TRPV1 agonist compounds, formulations, prodrugs, methods for using the same
View Patent ↗Described here are TRPV1 agonist compounds and their methods of synthesis and use. In addition to specifically identified compounds, capsaicin prodrugs, gemini dimers, and mutual prodrugs are also described. Formulations of the TRPV1 agonist compounds may be in the form of a liquid, tablets, capsules, gel, cream, emulsion, a patch, or the like. Methods for treating medical conditions using the compounds, compositions, or prodrugs described, are also provided.
1. A compound of the formula:
wherein R1 is selected from the group consisting of hydrogen, —(CH 2 ) n CH 3 wherein n is an integer from 6-19, and a substituted, saturated or unsaturated, linear or branched, C 1 -C 20 alkyl and R2 is selected from the group consisting of a substituted or unsubstituted, unsaturated, linear or branched C 2 -C 5 alkyl, or (3E)-2-methyloct-3 -ene, or (3Z)-2-methyloct-3 -ene.
2. The compound of claim 1 wherein R1 is selected from the group consisting of hydrogen and a substituted, saturated or unsaturated, linear or branched, C 1 -C 10 alkyl.
3. The compound of claim 1 wherein R1 is —(CH 2 ) n CH 3 and n is an integer from 6-19.
4. The compound of claim 3 wherein n is an integer from 6-10.
5. The compound of claim 3 wherein n is an integer from 11-19.
6. The compound of claim 1 wherein R2 is (3E)-2-methyloct-3-ene.
7. The compound of claim 1 wherein R2 is (3Z)-2-methyloct-3-ene.
8. A formulation comprising the compound of claim 1 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
9. A compound of the formula:
where R is selected from the group consisting of hydrogen, —(CH 2 ) n CH 3 wherein n is an integer from 6-19, and a substituted, saturated or unsaturated, linear or branched, C 2 -C 20 alkyl.
10. A formulation comprising the compound of claim 9 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
11. A compound of the formula:
where R is selected from the group consisting of hydrogen, —(CH 2 ) n CH 3 wherein n is an integer from 6-19, and a substituted, saturated or unsaturated, linear or branched C 2 -C 20 alkyl.
12. A formulation comprising the compound of claim 11 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
13. A compound of the formula:
where R is selected from the group consisting of hydrogen, —(CH 2 ) n CH 3 wherein n is an integer from 6-19, and a substituted, unsaturated, linear or branched, C 2 -C 20 alkyl.
14. A formulation comprising the compound of claim 13 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
15. A TRPV1 agonist prodrug comprising:
a TRPV1 agonist modified by covalent attachment of a prodrug moiety, wherein the prodrug moiety restricts binding to or activation of the TRPV1 receptor wherein the TRPV1 agonist is selected from the group consisting of civamide, olvanil, and resiniferatoxin.
16. The TRPV1 agonist prodrug of claim 15 wherein the TRPV1 agonist is a civamide.
17. The TRPV1 agonist prodrug of claim 15 wherein the TRPV1 agonist is olvanil.
18. The TRPV1 agonist prodrug of claim 15 wherein the prodrug moiety is attached to the TRPV1 agonist by substitution of the phenolic hydrogen of the TRPV1 agonist with the prodrug moiety.
19. The TRPV1 agonist prodrug of claim 18 wherein the prodrug moiety is an acyl or an alkoxy.
20. The TRPV1 agonist prodrug of claim 19 wherein the prodrug moiety is an acyl.
21. A formulation comprising the TRPV1 agonist prodrug of claim 15 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
22. A microreservoir, monolithic, or liquid reservoir patch comprising a compound of the-formula:
wherein R1 is selected from the group consisting of hydrogen and a substituted or unsubstituted, saturated or unsaturated, linear or branched, C 1 -C 20 alkyl and R2 is selected from the group consisting of a substituted or unsubstituted, saturated or unsaturated, linear or branched C 1 -C 20 alkyl.
23. A patch comprising the compound of claim 9 .
24. A patch comprising the compound of claim 11 .
25. A microreservoir, monolithic, or liquid reservoir patch comprising a compound of the formula:
where R is selected from the group consisting of hydrogen and a substituted or unsubstituted, saturated or unsaturated, linear or branched, C 2 -C 20 alkyl.
26. A patch comprising the TRPV1 agonist prodrug of claim 15 .
27. A pharmaceutical formulation comprising a capsaicin or capsaicinoid prodrug wherein the capsaicin or capsaicinoid prodrug comprises:
capsaicin or a capsaicinoid modified by covalent attachment of a prodrug moiety, wherein the prodrug moiety facilitates sustained release of capsaicin or the capsaicinoid.
28. The prodrug of claim 27 wherein the prodrug moiety is attached to the capsaicin or capsaicinoid by substitution of the phenolic hydrogen of cap saicin or capsaicinoid with the prodrug moiety.
29. A prodrug of claim 27 wherein the prodrug moiety is m-PEG.
30. A mutual prodrug comprising capsaicin covalently linked to at least one other compound wherein the at least one other compound is capable of treating pain.
31. The mutual prodrug of claim 30 wherein the at least one other compound is l-menthol.
32. The mutual prodrug of claim 30 wherein the at least one other compound is a COX inhibitor.
33. The mutual prodrug of claim 30 wherein the at least one other compound is an opioid analgesic.
34. A formulation comprising the mutual prodrug of claim 30 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
35. A composition comprising a gemini dimer of a TRPV1 agonist.
36. The composition of claim 35 wherein the TRPV1 agonist is a capsaicinoid.
37. The composition of claim 35 wherein the TRPV1 agonist is capsaicin.
38. The composition of claim 35 wherein the gemini dimer is composed of two different TRPV1 agonists.
39. A formulation comprising the composition of claim 35 , wherein the formulation is a liquid, tablet, capsule, gel, cream, emulsion or patch.
40. A method for treating pain comprising the step of locally, dermally, transdermally or systemically delivering the compound of claim 1 , the compound of claim 9 , the compound of claim 11 , the compound of claim 13 , the prodrug of claim 15 , the prodrug of claim 27 , the mutual prodrug of claim 30 , or the composition of claim 35 .
41. The method of claim 40 wherein the pain is associated with postherpetic neuralgia, diabetic neuropathy, HIV-associated neuropathy, complex regional pain syndrome, cancer, nerve injury, cancer chemotherapy, vulvodynia, trauma, surgery, chronic musculoskeletal pain, lower back pain, osteoarthritis or rheumatoid arthritis.
42. The method of claim 40 wherein the medical condition to be treated is selected from the group consisting of psoriasis, pruritis, itch, cancer, colon polyps, prostatic hypertrophy, wrinkles, sinusitis, rhinitis, alopecia and hirsutism.
43. A compound of claim 1 wherein the compound is a TRPV1 agonist prodrug.
44. A compound of claim 9 wherein the compound is a TRPV1 agonist prodrug.
45. A compound of claim 11 wherein the compound is a TRPV1 agonist prodrug.
46. A compound of claim 13 wherein the compound is a TRPV1 agonist prodrug.