Compositions and methods of inhibiting N-acylethanolamine-hydrolyzing acid amidase

Patent metadata

Field	Value
Publication number	US-10363237-B2
Application number	US-201615072194-A
Country	US
Kind code	B2
Filing date	Mar 16, 2016
Priority date	Oct 11, 2007
Publication date	Jul 30, 2019
Grant date	Jul 30, 2019

Abstract

Compounds and pharmaceutical compositions are contemplated that inhibit N-acyl-ethanolamine-hydrolyzing acid amidase (NAAA) to so increase the concentration of the substrate of NAAA, palmitoylethanolamide (PEA). NAAA inhibition is contemplated to be effective to alleviate conditions associated with a reduced concentration of PEA. Among other uses, various NAAA inhibitors are especially contemplated as therapeutic agents in the treatment of inflammatory diseases.

First claim

What is claimed is:

1. A method of treating a patient in need of increased levels of palmitoylethanolamide, comprising administering a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to Formula I

wherein
A is O; B is O, or NR a ; R 1 and R 2 are independently H, halogen, or optionally substituted lower alkyl; n is 1; X is NR b or CHR b ; Y is C(O), C(S), or CHR c ; Z is O, S, NR d , or CHR d ; V is optionally substituted lower alkyl or optionally substituted lower alkenyl; wherein W is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or C(R 3 R 4 R 5 ); and wherein Y and V may optionally form a 5- or 6 membered ring;
wherein R a , R b , R c , and R d are independently selected from the group consisting of H, optionally substituted lower alkyl, or optionally substituted lower thioalkyl; and
wherein R 3 , R 4 , and R 5 are independently H, optionally substituted lower alkyl, optionally substituted lower aryl, optionally substituted lower cycloheteroalkyl, or optionally substituted lower heteroaryl.

2. The method of claim 1 wherein X is NR b and Y is C(O) or C(S).

3. The method of claim 2 wherein Z is O or CHR d , V is lower alkyl, and wherein W is aryl or lower alkyl.

4. The method of claim 2 wherein W is aryl or lower alkyl.

5. The method of claim 1 wherein the patient has a condition associated with reduced levels of palmitoylethanolamide.

6. The method of claim 5 wherein the condition associated with reduced levels of palmitoylethanolamide includes an inflammatory component, and wherein administration of the composition reduces inflammation in the patient.

7. The method of claim 5 wherein the condition is rheumatoid arthritis, osteoarthritis, asthma, allergic dermatitis, psoriasis, an inflammatory bowel disease, or a spinal cord injury.

8. The method of claim 1 wherein the compound has the formula:

wherein
A is O; B is O, or NR a ; R 1 and R 2 are independently H, halogen, or optionally substituted lower alkyl; X is NR b or CHR b ; Y is C(O), C(S), or CHR c ; Z is O, S, NR d , or CHR d ; V is optionally substituted lower alkyl or optionally substituted lower alkenyl; wherein W is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted cycloheteroalkyl, or C(R 3 R 4 R 5 );
wherein R a , R b , R c , and R d are independently selected from the group consisting of H, optionally substituted lower alkyl, or optionally substituted lower thioalkyl; and
wherein R 3 , R 4 , and R 5 are independently H, optionally substituted lower alkyl, optionally substituted lower aryl, optionally substituted lower cycloheteroalkyl, or optionally substituted lower heteroaryl.

9. The method of claim 8 wherein R 3 , R 4 , and R 5 are independently H or lower alkyl.

10. The method of claim 8 wherein R 3 , R 4 , and R 5 are independently H.

11. The method of claim 8 wherein B is O.

12. The method of claim 8 wherein X is NR b and Y is C(O) or C(S).

13. The method of claim 8 wherein R 1 is H and R 2 is lower alkyl.

14. The method of claim 12 wherein R 1 is H and R 2 is lower alkyl.

15. The method of claim 8 wherein V is methyl, ethyl, n-propyl, n-butyl, t-butyl, i-butyl, 2-methylpropyl, cyclopropylmethyl, i-amyl, n-amyl, hexyl or optionally substituted lower alkenyl.

16. The method of claim 8 wherein V is n-amyl.

17. The method of claim 8 wherein Z is O or CHR d .

18. The method of claim 8 wherein W is phenyl substituted with hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido, nitro, carboxyl, cycloalkyl, heterocycle, cycloheteroalkyl, acyl, carboxyl, aryl, aryloxy, heteroaryl, arylalkyl, heteroarylalkyl, alkyl, alkenyl, alknyl or cyano.

19. The method of claim 8 wherein W is biphenyl.

20. The method of claim 8 wherein W is phenyl.

Assignees

• Univ California
• Univ Degli Studi Di Urbino “Carlo Bo”
• Univ Degli Studi Di Parma

Inventors

• Piomelli Daniele
• Tarzia Giorgio
• Mor Marco
• Duranti Andrea
• Tontini Andrea

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P29/00

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

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title

• A61P17/06

  Antipsoriatics · CPC title