Practical synthesis and regioselective alkylation of methyl 4(5)-(pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate to give DuP 532, a potent angiotensin II antagonist

Pierce, Michael E.; Carini, David J.; Huhn, George F.; Wells, Gregory J.; Arnett, John F.

doi:10.1021/jo00069a029

Cited by 46 publications

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“…The N,N 0 -bis-alkylation was generally accomplished under basic conditions [29] followed by the treatment of the resulting salt with the appropriate alkylating agent in excess. 4(5)-Butylimidazole (5a) was converted to the corresponding quaternary salts 7 and 8 under the general heterogeneous phase alkylation protocol.…”

Section: Chemistrymentioning

confidence: 99%

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Agelis

Resvani

Koukoulitsa

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tA series of symmetrically bis-substituted imidazole analogs bearing at the N-1 and N-3 two biphenyl moieties ortho substituted either with tetrazole or carboxylate functional groups was designed based on docking studies and utilizing for the first time an extra hydrophobic binding cleft of AT1 receptor. The synthesized analogs were evaluated for their in vitro antagonistic activities (pA 2 values) and binding affinities (elogIC 50 values) to the Angiotensin II AT1 receptor. Among them, the potassium (elogIC 50 ¼ 9.04) and the sodium (elogIC 50 ¼ 8.54) salts of 4-butyl-N,N 0 -bis{[2 0 -(2H-tetrazol-5-yl)biphenyl-4-yl]methyl} imidazolium bromide (12a and 12b, respectively) as well as its free acid 11 (elogIC 50 ¼ 9.46) and the 4-butyl-2-hydroxymethyl-N,N 0 -bis{[2 0 -(2H-tetrazol-5-yl)biphenyl-4-yl]methyl}imidazolium bromide (14) (elogIC 50 ¼ 8.37, pA 2 ¼ 8.58) showed high binding affinity to the AT1 receptor and high antagonistic activity (potency). The potency was similar or even superior to that of Losartan (elogIC 50 ¼ 8.25, pA 2 ¼ 8.25). On the contrary, 2-butyl-N,N 0 -bis{[2 0 -[2H-tetrazol-5-yl)]biphenyl-4-yl]methyl}imidazolium bromide (27) (elogIC 50 ¼ 5.77) and 2-butyl-4-chloro-5-hydroxymethyl-N,N 0 -bis{[2 0 -[2H-tetrazol-5-yl)]biphenyl-4-yl] methyl}imidazolium bromide (30) (elogIC 50 ¼ 6.38) displayed very low binding affinity indicating that the orientation of the n-butyl group is of primary importance. Docking studies of the representative highly active 12b clearly showed that this molecule has an extra hydrophobic binding feature compared to prototype drug Losartan and it fits to the extra hydrophobic cavity. These results may contribute to the discovery and development of a new class of biologically active molecules through bis-alkylation of the imidazole ring by a convenient and cost effective synthetic strategy.

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Section: Chemistrymentioning

confidence: 99%

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Agelis

Resvani

Koukoulitsa

et al. 2013

European Journal of Medicinal Chemistry

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“…Imidazole ring‐containing compounds, which are a subset of nitrogen‐containing heterocyclic compounds, exhibit wide ranges of biological and pharmacological activities that make them very attractive compounds for organic chemists . Many substituted imidazoles are known as biocides (in particular, herbicides, fungicides and growth 2regulators), potent angiotensin II receptor antagonists, glucagon receptor antagonists and inhibitors of interleukin‐1 and 5‐lipoxygenase . Using imidazoles in ionic liquids and in N‐heterocyclic carbenes has given a new dimension to the area of organometallics and ‘green chemistry’.…”

Section: Introductionmentioning

confidence: 99%

Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe₂O₃@TiO₂ (γ‐Fe₂O₃@TiO₂‐EG‐Cu(II)): A highly efficient magnetically separable heterogeneous nanocatalyst for one‐pot synthesis of highly substituted imidazoles

Nejatianfar

Akhlaghinia

Jahanshahi

2017

Applied Organom Chemis

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A simple, efficient and eco‐friendly procedure has been developed using Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe2O3@TiO2 (γ‐Fe2O3@TiO2‐EG‐Cu(II)) for the synthesis of 2,4,5‐trisubstituted and 1,2,4,5‐tetrasubstituted imidazoles, via the condensation reactions of various aldehydes with benzil and ammonium acetate or ammonium acetate and amines, under solvent‐free conditions. High‐resolution transmission electron microscopy analysis of this catalyst clearly affirmed the formation of a γ‐Fe2O3 core and a TiO2 shell, with mean sizes of about 10–20 and 5–10 nm, respectively. These data were in very good agreement with X‐ray crystallographic measurements (13 and 7 nm). Moreover, magnetization measurements revealed that both γ‐Fe2O3@TiO2 and γ‐Fe2O3@TiO2‐EG‐Cu(II) had superparamagnetic behaviour with saturation magnetization of 23.79 and 22.12 emu g−1, respectively. γ‐Fe2O3@TiO2‐EG‐Cu(II) was found to be a green and highly efficient nanocatalyst, which could be easily handled, recovered and reused several times without significant loss of its activity. The scope of the presented methodology is quite broad; a variety of aldehydes as well as amines have been shown to be viable substrates. A mechanism for the cyclocondensation reaction has also been proposed.

