THE SYNTHESIS OF POTENT MACROCYCLIC RENIN INHIBITORS

An efficient synthesis of a novel class of potent macrocyclic renin inhibitors exemplified by compounds 1 and 2, which involves the macrocyclization of 8 to 9 as the key step, is described. The macrocyclic design of renin inhibitors 1 and 2 disclosed here incorporates (2R,3S)-3-amino-4-cyclohexyl-2-hydroxybutanoic acid (norACHPA) as the transition-state isostere. Determination of stereochemistry of the substituent R (morpholinomethyl) at P2' position of the more potent diastereomer of the 13- membered cyclic renin inhibitors 1, 2, and 9 is presented.