Synthesis of Drug-like Polycyclic Compounds with known Pharmacological Activities

The Hantzsch reaction is known for more than 100 years. Medicinal chemists have used this reaction to gain easy access to very important heterocyclic scaffolds such as 1,4-Dihydropyridines and Pyrroles. Several 1,4-Dihydropyridine molecules are potent blockers of calcium channels as well as activators of potassium channels. The specific activities are reflected by different substitution patterns. Moreover, 2-heteroaryl-pyrrolopyridinones are potent Cdc7 kinase inhibitors. The same scaffold has also been used for the preparation of MK2 kinase inhibitors. We have developed a two-step synthesis towards Naphthyridines and Aza-Indoles. Our strategy relies on treating the appropriate Hantsczh reaction product, 1,4-Dihydropyridine or pyrrolopyridinone with N-Bromosuccinimide in DMF at ambient temperature. The scope of this unprecedented oxidation reaction has been studied. We have shown that many different 1,4-dihydropyridopyridinones as well as many pyrrolopyridinones can undergo this novel oxidation reaction. As a result, we are able to introduce more structural diversity into these scaffolds with proven pharmacological activity. For instance, one of the analogs made is a very potent potassium channel activator. In conclusion, the combination of a known multicomponent condensation reaction with our novel oxidation reaction provides an efficient synthetic route for the production of interesting drug-like polycyclic heterocyclic compounds. It consists an example of Diversity Oriented Synthesis for the production of analogs around scaffolds with known pharmacological activities.