Cathepsin and methods and compositions for inhibition thereof

A method of inhibiting .beta.-amyloid peptide production in cells producing .beta.-amyloid peptide, comprising administering to such cells an inhibitory amount of a compound of formula I:

• ##STR51## wherein:
• R is selected from the group consisting hydrogen, alkyl of from 1 to 6 carbon atoms, and where R and R.sup.2 are joined to form a ring structure of from 4 to 10 carbon atoms,
• R' is selected from the group consisting hydrogen, alkyl of from 1 to 6 carbon atoms and where R' and R.sup.3 are joined to form a ring structure of from 4 to 10 carbon atoms,
• R.sup.1 is selected from the group consisting of
• alkyl of from 1 to 4 carbon atoms substituted with 1 substituent selected from the group consisting of (a) aryl of from 6 to 10 carbon atoms, (b) aryl of from 6 to 10 carbon atoms substituted with 1 to 3 substituents selected from the group consisting of alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms, alkoxy of from 1 to 6 carbon atoms, aryloxy of from 6 to 10 carbon atoms, hydroxy, cyano, halo and amino, (c) cycloalkyl of from 3 to 8 carbon atoms and (d) heterocycles of from 3 to 14 carbon atoms having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur
• wherein said substituted alkyl group is optionally further substituted with from 1 to 2 hydroxyl groups,
• aryl of from 6 to 10 carbon atoms,
• aryl of from 6 to 10 carbon atoms substituted with 1 to 3 substituents selected from the group consisting of alkyl of from 1 to 6 carbon atoms, aryl of from 6 to 10 carbon atoms, alkoxy of from 1 to 6 carbon atoms, aryloxy of from 6 to 10 carbon atoms, hydroxy, cyano, halo and amino,
• heterocycles of from 3 to 14 carbon atoms having from 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;
• R.sup.2 and R.sup.3 arc independently D- or L-amino acid side chains of at least 2 carbon atoms with the proviso that said amino acid side chains do not include the proline side chain;
• R.sup.4 is selected from the group consisting of
• --C(O)R.sup.5 where R.sup.5 is hydrogen, alkyl of from 1 to 6 carbon atoms, and haloalkyl of from 1 to 6 carbon atoms and 1 to 2 halo groups;
• X is selected from the group consisting of --O--, --NR.sup.9 --, and --S-- where R.sup.9 is selected from the group consisting of hydrogen, alkyl of from 1 to 6 carbon atoms and aryl of from 6 to 10 carbon atoms;
• Y is selected from the group consisting of --C(O)-- and --C(S)--;
• m is equal to zero or one;
• and
• n is equal to zero to two,
• or pharmaceutically acceptable salts thereof with the proviso that when R.sup.1 is 1-naphthyl, R.sup.2 is --CH(CH.sub.2).sub.2 (L-isomer), R.sup.3 is --CH.sub.2 .phi. (L-isomer), Y is --C(O)--, m is zero and n is one, then R.sup.4 is not --N(CH.sub.3)OCH.sub.3, with the further proviso that when R.sup.1 is diphenylmethyl, R.sup.2 is p-(benzyloxy)benzyl (L-isomer), Y is --C(O)--and m and n are zero, then R.sup.4 is not --N(CH.sub.3)OCH.sub.3, and with still the further proviso that when R.sup.1 is (1,2-diphenyl)ethenyl, Y is --C(O)--, R.sup.2 is --CH.sub.2 .phi. (L-isomer), and m and n are zero, the R.sup.4 is not --N(CH.sub.3)OCH.sub.3.