Nrf and HIF activators/HDAC inhibitors and therapeutic methods using the same

Patent metadata

Field	Value
Publication number	US-10934255-B2
Application number	US-201816603266-A
Country	US
Kind code	B2
Filing date	Apr 25, 2018
Priority date	Apr 26, 2017
Publication date	Mar 2, 2021
Grant date	Mar 2, 2021

Abstract

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.

First claim

What is claimed is:

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

Assignees

• Univ Illinois

Inventors

• Gaisina Irina
• Kozikowski Alan

Classifications

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title

• A61K51/0453

  having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title

• C07D235/30

  Nitrogen atoms not forming part of a nitro radical · CPC title

• A61K31/4706

  4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine · CPC title