Peripherally restricted FAAH inhibitors

Patent metadata

Field	Value
Publication number	US-9187413-B2
Application number	US-201113812777-A
Country	US
Kind code	B2
Filing date	Jul 22, 2011
Priority date	Jul 28, 2010
Publication date	Nov 17, 2015
Grant date	Nov 17, 2015

Abstract

Peripherally restricted inhibitors of fatty acid amide hydrolase (FAAH) are provided. The compounds can suppress FAAH activity and increases anandamide levels outside the central nervous system (CNS). Despite their relative inability to access brain and spinal cord, the compounds attenuate behavioral responses indicative of persistent pain in rodent models of inflammation and peripheral nerve injury, and suppresses noxious stimulus-evoked neuronal activation in spinal cord regions implicated in nociceptive processing. CBi receptor blockade prevents these effects. Accordingly, the invention also provides methods, and pharmaceutical compositions for treating conditions in which the inhibition of peripheral FAAH would be of benefit. The compounds of the invention are according to the formula (I): in which R 1 is a polar group. In some embodiments, R 1 is selected from the group consisting of hydroxy and the physiologically hydro lysable esters thereof. R 2 and R 3 are independently selected from the group consisting of hydrogen and substituted or unsubstituted hydrocarbyl; each R 4 is independently selected from the group consisting of halogen and substituted or unsubstituted hydrocarbyl and n is an integer from 0 to 4; each R 5 is independently selected from the group consisting of halo and substituted or unsubstituted hydrocarbyl and m is an integer from 0 to 3; and R 6 is substituted or unsubstituted cyclohexyl; and the pharmaceutically acceptable salts thereof.

First claim

What is claimed is:

1. A compound having the formula:

wherein R 1 is selected from the group consisting of hydroxy and the physiologically hydrolyzable esters thereof, —OC(O)R 7 , —O—CO—NR 8 R 9 and —NR 8 R 9 , wherein R 7 is substituted or unsubstituted hydrocarbyl and R 8 and R 9 are independently selected from the group consisting of hydrogen and substituted or unsubstituted hydrocarbyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen and substituted or unsubstituted hydrocarbyl;
each R 4 is independently selected from the group consisting of halogen and substituted or unsubstituted hydrocarbyl and n is an integer from 0 to 4;
each R 5 is independently selected from the group consisting of halo and substituted or unsubstituted hydrocarbyl and m is an integer from 0 to 3;
R 6 is substituted or unsubstituted cyclohexyl; and
the pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein R 1 is —OC(O)R 7 , wherein R 7 is substituted or unsubstituted hydrocarbyl.

3. The compound of claim 1 , wherein R 1 is —O—CO—NR 8 R 9 .

4. The compound of claim 1 , wherein both of R 2 and R 3 are independently selected from (C 1 -C 3 )alkyl and H.

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

6. The compound of claim 1 , wherein R 4 and R 5 are each independently selected from halogen and substituted or unsubstituted (C 1 -C 3 )alkyl.

7. The compound of claim 1 , wherein R 7 is substituted or unsubstituted (C 1 -C 3 )alkyl.

8. The compound of claim 1 , wherein R 1 is the physiologically hydrolysable ester.

9. The compound of claim 1 , wherein R 1 is hydroxy and at least one of R 2 and R 3 is hydrogen.

10. The compound of claim 1 , wherein R 1 is hydroxy and both of R 2 and R 3 are hydrogen.

11. The compound of claim 1 in which m is 0.

12. The compound of claim 1 in which n is 0.

13. The compound of claim 1 wherein the sum of m and n is 1, 2, or 3.

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

and the pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition comprising a compound of claim 1 .

16. A pharmaceutical composition for selectively inhibiting peripheral Fatty Acid Amide Hydrolase (FAAH), said composition comprising a compound of claim 1 and a pharmaceutically acceptable excipient.

17. A method of treating pain by administering to a mammal in need thereof, a therapeutically effective amount of a compound of claim 1 , wherein the pains is post trigeminal neuralgia, peripheral or polyneuropathic pain, complex regional pain syndrome, reflex sympathetic dystrophy, diabetic neuropathy, toxic neuropathy, chronic neuropathy caused by chemotherapeutic agents, renal colic pain, liver pain, fibromyalgia, due to compression of a nerve, due to transection of a nerve, due to spinal cord injury, post-surgical pain, or due to scar formation.

18. A method of treating inflammation by administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 .

19. A method of increasing in a mammal in need thereof peripheral levels of anandamide, oleoylethanolamide (OEA), palmitylethanolamide (PEA), or stearoylethanolamide (SEA) by administering a compound of claim 1 .

20. The method of claim 19 , wherein the OEA, PEA, SEA or anandamide is endogenous to the mammal.

21. The method of claim 19 , wherein the OEA, PEA, SEA or anandamide was administered to the mammal before, after, or contemporaneous with the administration of the compound.

22. The method of claim 19 , wherein the administration of the OEA, PEA, SEA or anandamide is contemporaneous with the administration of the compound.

23. The compound of claim 1 , wherein R 2 , R 3 , R 7 , R 8 , and R 9 are independently selected from hydrogen and unsubstituted hydrocarbyl.

24. The compound of claim 1 , wherein R 2 , R 3 , R 7 , R 8 , and R 9 are independently hydrogen or unsubstituted C 1 to C 3 hydrocarbyl.

Assignees

• Piomelli Daniele
• Clapper Jason R
• Moreno-Sanz Guillermo
• Duranti Andrea
• Guiducci Giovanna
• Mor Marco
• Tarzia Giorgio
• Univ California
• Univ Parma
• Univ Degli Studi Urbino

Inventors

• Piomelli Daniele
• Clapper Jason R
• Moreno-Sanz Guillermo
• Duranti Andrea
• Tontini Andrea
• Mor Marco
• Tarzia Giorgio

Classifications

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P37/02

  Immunomodulators · 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