MMP inhibitors

#The invention relates to a hitherto unknown class of compounds, namely substituted 1,3,2 oxazaphosphacycloalkane derivatives, which exhibit matrix metalloprotease inhibitory effects, to pharmaceutical compositions comprising said compounds and to the use of said compounds in the manufacture of medicaments.

#The matrix metalloproteases (MMP) are a family of zinc containing enzymes capable of breaking down many protenaceous compounds in the extracellular matrix, such as collagen, gelatine, fibronectin, laminin and proteoglucan core protein.

#There are at least 23 different MMPs classified according to their domain structure and substrate preferences [Lauer-Fields, Exp.Opin.Ther.Patents, 10, 1873-1884, 2000]. MMP may be classified into four main groups: Collagenases degrade fibrilar collagen; stromelysin degrade proteoglucans and glucoproteins; gelatinases degrade non-fibrilar and degraded collagen, i.e. gelatine; and finally the membrane bound MMPs [O'Brien, J.Med.Chem.,43, 156-166, 2000]. The MMPs share a common multidomain structure, but are glycosylated at different sites and to different extent. All MMPs also share a common zinc-binding motif, HisGluXaaGlyHis, and the differences comprise the presence or absence of structural domains controlling such factors as substrate specificity, inhibitor binding, matrix binding and cell-surface localisation. The nomenclature for MMP is simple as they are named MMP-n, wherein n is an integer starting from 1.

#The exemplified compounds of formula Ia are listed in Table 4, exemplified compounds of general formula (II) in Table 3, intermediates of general formula (III) in Table 2, and intermediates of general formula (VII) in Table 1. Except if otherwise specified, the compounds are racemic.

#All melting points are uncorrected. For 1H nuclear magnetic resonance (NMR) spectra (300 MHz) and 13C NMR (75.6 MHz) chemical shift values (δ) (in ppm) are quoted, unless otherwise specified, for deuteriochloroform solutions relative to internal tetra-methylsilane (δ=0.00) or chloroform (δ=7.25) or deuteriochloroform (δ=76.81 for 13C NMR) standards. The value of a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted. (bs) indicates a broad singlet. Mass spectra were recorded on a QUATTRO II (Micromass). The organic solvents used were anhydrous. Chromatography was performed on silica gel.

#The following abbreviations have been used throughout: