124750-92-1

Basic information

• Product Name: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID
• Synonyms: LOSARTAN CARBOXY ACID;AKOS 91941;2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID;’-biphenyl)-4-yl)methyl)-;1h-imidazole-5-carboxylicacid,2-butyl-4-chloro-1-((2’-(14-tetrazol-5-yl)(1,1;e-3174;exp3174;l-158641
• CAS NO: 124750-92-1
• Molecular Formula: C₂₂H₂₁ClN₆O₂
• Molecular Weight: 436.89
• Product Categories: Intermediates & Fine Chemicals;Metabolites & Impurities;Pharmaceuticals;Heterocycles
• Mol File: 124750-92-1.mol
• Article Data: 23

Chemical Properties

• Melting Point: 130-132°C
• Boiling Point: 707.8 °C at 760 mmHg
• Flash Point: 381.8 °C
• Appearance: Light-Yellow Solid
• Density: 1.41 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: Dimethylformamide, Dimethyl Sulfoxide, Methanol
• PKA: 0.79±0.50(Predicted)
• CAS DataBase Reference: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID(CAS DataBase Reference)
• NIST Chemistry Reference: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID(124750-92-1)
• EPA Substance Registry System: 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID(124750-92-1)

Safety Data

• Safety Statements: 24/25
• Hazardous Substances Data: 124750-92-1(Hazardous Substances Data)

Usage

Description

2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID is a complex organic compound with a unique molecular structure that features a biphenyltetrazole group attached to an imidazole ring. 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID is characterized by its light-yellow solid appearance and is a metabolite of Losartan, a medication used to treat hypertension and heart failure.

Uses

Used in Pharmaceutical Industry:
2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID is used as a metabolite of Losartan for its physiological activity. As a potent AT1 antagonist, it contributes to the depressor response and vasodilation effects of the parent compound, Losartan. This makes it a valuable component in the development and study of antihypertensive and heart failure treatments.
Used in Research and Development:
In the field of pharmaceutical research and development, 2-BUTYL-4-CHLORO-1-[(2'-(1-H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL)METHYL]-1-H-IMIDAZOLE-5-CARBOXYLIC ACID serves as an important compound for understanding the metabolic pathways and effects of Losartan. Its study can lead to the discovery of new drug candidates and the optimization of existing treatments for cardiovascular diseases.

in vitro

e-3174 potently blocked the specific binding of [125i]-aii to vsmc isolated from rat aorta. e-3174 was able to dampen the platelet-derived growth factor-induced increase in cell dna synthesis and protein, which led to the blockade of the aii-induced increase in cell protein [1].

in vivo

rats were administrated e-3174 intravenously at a dose of l.0 mg/kg. after 6 hours, e-3174 markedly attenuated the cardiovascular effects of aii in rats. e-3174 induced a progressive fall in mean arterial pressure and a marked increase in renal flow only [2].

references

[1]. li, x. & widdop, r. angiotensin type i receptor antagonists cy-11974 and exp 3174 cause selective renal vasodilatation in conscious spontaneously hypertensive rats. clinical science, 1996; 91(2): 147-154. [2]. sachinidis, a., ko, y., weisser, p., zu bricbkwedde, m., dsing, r., & christian, r. et al. exp3174, a metabolite of losartan (mk954, dup753) is more potent than losartan in blocking the angiotensin ll-induced responses in vascular smooth muscle cells. journal of hypertension. 1993; 11(2): 155-162.

Synthetic route

2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl) 1,1'-biphenyl-methyl]imidazole-5-carboxylic acid ethyl ester (947330-97-4) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With sodium hydroxide In ethanol at 90℃; for 20h;	90%

cozaar (124750-99-8) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Stage #1: cozaar With potassium permanganate In water at -5 - 50℃; for 16h; Stage #2: With hydrogenchloride In water pH=2 - 3;	89.1%
Stage #1: cozaar With potassium hydroxide In water at 2℃; for 2h; Stage #2: With sodium periodate; ruthenium trichloride In water; isopropyl alcohol at 4 - 20℃; for 22h; Stage #3: With phosphoric acid In water; isopropyl alcohol for 0.5h;
Stage #1: cozaar With ruthenium trichloride; potassium hydroxide; sodium periodate In water at 0℃; Stage #2: With phosphoric acid In water; isopropyl alcohol at 30℃; for 0.5h;

