6-Substituted 1H-quinolin-2-ones and 2-methoxy-quinolines: synthesis and evaluation as inhibitors of steroid 5alpha reductases types 1 and 2.

A Negishi-type coupling reaction between 6-bromo-2-methoxyquinoline (1a) and various 4-bromo-N,N-dialkyl-benzamides gave access to 6-substituted 2-methoxy-quinolines 1-3 and 1H-quinolin-2-ones 4-12. Most of these compound proved to be inhibitors of steroid 5alpha reductases with activity and selectivity both being strongly dependent on the features of the heterocycle and the size of the N,N-dialkylamide substituent. The most active inhibitor for the human type 2 isozyme was 6-[4-(N,N-diisopropylcarbamoyl)phenyl]-1H-quinolin-2-one 4 (Ki 800 +/- 85 nM), showing mostly competitive inhibitory patterns. A type 1 selective inhibitor could be identified with 6-[4-(N,N-diisopropylcarbamoyl)phenyl]-N-methyl-quinolin-2-one (5, IC50 510 nM).