IONIZABLE INHIBITORS OF FATTY ACID AMIDE HYDROLASE

Abstract

Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity leads to increased levels of fatty acid amides. Esters of alkylcarbamic acids are disclosed that are inhibitors of FAAH activity. Compounds disclosed herein inhibit FAAH activity. Described herein are processes for the preparation of esters of alkylcarbamic acid compounds, compositions that include them, and methods of use thereof.

Description

Claims

1. A compound of Formula (II):

2. The compound of claim 1, wherein one of A or B is -L-G and the other is H.

3. The compound of claim 1, wherein A is -L-G.

4. The compound of claim 1, wherein B is -L-G.

5. The compound of claim 1, wherein R2 is H.

6. The compound of claim 1, wherein: L is a bond, or an optionally substituted group selected from among C1-C6 alkylene, C1-C6 ketoalkylene, —C(O)NR9—(CH2)n—, —NR9—C(O)—(CH2)n—, —S(O)2—(CH2)n—, and —S(O)2NH—(CH2)n—.

7. The compound of claim 6, wherein L is a bond.

8. The compound of claim 1, wherein if L is not a bond, L taken together with A or B can form a carbocyclic ring.

9. The compound of claim 1, wherein: G is —N(R9)2, —C(═NR10)N(R9)2, —NR9C(═NR10)N(R9)2, —NR9C(═NR10)NHC(═NR10)N(R9)2, NR9C(═CHR10)N(R9)2, —C(O)NR9C(═NR10)N(R9)2, or —C(O)NR9C(═CHR10)N(R9)2.

10. The compound of claim 1, wherein: each R10 is H.

11. The compound of claim 1, wherein: G is tetrazolyl, —NHS(═O)2R8, —S(═O)2NHR9, —OH, —SH, —C(O)NHC(O)R8, —C(O)NHS(═O)2R8, —S(═O)2NHC(O)R8, —S(═O)2NHC(O)NHR8, —CO2H, a carboxylic acid bioisostere, —(OP(═O)OH)xOH, —OP(═O)OR8OH, —OP(═O)R8OH, —NR9P(═O)OR8OH, —NR9P(═O)R8OH, —P(═O)OR8OH; —P(═O)R8OH, —S(O)nOH; —OS(O)yOH; or —NR9S(O)yOH.

12. The compound of claim 1, wherein: G is tetrazolyl, —C(O)NHC(O)R8, —C(O)NHS(═O)2R8, —S(═O)2NHC(O)R8, —S(═O)2NHC(O)NHR8, —CO2H, a carboxylic acid bioisostere, —(OP(═O)OH)xOH, —OP(═O)OR8OH, —OP(═O)R8OH, —P(═O)OR8OH; —P(═O)R8OH, or —S(O)yOH.

13. The compound of claim 1, wherein: G is tetrazolyl, —C(O)NHC(O)R8, —C(O)NHS(═O)2R8, —S(═O)2NHC(O)R8, —S(═O)2NHC(O)NHR8, —CO2H, carboxylic acid bioisosteres, —(OP(═O)OH)xOH, or —S(O)yOH;x is 1; andy is 1 or 2.

14. The compound of claim 1, wherein: R1 is selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclo-octyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl and cyclooctylmethyl.

15. The compound according to claim 15, wherein: R1 is selected from among cyclohexyl and cyclohexylmethyl.

16. A compound of claim 1, wherein the compound is selected from among:

17. A pharmaceutical composition comprising a compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of claim 1 and a pharmaceutically acceptable diluent, excipient or binder.

18. A method of inhibiting the activity of fatty acid amide hydrolase or of treating a disease, disorder, or condition, which would benefit from inhibition of fatty acid amide hydrolase activity in a patient comprising administering to the patient a therapeutically effective amount of a compound, pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate of claim 1.

19. The method of claim 23, wherein the disease, disorder or condition is selected from among acute or chronic pain, eating disorders, cardiovascular diseases, metabolic diseases, disorders or conditions, renal ischemia, cancers, disorders of the immune system, allergic diseases, parasitic, viral or bacterial infectious diseases, inflammatory diseases, osteoporosis, ocular conditions, pulmonary conditions, gastrointestinal diseases and urinary incontinence.

20. The method of claim 19, wherein said compound is an irreversible inhibitor of fatty acid amide hydrolase.

21. The method of claim 21, wherein said compound does not substantially cross the blood-brain barrier.

22. Use of a compound of claim 1 for inhibiting the activity of fatty acid amide hydrolase activity or for the treatment of a disease, disorder, or condition, that would benefit from inhibition of fatty acid amide hydrolase activity.

23. Use of a compound of claim 1 for the formulation of a medicament for the inhibition of fatty acid amide hydrolase (FAAH).

24. An article of manufacture, comprising packaging material, a compound of claim 1, which is effective for inhibiting the activity of fatty acid amide hydrolase (FAAH), within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for inhibiting the activity of fatty acid amide hydrolase (FAAH).

25. A compound having the structure of Formula (I):