IP Library › Granted Patent US 9,862,684

Granted Patent B2

US 9,862,684 · App. 14/815,480 · Granted Jan 9, 2018

Modulation of K2P channels

Inventors: Daniel L. Minor, Jr. (San Francisco, CA); Sviatoslav N. Bagriantsev (Guilford, CT); Adam R. Renslo (Oakland, CA)

Assignee: The Regents of the University of California

C07D209/88 A61K31/404 A61K31/405 A61K31/4045 A61K31/5415 C07D401/06

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Quick Facts

Patent No.: US 9,862,684
App. No.: 14/815,480
Granted: Jan 9, 2018
Kind: B2

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Abstract

Disclosed herein inter alia are compositions and methods useful in the treatment of diseases, for example pain, neurodegeneration, or mood disorders, and for modulating the activity of a K 2P channel.

Claims (38)

1. A compound having the formula:

wherein

L 1 is an unsubstituted C 1 -C 10 alkylene or unsubstituted C 3 -C 6 cycloalkylene;

L 2 is a bond, —O—, —S—, —NH—, —C(O)—, —C(O)NH—, —NHC(O)—, —S(O)—, or —S(O) 2 —;

R 1 and R 2 are independently halogen, —CF 3 , —CCl 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH 3 , —OCF 3 , —OCHF 2 , —N 3 ,

—C(CH 3 ) 3 , —OCH 2 CCH, —NHCH 2 CCH, —NHCH 3 , —N(CH 3 ) 2 , —NHS(O)CH 3 , —C(O)CH 3 , —CH 3 , —CH 2 CCH, —NHC(O)CH 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R 4 and R 5 are independently hydrogen, halogen, —CF 3 , —CCl 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH 3 , —OCF 3 , —OCHF 2 , —N 3 ,

where R 4 and R 5 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl;

R 3 is —C(O)OR 9 , —C(O)NR 7 R 8 , —SO 2 R 10 , —OPO(OH) 2 , —PO(OH) 2 , —SO 3 H, —SO 4 H, —C(O)R 9 , substituted or unsubstituted sulfonate, substituted or unsubstituted phosphate, substituted or unsubstituted 2 to 10 membered heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl;

R 7 , R 8 , R 9 , and R 10 , are independently hydrogen, oxo, halogen, —C(O)CH 3 , —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)CH 3 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF 3 , —OCHF 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; where R 7 and R 8 are bonded to the same nitrogen atom, they may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl;

W is —O—, —S—, —S(O)—, —S(O) 2 —, or —C(R 4 )(R 5 )—;

y is 0 or 1;

t1 and t2 are independently an integer from 1 to 4;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , having the formula:

3. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein W is —C(R 4 )(R 5 )—.

4. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 1 is halogen.

5. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 2 is halogen.

6. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 3 is substituted or unsubstituted heteroaryl.

7. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 3 is —COOH, substituted or unsubstituted sulfonate, phosphate, or tetrazolyl.

8. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound, or a pharmaceutically acceptable salt thereof, of claim 1 .

9. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 4 and R 5 are independently hydrogen, halogen, —CF 3 , —CCl 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 2 Cl, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH 3 , —OCF 3 , —OCHF 2 , —N 3 ,

where R 4 and R 5 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.

10. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 4 and R 5 are independently hydrogen, halogen, —CF 3 , —CCl 3 , —OH, —NH 2 , —COOH, —CONH 2 , —NO 2 , —SH, —SO 3 H, —SO 4 H, —SO 2 NH 2 , —NHNH 2 , —ONH 2 , —NHC═(O)NHNH 2 , —NHC═(O)NH 2 , —NHSO 2 H, —NHC═(O)H, —NHC(O)—OH, —NHOH, —OCH 3 , —OCF 3 , —OCHF 2 , —C(CH 3 ) 3 , —OCH 2 CCH, —NHCH 2 CCH, —NHCH 3 , —N(CH 3 ) 2 , —NHS(O)CH 3 , —C(O)CH 3 , —CH 3 , —CH 2 CCH, or —NHC(O)CH 3 ;

where R 4 and R 5 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.

11. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 4 and R 5 are independently hydrogen, —CF 3 , —CCl 3 , or substituted or unsubstituted C 1 -C 4 alkyl;

where R 4 and R 5 may optionally be joined to form a substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocycloalkyl.

12. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 4 and R 5 are joined to form a substituted or unsubstituted C 3 -C 8 cycloalkyl or substituted or unsubstituted 3 to 8 membered heterocycloalkyl.

13. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 4 and R 5 are joined to form an unsubstituted C 3 -C 6 cycloalkyl or unsubstituted 3 to 6 membered heterocycloalkyl.

14. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 4 and R 5 are joined to form an unsubstituted C 6 cycloalkyl.

15. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , wherein R 3 is substituted or unsubstituted

16. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , having the formula:

17. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , having the formula

18. The compound, or a pharmaceutically acceptable salt thereof, of claim 1 , having the formula

19. A method of treating a disease in a patient in need of such treatment, said method comprising administering a therapeutically effective amount of a compound of claim 1 to said patient, wherein said disease is selected from the group consisting of a neurological disease, pain, migraine, ischemic injury, brain ischemia, stroke, a neurodegenerative disease, a mood disorder, depression, and decompression sickness.

20. A method of increasing the level of activity of TREK-1 in a cell comprising contacting the cell with an effective amount of a compound of claim 1 .

Assignments (2)

CONFIRMATORY LICENSE Recorded Sep 10, 2015

From: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT

Reel/Frame 036585/0867 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 28, 2015

From: RENSLO, ADAM R.; MINOR, DANIEL L., JR; BAGRIANTSEV, SVIATOSLAV N.

To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

Reel/Frame 036452/0582 →

Continuity (3)

Continuation PCTUS2014027611 · Mar 14, 2014

Provisional Application 61785155 · Mar 14, 2013

Related Publication 20160031814A1 · Feb 4, 2016