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

A Negishi-type coupling reaction between 6-bromo-2-methoxyquinoline (la) an d various 4-bromo-N,N-dialkyl-benzamides gave access to 6-substituted 2-met hoxy-quinolines 1-3 and 1H-quinolin-2-ones 4-12. Most of these compound pro ved to be inhibitors of steroid 5a reductases with activity and selectivity both being strongly dependent on the features of the heterocycle and the s ize 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 (K-i 800 +/- 85 nM), showing mostly competitive inhibitory pattern s. A type 1 selective inhibitor could be identified with 6-[4-(N,N-diisopro pylcarbamoyl)phenyl]-N (5, IC50 510 nM). (C) 2000 Editions scientifiques et medicales Elsevier SAS.