# US 5,352,687 A · Substituted phenylacetamides

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- Number: US 5,352,687 A
- Document ID: US5352687A
- Status: Granted
- Kind: A
- Application number: 08/025,479
- Filed: 1993-03-03
- Granted: 1994-10-04
- Earliest claimed: 1992-03-13
- Assignees: Bayer Aktiengesellschaft
- Inventors: Ulrich E. Muller; Matthias Muller-Gliemann; Jurgen Dressel; Peter Fey; Rudolf Hanko; Walter Hubsch; Thomas Kramer; Martin Beuck; Stanislav Kazda; Stefan Wohlfeil; Ozkan Yalkinoglu; Andreas Knorr; Johannes-Peter Stasch
- Web page: https://patentgrep.com/patent/US5352687A

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 233/68: Halogen atoms
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Substituted phenylacetamides can be prepared by reaction of appropriately substituted phenylacetic acids with imidazoles and subsequent amidation. The substituted phenylacetic acid derivatives can be employed in medicaments for the treatment of high blood pressure and atherosclerosis.

## Claims

### Claim 1

A substituted phenylacetamide of the formula ##STR63## in which A represents straight-chain or branched alkyl or alkenyl each having up to 8 carbon atoms, or represents cycloalkyl having 3 to 8 carbon atoms,
R represents hydrogen, halogen or perfluoroalkyl having up to 5 carbon atoms,
D represents a group of the formula --CH.sub.2 OR.sup.3, --CO--R.sup.4, --CO--NR.sup.5 R.sup.6, ##STR64## in which R.sup.3 denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R.sup.4 represents hydrogen, hydroxyl or straight-chain or branched alkoxy having up to 8 carbon atoms,
R.sup.5 and R.sup.6 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 8 carbon atoms, or
R.sup.5 has the abovementioned meaning and
R.sup.6 denotes a group of the formula --SO.sub.2 R.sup.12, in which
R.sup.12 denotes straight-chain or branched alkyl having up to 6 carbon atoms, or benzyl or phenyl which are optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms,
a and b are identical or different and denote a number 0, 1 or 2,
R.sup.7 denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms or a hydroxyl protective group selected from the group consisting of trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldiphenylsilyl, tert-butyldiphenylsilyl, trimethylsilylethoxycarbonyl, benzyl, triphenylmethyl(trityl), monomethoxytrityl (MMTr), dimethoxytrityl (DMTr), benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, tert-butyloxycarbonyl, 4-methoxybenzyl, 4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl, 2,2,2-trichloroethoxycarbonyl, 2,4dimethoxybenzyl, 2,4-dimethoxybenzyloxycarbonyl, methoxymethyl, methylthiomethyl, methoxyethoxymethyl, [2-(trimethylsilyl)ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl, tetrahydropyranyl, benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl, 4-chlorobenzoyl, and methoxybenzoyl,
R.sup.8 and R.sup.10 are identical or different and denote hydrogen, straight-chain or branched alkyl having up to 6 carbon atoms, cycloalkyl having 3 to 8 carbon atoms, phenyl or thienyl,
R.sup.9 and R.sup.11 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
E represents hydrogen, halogen, nitro, hydroxyl, trifluoromethyl, trifluoromethoxy, straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, cyano or carboxyl,
L represents straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 8 carbon atoms or by phenyl, represents cycloalkyl having 3 to 12 carbon atoms, which is optionally substituted by straight-chain or branched alkyl having up to 6 carbon atoms,
R.sup.1 represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
R.sup.2 represents pyridyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, quinolinyl, dihydrobenzopyranyl or dihydrobenzofuranyl, which is optionally substituted up to 3 times by identical or different substituents from the group consisting of nitro, cyano, halogen, hydroxyl, trifluoromethyl, carboxyl, straight-chain or branched alkoxy or alkoxycarbonyl each having up to 6 carbon atoms, phenoxy, benzyloxy, phenoxycarbonyl and benzyloxycarbonyl, or represents a radical of the formula ##STR65## in which R.sup.13 denotes phenyl which is optionally substituted up to 3 times by identical or different substituents from the group consisting of halogen, hydroxyl and trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 8 carbon atoms,
c, d, e and f are identical or different and denote a number 0, 1, 2, 3 or 4,
R.sup.14 denotes hydrogen, trifluoromethyl, carboxyl or straight-chain or branched alkoxycarbonyl having up to 8 carbon atoms or the group --CO--NH.sub.2 or pyridyl or morpholinyl, or a salt thereof.

