New cyclic carboxylic acids are integrin antagonists, useful for treating inflammatory diseases, autoimmune and immune disorders, e.g. atherosclerosis, asthma and diabetes

摘要

Cyclic carboxylic acids (I) and their salts are new. Cyclic carboxylic acids of formula (I) and their salts are new. [Image] R1>e.g. a 4-9 membered heterocyclic residue containing 0-3 heteroatoms (N, O or S); where R1> is optionally annulated with a 4-8 membered cyclic residue, containing 0-2 heteroatoms (N, S or O); R2>e.g. H, 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl (all optionally substituted); R3>e.g. H, 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl (all optionally substituted); R4>e.g. H, 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl (all optionally substituted); R5>e.g. H, 1-10C alkyl, 2-10C alkenyl, 2-10C alkynyl (all optionally substituted); R6>e.g. phenyl or 5-6 membered aromatic heterocyclic residue; A : e.g. -C(O)-, -C(O)-C(O) , -SO-, -SO2-, -PO-, -PO2-, 2- or 4-pyrimidyl, or 2-pyridyl; X : -CRx1>Rx2>-; Rx1>, Rx2>e.g. H, 1-4C alkyl, 2-4C alkenyl or 2 4C alkynyl; Y : e.g. -C(O) , -S(O)-, -SO2-, -O- or -S-; D : N or CRD1>; RD1>e.g. a bond, H, 1-4C alkyl, 2-4C alkenyl or 2-4C alkynyl (all optionally substituted); with provisos. The full definitions are given in the DEFINITIONS (Full Definitions) Field. An independent claim is included for the preparation of protected compounds of formula (IV) comprising reacting a carboxylic acid of formula (II) with a carboxylic acid of formula (III), in the presence of a coupling agent and a base in inert solvent. [Image] PG : protecting group. - ACTIVITY : Antiarteriosclerotic; antiasthmatic; antiallergic; antiinflammatory; antidiabetic; neuroprotective; antirheumatic; antiarthritic; immunosuppressive. - MECHANISM OF ACTION : Integrin antagonists. In-vitro assays were carried out to determine adhesion of Jurkat or Ramos cells to immobilized VCAM-1 (domains 1-3). Test compounds typically had IC50 values less than 0.5 MicroM to 10 MicroM.