124750-92-1

Usage

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

• 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 
• 124750-99-8 cozaar 
• 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 losartan potassium 
• 114798-26-4 lorsartan 
• 114798-26-4 2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole 
• 114798-36-6 EXP 3179 

Downstream Products

• 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 
• 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 
• 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 
• 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 
• 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 academic research and scientific papers

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.

Identification and Enzymatic Activity Evaluation of a Novel CYP2C9 Allelic Variant Discovered in a Patient

Warfarin is a widely prescribed anticoagulant but the doses required to attain the optimum therapeutic effect exhibit dramatic inter-individual variability. Pharmacogenomics-guided warfarin dosing has been recommended to improve safety and effectiveness. We analyzed the cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genes among 120 patients taking warfarin. A new coding variant was identified by sequencing CYP2C9. The novel A > G mutation at nucleotide position 14,277 led to an amino acid substitution of isoleucine with valine at position 213 (I213V). The functional consequence of the variant was subsequently evaluated in vitro. cDNA of the novel variant was constructed by site-directed mutagenesis and the recombinant protein was expressed in vitro using a baculovirus–insect cell expression system. The recombinant protein expression was quantified at apoprotein and holoprotein levels. Its enzymatic activities toward tolbutamide, warfarin and losartan were then assessed. It exhibited changed apparent Km values and increases of 148%, 84% and 67% in the intrinsic clearance of tolbutamide, warfarin and losartan, respectively, compared to wild-type CYP2C9*1, indicating dramatically enhanced in vitro enzymatic activity. Our study suggests that the amino acid at position 213 in wild-type CYP2C9*1 may be important for the enzymatic activity of CYP2C9 toward tolbutamide, warfarin and losartan. In summary, a patient taking high-dose warfarin (6.0?mg/day) in order to achieve the target international normalized ratio was found to have a mutation in the CYP2C9 gene.

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.

A process for preparing a renin - angiotensin - aldosterone system dual inhibitor compound of intermediate

The invention relates to an intermediate compound for preparing RAAS (renin-angiotensin-aldosterone system) dual inhibitor compounds. RAAS dual inhibitors can be used for treating diseases related to an RAAS such as high blood pressure and heart diseases.

Preparing method for EXP-3174

The invention discloses a preparing method for EXP-3174. The preparing method is characterized in that losartan is used as a starting raw material and is prepared into EXP-3174 through two-step oxidation. The preparing method has the greatest advantages that a reaction is moderate, the number of side reactions is small, aftertreatment is simple, and EXP-3174 with the purity of 99.9% can be obtained without column chromatography isolation.

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.

New losartan-hydrocaffeic acid hybrids as antihypertensive-antioxidant dual drugs: Ester, amide and amine linkers

We report new examples of a series of losartan-hydrocaffeic hybrids that bear novel ester, amide and amine linkers. These compounds were made by linking hydrocaffeic acid to the side chain of losartan at the C-5 position of the imidazole ring through different strategies. Experiments performed in cultured cells demonstrate that these new hybrids retain the ability to block the angiotensin II effect and have increased antioxidant ability. Most of them reduced arterial pressure in rats better or as much as losartan.

ANGIOTENSIN II RECEPTOR ANTAGONISTS

A compound having the structure (A) wherein R is an angiotensin receptor antagonist active group, and Y is 1) -(CH2)3R5, 2) -C(O)(CH2)2R5, 3) -C(R1R2)OC(O)O(CH2)nR5, wherein n is 1 or 2, 4) -C(R1R2)OC(O)CH2CH2R5, 5) -C(R1R2)OC(O)OCH2CH2C(R3R4)R5, Formula (B), and Formula (C) provided that when Y is -C(O)(CH2)2R5, then R is Formula (D) R1, R2, R3 and R4 are independently selected from the group consisting of hydrogen and C1-4 alkyl; R5 is CH(ONO2)CH(ONO2)R6; R6 is selected from CH3, CH2CH3 and CH(CH3)2; or a pharmaceutically acceptable salt or hydrate thereof, which is useful for treating hypertension.

NEW ANGIOTENSIN II RECEPTOR BLOCKER DERIVATIVES

New angiotensin II receptor blocker nitroderivatives of general formula (I) and pharmaceutically acceptable salts or stereoisomers thereof: and their use for treating cardiovascular, renal and chronic liver diseases, inflammatory processes and metabolic syndromes.

ANGIOTENSIN II RECEPTOR ANTAGONISTS

The present invention relates to nitrooxyderivatives of angiotensin II receptor antagonist having the general formula (I): where in R is selected f rom the group consisting of (IIa) - (IIk): when R is selected from (Ilk), Y is selected from the group consisting of: 1) -C(O) (CH2) nR5; 2) -C(O)(CH2n-O-CH2-R5; 3) -C(O)-R6 wherein R6 is the following group: when R is selected from (IIa)-(IIh), Y is selected from the group consisting of: 4) -C(R1R2)OC(O)-(CH2)nR5; 5) -C(R1R2)OC(O)O-(CH2)nR5; 6) C(R1R2)OC(O)(CH2)n-O-CH2-R5; 7) C(R1R2)OC(O)O(CH2)n-O-CH2-R5; 8) -C(R1R2)OC(O)-R6 wherein R6 is as above defined; R1 and R2 are independently selected from the group consisting of hydrogen and C1-4 alkyl; R5 is -CH(ONO2)R7; R7 is CH3 or C1-4 alkyl; n is an integer from 1 to 4; or a pharmaceutically acceptable salt thereof.