57113-90-3

Usage

Chemical Properties

Yellow Solid

InChI:InChI=1/C13H16N2O6/c1-13(2,3)21-12(17)14-10-8(11(16)20-4)6-5-7-9(10)15(18)19/h5-7H,1-4H3,(H,14,17)

Synthetic route

methyl 2-carboxy-3-nitrobenzoate (21606-04-2) + triethylamine (121-44-8) + tert-butyl alcohol (75-65-0) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
Stage #1: methyl 2-carboxy-3-nitrobenzoate; triethylamine With diphenyl phosphoryl azide In DMF (N,N-dimethyl-formamide) at 20 - 35℃; for 3h; Industry scale; Stage #2: tert-butyl alcohol In DMF (N,N-dimethyl-formamide) at 85 - 90℃; for 4 - 7h; Heating / reflux;	86.7%

methyl 2-carboxy-3-nitrobenzoate (21606-04-2) + tert-butyl alcohol (75-65-0) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
Stage #1: methyl 2-carboxy-3-nitrobenzoate With diphenyl phosphoryl azide; triethylamine In N,N-dimethyl-formamide at 20 - 31℃; Inert atmosphere; Stage #2: tert-butyl alcohol In N,N-dimethyl-formamide at 85 - 87℃; for 9h; Stage #3: With methanol at 50 - 55℃; for 3h;	72.5%

2-Azidocarbonyl-3-nitro-benzoic acid methyl ester (856414-36-3) + tert-butyl alcohol (75-65-0) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
for 1.5h; Heating; Yield given;
for 2h; Heating / reflux;

methyl 2-carboxy-3-nitrobenzoate (21606-04-2) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: SOCl2, DMF / toluene / 0.5 h / Heating 2: NaN3 / acetone; H2O / 1 h 3: 1.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1.1: N,N-dimethyl-formamide; thionyl chloride / toluene / 2.5 h / 75 °C 2.1: sodium azide; tetrabutylammomium bromide / toluene / 4 h / -10 - -5 °C 2.2: 1 h / 80 - 85 °C View Scheme

acid chloride of 1-methylhydrogen-3-nitrophthalate (73833-13-3) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaN3 / acetone; H2O / 1 h 2: 1.5 h / Heating View Scheme

3-nitrophthalic acid (603-11-2) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: concd. H2SO4 / methanol 2: SOCl2, DMF / toluene / 0.5 h / Heating 3: NaN3 / acetone; H2O / 1 h 4: 1.5 h / Heating View Scheme
Multi-step reaction with 3 steps 1.1: sulfuric acid / 24.75 h / 20 - 65 °C 2.1: N,N-dimethyl-formamide; thionyl chloride / toluene / 2.5 h / 75 °C 3.1: sodium azide; tetrabutylammomium bromide / toluene / 4 h / -10 - -5 °C 3.2: 1 h / 80 - 85 °C View Scheme

acid chloride of 1-methylhydrogen-3-nitrophthalate (73833-13-3) + N,N-dimethyl-formamide (68-12-2, 33513-42-7) + tert-butyl alcohol (75-65-0) → methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3)

Conditions	Yield
Stage #1: acid chloride of 1-methylhydrogen-3-nitrophthalate; N,N-dimethyl-formamide With sodium azide; tetrabutylammomium bromide In toluene at -10 - -5℃; for 4h; Stage #2: tert-butyl alcohol In toluene at 80 - 85℃; for 1h;

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) + 1-bromomethyl-4-bromobenzene (589-15-1) → C20H21BrN2O6 (892505-87-2)

Conditions	Yield
With potassium carbonate In acetonitrile for 10h; Heating / reflux;	92%

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) + 7-(bromomethyl)-5-oxo-5H-dibenzocycloheptene-10-carbonitrile (169270-61-5) → methyl 2-<(tert-butoxycarbonyl)<(11-cyano-5-oxo-5H-dibenzocyclohepten-3-yl)methyl>amino>-3-nitrobenzoate (169270-79-5)

Conditions	Yield
With potassium carbonate In acetonitrile for 4h; Heating;	86%

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) + 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (114772-54-2) → methyl 2-amino>-3-nitrobenzoate (139481-38-2)

Conditions	Yield
With potassium carbonate In acetonitrile for 4h; Heating;	85%
With potassium carbonate In acetonitrile at 80 - 85℃; for 5h; Heating / reflux; Industry scale;

