Synthesis of sterically hindered 3-(azolyl)pyridines
Sergey M. Lukyanov,* Igor V. Bliznets, and Sergey V. Shorshnev
ChemBridge Corporation, Malaya Pirogovskaya 1, 119435 Moscow, Russian Federation
E-mail: semiluk@gmail.com
Dedicated to Professor Alexander F. Pozharskii on his 70th birthday
Abstract
Sterically hindered 2,4-disubstituted 3-(1,2,4-oxadiazol-3-yl)-, 3-(imidazol-2-yl)- and 3-(thiazol-2- yl)pyridines were synthesized from the corresponding nicotinonitriles via amidoximes, amidines and thioamides, respectively. N-Alkyl- and N-arylamidines were prepared directly from nicotinonitriles using microwave technology. The series of 3-(azolyl)pyridines form a combinatorial library of heterocyclic derivatives of nicotinic acid and were examined by prognostic software PASS.
Keywords: Nicotinonitriles, 1,2,4-oxadiazoles, imidazoles, thiazoles, microwave irradiation
Introduction
One of the most promising strategies for searching for new pharmaceuticals and improving the properties of known ones is a replacement of metabolically unstable functional groups with bioisosteric five-membered heterocyclic rings.1,2 The best-known azole that is used as a metabolism-resistant surrogate for the carboxylate group is 5-substituted tetrazole, since they both possess comparable acidity and size.3 Nicotinic acid and its derivatives can be very often found among the carboxylic acids investigated with respect to such replacements.2,4 Thus, 3-(5- tetrazolyl)pyridines were reported as a new class of lipolysis inhibitors5 and bioisosteres of arecoline.2
At the same time, other azoles can also serve as the isosteric equivalents for labile functional groups in the derivatives of nicotinic acid. Thus, 3-(1,3,4-oxadiazol-2-yl)pyridines show antimicrobial and antifungal activity6 and were tested as nonpeptidic inhibitors of human neutrophil elastase.7 The corresponding derivatives of 1,2,4-oxadiazole displayed high affinity and efficacy as muscarinic agonists.8 An antimycobacterial9 as well as an anthelmintic10 activity of pyridines substituted with 1,2,4-oxadiazoles as isosteres of nicotinic acid was described. 3-(Imidazol-2- yl)pyridines are known as inhibitors of xanthine oxidase,11 nonsteroidal antiinflammatory agents,12 potent and selective NPY5 receptor antagonists13 as well as being tested as KDR kinase inhibitors.14 3-(Thiazol-2-yl)pyridines are known as inhibitors of superoxide production by human neutrophils,15
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