Patent DE-19821483-A1 (DE)
Title: New imidazolidine derivatives useful as leukocyte adhesion and migration inhibitors and/or VLA-4 receptor antagonists for treating E.G. inflammatory and allergic disorders
Inventor: NEISES BERNHARD
IPC: A61K31/4166
Filed: 1998-05-14
Abstract: Imidazolidine amide derivatives (I) are new. Imidazolidine derivatives of formula (I) and their stereoisomers and salts are new: W = C(R13)A-R1, C=C(R13)A-R1 or a group of formula (i) or (ii) in which the ring system can contain 1-2 heteroatoms selected from N, O and S, can be saturated or mono- or polyunsaturated and can be substituted by 1-3 R13 groups and/or 1-2 oxo and/or thione groups: L = CR13 or N; m1, m2 = 0-6 and m1+m2 = 1-6; asterisk  = attachment points; Y = C=O, C=S or CH2; A = a bond, 1-6C alkylene, 3-7C cycloalkylene, phenylene, phenylene(1-6C)alkylene or phenylene(2-6C)alkenylene (with phenyl attached to R1) or 5-6 membered (un)saturated heterocyclylene that can contain 1-2 N atoms and can be mono- or disubstituted by 1-6C alkyl, oxo or thione; B' = 1-6C alkylene, 2-6C alkenylene, phenylene, phenylene(1-3C)alkylene, (1-3C)alkylenephenylene or (1-3C)alkylenephenylene(1-3C)alkylene, where the 1-6C alkylene and 2-6C alkenylene groups are optionally substituted by 1-8C alkyl, 2-8C alkenyl, 2-8C alkynyl, 3-10C cycloalkyl, (3-10C)cycloalkyl(1-6C)alkyl and optionally ring-substituted 6-14C aryl, (6-14C)aryl(1-6C)alkyl, heteroaryl and heteroaryl(1-6C)alkyl; E = tetrazolyl, P(O)(OR8)2, SO3R10, COR6, COR7 or COR10; R = H, 1-8C alkyl, 3-12C cycloalkyl, (3-12C)cycloalkyl(1-8C)alkyl or optionally ring-substituted 6-14C aryl, (6-14C)aryl(1-8C)alkyl, heteroaryl or heteroaryl(1-8C)alkyl; R1 = H, 1-10C alkyl (optionally fluorinated), 3-12C cycloalkyl, (3-12C)cycloalkyl(1-8C)alkyl, optionally ring-substituted R21(6-14C)aryl or R21(6-14C)aryl(1-8C)alkyl, Het, Het(1-8C)alkyl, -R20-C(NH)-NHX, -R20-NHX1, -R20-OR21, -R20-N(R21)2, COR21, COOR21, CONR21R22, N(R21)COR22, =NOR21, =O or =S; X = H, 1-6C alkyl, 2-7C alkanoyl, 2-7C alkoxycarbony, (2-11C)alkanoyloxy(2-7C)alkoxycarbonyl, CN, OH, 1-6C alkoxy, NH2, or optionally ring-substituted 7-15C aroyl, 7-15C aryloxycarbonyl, (6-14C)aryl(2-7C)alkoxycarbonyl or (6-14C)aryl(1-6C)alkoxy; X1 = X or C(NR)NHR'; R', R = X; R2 = H, 1-8C alkyl, 3-8C cycloalkyl or optionally ring-substituted 6-14C aryl or (6-14C)aryl(1-8C)alkyl; R3 = H, 1-8C alkyl, 3-8C cycloalkyl, (3-8C)cycloalkyl(1-8C)alkyl, (6-12C)bicycloalkyl, (6-12C)bicycloalkyl(1-8C)alkyl, (6-12C)tricycloalkyl, (6-12C)tricycloalkyl(1-8C)alkyl, 2-8C alkenyl, 2-8C alkynyl, NHR11, CON(Me)R4, CONHR4, COOR21, COOR15, CON(Me)R15, CONHR15, or optionally ring-substituted 6-14C aryl, (6-14C)aryl(1-6C)alkyl, heteroaryl or heteroaryl(1-6C)alkyl; R4 = H or 1-10C alkyl optionally substituted by OH, 1-8C alkoxy, R5, optionally substituted 3-8C cycloalkyl, COOH, CONH2, mono- or di(1-10C alkyl)carbamoyl, optionally ring-substituted (6-14C)aryl(2-7C)alkoxycarbonyl, COR6, COR7, tetrazolyl and/or CF3; R5 = optionally ring-substituted 6-14C aryl, (6-14C)aryl(1-8C)alkyl or heterocyclyl (mono- or bicyclic, 5-12 membered, aromatic, unsaturated