alpha,alpha-Difluoro-beta-aminodeoxystatine-containing renin inhibitory peptides.
The preparations of sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(S)- and -3(R)-[(4-methoxyphenyl)amino]-6-methylheptanoates (7a and 7b) from sodium 4(S)-[(tert-butyloxycarbonyl)amino]-2,2-difluoro-3(R)- and -3(S)-hydroxy-6-methylheptanoates (1a and 1b) are described. The key step involves the stereospecific intramolecular displacement via a Mitsunobu reaction for the conversion of a beta-hydroxy hydroxamate to a beta-lactam ring. Compounds 7a and 7b are useful as synthetic intermediates for the preparation of enzyme inhibitors that contain 3(S),4(S)- and 3(R),4(S)-diamino-2,2-difluoro-6-methylheptanoic acid inserts. Angiotensinogen analogues VII and VIII that contain these novel amino analogues of difluorostatine were shown to be inhibitors of the enzyme renin. The alpha,alpha-difluoro-beta-aminodeoxystatine-containing compounds were shown to be weaker inhibitors than the corresponding difluorostatine-containing congeners.
Thaisrivongs
S
S
Cardiovascular Diseases Research, Upjohn Company, Kalamazoo, Michigan 49001.
Schostarez
H J
HJ
Pals
D T
DT
Turner
S R
SR
D000596:Amino Acids; D000808:Angiotensinogen / Q000031:analogs & derivatives* / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D013237:Stereoisomerism; D000092502:Renin Inhibitors
D000596:Amino Acids; D000808:Angiotensinogen; D004791:Enzyme Inhibitors; D000092502:Renin Inhibitors; C013165:statine