(O)-5-isoxazolyl, —SO2NHC(O)-3-isoxazolyl-5-methyl, —SO2NHC(O)-1-pyrrolidyl, —SO2NHC(O)-4-morpholinyl, —SO2NHC(O)phenyl, —SO2NHC(O)-2-fluorophenyl, 1H-tetrazol-5-yl,
R3 is propyl, ethyl, butyl, or ethoxy;
R4 is —CH2SH, —CH2—S—C(O)CH3, —CH2N(OH)C(O)H, —CH2C(O)NH(OH), —CH(OH)C(O)NH(OH), —CH(OH)COOH, CH(OH)COOCH3, —CH2COOH, or —CH2COOCH3; and
R5 is i-butyl, —CH2-furan-2-yl, —CH2-thiophen-3-yl, benzyl, 2-bromobenzyl, 2-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-methylbenzyl, or 2-trifluoromethylbenzyl.

### Claim 10 (depends on 1)

The compound of claim 1, having formula IV:

### Claim 11 (depends on 10)

The compound of claim 10 where
Ar is:
R1 is —SO2NHC(O)CH3, —SO2NHC(O)CH2CH3, —SO2NHC(O)OCH3, —SO2NHC(O)OCH2CH3, —SO2NHC(O)CH2OCH3, —SO2NHC(O)CH2OH, —SO2NHC(O)CH(CH3)OH, —SO2NHC(O)C(CH3)2OH, —SO2NHC(O)CH2OCH3, —SO2NHC(O)(CH2)2OCH3, —SO2NHC(O)-cyclopropyl, —SO2NHC(O)NH(CH3), —SO2NHC(O)N(CH3)2, —SO2NHC(O)NH(CH2CH3), —SO2NHC(O)C(CH3)2NH2, —SO2NHC(O)-2-pyridyl, —SO2NHC(O)-4-pyridyl, —SO2NHC(O)-5-isoxazolyl, —SO2NHC(O)-3-isoxazolyl-5-methyl, —SO2NHC(O)-1-pyrrolidyl, —SO2NHC(O)-4-morpholinyl, —SO2NHC(O)phenyl, —SO2NHC(O)-2-fluorophenyl, 1H-tetrazol-5-yl,
R3 is propyl, ethyl, butyl, or ethoxy;
R4b is H or —OH; and R4c is H or —CH3; and
R5 is i-butyl, —CH2-furan-2-yl, —CH2-thiophen-3-yl, benzyl, 2-bromobenzyl, 2-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-methylbenzyl, or 2-trifluoromethylbenzyl.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 12)

The pharmaceutical composition of claim 12 further comprising a second therapeutic agent selected from the group consisting of diuretics, β1 adrenergic receptor blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, AT1 receptor antagonists, neprilysin inhibitors, non-steroidal anti-inflammatory agents, prostaglandins, anti-lipid agents, anti-diabetic agents, anti-thrombotic agents, renin inhibitors, endothelin receptor antagonists, endothelin converting enzyme inhibitors, aldosterone antagonists, angiotensin-converting enzyme/neprilysin inhibitors, vasopressin receptor antagonists, and combinations thereof.

### Claim 14 (depends on 1)

A process for preparing the compound of claim 1, comprising:
(a) coupling a compound of formula 1 with a compound of formula 2:
to produce a compound having the formula:
where: Ar* represents Ar—R1*, where R1* is R1 or a protected form of R1; and R4* represents R4 or a protected form of R4; and optionally deprotecting the product when R1* is a protected form of R1 and/or R4* is a protected form of R4.
(b) when R1* is a protected form of R1 and/or R4* is a protected form of R4, deprotecting the product of step (a) to produce a compound of formula I.

### Claim 15 (depends on 1)

An intermediate useful in the synthesis of the compound of claim 1, selected from the group comprising:
where: Ar* is Ar—R1*; R1* is —SO2NH—P6 or tetrazolyl-P4; R4* is —CH2—S—P3, —CH2—N(O—P5)—C(O)H, —CH(R4b)C(O)NH(O—P5), or —CH(R4b)COO—P2; P2 is a carboxy-protecting group; P3 is a thiol-protecting group; P4 is a tetrazole-protecting group; P5 is a hydroxyl-protecting group; and P6 is a sulfonamide-protecting group; or a salt thereof.

### Claim 16 (depends on 1)

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