lorsartan (114798-26-4) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With pyridine; potassium permanganate; tetrabutyl-ammonium chloride In water; acetone at 40 - 50℃; for 1h; Product distribution / selectivity;	78%
With sodium periodate; ruthenium(III) trichloride hydrate; potassium hydroxide In water at 0℃;
Stage #1: lorsartan With sodium periodate; ruthenium (III) chloride monohydrate; potassium hydroxide In water at 0℃; Stage #2: In water; isopropyl alcohol at 25℃; for 2.5h; Stage #3: With phosphoric acid In water; isopropyl alcohol at 30℃; for 0.5h;
With cytochrome P450 2C9 Enzymatic reaction;
With cytochrome b5; NADPH In aq. phosphate buffer at 37℃; for 0.75h; Kinetics; Reagent/catalyst; Enzymatic reaction;

losartan potassium (124750-99-8) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Stage #1: losartan potassium With pyridine; potassium permanganate; tetrabutyl-ammonium chloride In water; acetone at 40 - 50℃; for 1h; Stage #2: With hydrogenchloride In water; acetone Product distribution / selectivity;	72%
Stage #1: losartan potassium With potassium hydroxide In water at 2℃; for 2h; Stage #2: With sodium periodate; ruthenium trichloride In water at 4 - 6.5℃; for 19h;

cozaar (124750-99-8) → 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde (114798-36-6) + 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With manganese(IV) oxide In water at 80 - 180℃; for 0.833333h; microwave irradiation;	A 0.253 mmol B 64%
With manganese(IV) oxide In water at 80 - 180℃; for 0.25h; microwave irradiation;	A 60% B n/a

2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde (114798-36-6) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
With potassium permanganate; potassium hydroxide In water; N,N-dimethyl-formamide at 20 - 30℃; for 2h; Large scale;

2-n-butyl-5-chloro-3H-imidazole-4-carboxylic acid ethyl ester → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutylammomium bromide; sodium hydroxide / toluene / 20 h / 60 °C 2: sodium azide; trimethylamine hydrochloride / toluene; 1-methyl-pyrrolidin-2-one / 43 h / 60 °C 3: sodium hydroxide / ethanol / 20 h / 90 °C View Scheme

4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile (114772-54-2) → 2-butyl-4-chloro-1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl)methyl)-1H-imidazole-5-carboxylic acid (124750-92-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: tetrabutylammomium bromide; sodium hydroxide / toluene / 20 h / 60 °C 2: sodium azide; trimethylamine hydrochloride / toluene; 1-methyl-pyrrolidin-2-one / 43 h / 60 °C 3: sodium hydroxide / ethanol / 20 h / 90 °C View Scheme

Upstream product

• 947330-97-4 2-butyl-4-chloro-1-[2'-(1H-tetrazol-5-yl) 1,1'-biphenyl-methyl]imidazole-5-carboxylic acid ethyl ester 
• 114772-54-2 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile 
• 114798-36-6 2-n-Butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxaldehyde 
• 124750-99-8 cozaar 
• 124750-99-8 losartan potassium 
• 114798-26-4 lorsartan 
• 133910-00-6 2-n-Butyl-4-chloro-1-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl]-1H-imidazole-5-carboxaldehyde 
• 114798-36-6 EXP 3179 
• 114798-26-4 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 

