Syntheses of fused heterocyclic compounds and their inhibitory activities for squalene synthase

A variety of fused heterocyclic compounds (2-11) were synthesized as a modification of the lead compound la and evaluated for their inhibition of squalene synthase. 4,1-Benzothiazepine derivative 2. 1,4-benzodiazepine derivative 6, 1.3-benzodiazepine derivative 7, 1-benzazepine derivative 9. and 4,1-benzoxazocine derivative 10 potently inhibited squalene synthase activity, whereas the 4,1-benzoxazepine derivatives I was the most potent inhibitor. 4,1-Benzothiazepine S'-oxide derivative 4. 1,4-benzodiazepine derivative 5, 1,3,4-benzotriazepine derivatives 8, and 1,2,3,4-tetrahydroquinoline derivative 11 were found to be weakly active. Comparison of the X-ray structures of these compounds (1a, 2, 4, 5, 7 and 10) suggests that orientation of the 5- (or 6)-phenyl group is important for activity. (C) 2001 Elsevier Science Ltd. All rights reserved.