Dual alanylaminopeptidase and dipeptidylpeptidase IV inhibitors that functionally affect different cells and treat immune diseases, inflammatory diseases, neurological diseases, and other diseases

摘要

Acrylic acid derivatives (C1), hydrazones (C2), imines (C3), bicyclic compounds (C4), hydrazine or azo compounds (C5), hexafluoropropane derivatives (C6), amino acids (C7), heterocyclic compounds (C8), alkenyl cyclic compounds (C9), bicyclic compounds (C10), pyridine, pyrimidine, pyridazine or triazine derivatives (C11), cyclic imides (C12), carbonate-type compounds (C13), sulfone-type compounds (C14), heterocyclic compounds (C15) and thiazolidinone derivatives (C16) are used in medicine. [Image] Definitions for C1-C3: X', Z' : OH, SH, 1-12C alkoxy, 1-12C alkylthio, optionally substituted (hetero)aryl or (hetero)cycloalkyl, NH 2, NHR 2 or NR 2R 3; Y' : O, S or NR4; R 1-R 4Q'; Q' : H; optionally substituted 1-12C alkyl, 2-12C alkenyl or 2-12C alkynyl; OH, SH, 1-12C alkoxy or 1-12C alkylthio; or optionally substituted (hetero)aryl, (hetero)cycloalkyl, amino, carbonyl, thiocarbonyl or imino. Definitions for C4: X 1-X 4CH or CR 3; Y 1-Y 3optionally substituted C, N, O or P; R 11-4 of Q'; R 21-6 of Q'; R 3 is not defined. Definitions for C5: Y' : O, S, NH or NR5; R 1-R 5Q'. Definitions for C6: Y' : O, S, NH or NR 1; X', Z' : OH, SH, 1-8C alkoxy, 1-8C alkylthio, optionally substituted (hetero)aryl or (hetero)cycloalkyl, NH 2, NHR 2 or NR 2R 3; R 1-R 3Q'. Definitions for C7: Y' : O, S, NH or NR 4; X', Z' : OH, SH, 1-8C alkoxy, 1-8C alkylthio, optionally substituted (hetero)aryl or (hetero)cycloalkyl, NH 2, NHR 5 or NR 5R 6; R 1-R 6Q'. Definitions for C8: X' : an N, O, S or P heteroatom or a functional group containing this heteroatom as a ring atom; R 11-10 of Q'; the 6-membered ring can contain 1-3 further heteroatoms and 0-3 double bonds. Definitions for C9: X 1CH 2, CHR 3, CR 3R 4, NH, NR 4, O or S; X 2-X 4CH, CR 5 or N; R 1-R 5Q'. Definitions for C10: X', Z' : CH, CR 1 or N, at least one being N; R 1Q'; the rings are optionally substituted, optionally fused, contain 0-3 double bonds and can contain further N atoms. Definitions for C11: R 11-5 of Q'. Definitions for C12: Y1', Y2' : O, S, NH or NR 6; R 1-R 6Q'. Definitions for C13: X', Z' : OH, SH, 1-8C alkoxy, 1-8C alkylthio, optionally substituted (hetero)aryl or (hetero)cycloalkyl, NH 2, NHR 1 or NR 1R 2; Y' : O, S, NH or NR 3; R 1-R 3Q'. Definitions for C14: Y 1, Y 2O, S, NH or NR 3; R 1-R 3Q'. Definitions for C15: X' : O, S, NH or NR 9; R 1-R 9Q'. Definitions for C16: R 1-R 5H, Me, CH 2R 6, CHR 6R 7, CR 6R 7R 8, OH, OR 6, NH 2, NHR 6, NR 6R 7, COR 6, C(NH)R 6, C(NR 7)R 6, CSR 6, PH 2, PHR 6, PR 6R 7, PO(OH) 2, PO(OH)(OR 6), PO(OR 6)(OR 7) or CN; A', Y', Z' : CH 2, CHR 9, CR 9R 10, CO, CS, C(NH), C(NR 9), NH, NR 9, NOH, NOR 9, O, S, SO 2, PH, PR 9, P(O)OH, P(O)OR 9, P(OH) 3, P(OH) 2OR 9, P(OH)(OR 9)(OR 10), P(OR 9)(OR 10)(OR 11); X' : N, CH, CR 12, P, PO, P(OH) 2, P(OH)(OR 12) or P(OR 12)(OR 13); R 6-R 13Q'. ACTIVITY : Immunosuppressive; Antiinflammatory; Neuroprotective; Antiulcer; Antiarthritic; Antidiabetic; Antiallergic; Antiasthmatic; Dermatological; Antipsoriatic; Antiseborrheic; Nootropic; Antiparkinsonian; Anticonvulsant; Antibacterial; Antiarteriosclerotic; Vasotropic. MECHANISM OF ACTION : Alanyl aminopeptidase (APN) inhibitor; Dipeptidyl peptidase IV (DPIV) inhibitor. N-(1-(4-methyl-1-piperidinylcarbonyl)-2-(2-furyl)vinyl)-4-chlorobenzamide had an IC50 of 18.5 mu M against DPIV and 6.2 mu M against APN.