Inhibitors of fatty acid amide hydrolase (FAAH) enzyme with improved oral bioavailability and their use as medicaments

Patent metadata

Field	Value
Publication number	US-9822068-B2
Application number	US-201615287366-A
Country	US
Kind code	B2
Filing date	Oct 6, 2016
Priority date	Apr 7, 2014
Publication date	Nov 21, 2017
Grant date	Nov 21, 2017

Abstract

Described herein, inter alia, are compositions and methods useful for inhibiting fatty acid amide hydrolase.

First claim

The invention claimed is:

1. A compound, or a pharmaceutically acceptable salt thereof, of formula:

wherein,
R 1 is substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;
R 2 is independently halogen, —CX 3 , —OCX 3 ,or —OCHX 2 ;
R 3 is —SO 2 R 6 , —SO 2 NR 4 R 5 , or —C(O)NR 4 R 5 ;
R 4 , R 5 , and R 6 are independently hydrogen, substituted or unsubstituted C 1 -C 8 alkyl or substituted or unsubstituted 2 to 8 membered heteroalkyl; where R 4 and R 5 are optionally joined to form a substituted or unsubstituted 4 to 8 membered heterocycloalkyl or substituted or unsubstituted 5 to 6 membered heteroaryl;
the symbol z is an integer from 1 to 4; and
X is —F, —Cl, —Br, or —I;
with the proviso that the compound is not

2. The compound of claim 1 , wherein the compound is of formula:

3. The compound of claim 1 , wherein the compound is of formula:

4. The compound of claim 1 , wherein the compound is of formula:

5. The compound of claim 1 , wherein R 1 is unsubstituted C 3 -C 8 cycloalkyl or unsubstituted 3 to 8 membered heterocycloalkyl.

6. The compound of claim 1 , wherein R 2 is independently halogen or —OCHX 2 .

7. The compound of claim 1 , wherein R 3 is —C(O)NR 4 R 5 .

8. The compound of claim 1 , wherein R 3 is —SO 2 NR 4 R 5 .

9. The compound of claim 1 , wherein R 4 is hydrogen or unsubstituted C 1 -C 4 alkyl.

10. The compound of claim 1 , wherein R 5 is hydrogen or unsubstituted C 1 -C 4 alkyl.

11. The compound of claim 1 , wherein R 3 is —SO 2 R 6 .

12. The compound of claim 11 , wherein R 6 is unsubstituted methyl.

13. The compound of claim 1 , wherein R 1 is cyclobutyl, cyclopentyl, or cyclohexyl;
R 2 is —F or —OCHF 2 ;
R 3 is —SO 2 NH 2 , —SO 2 NHMe, —SO 2 NMe 2 , —CONH 2 , —CONHMe, —CONMe 2 , or —SO 2 Me; and
z is 1.

14. The compound of claim 1 , wherein the compound is not

15. The compound of claim 1 , wherein the compound is

16. The compound of claim 1 , wherein the compound has an oral bioavailability of greater than 35% in a subject.

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

18. A method of treating reduced appetite, gastric damage, enteric damage, tobacco smoking, substance abuse, anxiety, post-traumatic stress disorder, schizophrenia, pain, inflammation, or ocular glaucoma, in a subject comprising administering to the subject a compound of claim 1 , or pharmaceutically acceptable salt thereof.

19. A method of increasing the level of a fatty acid ethanolamide (FAE) in a subject, comprising administering to the subject a compound of claim 1 , or pharmaceutically acceptable salt thereof.

20. A method of inhibiting the level of activity of FAAH in a subject, comprising administering to the subject a compound of claim 1 , or pharmaceutically acceptable salt thereof.

Assignees

• Univ California
• Fondazione St Italiano Tecnologia
• Fondazione Istituto Italiano Di Tech

Inventors

• Piomelli Daniele
• Bandiera Tiziano
• Scarpelli Rita

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/34

  Tobacco-abuse · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• C07C2601/08

  the ring being saturated · CPC title