Nrf and HIF activators/HDAC inhibitors and therapeutic methods using the same
View Patent ↗Compounds that inhibit histone (HDACI) and/or activate Nrf2 and HIF, and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC and/or activation of Nrf2 and HIF provide a benefit, like a cancer, a neurodegenerative disorder, a peripheral neuropathy, a neurological disease, traumatic brain injury, stroke, hypertension, malaria, an autoimmune disease, autism, autism spectrum disorders, and inflammation, also are disclosed.
1. A compound having a structural formula
wherein A is
wherein X is —CH 2 — or
Y, independently, is selected from the group consisting of halo, —OH, —CN, —NO 2 , C 1-6 alkyl, aryl,
heteroaryl, —OR a , —N(R a ) 2 , —NHR a , —CO—N(R a ) 2 , —NHCO—R a , —CO 2 R a , —SR a , —OCOR a , —NHSO 2 R a , —SO 2 N(R a ) 2 , and —SO 2 R a ; or
two Y groups, positioned ortho to one another, are taken together with the carbon atoms to which they are attached to form a five or six-membered carbocylic ring or a five or six-membered heterocyclic ring containing one or two heteroatoms selected from O, S, and NR a ;
m is an integer 0, 1, 2, 3, or 4;
Z, independently, is selected from the group consisting of halo, —OH, —CN, —NO 2 , C 1-6 alkyl, aryl,
heteroaryl, —OR a , —N(R a ) 2 , —NHR a , —CO—N(R a ) 2 , —NHCO—R a , —CO 2 R a , —SR a , —OCOR a , —NHSO 2 R a , —SO 2 N(R a ) 2 , and —SO 2 R a ; or
two Z groups, positioned ortho to one another, are taken together with the carbon atoms to which they are attached to form a five or six-membered carbocyclic ring or a five or six-membered heterocyclic ring containing one or two heteroatoms selected from O, S, and NR a ;
n is an integer 0, 1, 2, 3, or 4;
R 1 and R 2 , independently, are hydrogen, halo, or C 1-6 alkyl, or R 1 is a five- or six-membered nitrogen-containing ring and R 2 is hydrogen, halo, or C 1-6 alkyl, or R 1 and R 2 are taken together with the carbon atoms to which they are attached to form a three to six-membered carbocyclic ring or heterocyclic ring;
R a is hydrogen, C 1-6 alkyl, aryl, or heteroaryl;
R 3 is hydrogen, C 1-6 alkyl, —CH 2 aryl, aryl, or heteroaryl;
R 4 is hydrogen or halo; and
R 5 is C 1-3 alkyl or aryl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein Y is null, Cl, F, —OCH 3 , —OBn, —NO 2 , —N(CH 3 ) 2 , —NHSO 2 CH 3 , —SCH 3 , —C 6 H 5 ,
or wherein two Y groups ortho to one another are taken together to form
3. The compound of claim 1 wherein m is 2 and each Y is halo.
4. The compound of claim 3 wherein a first Y is F and a second Y is Cl.
5. The compound of claim 1 wherein m is 0, 1, or 2.
6. The compound of claim 1 wherein R 1 and R 2 each are hydrogen, each are methyl, each are fluoro, or are taken together with the carbon to which they are attached to form a cyclopropyl group.
7. The compound of claim 1 wherein R 3 is H, —CH 3 , or —CH 2 C 6 H 5 .
8. The compound of claim 1 wherein R 4 is H or F.
9. The compound of claim 1 wherein R 5 is —CH 3 or —C 6 H 5 .
10. The compound of claim 1 wherein Z is null, Cl, or —OCH 3 .
11. A compound selected from the group consisting of
12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.
13. A method of treating a disease or condition wherein inhibition of HDAC and/or activation of Nrf2 and HIF provides a benefit comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof.
14. The method of claim 13 wherein the HDAC is HDAC6.
15. The method of claim 13 wherein the disease or condition is a cancer.
16. The method of claim 13 wherein the disease or condition is a neurological disease, a neurodegenerative disorder, peripheral neuropathy, a traumatic brain injury, stroke, an inflammation, or an autoimmune disease.
17. The compound of claim 1 wherein m is 1 and Y is Cl or F.
18. The compound of claim 11 selected from the group consisting of