2-Acyl, N-substituted pyrrolidine derivative inhibitors of rotamase enzyme activity and their use in treating neurological disorders

摘要

Disclosed is the use of a compound of formula (1), wherein: R1 is selected from the group consisting of a C1 -C9 straight or branched chain alkyl or alkenyl group optionally substituted with C3 -C8 cycloalkyl, C3 or C5 cycloalkyl, C5 -C7 cycloalkenyl, where the alkyl, alkenyl, cycloalkyl or cycloalkenyl groups may be optionally substituted with C1 -C4 alkyl, C1 -C4 alkenyl, or hydroxy, or Ar1, where Ar1 is selected from the group consisting of 1-napthyl, 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 the group consisting of 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 selected from the group consisting of oxygen, sulfur, CH2, or H2; Y is selected from the group consisting of oxygen or NR2, where R2 is hydrogen or C1 -C6 alkyl; and Z is selected from the group consisting of C1 -C7 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, C3 -C8 cycloalkyl, cycloalkyl connected by a C1 -C6 straight or unbranched alkyl or alkenyl chain, or Ar2 where Ar2 is selected from the group consisting of 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 the group consisting of hydrogen, halo, hydroxyl, nitro, trifluoromethyl, C1-C6 straight or branched alkyl or alkenyl, C1-C4 alkoxy or C1-C4 alkenyloxy, phenoxy, benzyloxy, and amino; Z may also be the fragment of formula (2), wherein R3 is selected from the group consisting of straight or branched alkyl C1-C8 optionally substituted with C3-C8 cycloalkyl, or Ar1 as defined above, and unsubstituted Ar1; X2 is O or NR5, where R5 is selected from the group consisting of hydrogen, C1-C6 straight or branched alkyl and alkenyl; R4 is selected from the group consisting of phenyl, benzyl, C1-C5 straight or branched alkyl or alkenyl, and C1 -C5 straight or branched alkyl or alkenyl substituted with phenyl. The compound is used in the preparation of a medicament for promoting neuronal growth and regeneration, for treating neurological disorder, for promoting neuroregeneration or for preventing neurodegeneration. Such diseases include Alzheimer's disease, Parkinson's disease and amytrophic lateral sclerosis.