Inhibitors of farnesyl protein transferase. Synthesis and biological activity of amide and cyanoguanidine derivatives containing a 5,11-dihydro[1]benzthiepin, benzoxepin, and benzazepin [4,3-b]pyridine ring system.
Bioisosteric replacement of the C-6 carbon atom in piperidine I and piperazine II with S, O, and N heteroatoms is described. Amide and cyanoguanidine derivatives of these compounds were evaluated in vitro and found to be good inhibitors of farnesyl-protein transferase. An improved method of preparing the 5,11-dihydro-[1]-benzthiepin nucleus 6 was accomplished in high yield and with excellent regioselectivity using an AlCl3 melt protocol.
Wolin
R
R
Schering-Plough Research Institute, Department of Chemistry, Kenilworth, New Jersey 07033, USA.
Connolly
M
M
Kelly
J
J
Weinstein
J
J
Rosenblum
S
S
Afonso
A
A
James
L
L
Kirschmeier
P
P
Bishop
W R
WR
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000577:Amides / Q000737:chemistry*; D001552:Benzazepines / Q000737:chemistry; D001584:Benzoxepins / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006146:Guanidines / Q000737:chemistry*; D008956:Models, Chemical; D010879:Piperazines / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D017368:Protein Prenylation / Q000187:drug effects*; D011725:Pyridines / Q000737:chemistry; D013329:Structure-Activity Relationship
D000577:Amides; D001552:Benzazepines; D001584:Benzoxepins; D004791:Enzyme Inhibitors; D006146:Guanidines; D010879:Piperazines; D010880:Piperidines; D011725:Pyridines; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C004711:dicyandiamido