Patent EA-001481-B1 (EA)
Title: Rotamase enzyme activity inhibitors
Inventor: STEINER JSEPH P
IPC: C07D401/12
Filed: 1996-08-26
Abstract: 1. A use of the compound, represented by the formula   and pharmaceutically acceptable salts thereof, wherein A is CH2, O, NH, or N-(C1-C4-alkyl); wherein B and D are independently Ar, (C5-C7)-cycloalkyl substituted (C1-C6)-straight or branched alkyl or -alkenyl, (C5-C7)-cycloalkenyl substituted (C1-C6)-straight or branched alkyl or -alkenyl, or Ar substituted (C1-C6)-straight or branched alkyl or -alkenyl, wherein in each case, one or two carbon atoms of the straight or branched alkyl or alkenyl groups may be substituted with 1-2 heteroatoms selected from the group consisting of oxygen, sulfur, SO and SO2 in chemically reasonable substitution patterns, or   wherein Q is hydrogen, (C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched alkenyl; wherein T is Ar or substituted 5-7 membered cycloalkyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl or O-(C1-C4)-alkenyl and carbonyl; wherein Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, monocyclic and bicyclic heterocyclic ring systems with individual ring sizes being 5 or 6 which may contain in either or both rings a total of 1-4 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halo atom, hydroxyl, hydroxymethyl, nitro, CF3, (C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched alkenyl, O-(C1-C4)-straight or branched alkyl or O-(C1-C4)-straight or branched alkenyl, O-benzyl, O-phenyl, amino, 1,2-methylenedioxy, carbonyl and phenyl; wherein L is either hydrogen or U; M is either oxygen or CH-U, provided that if L is hydrogen, then M is CH-U, or if M is oxygen then L is U; wherein U is hydrogen, O-(C1-C4)-straight or branched alkyl or O-(C1-C4)-straight or branched alkenyl, (C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or -cycloalkenyl substituted with (C1-C4)-straight or branched alkyl or (C1-C4)-straight or branched alkenyl, 2-indolyl, 3-indolyl, [(C1-C4)-alkyl or (C1-C4)-alkenyl]-Ar or Ar (Ar as described above); wherein J is hydrogen or (C1-C2)-alkyl or benzyl; K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylethyl; or wherein J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain an oxygen (O), sulfur (S), SO or SO2 substituted therein; and wherein n is 0-3; for preparation of medicine to influence the neurologic activity, activation of neuronal regeneration or stimulation of growth of damaged peripheral nerves, wherein said compound has an affinity for FKBP-type immunophilins. 2. A use of the compound, represented by formula:    and pharmaceutically acceptable salts thereof, wherein A is O, NH, or N-(C1-C4)-alkyl; wherein B is hydrogen, CHL-Ar, (C1-C6)-straight or branched alkyl substituted with (C5-C7)-cycloalkyl or -alkenyl, (C1-C6)-straight or branched alkyl substituted with (C5-C7)-cycloalkenyl or -alkenyl or Ar substituted (C1-C6)-alkyl or -alkenyl, or   wherein L and Q are independently hydrogen, (C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched alkenyl; wherein T is Ar or substituted cyclohexyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O-(C1-C4)-alkyl or O-(C1-C4)-alkenyl and carbonyl; wherein Ar is selected from the group consisting of 1-napthyl, 2-napthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl having one to three substituents which are independently selected from the group consisting of hydrogen, halo atom, hydroxyl, nitro, CF3, (C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched alkenyl, O-(C1-C4)-straight or branched alkyl or O-(C1-C4)-straight or branched alkenyl, O-benzyl, O-phenyl, amino and phenyl; wherein D is either hydrogen or U; E is either oxygen or CH-U, provided that if D is hydrogen, then E is CH-U, or if E is oxygen then D is U; wherein U is hydrogen, O-(C1-C4)-straight or branched alkyl or O-(C1-C4)-straight or branched alkenyl, (C1-C6)-straight or branched alkyl or (C1-C6)-straight or branched alkenyl, (C5-C7)-cycloalkyl or (C5-C7)-cycloalkenyl substituted with (C1-C4)-straight or branched alkyl or (C1-C4)-straight or branched alkenyl, 2-indolyl, 3-indolyl, [(C1-C4)-alkyl or (C1-C4)-alkenyl]-Ar or Ar (Ar as described above); wherein J is hydrogen, (C1-C2)-alkyl or benzyl; K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylethyl; or wherein J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain an oxygen (O), sulfur (S), SO or SO2 substituted therein. for preparation of medicine to influence the neurologic activity, activation of neuronal regeneration or stimulation of growth of damaged peripheral nerves, wherein said compound has an affinity for FKBP-type immunophilins. 3. A use in accordance with any of claims 1-2, wherein J is hydrogen, (C1-C2)-alkyl or benzyl; and K is (C1-C4)-straight or branched alkyl, benzyl or cyclohexylethyl; 4. A use in accordance with any of claims 1-2, wherein J and K may be taken together to form a 7-membered heterocyclic ring which may contain an oxygen (O), sulfur (S), SO or SO2 substituted therein. 5. A use in accordance with claim 1, wherein A represents O, B represents 3-(3-phenyl)propyl, D represents 3-(3-pyridyl)propyl, n is 0, J and K taken together with N-C form pyrrolidine, M represents oxygen, and L is 3,4,5,-trimethoxyphenyl. 6. A use in accordance with any of claims 1-5 for preparation of medicine for stimulation of growth of damaged peripheral nerves. 7. A use in accordance with any of claims 1-5 for preparation of medicine for promotion of neuronal regeneration and growth. 8. A use in accordance with any of claims 1-5 for preparation of medicine for prevention of neurodegeneration. 9. A use in accordance with claims 1-8 wherein said compound is administered to an animal in combination with an effective amount of additional neurotrophic factor selected from the group consisting of neurotrophic growth factor, brain derived growth factor, glial derived growth factor, cilial neurotrophic factor, and neurotropin-3. 10. A use in accordance with claims 1-9 wherein said compound is immunosuppressive. 11. A use in accordance with claims 1-10 wherein the neuronal activity is selected from the group consisting of stimulation of damaged neurons, promotion of neuronal regeneration, prevention of neurodegeneration and treatment of neurological disorders. 12. A use in accordance with claim 11 wherein the neurological disorder is selected from the group consisting of peripheral neuropathies caused by physical injury or disease state, physical damage to the spinal cord, stroke associated with brain damage, and neurological disorders relating to neurodegeneration. 13. A use in accordance with claim 12 wherein the neurological disorder is selected from the group consisting of Alzheimer's Disease and Parkinson's Disease. 14. A use in accordance with claims 1-9 wherein said compound is non-immunosuppressive.