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → Methyl 3-amino-2-[(tert-butoxycarbonyl)amino]benzoate (474708-09-3)

Conditions	Yield
With hydrogen; palladium on activated charcoal In methanol at 20℃; for 5h;	82%

1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole + methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-(N-tert-butoxycarbonyl-N-{(2'-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (1307853-80-0)

Conditions	Yield
With potassium carbonate In acetonitrile for 3h; Inert atmosphere; Reflux;	81%

1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole + methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-(N-tert-butoxycarbonyl-N-{(2'-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (1307853-80-0)

Conditions	Yield
With potassium carbonate In acetonitrile for 9h; Reflux; Inert atmosphere;	81%

5-[4'-(bromomethyl)biphenyl-2-yl]-1-(p-methoxybenzyl)-1H-tetrazole (1307853-40-2) + methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-(N-tert-butoxycarbonyl-N-{(2'-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate (1307853-69-5)

Conditions	Yield
With potassium carbonate In acetonitrile for 6h; Reflux; Inert atmosphere;	71.1%

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) + Methyl 4'-(bromomethyl)biphenyl-2-carboxylate (114772-38-2) → 4'-{[tert-Butoxycarbonyl-(2-methoxycarbonyl-6-nitro-phenyl)-amino]-methyl}-biphenyl-2-carboxylic acid methyl ester (150058-11-0)

Conditions	Yield
With potassium carbonate In acetonitrile for 4h; Heating;

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) + 7-(bromomethyl)dibenzooxepin-10-carbonitrile (169270-73-9) → 2-[tert-Butoxycarbonyl-(11-cyano-dibenzo[b,f]oxepin-3-ylmethyl)-amino]-3-nitro-benzoic acid methyl ester (1028312-00-6)

Conditions	Yield
With potassium carbonate In acetonitrile for 4h; Heating;

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 3-amino-2-[[(2'-cyanobiphenyl-4-yl)methyl]amino]benzoate (136304-78-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h View Scheme
Multi-step reaction with 2 steps 1.1: potassium carbonate; tetrabutylammomium bromide / toluene / 12 h / 80 - 85 °C 1.2: 3 h / Reflux 2.1: tin(ll) chloride / ethyl acetate / 1.5 h / Reflux 2.2: 4.5 h / -10 - 0 °C 2.3: 0.5 h / Reflux View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → ethyl 3-amino-2-<<(2'-cyanobiphenyl-4-yl)methyl>amino>benzoate (136285-69-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 78 percent / ethanol / 1.5 h / Heating View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 3-amino-2-<<<2'-(methoxycarbonyl)biphenyl-4-yl>methyl>amino>benzoate (139481-37-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: K2CO3 / acetonitrile / 4 h / Heating 2: 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-<<2'-cyanobiphenyl-4-yl)methyl>amino>-3-nitrobenzoate (139481-28-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 1-<(2'-cyanobiphenyl-4-yl)methyl>-2,3-dihydro-2-oxo-1H-benzimidazole-7-carboxylate (139481-33-7)

Conditions

Yield

Multi-step reaction with 5 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 90 percent / pyridine / 3 h / Ambient temperature 5: 89 percent / NaOMe / methanol / 21 h / Heating View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-chloro-1-<(2'-cyanobiphenyl-4-yl)methyl>-1H-benzimidazole-7-carboxylate (139481-34-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 90 percent / pyridine / 3 h / Ambient temperature 5: 89 percent / NaOMe / methanol / 21 h / Heating 6: 34 percent / POCl3 / 8 h / Heating View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → ethyl 1-<(2'-cyanobiphenyl-4-yl)methyl>-2-methyl-1H-benzimidazole-7-carboxylate (136304-69-3)

Conditions

Yield

Multi-step reaction with 5 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 78 percent / ethanol / 1.5 h / Heating 5: 73 percent / Et3N / CH2Cl2 / 2 h / Ambient temperature View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → 1-<(2'-cyanobiphenyl-4-yl)methyl>-2-<(methylthio)methyl>-1H-benzimidazole-7-carboxylic acid

