Aromatic sulfone hydroxamic acids and their use as protease inhibitors

a technology of aromatic sulfone and hydroxamic acid, which is applied in the field of proteinase, can solve the problems of toxic side effects, toxicity, and reportedly observed toxic side effects, and achieve the effect of little or no inhibition

Inactive Publication Date: 2005-05-12
PHARMACIA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0177] Further benefits of Applicants' invention will be apparent to one skilled in the art from reading this patent.

Problems solved by technology

Chronic release of active TNF-α can cause cachexia and anorexia.
This preference stems from the fact that both MMP-1 and MMP-14 are involved in several homeostatic processes, and inhibition of MMP-1 and / or MMP-14 consequently tends to interfere with such processes.
Although Marimastat exhibited some measure of efficacy via these markers, toxic side effects reportedly were observed.
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, and then 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.

Method used

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  • Aromatic sulfone hydroxamic acids and their use as protease inhibitors
  • Aromatic sulfone hydroxamic acids and their use as protease inhibitors
  • Aromatic sulfone hydroxamic acids and their use as protease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

embodiment no.1

Preferred Embodiment No. 1

[0193] In some embodiments of this invention, the compound has a structure corresponding to Formula II:

[0194] A1, A2, and A3 are as defined above for Formula I.

[0195] E1 is —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, or —C(R1)(R2)—. E1 alternatively may be —S—.

[0196] E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[0197] In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.

[0198] In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.

[0199] In some preferred embodiments, E2 is C...

embodiment no.2

Preferred Embodiment No. 2

[0273] In some embodiments of this invention, the compound has a structure corresponding to Formula III:

[0274] A1, A2, and A3 are as defined above for Formula I.

[0275] E1 is —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, or —C(R1)(R2)—. E1 alternatively may be —S—.

[0276] E2 forms a link of at least 2 carbon atoms between E1 and E3. E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[0277] In some preferred embodiments, E2 is C2-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.

[0278] In some preferred embodiments, E2 is C2-C6-alkyl optionally substituted with one or more halogen.

[0279] In some preferred embodiments, E2 is ...

embodiment no.3

Preferred Embodiment No. 3

[0345] In some embodiments of this invention, the compound has a structure corresponding to Formula IV:

[0346] A1, A2, and A3 are as defined above for Formula I.

[0347] E1 is S —O—, —S(O)2—, —S(O)—, —N(R1)—, —C(O)—N(R1)—, —N(R1)—C(O)—, or —C(R1)(R2)—.

[0348] E2 is alkyl, cycloalkyl, alkylcycloalkyl, cycloalkylalkyl, or alkylcycloalkylalkyl. Any member of this group optionally is substituted.

[0349] In some preferred embodiments, E2 is C1-C20-alkyl, cycloalkyl, C1-C10-alkylcycloalkyl, cycloalkyl-C1-C10-alkyl, or C1-C10-alkylcycloalkyl-C1-C10-alkyl. Any member of this group optionally is substituted with one or more substituents independently selected from the group consisting of halogen, C1-C6-alkyl, and halo-C1-C6-alkyl.

[0350] In some preferred embodiments, E2 is C1-C6-alkyl, cycloalkyl, C1-C6-alkylcycloalkyl, cycloalkyl-C1-C6-alkyl, or C1-C6-alkylcycloalkyl-C1-C6-alkyl. Any member of this group optionally is substituted with one or more substituents inde...

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Abstract

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.

Description

PRIORITY CLAIM TO RELATED PATENT APPLICATION [0001] This patent claims priority to U.S. Provisional Patent Application Ser. No. 60 / 290,375 (filed May 11, 2001). The entire text of U.S. Provisional Patent Application Ser. No. 60 / 290,375 is incorporated by reference into this patent.FIELD OF THE INVENTION [0002] This invention is directed generally to proteinase (also known as “protease”) inhibitors, and, more particularly, to aromatic sulfone hydroxarnates (also known as “aromatic sulfone hydroxamic acids”) that, inter alia, inhibit matrix metalloproteinase (also known as “matrix metalloprotease” or “MMP”) activity and / or aggrecanase activity. This invention also is directed to compositions of such inhibitors, intermediates for the syntheses of such inhibitors, methods for making such inhibitors, and methods for preventing or treating conditions associated with MMP activity and / or aggrecanase activity, particularly pathological conditions. BACKGROUND OF THE INVENTION [0003] Connectiv...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/35A61K31/351C07D491/048A61K31/357A61K31/381A61K31/397A61K31/4025A61K31/404A61K31/41A61K31/4178A61K31/4184A61K31/42A61K31/423A61K31/4245A61K31/427A61K31/428A61K31/4355A61K31/4433A61K31/445A61K31/453A61K31/454A61K31/4545A61K31/455A61K31/4709A61K31/4725A61K31/506A61K31/53A61K31/5377A61P1/02A61P1/04A61P1/16A61P7/00A61P7/02A61P7/04A61P9/00A61P9/04A61P9/10A61P11/00A61P13/12A61P17/02A61P17/06A61P19/00A61P19/02A61P25/00A61P25/18A61P25/28A61P27/02A61P27/16A61P29/00A61P31/04A61P35/00A61P35/04A61P37/02A61P37/06A61P39/00A61P43/00C07D211/66C07D309/08C07D309/12C07D401/12C07D405/12C07D405/14C07D407/12C07D409/12C07D409/14C07D413/12C07D413/14C07D417/12C07D417/14C07D491/04
CPCA61K31/351A61K31/41A61K31/453A61K31/454C04B35/632C07D211/66C07D309/08C07D309/12C07D401/12C07D405/12C07D405/14C07D407/12C07D409/12C07D413/12C07D413/14C07D417/12C07D417/14C07D491/04A61P1/02A61P1/04A61P1/16A61P11/00A61P13/12A61P17/02A61P17/06A61P19/00A61P19/02A61P25/00A61P25/18A61P25/28A61P27/02A61P27/16A61P29/00A61P31/04A61P35/00A61P35/04A61P37/02A61P37/06A61P39/00A61P43/00A61P7/00A61P7/02A61P7/04A61P9/00A61P9/04A61P9/10Y02A50/30
Inventor FRESKOS, JOHNFOBIAN, YVETTEBARTA, THOMASBECKER, DANIELBEDELL, LOUISBOEHM, TERRICARROLL, JEFFERYDECRESCENZO, GARYHOCKERMAN, SUSANKASSAB, DARRENKOLODZIEJ, STEVEMCDONALD, JOSEPHMISCHKE, DEBORAHNORTON, MONICARICO, JOSEPHTALLEY, JOHNVILLAMIL, CLARAWANG, LIJUAN
Owner PHARMACIA CORP
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