Necroptosis inhibitors and methods of use therefor

Patent metadata

Field	Value
Publication number	US-9643977-B2
Application number	US-201214004474-A
Country	US
Kind code	B2
Filing date	Mar 12, 2012
Priority date	Mar 11, 2011
Publication date	May 9, 2017
Grant date	May 9, 2017

Abstract

Described herein are compositions that inhibit the production of TNFα downstream of CD40 activation. As such, also described are various methods of using compositions exhibiting this activity for the treatment or prevention of inflammatory diseases associated with TNFα production or CD40 activation.

First claim

I claim:

1. A compound having formula I:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence,
{circle around (A)} represents a substituted or unsubstituted furan, isothiazole, oxazole, thiazole, thiadiazole, or triazole;
represents a double bond or a single bond;
R 1 is —H or alkyl; and
X represents —O—, —NR 1 —, or —S—.

2. A method of treating an inflammatory disease or other disease associated with RIP1 kinase-mediated TNFα production, comprising administering to a subject a therapeutically effective amount of a compound having formula I:

or a pharmaceutically acceptable salt thereof,
wherein, independently for each occurrence,
{circle around (A)} represents a substituted or unsubstituted 5-membered heteroaryl;
represents a double bond or a single bond;
R 1 is —H or alkyl; and
X represents —O—, —NR 1 —, or —S—.

3. The method of claim 2 , wherein the compound is selected from the group consisting of

4. The method of claim 2 , wherein the subject is a subject in need thereof; and the subject in need thereof is a subject who has been diagnosed with an inflammatory disease or a subject who is at high risk for an inflammatory disease.

5. The method of claim 2 , wherein the method is a method of treating an inflammatory disease; and the inflammatory diseases is inflammatory bowel disease, rheumatoid arthritis, psoriatic arthritis, psoriasis, diabetes mellitus, Alzheimer's disease, refractory asthma, multiple sclerosis, atherosclerosis, or vasculitis.

6. The compound of claim 1 , wherein {circle around (A)} is unsubstituted.

7. The compound of claim 1 , wherein {circle around (A)} represents substituted or unsubstituted isothiazole.

8. The compound of claim 1 , wherein R 1 is —H.

9. The compound of claim 1 , wherein at least one instance of R 1 is alkyl.

10. The compound of claim 1 , wherein at least one instance of R 1 is methyl, ethyl, n-propyl, or isopropyl.

11. The compound of claim 1 , wherein at least one instance of R 1 is methyl.

12. The compound of claim 1 , wherein at least one instance of R 1 is ethyl.

13. The compound of claim 1 , wherein one instance of R 1 is methyl, ethyl, n-propyl, or isopropyl.

14. The compound of claim 1 , wherein one instance of R 1 is methyl.

15. The compound of claim 1 , wherein one instance of R 1 is ethyl.

16. The compound of claim 1 , wherein X represents —NR 1 —.

17. The compound of claim 1 , wherein X represents —NH—.

18. The compound of claim 1 , wherein X represents —N(CH 3 )—.

19. The method of claim 2 , wherein {circle around (A)} represents an unsubstituted 5-membered heteroaryl.

20. The method of claim 2 , wherein {circle around (A)} represents substituted or unsubstituted furan, imidazole, isoxazole, isothiazole, oxadiazole, oxazole, pyrazole, pyrrole, thiazole, thiadiazole, thiophene, or triazole.

21. The method of claim 2 , wherein {circle around (A)} represents

22. The method of claim 2 , wherein {circle around (A)} represents

23. The method of claim 2 , wherein {circle around (A)} represents

24. The method of claim 2 , wherein R 1 is —H.

25. The method of claim 2 , wherein at least one instance of R 1 is alkyl.

26. The method of claim 2 , wherein at least one instance of R 1 is methyl, ethyl, n-propyl, or isopropyl.

27. The method of claim 2 , wherein at least one instance of R 1 is methyl.

28. The method of claim 2 , wherein at least one instance of R 1 is ethyl.

29. The method of claim 2 , wherein one instance of R 1 is methyl, ethyl, n-propyl, or isopropyl.

30. The method of claim 2 , wherein one instance of R 1 is methyl.

31. The method of claim 2 , wherein one instance of R 1 is ethyl.

32. The method of claim 2 , wherein X represents —NR 1 —.

33. The method of claim 2 , wherein X represents —NH—.

34. The method of claim 2 , wherein X represents —N(CH 3 )—.

35. The method of claim 5 , wherein the disease is Alzheimer's disease.

Assignees

• Yuan Junying
• Harvard College

Inventors

• Yuan Junying

Classifications

• A61P29/00

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

• C07D403/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D277/46

  by carboxylic acids, or sulfur or nitrogen analogues thereof · CPC title

• C07D237/18

  Sulfur atoms · CPC title

• C07D231/40

  Acylated on said nitrogen atom · CPC title