Dihydropyridines for the treatment of cognitive impairment or traumatic brain injury

Patent metadata

Field	Value
Publication number	US-11512052-B2
Application number	US-201816763962-A
Country	US
Kind code	B2
Filing date	Nov 20, 2018
Priority date	Nov 21, 2017
Publication date	Nov 29, 2022
Grant date	Nov 29, 2022

Abstract

A genus of dihydropyridine chemical modulators of synaptojanin is disclosed. These modulators are selective inhibitors of synaptojanin 1 and may be used to treat cognitive impairment or traumatic brain injury, including promoting regeneration in cases of traumatic brain injury, or for treating neurodegenerative disorders.

First claim

The invention claimed is:

1. A compound having a structure represented by a formula:

wherein
R 1 is selected from hydrogen, C 1 -C 6 alkyl, and C 3 -C 6 cycloalkyl; and
R 2 is selected from hydrogen, halogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 haloalkyl, nitro, cyano, C 1 -C 6 alkylthio, and C 1 -C 6 haloalkylthio;
with the provisos that:
when R 1 is hydrogen, R 2 is not chloro;
when R 1 is methyl, R 2 is not trifluoromethyl, trifluoromethoxy, cyano, chloro, or fluoro;
when R 1 is cyclopropyl, R 2 is not trifluoromethyl or trifluoromethoxy; and
when R 1 is ethyl, R 2 is not trifluoromethyl or trifluoromethoxy,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 1 is isopropyl.

3. The compound of claim 1 , wherein R 1 is hydrogen.

4. The compound of claim 1 , wherein R 2 is selected from C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, and nitro.

5. The compound of claim 4 , wherein R 2 is selected from methyl, methoxy, t-butyl, and nitro.

6. The compound of claim 1 , wherein R 1 is selected from hydrogen and isopropyl; and R 2 is selected from methyl, methoxy, t-butyl, and nitro.

7. The compound of claim 6 , wherein R 1 is hydrogen.

8. The compound of claim 1 , wherein the compound is selected from:

9. The compound of claim 8 , wherein the compound is selected from:

10. The compound of claim 9 , wherein the compound is:

11. The compound of claim 9 , wherein the compound is:

12. The compound of claim 1 , wherein the compound has a structure represented by a formula:

13. The compound of claim 1 , wherein the compound has a structure represented by a formula:

14. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the compound of claim 1 .

15. A method for treating cognitive impairment or traumatic brain injury in a patient, comprising administering to the patient a therapeutically effective amount of the compound of claim 1 .

16. The method of claim 15 , wherein said cognitive impairment or traumatic brain injury is selected from Alzheimer's disease, mild cognitive impairment, Lewy body dementia (LBD), frontotemporal dementia (FTD), vascular dementia, mixed dementia, or Down Syndrome.

17. The method of claim 16 , wherein said cognitive impairment or traumatic brain injury is Alzheimer's disease.

18. The method of claim 15 , wherein said cognitive impairment or traumatic brain injury is traumatic brain injury.

19. The method of claim 15 , wherein R 1 is selected from hydrogen and isopropyl; and R 2 is selected from methyl, methoxy, t-butyl, and nitro.

20. The method of claim 15 , wherein the compound is selected from:

Assignees

• Icahn School Med Mount Sinai
• Us Gov Veterans Affairs

Inventors

• Ohlmeyer Michael
• Cai Dongming

Classifications

• 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

• C07D211/90 Primary

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen · CPC title