Small molecule inhibitors of rotamase enzyme activity and their use in the treatment of neurological disorders

摘要

The disclosed relates to neurotrophic N-glyoxyl-prolyl ester compounds having an affinity for FKBP-type immunophilins, their preparation and use as inhibitors of the enzyme activity associated with immunophilin proteins, and particularly inhibitors of peptidyl-prolyl isomerase or rotamase enzyme activity. Described is a non-immunosupressive compound of formula (I), wherein: R1 is selected from the group consisting of an optionally substituted C1-C9 straight or branched chain alkyl or alkenyl group, C3 or C5 cycloalkyl, C5-C7 cycloalkenyl, where the alkyl, alkenyl, cycloalkyl, or cycloalkenyl groups may optionally have one or more hydrogen atoms replaced with C1-C4 alkyl, C1-C4 alkenyl or hydroxy, or Ar1, wherein Ar1 is selected from 1-naphthyl, 2-napthyl, 2- indolyl, 3-indolyl, 2-furyl, 3-furyl, 2-thiazolyl, 2- thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkoxy or C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino; X is oxygen, sulphur, methylene, or (CH2), or H2; Y is oxygen or NR2, wherein R2 is hydrogen or C1-C6 alkyl; and Z is C2-C6 straight or branched chain alkyl or alkenyl, wherein the alkyl or alkenyl chain is substituted in one or more positions with Ar1 as defined above, or C3-C8 cycloalkyl; cycloalkyl connected by a C1-C6 straight or branched alkyl or alkenyl chain, or Ar2 where Ar2 is selected from 2-indolyl, 3-indolyl, 2-furyl, 3-furyl, 2- thiazolyl, 2-thienyl, 3-thienyl, 2-, 3-, or 4-pyridyl, and phenyl, having one to three substituents which are independently selected from hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkoxy or C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino.