Inhibitors of cellular necrosis and related methods

Patent metadata

Field	Value
Publication number	US-9499521-B2
Application number	US-201615194413-A
Country	US
Kind code	B2
Filing date	Jun 27, 2016
Priority date	Dec 11, 2014
Publication date	Nov 22, 2016
Grant date	Nov 22, 2016

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.

First claim

The invention claimed is:

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

or a pharmaceutically acceptable salt or tautomer thereof.

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

or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

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):

or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier, diluent or excipient.

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

or a pharmaceutically acceptable salt thereof.

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.

Assignees

• Harvard College
• Shanghai Inst Organic Chemistry Cas
• Shanghai Inst Of Organic Chemistry

Inventors

• Yuan Junying
• Zhou Yijun
• Qian Shan
• Ma Dawei

Classifications

• C07D403/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D233/78

  Radicals substituted by oxygen atoms · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title