G.d. Searle & Company

Pharmacia Corporation

Monsanto Company

Pfizer Corporation

Warner-lambert Company

Joseph Gerace Rico

Thomas Edward Rogers

Deborah A Mischke

Terri L Boehm

Philippe R Bovy

Gary A DeCrescenzo

Jeffery N Carroll

Jeffery A Zablocki

Darren J Kassab

Susan Landis Hockerman

John Nicholas Freskos

Daniel Paul Becker

Joseph J McDonald

Thomas E Barta

Clara I Villamil

Foe S Tjoeng

Masateru Miyano

Louis J Bedell

Yvette M Fobian

Mark Andrew Russell

Peter Gerrard Ruminski

Shashidhar N Rao

James W Malecha

Nathan W Stehle

Steve A Kolodziej

Daniel P Getman

William F Vernier

Richard John Lindmark

John Jeffrey Talley

Thomas Dale Penning

Michael John Clare

Ish K Khanna

Steven P Adams

Michael B Tollefson

Lijuan Jane Wang

Julie M Miyashiro

Monica B Norton

Barbara B Chen

Stella S Yu

Helen Y Chen

Robert B Garland

Bipinchandra N Desai

Madeleine H Li

Balekudru Devadas

Paul Waddell Collins

Alan Frank Gasiecki

Richard A Haack

Yi Yu

Susan C Howard

Stephen A Kolodziej

Patrick B Mullins

Carol Pearcy Howard

Glen J Gesicki

Philippe Roger Bovy

Jeffrey N Carroll

Gunnar J Hanson

Daniel L Flynn

Richard M Weier

David B Reitz

Robert M Heintz

David Louis Brown

Srinivasan Raj Nagarajan

Margaret Lanahan Grapperhaus

Mark A Massa

Mihaly V Toth

Francis J Koszyk

Nizal S Chandrakumar

Xiangdong Xu

Stephen Hermann Docter

Dudley E McMackins

Brent V Mischke

Joe T Collins

Marvin Jay Meyers

Hui Li

Renee Huff

Graciela B Arhancet

Xiangyang Chen

Michelle A Schmidt

Jeffery Alan Zablocki

Theresa R Fletcher

Hwang-fun Lu

Yiyuan Chen

Mark A Nagy

Thomas A Wynn

Phillipe R Bovy

Norman Anthony Abood

Gary A DeCrezcenzo

Foe Siong Tjoeng

Compounds and pharmaceutically acceptable salts of the compounds are disclosed, wherein the compounds have the structure of Formula I: wherein R, R, R, R, R, R, R, R, R, and X are as defined in the detailed description of the invention. Corresponding pharmaceutical compositions, methods of treatment, and intermediates are also disclosed.

Pyrazoline compounds

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 sulfamato hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a process for preparing the same, intermediate compounds useful in those syntheses, and a treatment process that comprises administering a contemplated sulfamato hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

Sulfamato 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. 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

This invention is directed to aromatic sulfone hydroxamic acids (including hydroxamates) and salts thereof that, inter alia, inhibit matrix metalloproteinase (also known as 'matrix metalloprotease' or 'MMP') activity and/or aggrecanase activity. This invention also is directed to a prevention or 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 and/or aggrecanase activity.

Aromatic sulfone hydroxamic acids and their use as protease inhibitors

Pyrimidine compounds and derivatives thereof

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,

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.

This invention is directed to aromatic sulfone hydroxamates (also known as &ldquo;aromatic sulfone hydroxamic acids&rdquo;) and salts thereof that, inter alia, inhibit matrix metalloproteinase (also known as &ldquo;matrix metalloprotease&rdquo; or &ldquo;MMP&rdquo;) activity and/or aggrecanase activity. This invention also is directed to a prevention or 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 and/or aggrecanase activity.

Aromatic sulfone hydroxamates and their use as protease inhibitors

Heterocyclic glycyl &bgr;-alanine derivatives

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.

A sulfamato hydroxamic acid compound that, inter alia, inhibits matrix metalloprotease (mmp) activity is disclosed as are a process for preparing the same, intermediate compounds useful in those syntheses, and a treatment process that comprises administering a contemplated sulfamato hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

Growing community of inventors

Ballwin, MO, United States of America

Joseph Gerace Rico