Pharmacia Corporation

Cedarburg Pharmaceuticals, Inc.

Nathan W Stehle

John Nicholas Freskos

Daniel Paul Becker

Deborah A Mischke

Joseph J McDonald

Thomas E Barta

Clara I Villamil

Joseph Gerace Rico

Susan Landis Hockerman

Terri L Boehm

Louis J Bedell

Daniel P Getman

Yvette M Fobian

William F Vernier

Jeffery N Carroll

Gary A DeCrescenzo

Michael B Tollefson

Steve A Kolodziej

Madeleine H Li

Richard J Pariza

Darren J Kassab

Susan C Howard

Kevin Kunnen

Stephen A Kolodziej

Scot W Weis

Carol Pearcy Howard

Patrick B Mullins

John M Pascone

Scott G Van Ornum

Paul Zizelman

John Jeffrey Talley

Gunnar J Hanson

Ish K Khanna

Robert M Heintz

David Louis Brown

Lijuan Jane Wang

Margaret Lanahan Grapperhaus

Mark A Massa

Monica B Norton

Alan Frank Gasiecki

Brent V Mischke

Hui Li

Michelle A Schmidt

Theresa R Fletcher

Jeffrey N Carroll

Thomas A Wynn

Gary A DeCrezcenzo

Yiyuan Chen

Mark A Nagy

A method is provided for preparing an aromatase inhibitor of formula (I) wherein each of R, R, R, R, independently, is hydrogen, halogen or C-Calkyl. In one form, the aromatase inhibitor is exemestane wherein each of R, R, R, Ris hydrogen. In the method, a compound of formula (II) wherein R, R, R, Rare as defined above and R is alkylene, is reacted with a deprotonating agent and a compound of the formula RSOX wherein Ris C-Calkyl and X is halogen so as to obtain a compound of formula (III) wherein R, R, R, R, Rare as defined above. The compound of Formula (III) is then reacted with a base to form an aromatase inhibitor of formula (I).

Exemestane and its intermediates and methods of making the same

A method is provided for preparing an aromatase inhibitor of formula (I) wherein each of R, R, R, R, independently, is hydrogen, halogen or C-Calkyl. In one form, the aromatase inhibitor is exemestane wherein each of R, R, R, Ris hydrogen. In the method, a compound of formula (II) wherein R, R, R, Rare as defined above and R is alkylene, is reacted with a deprotonating agent and a compound of the formula RSOX wherein Ris C-Calkyl and X is halogen so as to obtain a compound of formula (III) wherein R, R, R, R, Rare as defined above. The compound of Formula (III) is then reacted with a base to form an aromatase inhibitor of formula (I). 

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

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 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

Growing community of inventors

Grafton, WI, United States of America

Nathan W Stehle