Conditions

Yield

Multi-step reaction with 7 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 78 percent / ethanol / 1.5 h / Heating 5: 76 percent / CH2Cl2 / 2 h / Ambient temperature 6: acetonitrile; H2O / 41 h / 80 °C 7: 1 N aq. NaOH / ethanol / 3 h / Heating View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → 3-(2'-Cyano-biphenyl-4-ylmethyl)-2-methoxy-3H-benzoimidazole-4-carboxylic acid methyl ester (139481-47-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 70 percent / acetic acid / 0.67 h / 80 - 90 °C View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → 3-(2'-Cyano-biphenyl-4-ylmethyl)-2-methylamino-3H-benzoimidazole-4-carboxylic acid methyl ester (139481-48-4)

Conditions

Yield

Multi-step reaction with 5 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: ethanol / 17 h / 50 °C 5: 1.) methyl iodide, 2.) HCl / 1.) EtOH, reflux, 24 h, 2.) EtOH, H2O View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → ethyl 1-<(2'-cyanobiphenyl-4-yl)methyl>-2-mercapto-1H-benzimidazole-7-carboxylate (139481-43-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 78 percent / ethanol / 1.5 h / Heating 5: 82 percent / ethanol / 8 h / Heating View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-<<<2'-(methoxycarbonyl)biphenyl-4-yl>methyl>amino>-3-nitrobenzoate (139481-36-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3 / acetonitrile / 4 h / Heating 2: 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → methyl 2-<<(2'-cyanobiphenyl-4-yl)methyl>amino>-3-<(methoxycarbonyl)amino>benzoate (139481-35-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: 90 percent / pyridine / 3 h / Ambient temperature View Scheme

methyl 2-(N-tert-butoxycarbonylamino)-3-nitrobenzoate (57113-90-3) → 2-[(2'-Cyano-biphenyl-4-ylmethyl)-amino]-3-(3-methyl-thioureido)-benzoic acid methyl ester (139481-31-5)

Conditions	Yield
Multi-step reaction with 4 steps 1: 85 percent / K2CO3 / acetonitrile / 4 h / Heating 2: 77 percent / 30percent ethanolic HCl / ethyl acetate / 1 h / Ambient temperature 3: 1.) FeCl3*6H2O, activated carbon, 2.) hydrazine monohydrate / 1.) MeOH, THF, reflux, 30 min, 2.) MeOH, THF, reflux, 14 h 4: ethanol / 17 h / 50 °C View Scheme

Upstream product

• 21606-04-2 methyl 2-carboxy-3-nitrobenzoate 
• 75-65-0 tert-butyl alcohol 
• 73833-13-3 acid chloride of 1-methylhydrogen-3-nitrophthalate 
• 68-12-2 N,N-dimethyl-formamide 
• 121-44-8 triethylamine 
• 603-11-2 3-nitrophthalic acid 
• 856414-36-3 2-Azidocarbonyl-3-nitro-benzoic acid methyl ester 

Downstream Products

• 139481-38-2 methyl 2-amino>-3-nitrobenzoate 
• 145040-37-5 candesartan cilexetil 
• 139481-72-4 2-Ethoxy-1-[[2'-(N-triphenylmethyltetrazol-5-yl)-biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid 
• 139481-28-0 methyl 2-<<2'-cyanobiphenyl-4-yl)methyl>amino>-3-nitrobenzoate 
• 1215298-35-3 methyl 2-ethoxy-1-({2′-[1-(phenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl}methyl)-1H-benzimidazole-7-carboxylate 
• 1307853-85-5 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl 1-({4-[2-(1-benzyl-1H-1,2,3,4-tetrazol-5-yl)phenyl]phenyl}methyl)-2-ethoxy-1H-1,3-benzodiazole-7-carboxylate 
• 1307853-71-9 methyl 2-[({2'-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate 
• 1307853-72-0 methyl 2-[({2'-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-aminobenzoate 
• 1215298-30-8 methyl 2-[({2'-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-nitrobenzoate 
• 1307853-81-1 methyl 2-[({2'-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)amino]-3-aminobenzoate 
• 1307853-73-1 C₃₃H₃₀N₆O₄ 
• 1307853-80-0 methyl 2-(N-tert-butoxycarbonyl-N-{(2'-[1-benzyl-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate 
• 1307853-69-5 methyl 2-(N-tert-butoxycarbonyl-N-{(2'-[1-(p-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl)methyl}amino)-3-nitrobenzoate 
• 1202261-17-3 methyl 2-[(tert-butoxycarbonyl)(4-methoxybutyl)amino]-3-nitrobenzoate 

