Meta-substituted biphenyl peripherally restricted FAAH inhibitors

Patent metadata

Field	Value
Publication number	US-9745255-B2
Application number	US-201414183073-A
Country	US
Kind code	B2
Filing date	Feb 18, 2014
Priority date	Aug 19, 2011
Publication date	Aug 29, 2017
Grant date	Aug 29, 2017

Abstract

The present invention provides methods of making and using peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH). The present invention provides compounds and compositions that suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). The present invention also sets forth methods for inhibiting FAAH as well as methods for treating conditions such as, but not limited to, pain, inflammation, immune disorders, dermatitis, mucositis, the over reactivity of peripheral sensory neurons, neurodermatitis, and an overactive bladder. Accordingly, the invention also provides compounds, methods, and pharmaceutical compositions for treating conditions in which the selective inhibition of peripheral FAAH (as opposed to CNS FAAH) would be of benefit.

First claim

What is claimed is:

1. A compound having the formula:

wherein:
R 1 is selected from the group consisting of hydrogen, hydroxy and the physiologically hydrolyzable esters thereof, carboxy and the physiologically hydrolysable esters thereof, hydroxyl-(C 1 -C 3 )alkyl and the physiologically hydrolyzable esters thereof, and —NR 7 R 8 , wherein R 7 and R 8 are independently selected from hydrogen or (C 1 -C 3 )alkyl and R 9 is selected from hydrogen, methyl, ethyl, trifluoromethyl or trifluoroethyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen and unsubstituted (C 1 -C 3 )alkyl;
each R 4 is independently selected from the group consisting of hydrogen and unsubstituted (C 1 -C 3 )alkyl and n is an integer from 0 to 4;
R 5 is hydrogen, carboxy and the physiologically hydrolysable esters thereof, or hydroxyl-(C 1 -C 3 )alkyl and the physiologically hydrolyzable esters thereof,
R 6 is an unsubstituted or substituted cyclohexyl, cyclopentyl, cyclobutyl or tetrahydropyran-4-yl;
or a pharmaceutically acceptable salt thereof,
wherein only one of R 1 and R 5 is hydrogen.

2. The compound of claim 1 , wherein R 2 and R 3 are each H.

3. The compound of claim 1 , wherein, R 6 is unsubstituted.

4. The compound of claim 1 , wherein R 6 is cyclohexyl.

5. The compound of claim 1 , wherein, R 7 and R 8 are each H.

6. The compound of claim 1 , wherein n is 0 or 1.

7. The compound of claim 1 , wherein each member of the R 1 , R 6 , R 7 , and R 8 Markush groups is unsubstituted.

8. The compound of claim 1 , wherein R 1 is hydroxy or a physiologically hydrolysable ester thereof.

9. The compound of claim 8 , wherein the physiologically hydrolysable ester is of the formula —OC(O)R 10 and R 10 is substituted or unsubstituted hydrocarbyl.

10. The compound of claim 1 , wherein R 5 is COOH or CH 2 OH.

11. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

12. A method of treating a condition selected from the group consisting of pain and inflammation in a mammal in need thereof, comprising administering to the mammal an effective amount of a compound of claim 1 .

13. The compound of claim 1 , wherein R 1 is hydrogen; and R 5 is independently hydroxyl-(C 1 -C 3 )alkyl or the physiologically hydrolyzable esters thereof or carboxy or the physiologically hydrolysable esters thereof.

14. The compound of claim 1 wherein R 1 is hydroxy or the physiologically hydrolyzable esters thereof, carboxy or the physiologically hydrolysable esters thereof, hydroxyl-(C 1 -C 3 )alkyl or the physiologically hydrolyzable esters thereof, —NR 7 R 8 , R 7 and R 8 are independently selected from hydrogen or (C 1 -C 3 )alkyl; and R 5 is hydrogen.

15. The compound of claim 1 , wherein R 5 is COOH or a physiologically hydrolyzable ester thereof.

16. The compound of claim 1 , wherein R 5 is CH 2 OH, or a physiologically hydrolyzable ester thereof.

17. The compound of claim 1 , wherein the compound has the formula:

18. The compound of claim 1 , wherein the compounds has the formula:

19. The compound of claim 1 , wherein the compounds has the formula:

20. The compound of claim 1 , wherein the compounds has the formula:

Assignees

• Univ California
• Fond St Italiano Tecnologia
• Univ Degli Studi Di Urbino “Carlo Bo”
• Univ Degli Studi Di Parma
• Fond St Italiano Di Tech

Inventors

• Piomelli Daniele
• Moreno-Sanz Guillermo
• Bandiera Tiziano
• Mor Marco
• Tarzia Giorgio

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P25/02

  for peripheral neuropathies · CPC title