5-PHENYL-PENTANOIC ACID DERIVATIVES AS MATRIX METALLOPROTEINASE INHIBITORS FOR THE TREATMENT OF ASTHMA AND OTHER DISEASES

摘要

The present invention relates to C ompounds having the structure of Formula I:wherein n is an integer from 1 to 5; R1 is optionally substituted alkyl,alkenyl, alkynyl,cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, alkoxy, aryloxy,alkenyloxy or alkynyloxy; R2is alkenyl, allcynyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, NR4R5, -NHC(=Y)R4, -NHC(=Y)NR5R.chi., -NHC(=O)OR4, -NHSO2R4, C(=Y)NR4R5, C(=O)OR6 [wherein Y isoxygen or sulphur], ORS, -O(C=O)NR4R5, O-acyl, S(O)m R4, -SO2N(R4)2, cyano,amidino orguanidino [wherein R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, heteroaryl,aralkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl and m is aninteger 0-2; R5 ishydrogen or R4; Rx is R4 or -SO2N(R4)2 and R6 is hydrogen, alkyl, cycloalkyl,aralkyl,heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl]; R3 is hydrogen,fluorine, alkyl,cycloalkylalkyl or aralkyl; A is OH, OR4, -OC(=O)NR4R5, O-acyl, NH2, NR4R5,NEC(=Y)R4, -NHC(=Y)NR5Rx, -NHC(=O)OR4, -NHSO2R4, and to processes for thesynthesis of the same. This invention also relates to pharmacologicalcompositions containingthe compounds of the present invention, and methods of treating asthma,rheumatoid arthritis,COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonaryfibrosis pulmonaryinflammation, acute respiratory distress syndrome, perodontitis, multiplesclerosis, gingivitis,atherosclerosis, neointimal proliferation, which leads to restenosis andischemic heart failure,stroke, renal diseases, tumor metastasis, and other inflammatory disorderscharacterized by overexpression and over-activation of an matrix metalloproteinase, using thecompounds.