Current Organic Chemistry - Volume 4, Issue 7, 2000

The 4-(phenylamino)pyrimidine pharmacophore is found in a variety of different compounds that function as ATP-competitive inhibitors of several important protein kinase enzymes. Specific inhibitors of the epidermal growth factor receptor (EGFR) tyrosine kinase have received the most attention, and several elaborations of the fundamental 4-(phenyl­amino)­­pyrimidine pharma­co­phore have now been reported as potent and selective inhibitors of this class of enzyme. Three separate pharmaceutical companies have now entered quinazoline EGFR inhibitors into clinical trials for the treatment of cancer, demonstrating the competitive nature of this area. Recent work with vascular endothelial growth factor (VEGF) and cyclin-dependent kinase (CDK) inhibitors has shown that the field is still expanding, and will undoubtably continue to show potential for some time to come. This review article concentrates on the synthetic approaches and chemical procedures that have been used for the production of these novel pharmaceutical agents.

N-alkyl-1,2-benzenediamines, 4-substituted-3-nitro-1,2-benzenediamines and 3,4-diamino-2-nitrophenols are readily obtained by deselenation of alkyl quaternary salts of 2,1,3-benzoselenadiazoles (bsd) and 5-substituted-4-nitro-bsd. The latter are easily obtained by nitration of 5-X-bsd (X = Me, Br, Cl, F, OMe, NHMe). Nitration of 5-fluoro-bsd yields the 4-nitro derivatives that are accompanied by substantial amounts of the corresponding 4-nitro-bsd-5-ols. ipso-Nitration of 5-fluoro-4-methyl-bsd is followed by instantaneous hydrolysis to (±)-4-methyl-4-nitro-bsd-5(4H)-one. Batcho-Leimgruber indole synthesis on 5-methyl-4-nitro-bsd followed by reductive deselenation of 1,2,5-selenadiazolo[3,4-g]indole affords 6,7-diaminoindole. Cyclocondensation of 3-nitro-1,2-benzenediamines with acetylacetone provides a convenient route for the preparation of 2-methyl-4-nitrobenzimidazoles. Less-accessible 6-halo-5-nitro- and 6-methoxy-5-nitroquinoxalines are efficiently synthesized by regioselective condensation of a-dicarbonyls with 4-halo- and 4-methoxy-3-nitro-1,2-benzenediamines. The reactive halogen atom or methoxyl group ortho to the nitro substituent renders these quinoxalines versatile intermediates to further heterocycles. The 77Se, 13C and 1H NMR chemical shifts of sixteen bsd derivatives, and the 13C NMR chemical shifts of eight derivatives of 2-methylquinoxalines are presented.

This article presents a comprehensive review of synthetically useful intramolecular annulation reactions of nitrene and nitrenoid intermediates leading to heterocyclic compounds. Thermal, photochemical, and metal mediated reactions of aryl- and vinylazides, azirines, nitroso, and nitro compounds leading to synthetically useful yields of heterocycles are discussed.

The structures, origins, biogenesis, synthesis and bioactivity of a selection of N-heterocyclic marine alkaloids are reviewed. The emphasis is on compounds poised as potential anticancer drugs: lamellarins (pyrroles), cephalostatins/ritterazines (pyrazines) and ecteinascidins (isoquinolines). Also discussed are examples of bioactive marine alkaloids that have emerged as novel leads. These include manzamines (beta-carbolines), variolins (pyridopyrrolopyrimidines) and the pyrroloquinoline family. This review emphasises the role of marine alkaloids as an important source of leads for drug discovery.