Relevant academic research and scientific papers

PROCESS FOR PRODUCTION OF BIPHENYL DERIVATIVE

The invention provides a production method of a biaryltetrazole derivative useful as an intermediate for an angiotensin II receptor antagonist. The method comprises reacting an aryltetrazole derivative with a benzene derivative, deprotecting or reducing the resulting compound, and halogenating the deprotected or reduced compound

PROCESS FOR PREPARATION OF CANDESART AN CILEXETIL SUBSTANTIALLY FREE OF DES-CANDESARTAN CILEXETIL IMPURITY

The present invention provides a process for preparation of candeartan cilexetil substantially free of 2,3-dihydro-2-oxo-3-[[2'-(2H-tetrazol-5-yl)[l,l-biphenyl]-4- yl]methyl]-l-[[(cyclohexyloxy)carbonyl]oxy]ethylester-lH-benzimidazole-7- carboxylate (des-candesartan cilexetil) impurity.

METHOD FOR PRODUCTION OF CANDESARTAN

The invention relates to novel methods for the production of Candesartan, or a protected form of Candesartan, a Candesartan salt or ester, compounds of application in said method, methods for production thereof, use thereof in said method, a novel polymorph of Candesartan cilexetil, a method for production and use thereof for production of a medicament.

CRYSTAL AND PROCESS FOR PRODUCING THE SAME

A process for producing crystals of 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimdazole-7-carboxylic acid (compound (I)), characterized by dissolving or suspending the compound (I) or a salt thereof in a solvent comprising an aprotic polar solvent and crystallizing it. By the process, the contaminants which are contained in the compound (I) or its salt and are difficult to remove, such as tin compounds, analogues of the compound (I), and a residual organic solvent, can be easily removed. Crystals of the compound (I) can be efficiently and easily mass-produced in high yield on an industrial scale.

Production method of aminobenzene compound

The present invention is to provide an industrially useful production method of an aminobenzene compound represented by the formula: which is characterized by reacting a mixture of a mono-halogeno compound represented by the formula: and di-halogeno compound represented by the formula: with a compound of the formula:

Nonpeptide Angiotensin II Receptor Antagonists. Synthesis and Biological Activity of Benzimidazolecarboxylic Acids

A series of 2-substituted-1--1H-benzimidazole-7-carboxylic acids was prepared from the key intermediate 3-amino-2-amino>benzoate (6a-c) in order to clarify the structure-activity relationships of various analogues of 2-butyl-1-methyl>-1H-benzimidazole-7-carboxylic acid (CV-11194), a potent and long acting angiotensin II (AII) receptor antagonist.The AII antagonistic activity of the benzimidazoles was investigated by in vitro assays, which included an AII receptor binding assay and AII-induced vasocontraction assay, as well as by in vivo assays such as an AII-induced pressor response in rats.Most of the benzimidazoles showed high affinity for the AII receptor (IC50 value, 10-6-1--7 M) and inhibited the AII-induced pressor response at 1 or 3 mg/kg po, and the effects were more potent than those of CV-11194 and DuP 753.The structure-activity relationship studies on the binding affinity and the inhibition of AII-induced pressor response suggested that straight chains of a certain length (e.g., ethoxy groups, ethyl groups) were the best as substituents at the 2-position and that their steric factors, lipohilicity, and electronic effects affected the potency of the AII antagonistic action.Both a carboxyl group at the 7-position and a tetrazole ring at the 2'-position were particularly important for potent and orally active AII antagonistic activity and a long-acting hypotensive effect.The representative compound, 2-ethoxy-1-methyl>-1H-benzimidazole-7-carboxylic acid (26b, CV-11974), inhibited the specific binding of AII to bovine adrenal cortical membrane with an IC50 value of 1.1*10-7 M.The AII-induced contraction of rabbit aortic strips was antagonized by CV-11974 (IC50 value, 3.0*1--10 M).Oral administration of CV-11974 to conscious normatensive rats at 1 mg/kg resulted in long-lasting inhibition of the AII-induced pressor response.CV-11974 at 0.1-1 mg/kg iv reduced blood pressure dose-dependently in spontaneously hypertensive rats.