MACROCYCLIC COMPOUNDS HAVING ASPARTIC PROTEASE INHIBITING ACTIVITY AND PHARMACEUTICAL USES THEREOF.

摘要

The present invention relates to macrocyclic compounds of formula (I), wherein R1, is (C1-8)alkyl, (C1-4)alkoxy(C1-4)alkyl, hydroxy(C1-6)alkyl, (C1-4)alkylthio(C1-4)alkyl, (C1-6)alkenyl, (C3- -7)cycloalkyl, (C3-7)cycloalkyl(C1-4)alkyl, piperidinyl or pyrrolidinyl, R2 and R4, independently, are hydrogen or optionally substituted (C1-8)alkyl, (C3-7) cycloalkyl, (C3-7)cycloalkyl(C1-4)alkyl, aryl, aryl(C1-4)alkyl, heteroaryl or heteroaryl(C1-4) alkyl, or R2 and R4, together with the nitrogen to which they are attached, form an optionally substituted piperidino, pyrrolidinyl, morpholino or piperazinyl group, R3 is hydrogen or (C1-4)alkyl, X1 is CH2, X2 is CH2, O, S, CO, COO, OCO, NHCO, CONH, or NR, R being hydrogen or (C1-4)alkyl, Y is (C1-8)alkylen or (C1- -8)alkylenoxy(C1-6)alkylen, (C1-8)alkenylen or (C1-8)alkenylenoxy(C1-6)alkylen, Ar is a phenyl ring optionally mono- di - or trisubstituted by, independently, hydroxy or halogen, whereby X1, and X2 are in meta or para position to each other, and either Z is CO, AA is a natural or unnatural alpha-amino-acid, and n is 0 or 1, or Z is S02, AA is an optionally substituted ethylencarbonyl group (derived from a natural or unnatural alpha-amino acid by replacement of the nitrogen by a methylen group), and n is 1; processes for the preparation of these compounds; pharmaceutical compositions and combinations comprising the same; and their use in the treatment of neurological and vascular disorders related to beta-amyloid generation and/or aggregation.