Downstream Products

• 1070174-98-9 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) (1,1'-biphenyl)-4-yl)methyl]-1H-imidazole-5-carboxylic acid 4-(3H-1,2-dithiole-3-thione-5-yl)-phenyl ester 
• 2387-23-7 1,3-Dicyclohexylurea 
• 1070174-99-0 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-1H-imidazole-5-carboxylic acid 2-(methylsulfonylthio)ethyl ester 
• 1196117-80-2 (3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl 2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 1370339-86-8 2-n-butyl-5-chloro-3-[2'-(2H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylic acid[3-(3,4-bis-benzyloxyphenyl)propyl]amide 
• 1200445-28-8 1-(((3R,3aR,6R,6aR)-6-(5,6-bis(nitrooxy)hexanoyloxy)hexahydrofuro[3,2-b]furan-3-yloxy)carbonyloxy)ethyl 1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxylate 
• 1186124-18-4 1-[({[(R)-5-(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 1186123-58-9 1-[({[(R)-5-(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 1185768-56-2 (S)-((R)-5,6-bis(nitrooxy)hexyl) 2-(1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-4-chloro-1H-imidazole-5-carboxamido)-3-phenylpropanoate 
• 1185769-66-7 (2S)-2-{[(2-butyl-4-chloro-1-{[2'-(1h-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)carbonyl]amino}-3-phenylpropanoic acid 
• 1185769-65-6 methyl (2S)-2-{[(2-butyl-4-chloro-1-{[2'-(1h-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)carbonyl]amino}-3-phenylpropanoate 
• 913611-27-5 2-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]-imidazole-5-carboxylic acid monohydrate 
• 1185768-61-9 (3S,3aR,6R,6aS)-6-(nitrooxy)hexahydrofuro[3,2-b]furan-3-yl {[(2-butyl-4-chloro-1-{[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazol-5-yl)carbonyl]amino}acetate 
• 947331-05-7 Allisartan 

Relevant articles and documents

Design, synthesis and antihypertensive evaluation of novel codrugs with combined angiotensin type 1 receptor antagonism and neprilysin inhibition

The multifactorial etiology of hypertension has promoted the research of blood pressure-lowering agents with multitarget actions to achieve better clinical outcomes. We describe here the discovery of novel dual-acting antihypertensive codrugs combining pharmacophores with angiotensin type 1 (AT1) receptor antagonism and neprilysin (NEP) inhibition. Specifically, the codrugs combine the AT1 antagonists losartan or its carboxylic acid active metabolite (E-3174) with selected monocarboxylic acid NEP inhibitors through a cleavable linker. The resulting codrugs exhibited high rates of in vitro conversion into the active molecules upon incubation with human/rat liver S9 fractions and in vivo conversion after oral administration in rodents. Moreover, the acute effects of one of the designed codrugs (3b) was confirmed at the doses of 10, 30 and 60 mg/kg p.o. in the spontaneous hypertensive rat (SHR) model, showing better antihypertensive response over 24 hours than the administration of an equivalent fixed-dose combination of 15 mg/kg of losartan and 14 mg/kg of the same NEP inhibitor used in 3b. The results demonstrate that the codrug approach is a plausible strategy to develop a single molecular entity with combined AT1 and NEP activities, aiming at achieving improved pharmacokinetics, efficacy and dosage convenience, as well as reduced drug-drug interaction for hypertension patients. In addition, the developability of the codrug should be comparable to the one of marketed AT1 antagonists, most of them prodrugs, but bearing only the AT1 pharmacophore.

MANUFACTURING METHOD OF LOSARTAN METABOLITE EXP-3174

The present invention provides a manufacturing method capable of manufacturing a losartan metabolite EXP-3174 with high purity and high yield using inexpensive starting materials and under mild reaction conditions. The losartan metabolite EXP-3174 is represented by chemical formula 5.

RAAS system as a dual inhibitor compounds

The invention discloses a compound used as a dual inhibitor for RAAS (rennin angiotensin aldosterone system) and particularly relates to a compound shown in formula (I), a stereisomer thereof or a pharmaceutically acceptable salt thereof. The compound can be used for treating and blocking RAS-associated diseases such as hypertension and heart disease, can be used for preventing or treating hypertension, congestive heart failure, pulmonary hypertension, renal insufficiency, renal ischemia, kidney failure, renal fibrosis, cardiac insufficiency, cardiac hypertrophy, cardiac fibrosis, myocardial ischemia, cardiomyopathy, glomerulonephritis, renal colic, complications such as nephropathy caused by diabetes, vasculopathy, vasculopathy, glaucoma, intraocular pressure elevation, atherosis, restenosis after revascularization, complications after blood vessel or cardiac operation, erectile dysfunction, hyperaldosteronism, lung fibrosis, scleroderma, anxiety, cognitive disorder, complications caused by immunosuppressor treatment as well as other known diseases associated with the rennin angiotensin aldosterone system.