Selective potassium channel agonists

Patent metadata

Field	Value
Publication number	US-11358930-B2
Application number	US-201917048878-A
Country	US
Kind code	B2
Filing date	Mar 8, 2019
Priority date	Apr 20, 2018
Publication date	Jun 14, 2022
Grant date	Jun 14, 2022

Abstract

Selective potassium channel agonists and methods of use thereof are disclosed. A compound, or a pharmaceutically acceptable salt thereof, having a formula Iwherein R1 is H or optionally-substituted alkyl; R2 is optionally-substituted C1-C6 alkyl or optionally-substituted cyclopropyl; R3 and R4 are each independently H or optionally-substituted alkyl; R5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl; R6 and R7 are each independently H, optionally-substituted alkyl, or R6 and R7 together form a carbocycle; R8 is substituted phenyl or optionally-substituted pyridinyl, provided that if R8 is substituted phenyl, then R2 is optionally-substituted cyclopropyl; and R9, R10 and R11 are each independently H, halo, or optionally-substituted alkyl.

First claim

I claim:

1. A compound, or a pharmaceutically acceptable salt thereof, having a formula I

wherein:
R 1 is H or optionally-substituted alkyl;
R 2 is optionally-substituted cyclopropyl or optionally-substituted C 1 -C 6 alkyl;
R 3 and R 4 are each independently H or optionally-substituted alkyl;
R 5 is H, optionally-substituted alkyl, acyl, or alkoxycarbonyl;
R 6 and R 7 are each independently H, optionally-substituted alkyl, or R 6 and R 7 together form a carbocycle;
R 8 is substituted phenyl or optionally-substituted pyridinyl, provided that if R 8 is substituted phenyl, then R 2 is optionally-substituted cyclopropyl; and
R 9 , R 10 and R 11 are each independently H, halo, or optionally-substituted alkyl.

2. The compound according to claim 1 , wherein:
(i) R 1 and R 5 are H;
(ii) R 3 and R 4 are H;
(iii) R 7 and R 8 are H; or
(iv) any combination of (i), (ii), and (iii).

3. The compound according to claim 1 , wherein R 2 is cyclopropyl or unsubstituted C 1 -C 6 alkyl.

4. The compound according to claim 3 , wherein R 2 is cyclopropyl or ethyl.

5. The compound according to claim 1 , wherein R 8 is

and
wherein:
Y 1 and Y 2 independently are CH, CX where X is halo, N, or CCN, provided that at least one of Y 1 and Y 2 is CH or CX;
R 12 is halo or substituted sulfanyl; and
n is 0, 1, or 2.

6. The compound according to claim 5 having a formula II:

wherein if Y 1 and Y 2 independently are CH or CX, then R 2 is cyclopropyl.

7. The compound according to claim 5 , wherein:
one of Y 1 and Y 2 is N;
the other of Y 1 and Y 2 is CH; and
R 2 is cyclopropyl or ethyl.

8. The compound according to claim 5 wherein Y 1 and Y 2 independently are CH or CX, and the compound has a formula III

9. The compound according to claim 5 , wherein n is 0 or 1.

10. The compound according to claim 9 , wherein n is 1, R 12 is F, and R 12 is at the C6 position.

11. The compound according to claim 5 , wherein n is 0.

12. The compound according to claim 1 , wherein:
R 9 and R 10 independently are H, F, or haloalkyl; and
R 11 is F.

13. The compound according to claim 1 , wherein the compound is:

14. A pharmaceutical composition comprising at least one compound according to claim 1 , and at least one pharmaceutically acceptable additive.

15. A method of activating a potassium channel, comprising contacting the potassium channel with an effective amount of at least one compound according to claim 1 or a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable additive.

16. The method of claim 15 , wherein the potassium channel is KCNQ2/3.

17. The method of claim 15 , wherein contacting the potassium channel with an effective amount of the compound or pharmaceutical composition comprises administering the effective amount of the compound or pharmaceutical composition to a subject.

18. A method of treating a subject suffering from or susceptible to tinnitus or epilepsy, comprising administering to the subject a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable additive.

Assignees

• Univ Of Pittsburgh—Of The Commonwealth System Of Higher Education

Inventors

• Wipf Peter

Classifications

• A61P27/16

  Otologicals · CPC title

• C07D213/84

  Nitriles · CPC title

• A61P25/08 Primary

  Antiepileptics; Anticonvulsants · CPC title

• C07D213/61

  Halogen atoms or nitro radicals · CPC title

• C07C271/26 Primary

  with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring · CPC title