or saturated, with 1-3 heteroatoms selected from N, O and S); R6 = the residue of an amino acid, imino acid, azaamino acid (optionally N-substituted by 1-8C alkyl or optionally ring-substituted (6-14C)aryl(1-8C)alkyl) or di-, tri- or tetrapeptide, optionally in ester or amide form and optionally protected, the amide nitrogen of COR6 being optionally substituted by R; R7 = N-bonded, 5-10 membered, saturated, mono- or polycyclic heterocyclyl that can contain 1-4 additional heteroatoms selected from O, N and S and can be C-substituted and can be substituted on an additional N atom by H, Rh, CHO, CORh, COORh, or 1-4C alkyl substituted by COOH or COORh; Rh = 1-8C alkyl, 3-8C cycloalkyl or optionally ring-substituted 6-14C aryl or (6-14C)aryl(1-8C)alkyl; R8 = H, 1-10C alkyl or optionally ring-substituted 6-14C aryl or (6-14C)aryl(1-8C)alkyl; R9 = H, CONH2, (1-10C alkyl)carbamoyl, (3-8C cycloalkyl)carbamoyl, 1-10C alkyl, 3-8C cycloalkyl or optionally ring-substituted 6-14C aryl or (6-14C aryl)carbamoyl; R10 = OH, 1-10C alkoxy, (2-9C)alkanoyloxy(1-6C)alkoxy, NH2, mono- or di(1-10C alkyl)amino or optionally ring-substituted (6-14C)aryl(1-8C)alkoxy, 6-14C aryloxy or (6-14C aryl)carbonyloxy(1-6C)alkoxy; R11 = H, R12a, COR12a, CHO, COOR12a, COR12b, CSR12b, SO2R12a or SO2R12b; R12a = 1-10C alkyl, 2-8C alkenyl, 2-8C alkynyl, 3-12C cycloalkyl, (3-12C)cycloalkyl(1-8C)alkyl, R15 or optionally ring-substituted 6-14C aryl, (6-14C)aryl(1-8C)alkyl, heteroaryl or heteroaryl(1-8C)alkyl; R12b = NH2, di(1-10C alkyl)amino or NHR12a; R13 = H, 1-6C alkyl (optionally fluorinated), 3-8C cycloalkyl, (3-8C)cycloalkyl(1-6C)alkyl or optionally ring-substituted 6-14C aryl or (6-14C)aryl(1-6C)alkyl; R15 = R16 or 1-6C alkyl substituted by R16; R16 = a 6-24 membered saturated or partially unsaturated bi- or tricyclic group that can contain 1-4 heteroatoms selected from N, O and S and can be substituted by 1-4C alkyl and/or oxo; R20 = a bond or 1-6C alkylene; R21 = H, 1-8C alkyl (optionally fluorinated), 3-12C cycloalkyl, (3-12C)cycloalkyl(1-8C)alkyl, optionally substituted 6-14C aryl, optionally ring-substituted (6-14C)aryl(1-8C)alkyl, Het or Het(1-8C)alkyl; R22 = R21, OR21, N(R21)2, COR21, COOR21, CON(R21)2, C(NR21)N(R21)2 or N(R21)COR21; R30 = -R31-(CRR)m-R32, -R31-CR=CR-R32, -R31-C?=C-R32, -R31-O-R32 or -R31-S-R32; m = 1-3; R31 = -R33-R34-R35-R36- with R36 bonded to the imidazolidine N; R32 = H, 1-8C alkyl (optionally fluorinated), 2-8C alkenyl, 2-8C alkynyl, 3-12C cycloalkyl, (3-12C)cycloalkyl(1-8C)alkyl, (6-12C)bicycloalkyl, (6-12C)bicycloalkyl(1-8C)alkyl, (6-12C)tricycloalkyl, (6-12C)tricycloalkyl(1-8C)alkyl, or optionally ring-substituted 6-14C aryl, (6-14C)aryl(1-8C)alkyl, heteroaryl or heteroaryl(1-8C)alkyl; R33 = a bond or 1-6C alkylene; R34 = 3-12C cycloalkylene, 6-12C bicycloalkylene, 6-12C tricycloalkylene or optionally substituted 6-14C arylene or heteroarylene; R35 = a bond or 1-8C alkylene; R36 = a bond, CO or SOn; Het = optionally substituted 4-14 membered, mono- or polycyclic, aromatic or non aromatic heterocyclyl containing 1-4 heteroatoms selected from N, O and S; e, h = 0 or 1; and n = 1 or 2.