e.g. Filippa Pettersson or Cancer Res. 75(6) , 1102-12, (2015) or 10.1002/anie.201600521

Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl) imidazoles as potent, orally active antihypertensives

DJ Carini, JV Duncia, PE Aldrich, AT Chiu…

Index: Carini, David J.; Duncia, John V.; Aldrich, Paul E.; Chiu, Andrew T.; Johnson, Alexander L.; et al. Journal of Medicinal Chemistry, 1991 , vol. 34, # 8 p. 2525 - 2547

Full Text: HTML

Citation Number: 454

Abstract

Discussion Compounds with the core structure 1 have previously been found to be potent antagonists of the AI1 receptor and to be antihypertensive upon iv administrations3 Replacement of the polar carboxylic acid group (A) with acid isosteres of greater lipophilicity, such as NHS02CF3, resulted in some oral activity. However, none of these compounds when dosed orally produced an effect to compare with their intravenous antihypertensive ...

N-(2-HYDROXY-1,1-DIMETHYLETHYL)-2-METHOXYBENZENECARBOXAMIDE Structure

N-(2-HYDROXY-1,...

~%

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

2-Methoxybenzoic acid Structure

2-Methoxybenzoi...

~%

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

o-anisoyl chloride Structure

o-anisoyl chloride

~%

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline Structure

2-(2-methoxyphe...

P-TOLYLMAGNESIUM BROMIDE Structure

P-TOLYLMAGNESIU...

~%

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline Structure

2-(2-methoxyphe...

~%

5-(4'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole Structure

5-(4'-methyl-[1...

N-(2-HYDROXY-1,1-DIMETHYLETHYL)-2-METHOXYBENZENECARBOXAMIDE Structure

N-(2-HYDROXY-1,...

~%

5-(4'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole Structure

5-(4'-methyl-[1...

2-Methoxybenzoic acid Structure

2-Methoxybenzoi...

~%

5-(4'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole Structure

5-(4'-methyl-[1...

o-anisoyl chloride Structure

o-anisoyl chloride

~%

5-(4'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole Structure

5-(4'-methyl-[1...

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

~%

5-(4'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole Structure

5-(4'-methyl-[1...

4'-Methyl-2-cyanobiphenyl Structure

4'-Methyl-2-cya...

Triphenylmethyl Chloride Structure

Triphenylmethyl...

~%

5-(4'-methyl-[1,1'-biphenyl]-2-yl)-2-trityl-2H-tetrazole Structure

5-(4'-methyl-[1...

4-Iodotoluene Structure

Methyl 2-iodobenzoate Structure

Methyl 2-iodobe...

~11%

Methyl-4'-methylbiphenyl-2-carboxylat Structure

Methyl-4'-methy...

4'-Methyl-2-cyanobiphenyl Structure

4'-Methyl-2-cya...

~%

4'-[(2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile Structure

4'-[(2-Butyl-4-...

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline Structure

2-(2-methoxyphe...

~%

4'-[(2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile Structure

4'-[(2-Butyl-4-...

N-(2-HYDROXY-1,1-DIMETHYLETHYL)-2-METHOXYBENZENECARBOXAMIDE Structure

N-(2-HYDROXY-1,...

~%

4'-[(2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile Structure

4'-[(2-Butyl-4-...

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

~%

4'-[(2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile Structure

4'-[(2-Butyl-4-...

2-Methoxybenzoic acid Structure

2-Methoxybenzoi...

~%

4'-[(2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile Structure

4'-[(2-Butyl-4-...

o-anisoyl chloride Structure

o-anisoyl chloride

~%

4'-[(2-Butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-1,1'-biphenyl-2-carbonitrile Structure

4'-[(2-Butyl-4-...

(2-Butyl-5-chloro-1H-imidazol-4-yl)methanol Structure

(2-Butyl-5-chlo...

~78%

2-Butyl-4-chloro-5-formylimidazole Structure

2-Butyl-4-chlor...

