Inhibitors of cellular necrosis and related methods

• US 9,499,521 B2
• Filed: 06/27/2016
• Issued: 11/22/2016
• Est. Priority Date: 12/11/2014
• Status: Active Grant

• Current Assignee: Shanghai Institute of Organic Chemistry Chinese Academy of Sciences (Chinese Academy of Sciences), President and Fellows of Harvard College (Harvard Corporation)
• Original Assignee: Shanghai Institute of Organic Chemistry Chinese Academy of Sciences (Chinese Academy of Sciences), President and Fellows of Harvard College (Harvard Corporation)
• Inventors: Yuan, Junying, Zhou, Yijun, Qian, Shan, Ma, Dawei
• Primary Examiner(s): Yoo, Sun Jae
• Application Number:
  US15/194,413
• Publication Number:
  US 20160304498A1
• Time in Patent Office: 148 Days
• US Class Current: 1/1
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 233/78 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

A compound having the following structure (I):

or a pharmaceutically acceptable salt, prodrug, stereoisomer or tautomer thereof, is provided. Related compounds, methods for preparation of the same and uses of the compounds for treatment of various indications, including treatment of necrotic cell diseases and/or inflammation, are also provided.

Claims

1. A compound having the following structure (Ia):

4. The compound of claim 1 having the following structure (Ia):

5. A method of inhibiting receptor interacting protein kinase 1 (RIP1 kinase) in a subject, the method comprising delivering an effective amount of the compound of claim 1.

6. The compound of claim 1, (R)-5-((7-chloro-6-fluoro-1H-indol-3-yl)methyl)-3-methylimidazolidine-2,4-dione.

2. A pharmaceutical composition comprising a compound having the following structure (Ia):

3. A method of inhibiting receptor interacting protein kinase 1 (RIP1 kinase) in a subject, the method comprising administering an effective amount of a pharmaceutical composition to the subject, wherein the pharmaceutical composition comprises a compound having the following structure (Ia):