G. Srinivasulu, Ρ. P. Reddy,, Pragathi Hegde
2005
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0
Influential Citations
4
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Journal
Heterocyclic Communications
Abstract
New Cinitapride related benzimidazole derivatives are prepared from the condensation of corresponding diamines with carboxylic acids. Their anti-ulcerative activity is studied. 4-Amino-N-[l-(3-cyclohexen-l-ylmethyl)-4-piperidyl]-2-ethoxy-5-nitro benzamide (+)-tartarate (Cinitapride hydrogen tartrate) is a prokinetic benzamide derivative, a simulating gastrointestinal motility agent and is a commercially successful anti-ulcerative drug substance. Reported general method for the preparation of this compound involved condensation of 4-amino-2-ethoxy-5-nitrobenzoic acid with 4-amino-l-(3-cyclohexen-lylmethyl)piperidine in the presence of triethylamine and ethyl chloroformate and subsequent salt formation with L(+) tartaric acid. Benzimidazole moiety is the common pharmocophore of potential proton pump inhibitors (anti ulcerative agents) such as Omeprazole, Pantoprazole, Lansoprazole and Rabeprazole. We have surmised that, incorporation of benzimidazole moiety into Cinitapride skeleton will have marked effect on the activity. With this objective, we have prepared various new benzimidazole derivatives and studied their anti ulcer activity. 4, 5-Diamino-N-(piperidin-4-yl)benzamide derivatives (2a/2b) are identified as apt starting materials for our desired compounds. These diamines 2a/2b are readily accessed from the catalytic hydrogenation of corresponding 4-amino-N-[lH~4-piperidinyl]-2-ethoxy-5nitrobenzamide derivatives (la/lb). '•'Address for corresponding Vol. 11, No. I. 2005 Synthesis and biological activity study of cinitapride related compounds As anti-ulcer at ive drug candidates As a representive example, 2a was refluxed in formic acid and usual workup afforded a crystalline compound, characterised as 3a. The reaction was extended to other carboxylic acids such as acetic acid, α-hydroxy propionic acid and butyric acid. In all the cases, corresponding benzimidazole derivative was obtained in quantitative yields. Piperidine nitrogen substituted diamine 2b also furnished the corresponding benzimidazole derivatives 3 on reacting with carboxylic acids. SCHEME Ο