### Claim 2 (depends on 1)

A substituted phenylacetamide according to claim 1 in which
A represents straight-chain or branched alkyl or alkenyl each having up to 6 carbon atoms, or represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl,
R represents hydrogen, fluorine, chlorine, bromine or perfluoroalkyl having up to 4 carbon atoms,
represents a group of the formula --CH.sub.2 OR.sup.3, --CO--R.sup.4, --CO--NR.sup.5 R.sup.6, ##STR66## in which R.sup.3 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R.sup.4 denotes hydrogen, hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms,
R.sup.5 and R.sup.6 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, or
R.sup.5 has the abovementioned meaning and
denotes a group of the formula --SO.sub.2 R.sup.12, in which
R.sup.12 denotes straight-chain or branched alkyl having up to 4 carbon atoms, or benzyl or phenyl which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms,
a and b are identical or different and denote a number 0 or 1,
R.sup.7 denotes hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms or acetyl,
R.sup.8 and R.sup.10 are identical or different and denote straight-chain or branched alkyl having up to 4 carbon atoms, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, phenyl or thienyl,
R.sup.9 and R.sup.11 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
E represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, carboxyl or straight-chain or branched alkyl, alkoxy or alkoxycarbonyl each having up to 4 carbon atoms,
L represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl or phenyl, represents cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl which are optionally substituted by straight-chain or branched alkyl having up to 4 carbon atoms,
R.sup.1 represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
R.sup.2 represents pyridyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl, quinolinyl, dihydrobenzopyranyl or dihydrobenzofuranyl which are optionally substituted up to 2 times by identical or different substituents selected from the group consisting of nitro, cyano, fluorine, chlorine, bromine, hydroxyl, straight-chain or branched alkoxy having up to 4 carbon atoms, phenoxy and benzyloxy, or represents a radical of the formula ##STR67## in which R.sup.13 denotes phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, hydroxyl and trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 6 carbon atoms,
c, d, e and f are identical or different and denote a number 0, 1, 2 or 3,
R.sup.14 denotes hydrogen, trifluoromethyl, carboxyl or straight-chain or branched alkoxycarbonyl having up to 6 carbon atoms or the group --CO--NH.sub.2, pyridyl or morpholinyl, or a salt thereof.

### Claim 3 (depends on 1)

A substituted phenylacetamide according to claim 1 in which
A represents straight-chain or branched alkyl or alkenyl each having up to 4 carbon atoms, or represents cyclopropyl, cyclopentyl or cyclohexyl,
R represents hydrogen, fluorine, chlorine or perfluoroalkyl having up to 2 carbon atoms,
D represents a group of the formula --CH.sub.2 OR.sup.3, --CO--R.sup.4, --CO--NR.sup.5 R.sup.6, ##STR68## in which R.sup.3 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R.sup.4 denotes hydrogen, hydroxyl or straight-chain or branched alkoxy having up to 4 carbon atoms,
R.sup.5 and R.sup.6 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, or
R.sup.5 has the abovementioned meaning and
R.sup.6 denotes a group of the formula --SO.sub.2 R.sup.12, in which
R.sup.12 denotes methyl, ethyl, benzyl, p-tolyl or phenyl,
a and b are identical or different and denote a number 0 or 1,
R.sup.7 denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R.sup.8 and R.sup.10 are identical or different and denote cyclopropyl, cyclohexyl or phenyl,
R.sup.9 and R.sup.11 are identical or different and denote hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
E represents hydrogen, fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy or methyl,
L represents straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl, represents cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl,
R.sup.1 represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
R.sup.2 represents pyridyl, morpholinyl, tetrahydropyranyl or tetrahydrofuranyl, or represents a radical of the formula ##STR69## in which R.sup.13 denotes phenyl which is optionally substituted by fluorine, hydroxyl, trifluoromethyl or by straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms or by methylenedioxy,
c, d, e and f are identical or different and denote a number 0, 1 or 2,
R.sup.14 denotes hydrogen, trifluoromethyl, carboxyl or straight-chain or branched alkoxycarbonyl having up to 4 carbon atoms or the group --CO--NH.sub.2 or pyridyl, or a salt thereof.

### Claim 4 (depends on 1)

A compound according to claim 1 wherein such compound is N-(1-phenyl-1-pyrid-2-yl)methyl]-2-[4-(2-butyl-4-chloro-5-formyl-imidazol- 1-yl-methyl)phenyl]-2-cyclopentyl-acetamide of the formula ##STR70## or a salt thereof.

### Claim 5 (depends on 1)

A composition for the treatment of atriable hypertension and arteriosclerosis comprising an mount effective therefor of a compound or salt thereof according to claim 1 and a pharmacologically acceptable diluent.

### Claim 6 (depends on 1)

The method of treating atriable hypertension and arteriosclerosis in a patient in need thereof which comprises administering to such patient an amount effective therefor of a compound or salt thereof according to claim 1.