Pharmacia Corporation

Monsanto Company

Patrick B Mullins

John Nicholas Freskos

Daniel Paul Becker

Joseph J McDonald

Thomas E Barta

Clara I Villamil

Daniel P Getman

Deborah A Mischke

Robert M Heintz

Joseph Gerace Rico

Susan Landis Hockerman

Terri L Boehm

Louis J Bedell

Jeffery N Carroll

Brent V Mischke

Nathan W Stehle

Stephen A Kolodziej

John Jeffrey Talley

Gunnar J Hanson

Gary A DeCrescenzo

Ish K Khanna

David Louis Brown

Yvette M Fobian

Lijuan Jane Wang

Margaret Lanahan Grapperhaus

Mark A Massa

Monica B Norton

William F Vernier

Alan Frank Gasiecki

Darren J Kassab

Madeleine H Li

Theresa R Fletcher

Michelle A Schmidt

Carol Pearcy Howard

Yiyuan Chen

Mark A Nagy

Thomas A Wynn

Gary A DeCrezcenzo

This invention is directed generally to proteinase (also known as 'protease') inhibitors, and, more particularly, to piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids that, inter alia, inhibit matrix metalloproteinase (also known as 'matrix metalloprotease' or &#x201c;MMP&#x201d;) activity and/or aggrecanase activity. Such hydroxamic acids generally correspond in structure to the following formula: (wherein A, A, Y, E, E, E, and Rare as defined in this specification), and further include salts of such compounds. This invention also is directed to compositions of such hydroxamic acids, intermediates for the syntheses of such hydroxamic acids, methods for making such hydroxamic acids, and methods for treating conditions (particularly pathological conditions) associated with MMP activity and/or aggrecanase activity.

Piperidinyl- and piperazinyl-sulfonylmethyl hydroxamic acids and their use as protease inhibitors

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

An N-hydroxy sulfonyl butanamide compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated N-hydroxy sulfonyl butanamide compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

N-hydroxy 4-sulfonyl butanamide compounds

Growing community of inventors

St. Louis, MO, United States of America

Patrick B Mullins