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

~95%

4'-Methyl-2-cyanobiphenyl Structure

4'-Methyl-2-cya...

3-Bromobenzonitrile Structure

3-Bromobenzonitrile

chlorozinc(1+),methylbenzene Structure

chlorozinc(1+),...

~%

4'-METHYL-[1,1'-BIPHENYL]-3-CARBONITRILE Structure

4'-METHYL-[1,1'...

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline Structure

2-(2-methoxyphe...

~%

2-(4-methylphenyl)benzoyl chloride Structure

2-(4-methylphen...

N-(2-HYDROXY-1,1-DIMETHYLETHYL)-2-METHOXYBENZENECARBOXAMIDE Structure

N-(2-HYDROXY-1,...

~%

2-(4-methylphenyl)benzoyl chloride Structure

2-(4-methylphen...

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

~%

2-(4-methylphenyl)benzoyl chloride Structure

2-(4-methylphen...

2-Methoxybenzoic acid Structure

2-Methoxybenzoi...

~%

2-(4-methylphenyl)benzoyl chloride Structure

2-(4-methylphen...

o-anisoyl chloride Structure

o-anisoyl chloride

~%

2-(4-methylphenyl)benzoyl chloride Structure

2-(4-methylphen...

4-Iodotoluene Structure

~%

1-[4-(bromomethyl)phenyl]-2-nitrobenzene Structure

1-[4-(bromometh...

1-[(2'-Carbomethoxybiphenyl-4-yl)methyl]-2-(1-trans-butenyl)-4-chloro-5-hydroxymethylimidazole Structure

1-[(2'-Carbomet...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

2-(2-methoxyphenyl)-4,4-dimethyl-2-oxazoline Structure

2-(2-methoxyphe...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

4-Iodotoluene Structure

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

Methyl 2-iodobenzoate Structure

Methyl 2-iodobe...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

4'-Methyl-[1,1'-biphenyl]-2-carboxylic acid Structure

4'-Methyl-[1,1'...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

Methyl-4'-methylbiphenyl-2-carboxylat Structure

Methyl-4'-methy...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

N-(2-HYDROXY-1,1-DIMETHYLETHYL)-2-METHOXYBENZENECARBOXAMIDE Structure

N-(2-HYDROXY-1,...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

Methyl α-bromo-2-(p-tolyl)benzoate Structure

Methyl α-bromo-...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

2-Methoxybenzoic acid Structure

2-Methoxybenzoi...

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

o-anisoyl chloride Structure

o-anisoyl chloride

~%

2-[4-[[2-but-1-enyl-4-chloro-5-(hydroxymethyl)imidazol-1-yl]methyl]phenyl]benzoic acid Structure

2-[4-[[2-but-1-...

Butyraldehyde Structure

acetol Structure

~%

4-METHYL-2-PROPYL-1H-IMIDAZOLE Structure

4-METHYL-2-PROP...

4,4-dimethyl-2-[2-(4-methylphenyl)phenyl]-5H-1,3-oxazole Structure

4,4-dimethyl-2-...

~89%

4'-Methyl-[1,1'-biphenyl]-2-carboxylic acid Structure

4'-Methyl-[1,1'...

Trityl losartan Structure

Trityl losartan

~89%

Losartan Structure

Uncatalysed coupling of an activated aryl chloride with aryl...

[Astley, Demet; Saygi, Hava; Gezer, Sibel; Astley, Stephen T. Tetrahedron Letters, 2004 , vol. 45, # 39 p. 7315 - 7317]

Uncatalysed coupling of an activated aryl chloride with aryl...

[Astley, Demet; Saygi, Hava; Gezer, Sibel; Astley, Stephen T. Tetrahedron Letters, 2004 , vol. 45, # 39 p. 7315 - 7317]

Uncatalysed coupling of an activated aryl chloride with aryl...

[Astley, Demet; Saygi, Hava; Gezer, Sibel; Astley, Stephen T. Tetrahedron Letters, 2004 , vol. 45, # 39 p. 7315 - 7317]