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 benfit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
1. A compound of the formula:
or a salt thereof, wherein
R 19 is
wherein:
each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from CR 20 or CR 1 ′;
wherein:
zero to one R 20 is a solubilizing group; and
zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl;
each R 20 is independently selected from H or a solubilizing group;
R 21 is —NR 1 ′—C(O)—;
each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that R 31 is not 4-cyanophenyl or
2. A compound of the formula:
or a salt thereof wherein
R 19 is
wherein:
each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from CR 20 or CR 1 ′;
wherein:
zero to one R 20 is a solubilizing group; and
zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl;
each R 20 is independently selected from H or a solubilizing group;
R 20a is independently selected from H or a solubilizing group;
R 21 is —NR 1 ′—C(O)—;
wherein
each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, wherein when Z 10 , Z 11 , Z 12 and Z 13 are each CH, R 20a is a solubilizing group.
3. A compound of the formula:
or a salt thereof, wherein
R 21 is —NR 1 ′—C(O)—;
wherein
R 1 ′ is H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 32 is an optionally substituted monocyclic or bicyclic heteroaryl, or an optionally substituted bicyclic aryl, wherein:
when R 21 is —NH—C(O)—, R 32 is not furan-2-yl, 5-bromofuran-2-yl, or 2-phenyl-4-methylthiazol-5-yl.
4. A compound of the formula:
or a salt thereof, wherein:
R 21 is —NR 1 ′—C(O)—,
wherein R 1 ′ is optionally substituted C 1 -C 3 straight or branched alkyl; and
R 33 is an optionally substituted phenyl.
5. A compound of the formula:
or a salt thereof wherein:
R 21 is —NH—C(O)—; and
R 33 is phenyl substituted with
a) one —N(CH 3 ) 2 group;
b) one CN group at the 3 position;
c) one —S(CH 3 ) group; or
d)
bridging the 3 and 4 positions.
6. A composition comprising a compound of the formula:
or a salt thereof, wherein
R 19 is selected from:
wherein:
each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from CR 20 or CR 1 ′;
wherein:
zero to one R 20 is a solubilizing group; and
zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl;
each R 20 is independently selected from H or a solubilizing group;
R 21 is —NR 1 ′—C(O)—;
each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R 19 is
Z 10 , Z 11 , Z 12 and Z 13 are each CH, R 20 is H, and R 21 is —NHC(O)—, R 31 is not an optionally substituted phenyl,
wherein the composition is pyrogen-free.
7. A pharmaceutical composition comprising:
a) a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R 19 is selected from:
wherein:
each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from CR 20 or CR 1 ′;
wherein:
zero to one R 20 is a solubilizing group; and
zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl;
each R 20 is independently selected from H or a solubilizing group;
R 21 is —NR 1 ′—C(O)—;
each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that
when R 19 is
Z 10 , Z 11 , Z 12 and Z 13 are each CH, R 20 is H, and R 21 is —NHC(O)—, R 31 is not an optionally substituted phenyl; and
b) a pharmaceutically acceptable carrier or diluent.
8. A packaged pharmaceutical comprising a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein
R 19 is selected from:
wherein:
each Z 10 , Z 11 , Z 12 and Z 13 is independently selected from CR 20 or CR 1 ′;
zero to one R 20 is a solubilizing group; and
zero to one R 1 ′ is an optionally substituted C 1 -C 3 straight or branched alkyl;
each R 20 is independently selected from H or a solubilizing group;
R 21 is —NR 1 ′—C(O)—;
each R 1 ′ is independently selected from H or optionally substituted C 1 -C 3 straight or branched alkyl; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl, with the proviso that when R 19 is
Z 10 , Z 11 , Z 12 and Z 13 are each CH, R 20 is H and R 21 is —NHC(O)—, R 31 is not an optionally substituted phenyl.
9. The compound of claim 1 , having the formula:
wherein
R 20 is selected from H or a solubilizing group;
R 21 is —NH—C(O)—; and
R 31 is selected from an optionally substituted monocyclic or bicyclic aryl, or an optionally substituted monocyclic or bicyclic heteroaryl.
10. The compound according to claim 1 , wherein:
R 20 is selected from H, —CH 2 —N(CH 3 ) 2 ,
11. The compound according to claim 1 , wherein:
R 31 is selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidinyl, thienyl, naphthyl, benzopyrazolyl, benzofuryl, quinolinyl, quinoxalinyl, or benzothienyl and wherein R 31 is optionally substituted.
12. The compound according to claim 2 , wherein:
R 20a is selected from H, —CH 2 —N(CH 3 ) 2 ,
13. The compound according to claim 2 , wherein:
R 31 is selected from phenyl, pyrazolyl, furyl, pyridyl, pyrimidinyl, thienyl, naphthyl, benzopyrazolyl, benzofuranyl, quinolinyl, quinoxalinyl, or benzothienyl and wherein R 31 is optionally substituted.
14. The compound according to claim 3 , wherein:
R 32 is selected from pyrrolyl, pyrazolyl, pyrazinyl, furyl, pyridyl, pyrimidinyl, or thienyl, and R 32 is optionally substituted and is optionally benzofused.
15. The compound according to claim 3 , wherein
R 32 is selected from benzofuryl, methylfuryl, benzothienyl, pyridyl, pyrazinyl, pyrimidinyl, pyrazolyl, wherein said methyfuryl, pyridyl, pyrazinyl, pyrimidinyl or pyrazolyl is optionally benzofused and wherein R 32 is optionally substituted or further substituted.
16. A composition comprising a compound of claim 1 , wherein the composition is pyrogen-free.
17. A composition comprising a compound of claim 2 , wherein the composition is pyrogen-free.
18. A composition comprising a compound of claim 3 , wherein the composition is pyrogen-free.
19. A composition comprising a compound of claim 4 , wherein the composition is pyrogen-free.
20. A composition comprising a compound of claim 5 , wherein the composition is pyrogen-free.
21. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 1 .
22. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 2 .
23. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 3 .
24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 4 .
25. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of claim 5 .
26. A packaged pharmaceutical comprising a compound of claim 1 .
27. A packaged pharmaceutical comprising a compound of claim 2 .
28. A packaged pharmaceutical comprising a compound of claim 3 .
29. A packaged pharmaceutical comprising a compound of claim 4 .
30. A packaged pharmaceutical comprising a compound of claim 5 .