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

摘要

The present invention relates to Compounds 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; R2 is alkenyl, allcynyl, aryl, heterocyclyl, heteroaryl, cycloalkyl, NR4R5,—NHC(═Y)R4,—NHC(═Y)NR5Rχ,—NHC(═O)OR4,—NHSO2R4, C(═Y)NR4R5, C(═O)OR6 [wherein Y is oxygen or sulphur], OR5,—O(C═O)NR4R5, O-acyl, S(O)mR4,—SO2N(R4)2, cyano, amidino or guanidino [wherein R4 is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, heteroarylalkyl, heterocyclylalkyl or cycloalkylalkyl and m is an integer 0-2; R5 is hydrogen 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,—NHC(═Y)R4,—NHC(═Y)NR5Rx,—NHC(═O)OR4,—NHSO2R4, and to processes for the synthesis of the same. This invention also relates to pharmacological compositions containing the compounds of the present invention, and methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, neointimal proliferation, which leads to restenosis and ischemic heart failure, stroke, renal diseases, tumor metastasis, and other inflammatory disorders characterized by over-expression and over-activation of an matrix metalloproteinase, using the compounds.