Several novel analogues of Losartan 2 were synthesized as potential non-peptide angiotensin (II) receptor antagonists. In these non-peptide analogues, the tetrazole and the substituted imidazole rings of Losartan 2 were replaced, respectively, by a carboxylic acid function or its methyl ester and substituted triazole, imidazole or benzimidazole moieties. The biphenyl bromide precursor 3 (BPE) used to introduce the linker between the acid/ester function and the heterocyclic moiety was synthesized using Suzuki biphenyl coupling and then incorporated into the target molecule by simple nucleophilic substitution. The fixed N-aryl isomeric forms of several azole and benzimidazole tautomers were successfully separated by HPLC using 50% aqueous acetonitrile as eluent. Intermediate reaction products and final target compounds were fully characterized spectroscopically.
Diazotization at 0 o C of N-[2-amino-1,2-dicyanovinyl]ethanamide 2aor propanamide 2b prepared from diaminomaleonitrile (DAMN) 1 using aqueous acetic acid and NaNO 2 solution furnished sodium complex 3. The X-ray structure of the complex 3 showed that it is a 1:1 mixture of the neutral 2H-triazole heterocycle 4ii and its anion deprotonated at the central (N) atom of the ring, together with a sodium counter ion and two coordinated water molecules.However, when the diazotization reaction was carried out in the presence of aqueous HCl, the product was 5-cyano-2H-[1,2,3]triazole-4-carboxylic acid amide monohydrate 4ii. Diazotization of DAMN 1 using aqueous HCl furnished 1H-1,2,3-triazole-4,5-dicarbonitrile 5, whereas with acetic acid there was no reaction, and hence no route analogous to that leading to complex 3. The structure of both complex 3 and the triazole monohydrate 4ii were solved using X-ray crystallography, and the compounds under study were fully characterized using spectroscopic techniques.
Antagonists. -Analogues of losartan, the most successful antagonist in antihypertensive therapy, are synthesized by replacing the tetrazole and the imidazole rings with a carboxylic acid function or its methyl ester and substituted triazole, imidazole or benzimidazole moieties. -(AL-AZMI*, A.; GEORGE, P.; EL-DUSOUQUI, O. M. E.; J. Heterocycl. Chem. 44 (2007) 3, 515-520; Dep. Chem., Fac. Sci., Univ. Kuwait, Safat 13060, Kuwait; Eng.) -H. Hoennerscheid 40-220
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