Inhibitors of matrix metalloproteinase

Abstract

Compounds of formula (I):whereinR1 represents optionally substituted C4-12 alkyl, optionally substituted C2-6alkylaryl, or optionally substituted 5- or 6-membered aryl or heteroaryl;Z represents a bond, CH2, O, S, SO, SO2, NR4, OCR4R5, CR4R5O, or Z, R1 and Q together form an optionally substituted fused tricyclic group;Q represents an optionally substituted 5- or 6-membered aryl or heteroaryl ring;X represents COR3 or N(OR8)COR9;R2 represents SO2R10 or SO2NR10R11;R3 represents OR6NR6R7 or NR6OH;R4 and R5 each independently represents H, C1-6 alkyl or C1-4 alkylaryl;R6 and R7 each independently represents H, C1-6 alkyl, or C1-6 alkyl substituted with one or more heteroaryl groups, or R6 and R7 together with the nitrogen atom to which they are attached form a 5- or 6-membered ring which may optionally include 1 or more further heteroatoms selected from O, S and N;R8 and R9 each independently represents H or C1-6 alkyl;R10 and R11 each independently represents H or C1-6 alkyl; and and physiologically functional derivatives thereof, with the exception of N-(ethoxycarbonyl)-N-[4-(1H-tetrazol-1-yl)phenyl]glycine, processes for their preparation, pharmaceutical formulations containing them and their use as inhibitors of matrix metalloproteinase enzymes (MMPs) are described.

Description

CROSS REFERENCE TO PRIOR APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 561,055 filed 16 Dec. 2005 (allowed), which is a 371 application of PCT / EP2004 / 006553 filed 16 Jun. 2004 which claims priority to GB application 0314488.8 filed 20 Jun. 2003.FIELD OF THE INVENTION[0002]This invention relates to novel chemical compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.SUMMARY OF THE INVENTION[0003]The compounds of the invention are inhibitors of matrix metalloproteinase enzymes (MMPs).BACKGROUND OF THE INVENTION[0004]Matrix metalloproteinase enzymes play a major role in extracellular matrix component degradation and remodelling. Examples of MMPs include collagenase 1, 2 and 3, gelatinase A and B, stromelysin 1, 2 and 3, matrilysin, macrophage metalloelastase, enamelysin and membrane type 1, 2, 3 and 4 MMP. The enzymes are secreted by connective tissue cells and inflammatory cells. Enzyme a...

AI Technical Summary

Benefits of technology

[0004]Matrix metalloproteinase enzymes play a major role in extracellular matrix component degradation and remodelling. Examples of MMPs include collagenase 1, 2 and 3, gelatinase A and B, stromelysin 1, 2 and 3, matrilysin, macrophage metalloelastase, enamelysin and membrane type 1, 2, 3 and 4 MMP. The enzymes are secreted by connective tissue cells and inflammatory cells. Enzyme activation can not only initiate tissue damage but induce increased inflammatory cell infiltration into the tissue, leading to more enzyme production and subsequent tissue damage. For example, elastin fragments produced by MMP degradation are believed to stimulate inflammation by attracting macrophages to the site of MMP activity. Inhibition of MMPs provides a means for treating disease states wherein inappropriate metalloprotease activity results in degradation of connective tissue and inflammation.

Problems solved by technology

Enzyme activation can not only initiate tissue damage but induce increased inflammatory cell infiltration into the tissue, leading to more enzyme production and subsequent tissue damage.

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