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“…Many of the substituted imidazoles are used as biocides [2], potent angiotensin II receptor antagonists [3], glucagon receptor antagonists [4], and inhibitors of IL-1 and 5-lipoxygenase [5]. Owing to their wide range of biological, industrial, and synthetic applications, they have received much attention recently.…”

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confidence: 99%

A modified procedure for the synthesis of 2,4,5-tri- and 1,2,4,5-tetrasubstituted imidazoles

2013

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UDC 547.781 As an important member of five-membered heterocycle compounds, the imidazole moiety has many pharmacological properties and play important roles in biochemical process [1]. Many of the substituted imidazoles are used as biocides [2], potent angiotensin II receptor antagonists [3], glucagon receptor antagonists [4], and inhibitors of IL-1 and 5-lipoxygenase [5]. Owing to their wide range of biological, industrial, and synthetic applications, they have received much attention recently. There are several methods reported in the literature for the synthesis of highly substituted imidazoles [6-13].Among the above methods, the method of one-pot condensation of dione with aldehyde or aldehyde and amine resulting in 2,4,5-tri-or 1,2,4,5-tetrasubstituted imidazoles, respectively, using ammonium acetate as the ammonia source in the presence of various catalysts [13][14][15][16], is well known. Is a well-established multicomponent reaction (MCR) for the preparation of highly substituted imidazoles. In this type of reaction, at least three easily accessible components are reacted to form a single product, which incorporates essentially all of the atoms of the starting materials. One-pot MCRs for synthesis of highly substituted imidazoles in the presence of AcOH have been widely reported [17][18][19][20]. However, the use of high temperatures (180qC), expensive instrument likes microwave, 10 equiv. NH 4 OAc, and large excess of AcOH limit this method. We report here a simple and efficient one-pot MCR of 1,2-diphenylethanedione with aldehyde or aldehyde and amine using ammonium acetate as the ammonia source in the presence of acetic acid in refluxing ethanol.Initially, the effect of solvents (10 mL) on the three-component reaction of benzil, benzaldehyde, and NH 4 OAc in the presence of AcOH (10 mmol) was examined. After refluxing for 1 h, we found that the reaction goes well with AcOH-EtOH (64%). Lower yields (< 50%) were obtained in MeOH, MeCN, and EtOAc. No product was obtained in CH 2 Cl 2 , THF, DMF, H 2 O, and EtOH-H 2 O (1:1, v/v) under solvent-free conditions at 80qC. Comparison of different solvents showed that EtOH was the most suitable solvent for the synthesis of 1a, and therefore it was used in all subsequent experiments. The optimal amounts of EtOH and AcOH were found to be 10 mL and 10 mmol, respectively.The optimal conditions were then applied for the preparation of the series of 2,4,5-trisubstituted imidazoles 1a-k (Table 1). Aromatic aldehydes carrying either electron-donating groups or electron-withdrawing groups were all suitable for this modified procedure. The position of the substituents on the aromatic ring of aldehydes has no obvious effects on the formation of the final product. Heteroaromatic aldehyde and aliphatic aldehyde afforded the corresponding trisubstituted imidazoles in moderate yields. In all cases, the reactions were clean and no side products were detected.

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Practical synthesis and regioselective alkylation of methyl 4(5)-(pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate to give DuP 532, a potent angiotensin II antagonist

Cited by 46 publications

References 0 publications

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe₂O₃@TiO₂ (γ‐Fe₂O₃@TiO₂‐EG‐Cu(II)): A highly efficient magnetically separable heterogeneous nanocatalyst for one‐pot synthesis of highly substituted imidazoles

A modified procedure for the synthesis of 2,4,5-tri- and 1,2,4,5-tetrasubstituted imidazoles

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Practical synthesis and regioselective alkylation of methyl 4(5)-(pentafluoroethyl)-2-propylimidazole-5(4)-carboxylate to give DuP 532, a potent angiotensin II antagonist

Cited by 46 publications

References 0 publications

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Rational design, efficient syntheses and biological evaluation of N , N ′-symmetrically bis-substituted butylimidazole analogs as a new class of potent Angiotensin II receptor blockers

Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe2O3@TiO2 (γ‐Fe2O3@TiO2‐EG‐Cu(II)): A highly efficient magnetically separable heterogeneous nanocatalyst for one‐pot synthesis of highly substituted imidazoles

A modified procedure for the synthesis of 2,4,5-tri- and 1,2,4,5-tetrasubstituted imidazoles

Contact Info

Product

Resources

About

Cu(II) immobilized on guanidinated epibromohydrin‐functionalized γ‐Fe₂O₃@TiO₂ (γ‐Fe₂O₃@TiO₂‐EG‐Cu(II)): A highly efficient magnetically separable heterogeneous nanocatalyst for one‐pot synthesis of highly substituted imidazoles