4-amino-phenylalanine compounds which inhibit leukocyte adhesion mediated by VLA-4

摘要

The compounds of formula I bind VLA-4 and inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. The compounds may be used in the treatment of inflammatory diseases such as asthma, Alzheimer's disease, atherosclerosis, AIDS dementia, diabetes, inflammatory bowel disease, rheumatoid arthritis, tissue transplantation, tumour metastasis, multiple sclerosis, rheumatoid arthritis, tissue transplantation, tumor mestasis, meningitis, encephalitis, stroke, nephritis, retinitis, atopic dermatitis, psoriasis, myocardial ischemia and acute leukocyte-mediated lung injury. In formula I; R1 is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic and optionally substituted heteroaryl; R2 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocyclic, optionally substituted aryl, optionally substituted heteroaryl; or R1 and R2 together with the N atom and the SO2 group form a optionally substituted heterocyclic; R3 is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted heterocyclic and optionally substituted heteroaryl; or when R2 does not form a heterocyclic group with R1, R2 and R3 together with the N atom can form an optionally substituted heterocyclic group; R5 is (CH2)xArR5', where R5' is selected from NR12C(Z)NR8R8' and NR12C(Z)R13, wherein R12 is selected from hydrogen, alkyl and aryl; R8 and R8' are independently selected from hydrogen, optionally substituted alkyl, aryl, cycloalkyl, heterocyclic or heteroaryl, provided that when Z is O, at least one of R8 and R8' is substituted alkyl, optionally substituted cycloalkyl, saturated heterocyclic other than morpholino and thiomorpholino, or substituted heterocyclic, and R8 and R8' can be joined to form a saturated substituted heterocycle or a saturated/unsaturated heterocycle having an amino group substituted with an alkoxycarbonyl substituent; and further provided that when Z is S, at least one of R8 and R8' is a group other than optionally substituted aryl or heteroaryl; and R13 is saturated heterocycle or substituted heterocycle; Ar is optionally substituted aryl or heteroaryl; and x is 1 to 4; and Q is C(X)NR7, where R7 is hydrogen or alkyl; and X is O or S.