Patent DE-19962936-A1 (DE)
Title: New beta-aminoacid amide derivatives, are integrin antagonists useful for treating inflammatory, autoimmune or immunological disorders e.g. asthma, diabetes or rheumatoid arthritis
Inventor: ALBERS MARKUS
IPC: A61K31/445
Filed: 1999-12-24
Abstract: N,N'-Disubstituted  beta -aminoacid amide derivatives (I) are new. beta -Aminoacid derivatives of formula (I) and their salts are new. R1 - R5, R7-R9 = H, 1-10C alkyl, 2-10C alkenyl, 6C or 10C aryl, 3-7C cycloalkyl or Het1; Het1 = 4-9 membered saturated or unsaturated heterocyclyl containing 1 or 2 of O, S and N heteroatom(s), optionally substituted by 1-3 R10 and additionally optionally monosubstituted by 3-7C cycloalkyl, 6C or 10C aryl, 4-9C heteroaryl or Het2; Het2 = 4-9 membered heterocyclyl containing 1 or 2 of O, S and N as heteroatom(s), optionally substituted by 1-3 R10; R10 = T, CF3, OCF3, OR11, SR11, NR13R14, COR11, SOR11, SO2R11, COOR11, OCOR11, CONR13R14, NR11COR11, SO2NR13R14, NR11SO2R11, NR11CONR13R14, NR11COOR11, OCONR13R14, halo, CN, NO2 or =O; T = 1-4C alkyl; R11 = H, T, 3-6C cycloalkyl or 6C or 10C aryl (optionally substituted (os) by T, OT, Ph, 3-6C cycloalkyl, halo, NO2 or CN); R13, R14 = H, T, 3-6C cycloalkyl or 6C or 10C aryl, or NR13R14 = 4-7 membered heterocyclyl, optionally containing 1 or 2 additional O, S or N heteroatoms and/or 1 or 2 double bonds; R6 = H, 1-10C alkyl, 2-10C alkenyl, 6C or 10C aryl, 3-7C cycloalkyl or Het3; Het3 = 4-9 membered saturated or unsaturated heterocyclyl containing 1 or 2 of O, S and N heteroatom(s), os by 1-3 R31 and additionally os by one of 3-7C cycloalkyl, 6C or 10C aryl, 4-9C heteroaryl or Het4; Het4 = 4-9 membered heterocyclyl containing 1 or 2 of O, S and N heteroatom(s), os by 1-3 R10 or fused to benzo; R31 = T, CF3, OCF3, OR32, SR32, NR33R34, COR32, SOR32, SO2R32, COOR32, OCOR32, CONR33R34, NR32COR32, SO2NR33R34, NR32SO2R32, NR32CONR33R34, NR32COR32, OCONR33R34, halo, CN, NO2 or =O; R32 = H, T, 3-6C cycloalkyl or 6C or 10C aryl (os by 1-3 of T, 1-4C alkoxy, Ph, 3-6C cycloalkyl, halo, NO2 or CN); R33, R34 = H, T, 3-6C cycloalkyl, 6C or 10C aryl or Het5, or NR33R34 = 4-7 membered heterocycle, optionally containing 1 or 2 additional O, S or N heteroatoms and/or 1 or 2 double bonds and os by 1 or 2 of T, Ph, benzyl, 3-7C cycloalkyl, OT, halo, NO2, CN or =O; Het5 = 4-9 membered saturated or unsaturated heterocyclyl containing 1 or 2 of O, S and N as heteroatom(s), os by 1 or 2 of T, Ph, 3-7C cycloalkyl, OT, halo, NO2 or CN, or R1 + R2, R4 + R2 or R6 + R12  = a group completing a 4-7 membered heterocycle, optionally containing 1 or 2 additional O, S or N heteroatoms and/or 1 or 2 double bonds, optionally substituted by 1 or 2 of T, Ph, benzyl, 3-7C cycloalkyl, OT, halo, NO2, CN or =O and optionally fused with a 3-7 membered homocyclic or heterocyclic, saturated or unsaturated ring, or R1 + R4, R1 + R5 or R3 + R4  = a group completing a 4-7 membered ring, optionally containing 1 or 2 O, S or N heteroatoms and/or 1 or 2 double bonds, optionally substituted by 1 or 2 of T, Ph, benzyl, 3-7C cycloalkyl, OT, halo, NO2, CN or =O and optionally fused with a 3-7 membered homocyclic or heterocyclic, saturated or unsaturated ring; A = (i) C(O), C(O)-C(O)-, C(S), SO, SO2, PO, PO2, 2- or 4-pyrimidyl, 2-pyridyl, 2- or 4-imidazolyl or 2-benzimidazolyl; or (ii) 4- or 5-(X)-thiazol-2-yl, 4- or 5-(X)-oxazol-2-yl, 4- or 5-(X)-pyrazol-3-yl, 4- or 5-(X)-isothiazol-3-yl, 4- or 5-(X)-isoxazol-3-yl, 5-(X)-4H-1,2,4-triazol-3-yl, 5-(X)-1,3,4-thiadiazol-2-yl, 5-(X)-1,3,4-oxadiazol-2-yl, 3-(X)-1,2,4-thiadiazol-5-yl, 3-(X)-1,3,4-oxadiazol-5-yl, 5-(X)-1,2,4-thiadiazol-3-yl, 5-(X)-1,3,4-oxadiazol-3-yl, 4- or 5-(X)-4,5-dihydrothiazol-2-yl, 4- or 5-(X)-4,5-dihydroimidazol-2-yl, 4-, 5-,6- or 7-benzothiazol-2-yl, 4-, 5-,6- or 7-benzoxazol-2-yl, 3-, 5- or 6-(X)-pyrazin-2-yl or 4-, 5- or 6-(X)-pyridazin-3-yl (all os in the ring by T, OT, halo, NO2 or CN); X = a direct bond, O or NR12; R12 = H, T, 2-4C alkenyl, 2-4C alkynyl (os by Ph) or group forming a ring with R6 (as described above); Y = O or S; Z' = COOR47, CONR48R49, SO2NR48R49, SO(OR47), SO2(OR47), P(O)R47(OR49), P(O)(OR47)(OR49) or 5-tetrazolyl; R48 = COR50 or SO2R50; R50 = T, 2-6C alkenyl, 2-6C alkynyl, 3-6C cycloalkyl or 6C or 10C aryl (os by 1-3 of halo, NO2 or CN), and R47, R49 = H, polymeric resin, T, 2-6C alkenyl, 2-6C alkynyl, 3-6C cycloalkyl or 6C or 10C aryl (os by 1-3 of T, OT, halo, NO2 or CN).