Aromatic sulfone hydroxamic acid metalloprotease inhibitor

Abstract

A treatment process is disclosed that comprises administering an effective amount of an aromatic sulfone hydroxamic acid that exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibition at least of MMP-1 to a host having a condition associated with pathological matrix metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula (I), below, or a pharmaceutically acceptable salt thereof, wherein R¹ and R² are both hydrido or R¹ and R² together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two, or three heteroatoms in the ring that are oxygen, sulfur, or nitrogen. R³ in formula (I) is an optionally substituted aryl or optionally substituted heteroaryl radical. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor.

Description

TECHNICAL FIELD [0001] This invention is directed to proteinase (protease) inhibitors, and more particularly to the use of aromatic sulfone hydroxamic acid compounds that, inter alia, are selective inhibitors of matrix metalloproteinases in a process for treating conditions associated with pathological matrix metalloproteinase activity, the selective inhibitors themselves, compositions of proteinase inhibitors, intermediates for the syntheses of proteinase inhibitors, and processes for the preparation of proteinase inhibitors. BACKGROUND OF THE INVENTION [0002] Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These bio...

AI Technical Summary

Benefits of technology

[0094] An advantage of the invention is the provision of compounds, compositions and methods effective for treating such pathological conditions by selective inhibition of a metalloproteinase such as MMP-2, MMP-9 or MMP-13 associated with such conditions with minimal side effects resulting from inhibition of other metalloproteinases, such as MMP-1, whose activity is necessary or desirable for normal body function.

[0095] Yet another advantage of the invention is the provision of a process for preparing such compounds.

[0096] Another benefit is the provision of a method for treating a pathological condition associated with abnormal matrix metalloproteinase activity.

[0097] A further advantage of the invention is the provision of a process for preparing such compositions.

[0098] Still further benefits and advantages of the invention will be apparent to the skilled worker from the disclosure that follows.

Problems solved by technology

The loss of this balance for whatever reason leads to a number of disease states.

This can produce improper wound healing leading to weak repairs, adhesions and scarring.

These latter defects can lead to disfigurement and / or permanent disabilities as with post-surgical adhesions.

Chronic release of active TNF can cause cachexia and anorexia.

One possible problem associated with known MMP inhibitors is that such compounds often exhibit the same or similar inhibitory effects against each of the MMP enzymes.

Although marimastat exhibited some measure of efficacy via these markers, toxic side effects were noted.

The most common drug-related toxicity of marimastat in those clinical trials was musculoskeletal pain and stiffness, often commencing in the small joints in the hands, spreading to the arms and shoulder.

It is thought that the lack of specificity of inhibitory effect among the MMPs may be the cause of that effect.

Although many of the known MMP inhibitors such as batimastat, marimastat and the hydroxamates of WO 98 / 37877 and WO 98 / 38163 exhibit a broad spectrum of activity against MMPS, those compounds are not particularly selective in their inhibitory activity.

This lack of selectivity may be the cause of the musculoskeletal pain and stiffness observed with their use.

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