Substituted 4-biarylbutyric or 5-pentanoic acids useful as matrix metalloprotease inhibitors

摘要

A 4-biarylbutyric or 5-pentanoic acid derivative has the formula (I) (T)xA-B-D-E-G or pharmaceutically acceptable salts thereof wherein: A represents an optionally substituted aromatic or heteroaromatic moiety of formula (2); R1 is H or alkyl; each T is halogen, alkyl, haloalkyl, alkenyl, alkynyl, -(CH2)pQ or -alkenyl-Q; p is 0 to 4; x is 0, 1, or 2; B is an optionally substituted aromatic or heteroaromatic moiety of formula (3); D represents -C(=O)-, -C(OH)(H)-, -C(=NOH)- or -C(=S)-; E represents a chain of n carbon atoms bearing m substituents R6; each group R6 is independently of: i) alkyl provided that if the A unit is phenyl, the B unit is phenylene, m is 1, n is 2, and the alkyl group is located on the alpha carbon relative to the D unit, then x is 1 or 2 but if the alkyl group is located in the beta carbon relative to the D unit then the alkyl group contains 4-10 carbons; j) aryl of 6 - 10 carbons, provided that if the A unit is phenyl, the B unit is phenylene, the aryl group is phenyl, n is 2, and m is 1 or 2, then x is 1 or 2; k) heteroaryl having at least one N, O, or S heteroatom; l) arylalkyl; m) heteroaryl-alkyl having at least one N, O, or S heteroatom; n) alkenyl; o) aryl-alkenyl; p) heteroaryl-alkenyl at least one N, O, or S heteroatom; q) alkynyl; r) aryl-alkynyl; s) heteroaryl-alkynyl having at least one N, O, or S heteroatom; t) -(CH2)tR7; u) -(CH2)vZR8 and v) -(CH2)wSiR10 or two groups of R6 together can form with the chain atom(s) to which they are attached, and any intervening chain atoms, constitute a 3 - 7 membered ring, or one group R6 can form together with the chain atom(s) to which it is attached, and any intervening chain atoms, constitutes a 3 - 7 membered ring with the number of carbons in the totality of R6 groups is at least two; n is 2 or 3; m is 1 to 3; G is -M, or a group of formula (4); M is -CO2H, -CON(R11)2 or -CO2R12; R13 is any of the side chains of the 19 noncyclic naturally occurring amino acid and Q, R7, t, v, Z, R8, w and R10 to R12 are as defined in the specification. A pharmaceutical composition having matrix metalloprotease inhibitory activity thereof is useful for the alleviation of osteoarthritis, rheumatoid arthritis, septic arthritis, periodontal disease, corneal ulceration, proteinuria, aneurismal aortic disease, dystrophobic epidermolysis bullosa, conditions leading to inflammatory responses, osteopenias mediated by MMP activity, tempero mandibular joint disease, or demyelating diseases of the nervous system; retardation of tumor metastasis or degenerative cartilage loss following traumatic joint injury; reduction of coronary thrombosis from atherosclerotic plaque rupture; or improved birth control.