Pharmacia Corporation

G.d. Searle & Company

Madeleine H Li

Daniel P Getman

John Nicholas Freskos

Daniel Paul Becker

Thomas E Barta

Clara I Villamil

Susan Landis Hockerman

Louis J Bedell

Gary A DeCrescenzo

Deborah A Mischke

Joseph J McDonald

Joseph Gerace Rico

Terri L Boehm

Nathan W Stehle

Yvette M Fobian

Michael B Tollefson

William F Vernier

Jeffery N Carroll

Steve A Kolodziej

Carol Pearcy Howard

Gunnar J Hanson

Robert M Heintz

Brent V Mischke

Darren J Kassab

Susan C Howard

Stephen A Kolodziej

Patrick B Mullins

Theresa R Fletcher

Jeffrey N Carroll

Gary A DeCrezcenzo

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 Rand Rare both hydrido or Rand Rtogether 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. Rin 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.

Aromatic sulfone hydroxamic acid metalloprotease inhibitor

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. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor. A contemplated compound corresponds in structure to formula B, below,

This invention is directed to aromatic sulfone hydroxamates (also known as aromatic sulfone hydroxamic acids) and salts thereof that, inter alia, tend to inhibit matrix metalloproteinase (also known as matrix metalloprotease or MMP) activity and/or aggrecanase activity. This invention also is directed to a treatment method that comprises administering such a compound or salt in an MMP-inhibiting and/or aggrecanase-inhibiting effective amount to an animal, particularly a mammal having (or disposed to having) a pathological condition associated with MMP activity and/or aggrecanase activity.

Aromatic sulfone hydroxamic acids and their use as protease inhibitors

A family of molecules is disclosed that inhibit matrix metalloprotease (MMP) activity, and particularly inhibit the activity of one or more of MMP-2, MMP-9, or MMP-13, while generally exhibiting little activity against MMP-1. A contemplated compound also exhibits little inhibition of the production of TNF. A contemplated compound is an &agr;-amino-&bgr;-sulfonyl carbocyclo, heterocyclo, aryl, or heteroaryl hydroxamic acid. Also disclosed are processes for preparing a contemplated compound and for treating a mammal having a condition associated with pathological matrix metalloprotease activity.

&agr;-amino-&bgr;-sulfonyl hydroxamic acid compounds

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Vernon Hills, IL, United States of America

Madeleine H Li