Patent NZ-335480-A (NZ)
Title: Neurotrophic low molecular weight N-linked sulfonamides of heterocyclic thioesters and their use as inhibitors of immunophilin proteins
Inventor: HAMILTON GREGORY S
IPC: A61K31/40
Filed: 1997-12-22
Abstract: Compounds of formula I have an affinity for FKBP-type immunophilins, and may be used as inhibitors of the enzyme activity associated with immunophilin proteins, particularly peptidyl-prolyl isomerase, or rotamase enzyme activity.  The compounds may be used in medicaments for the stimulation of damaged neurons, promotion of neuronal regeneration, and treatment of neurological disorders such as peripheral neuropathy caused by physical injury or disease state, physical damage to the brain, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders related to neurodegeneration such as Alzheimer's Disease, Parkinson's Disease and amyotrophic lateral sclerosis. In formula I: A and B are taken together, with the nitrogen and carbon atoms to which they are respectfully attached, to form a 5 to 7 membered saturated or unsaturated heterocyclic ring; X is either O or S; Y is a direct bond to Z, or a C1-C6 straight or branched chain alkyl or alkenyl, wherein any of the carbon atoms of said alkyl or alkenyl are optionally substituted in one or more positions with amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is selected from the group consisting of hydrogen, C1-C6-straight or branched chain alkyl, C3-C6-straight or branched chain alkenyl or alkynyl, and C1-C4 bridging alkyl, wherein said bridging alkyl forms a heterocyclic ring starting with the N of NR1 and ending with one of the carbon atoms of said alkyl or alkenyl chain, and wherein said heterocyclic ring is optionally fused to an Ar group; Z is selected from the substituents listed for Y above, C and D are independently hydrogen, Ar, C1-C6 straight or branched chain alkyl or alkenyl, which is optionally substituted in one or more positions with C3-C8 cycloalkyl, C5-C7 cycloalkenyl, hydroxyl, carbonyl oxygen, or Ar, where said alkyl, alkenyl, cycloalkyl or cycloalkenyl groups is optionally substituted with the C1-C6 alkyl, C2-C6 alkenyl, hydroxy, amino, halo, haloalkyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, wherein any of the carbon atoms of the alkyl or alkenyl are optionally substituted with oxygen to form a carbonyl, or wherein any of the carbon atoms of said alkyl or alkenyl are optionally replaced with O, NH, NR2, S, SO, or SO2, wherein R2 is defined above; R1 is selected from the group consisting of Ar, C3-C8 cycloalkyl, C1-C6 straight or branched chain alkyl or alkenyl, which is optionally substituted in one or more positions with Ar, amino, halo, haloalkyl, hydroxy, trifluoromethyl, C1-C6 straight or branched chain alkyl or alkenyl, carbonyl, thiocarbonyl, ester, thioester, alkoxy, alkenoxy, cyano, nitro, imino, alkylamino, aminoalkyl, sulfhydryl, thioalkyl, sulfonyl, or substituted alkyl or alkenyl, wherein any of the carbon atoms of the alkyl or alkenyl are optionally replaced with S, SO, SO2, O or NR2, wherein R2 is defined above; and  wherein Ar is an optionally substituted aryl or heteroaryl moiety.