Tetrahydroquinoline substituted hydroxamic acids as selective histone deacetylase 6 inhibitors

Patent metadata

Field	Value
Publication number	US-10456394-B2
Application number	US-201715998610-A
Country	US
Kind code	B2
Filing date	Feb 15, 2017
Priority date	Feb 16, 2016
Publication date	Oct 29, 2019
Grant date	Oct 29, 2019

Abstract

Histone deacetylases inhibitors (HDACIs) and compositions containing the same are disclosed. Methods of treating diseases and conditions wherein inhibition of HDAC provides a benefit, like a cancer, a neurodegenerative disorder, a neurological disease, traumatic brain injury, stroke, malaria, an autoimmune disease, autism, and inflammation, also are disclosed.

First claim

What is claimed is:

1. A compound having Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
represents a single or double bond;
n=0, 1, or 2;
R 1 and R 2 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, trifluoromethyl, cyano, —NR a R b , —C(O)NR a R b , acetyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, aryl, heteroaryl, or C 5 -C 6 heterocyclyl;
R a and R b are independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, or these groups may be joined to form a 3-7 membered heterocycyl;
A is CR c R d or C═O;
B is CR c R d when represents a single bond or CR c when represents a double bond;
D is CR c R d , C═O, NR e , O, S, S═O when represents a single bond or CR c or N when represents a double bond;
R c and R d are independently hydrogen, C 1 -C 6 alkyl, or are joined together to form a 3-6 membered cycloalkyl;
R e is independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, aryl, heteroaryl, or C 5 -C 6 heterocycloalkyl; and
R 3 and R 4 are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl; in the case where one of R 3 or R 4 is a hydrogen atom, and the other group is alkyl, a chiral center is generated which may be of the R or S configuration.

2. A compound according to claim 1 of formula Ib

wherein
R 1 , R 2 , and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxyl, trifluoromethyl, cyano, —NR a R b , C(O)NR a R b , acetyl, C 1 -C 6 alkyl, C 1 -C 6 alkenyl, C 1 -C 6 alkynyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 6 cycloalkyl, aryl, heteroaryl, and C 5 -C 6 heterocycloalkyl; and
R a and R b are independently selected from the group consisting of hydrogen and C 1 -C 6 alkyl, or these groups may be joined to form a 3-7 membered heterocyclyl.

3. A compound according to claim 1 of formula 1c

wherein R 1 and R 2 are independently selected from H, Cl and F; and
R 3 is H or F.

4. A composition comprising (a) compound of claim 1 , (b) a second therapeutic agent useful in the treatment of a disease or condition wherein inhibition of HDAC provides a benefit, and (c) an optional excipient and/or pharmaceutically acceptable carrier.

5. The composition of claim 4 wherein the second therapeutic agent comprises a chemotherapeutic agent useful in the treatment of a cancer.

6. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or vehicle.

7. A method of treating a disease or condition wherein inhibition of HDAC provides a benefit comprising administering a therapeutically effective amount of a compound of claim 1 to an individual in need thereof.

8. The method of claim 7 wherein the HDAC is HDAC6.

9. The method of claim 7 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the disease or condition.

10. The method of claim 9 wherein the compound and the second therapeutic agent are administered simultaneously.

11. The method of claim 9 wherein the compound and the second therapeutic agent are administered separately.

12. The method of claim 7 wherein the disease or condition is a cancer.

13. The method of claim 9 wherein the disease is a cancer and the second therapeutic agent is one or more of a chemotherapeutic agent, radiation, and an immunotherapy.

14. The method of claim 13 wherein the second therapeutic agent comprises radiation, and the radiation optionally is administered in conjunction with radiosensitizers and/or therapeutic agents.

15. The method of claim 7 wherein the disease or condition is a neurological disease, a neurodegenerative disorder, peripheral neuropathy, or a traumatic brain injury.

16. The Method of claim 15 wherein the disease or condition is a stroke.

17. The method of claim 7 wherein the disease or condition is an inflammation or an autoimmune disease.

18. The method of claim 17 further comprising administering a therapeutically effective amount of a second therapeutic agent useful in the treatment of the autoimmune disease or the inflammation.

19. A method of increasing sensitivity of a cancer cell to cytotoxic effects of a radiotherapy and/or a chemotherapy comprising contacting the cell with a compound of claim 1 in an amount sufficient to increase the sensitivity of the cell to the radiotherapy and/or the chemotherapy.

Assignees

• Univ Illinois

Inventors

• Kozikowski Alan
• Shen sida
• Bergman Joel
• Gaisina Irina

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D215/18

  Halogen atoms or nitro radicals · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• C07D215/227

  only one oxygen atom which is attached in position 2 · CPC title