2-aryl-propionic acid and medicine composition containing same

Abstract

(R,S)-2-Aryl-propionic acids are useful as inhibitors of interleukin-8 induced human polymorphonucleated neutrophils (PMN) chemotaxis. (R,S)-2-Aryl-propionic acids of formula (I), their single (R) and (S) enantiomers or salts are useful as inhibitors of interleukin-8 (IL-8) induced human polymorphonucleated neutrophils (PMN) chemotaxis. [Image] Ar : phenyl ring (substituted by T in meta position, T1 in para position or T2 in ortho position); T : linear or branched 1-5C alkyl, 2-5C alkenyl, or 2-5C alkynyl (optionally substituted by 1-5C alkoxycarbonyl, optionally substituted phenyl, linear or branched 1-5C hydroxyalkyl or arylhydroxymethyl); T1benzoyloxy, benzoylamino, benzenesulfonyloxy, benzenesulfonylamino, benzenesulfonylmethyl (all optionally substituted), 1-5C acyloxy, 1-5C acylamino, 1-5C sulfonyloxy, 1-5C alkanesulfonylamino, 1-5C alkanesulfonylmethyl, 3-6C cycloalkyl, 2-furyl, 3-tetrahydrofuryl, 2- thiophenyl, 2-tetrahydrothiophenyl or ((1-8C)-alkanoyl, -cycloalkanoyl or -arylalkanoyl)-1-5C-alkylamino (preferably acetyl-N-methyl-amino or pivaloyl-N-ethyl-amino); and T2arylmethyl, aryloxy or acylamino (all optionally substituted by 1-4C alkyl, 1-4C-alkoxy, chlorine, fluorine or trifluoromethyl). The meta linear or branched 1-5C alkyl together with a substituent in ortho or para position and the benzene ring forms optionally saturated or optionally substituted bicyclo aryls. INDEPENDENT CLAIM are included for the following: (1) preparation of (I); and (2) use of (I) in the preparation of a medicament for the treatment of e.g. psoriasis, ulcerative colitis, melanoma and chronic obstructive pulmonary disease (COPD). - ACTIVITY : Antipsoriatic; Antiulcer; Respiratory-Gen.; Antirheumatic; Antiarthritic; Nephrotropic; Vasotropic; Antiinflammatory; Gastrointestinal-Gen.; Cytostatic. - MECHANISM OF ACTION : Interleukin-8 (IL-8) inhibitor; GROalpha inhibitor; CXCR2 agonist / antagonist. The ability of (R,S) 2-[(3'-isopropyl)phenyl]propionic acid (A) to inhibit IL-8 induced chemotaxis of human monocytes was tested as described in Van Damme J. et al. (Eur. J. Immunol., 19, 2367, 1989). (A) showed inhibition (%) of 51+-12.

Description

technical field [0001] The present invention relates to (R,S)2-aryl-propionic acids, their single enantiomers (R) and (S), and pharmaceutical compositions containing these compounds, useful for the prevention and treatment of polynuclear neutrophils Tissue damage caused by the acute recruitment of cells (PMN leukocytes) at sites of inflammation. Background of the invention [0002] Specific blood cells (macrophages, granulocytes, neutrophils, polymorphonuclear cells) respond to a chemical stimulus by migrating along a concentration gradient of the chemical stimulus through a process called chemotaxis (when called chemotaxis). When stimulated by the substance of chemical factor). The main known stimulators or chemokines are represented by breakdown products of complement C5a, some N-formyl peptides lysed from bacterial surfaces, or synthetic peptides such as formyl-methionyl-leucyl-phenylalanine (f-MLP), mainly various cytokines, including interleukin-8 (IL-8). Interleukin...

AI Technical Summary

Problems solved by technology

Conversion of some (R) enantiomers to the corresponding (S) enantiomer in certain animal species and humans restores COX inhibitory activity, greatly limiting the usefulness of these compounds in the treatment of IL-8-mediated pathologies. application

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