Sirtuin modulating compounds
Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
1. A compound represented by Structural Formula (II):
or a salt thereof, wherein:
two of X 1 to X 4 are selected from —CR*— and —N—;
the other two of X 1 to X 4 are —CR*—;
R* is independently selected at each occurrence from —H, lower alkyl or halogen;
R 1 is a solubilizing group; and
R 2 is selected from phenyl optionally substituted with one or more substituents independently selected from —CN, —F, —Cl and —CF 3 , and when each of X 1 to X 4 is —CR*—, R 2 is additionally selected from a 5- to 6-membered heterocycle containing an N heteroatom and, optionally, a second heteroatom selected from N, O or S, wherein said heterocycle is optionally substituted with methyl.
2. The compound of claim 1 , wherein:
X 1 to X 4 is —CR*—; and
R 2 is selected from phenyl, fluorophenyl, difluorophenyl, chlorophenyl, difluorophenylmethylthiazolyl, pyrimidinyl, pyridyl and pyrazolyl.
3. The compound of claim 2 , wherein R 2 is selected from phenyl, fluorophenyl, difluorophenyl, chlorophenyl, 2-methylthiazol-4-yl, pyridyl and pyrazol-1-yl.
4. The compound of claim 3 , wherein R 2 is phenyl or pyridyl.
5. The compound of claim 1 , wherein one of X 1 to X 4 are —N—.
6. The compound of claim 1 , wherein two of X 1 to X 4 are —N—.
7. The compound of claim 5 , wherein X 1 is N.
8. The compound of claim 6 , wherein X 1 and X 2 are —N—.
9. The compound of claim 6 , wherein X 1 and X 4 are —N—.
10. The compound of claim 1 , wherein:
R 1 is —CH 2 —R 3 ; and
R 3 is a nitrogen-containing heterocycle optionally substituted with one or more substituents selected from C 1 -C 4 alkyl, amino, halogen, methoxy and methoxy-C 1 -C 4 alkyl.
11. The compound of claim 10 , wherein R 2 is phenyl, pyridyl or 3-fluorophenyl.
12. The compound of claim 11 , wherein X 2 and X 3 are —CH— and X 1 and X 4 are independently selected from —CR*— or —N—.
13. The compound of claim 10 , wherein:
R 1 is —CH 2 —R 3 ; and
R 3 is selected from piperazin-1-yl, 4-(methoxyethy-piperazin-1-yl, 3,5-dimethylpiperazin-1-yl, morpholin-4-yl, piperidin-1-yl, 4-aminopiperidin-1-yl, pyrrolidin-1-yl, 3-fluoropyrrolidin-1-yl, —NH—(pyrrolidin-3-yl), and 1,4-diaza-bicyclo[2.2.1]heptan-1-yl.
14. The compound of claim 13 , wherein R 3 is selected from 4-(methoxyethy)-piperazin-1-yl, morpholin-4-yl, piperidin-1-yl and 4-aminopiperidin-1-yl.
15. The compound of claim 14 , wherein R 2 is phenyl, 3-fluorophenyl or pyridyl.
16. The compound of claim 15 , wherein X 2 and X 3 are —CH— and X 1 and X 4 are independently selected from —CR*— or —N—.
17. The compound of claim 1 , wherein R* is H.
18. The compound of claim 1 , represented by formula (IV):
or a salt thereof, wherein:
one X variable is selected from —CH— and —N—;
the other two X variables are —CH—;
R 1 is a solubilizing group; and
R 2 is selected from phenyl and fluorophenyl, and, when each X variable is —CH—, R 2 is additionally selected from a 5- to 6-membered heterocycle containing an N heteroatom and, optionally, a second heteroatom selected from N, O or S, wherein said heterocycle is optionally substituted with methyl.
19. A pyrogen-free composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a carrier.
20. A compound represented by the structural formula:
or a salt thereof.
21. A compound represented by the structural formula:
or a salt thereof.
22. A pharmaceutical composition comprising a compound of any of one claims 1 , 20 or 21 and a pharmaceutically acceptable carrier.
23. The pharmaceutical composition of claim 22 , further comprising an additional active agent.