Alpha 7 nicotinic receptor selective ligands
View Patent ↗The invention relates to the design and synthesis of 3-arylidene-anabaseine compounds that exhibit enhanced selectivity toward alpha7 nicotinic receptors. The compounds are expected to be useful in treating a wide variety of conditions, including neurodegenerative conditions such as Alzheimer's Disease, neurodevelopmental diseases such as schizophrenia, and certain peripherally located inflammations mediated by macrophage infiltration.
1. A 3-benzylidene-anabaseine of the formula:
where R 1 is, independently, acetoxy, acetamido, amino, dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, difluoromethoxy, diethylaminopropoxy, trimethylammoniumpropoxy, trimethylammoniumpentoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, hydroxyl, C 1 -C 3 alkoxy, trifluoromethoxy, methylamino or thiomethoxy and n is 0-5; R 2 is independently C 1 -C 3 alkyl and n′ is 1-3, wherein at least one R 2 is present at position 4, 5, or 6; R 3 is independently C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benzyl and n″ is 0-4; R 4 is hydrogen or C 1 -C 3 alkyl or C 1 -C 3 alkylhydroxy; or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
2. The 3-benzylidene-anabaseine of claim 1 , wherein n is 1-3.
3. The 3-benzylidene-anabaseine of claim 2 , wherein R 2 is methyl.
4. The 3-benzylidene-anabaseine of claim 1 , wherein R 1 is, independently, hydroxy, amino, methylamino, thiomethoxy, or methoxy.
5. The 3-benzylidene-anabaseine of claim 4 , wherein each R 1 is methoxy.
6. The 3-benzylidene-anabaseine of claim 1 , wherein R 1 is at the 2″ and 4″ positions.
7. The 3-benzylidene-anabaseine of claim 1 , wherein n is 1 and R 1 is at the 4″ position.
8. The 3-benzylidene-anabaseine of claim 1 , wherein the anabaseine is 4-methyl-DMXBA.
9. The 3-benzylidene-anabaseine of claim 1 , wherein the 3-benzylidene-anabaseine is a α7 nicotinic receptor agonist.
10. The 3-benzylidene-anabaseine of claim 1 , wherein the 3-benzylidene-anabaseine is a α7 nicotinic receptor antagonist.
11. A 3-benzylidene-anabaseine of the formula:
where the 2″R and 4″R are, independently, acetoxy, acetamido, amino, methylamino, dimethylamino, dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, difluoromethoxy, dimethylaminopropoxy, hydroxyl, C 1 -C 5 alkoxy, trifluoromethoxy, methylamino or thiomethoxy, provided that at least one of 2″R or 4″R is, independently, methylamino, dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, or ethylcarbamoyl; or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
12. The 3-benzylidene-anabaseine of claim 11 , wherein the 3-benzylidene-anabaseine is a α7 nicotinic receptor agonist.
13. The 3-benzylidene-anabaseine of claim 11 , wherein the 3-benzylidene-anabaseine is a α7 nicotinic receptor antagonist.
14. A 3-cinnamylidene-anabaseine of the formula:
where R 1 is independently, acetoxy, acetamido, amino,diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, difluoromethoxy, dimethylaminopropoxy, trimethylammoniumpropoxy, trimethylammoniumpentoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, hydroxyl, C 1 -C 3 alkoxy, trifluoromethoxy, methylamino or thiomethoxy and n is 0-5; R 2 is independently C 1 -C 3 alkyl and n′ is 1-3, wherein at least one R 2 is present at position 4, 5, or 6; R 3 is independently C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benzyl and n″ is 0-4; R 4 , R 5 and R 6 are, independently, hydrogen or C 1 -C 3 alkyl or C 1 -C 3 alkylhydroxy; or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
15. The 3-cinnamylidene-anabaseine of claim 14 , wherein n is 1-3.
16. The 3-cinnamylidene-anabaseine of claim 15 , wherein R 2 is methyl.
17. The 3-cinnamylidene-anabaseine of claim 14 , wherein the anabaseine is a α7 nicotinic receptor agonist.
18. The 3-cinnamylidene-anabaseine of claim 14 wherein the anabaseine is a α7 nicotinic receptor antagonist.
19. A 3-(benzofuran-2-ylmethylene)-anabaseine of the formula:
where R 1 is, independently, acetoxy, acetamido, amino, dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, difluoromethoxy dimethylaminopropoxy, trimethylammoniumpropoxy, trimethylammoniumpentoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, hydroxyl, C 1 -C 3 alkoxy, trifluoromethoxy, methylamino or thiomethoxy and n is 0-4; R 2 is independently C 1 -C 3 alkyl and n′ is 1-3, wherein at least one R 2 is present at position 4, 5, or 6; R 3 is independently C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benzyl and n″ is 0-4; R 4 and R 5 are, independently, hydrogen, C 1 -C 3 alkyl or C 1 -C 3 alkylhydroxy; or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
20. The 3-(benzofuran-2-ylmethylene)-anabaseine of claim 19 , wherein n is 1-3.
21. The 3-(benzofuran-2-ylmethylene)-anabaseine of claim 20 , wherein R 2 is methyl.
22. The 3-(benzofuran-2-ylmethylene)-anabaseine of claim 19 , wherein the anabaseine is a α7 nicotinic receptor agonist.
23. The 3-(benzofuran-2-ylmethylene)-anabaseine of claim 19 wherein the anabaseine is a α7 nicotinic receptor antagonist.
24. A 3-(1H-indol-2-ylmethylene)-anabaseine having the formula:
where R 1 is, independently, acetoxy, acetamido, amino, dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, difluoromethoxy, dimethylaminopropoxy, trimethylammoniumpropoxy, trimethylammoniumpentoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, hydroxyl, C 1 -C 3 alkoxy, trifluoromethoxy, methylamino or thiomethoxy and n is 0-4; R 2 is independently C 1 -C 3 alkyl and n′ is 1-3, wherein at least one R 2 is present at position 4, 5, or 6; R 3 is independently C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benzyl and n″ is 0-4; R 4 and R 5 are, independently, hydrogen, C 1 -C 3 alkyl or C 1 -C 3 alkylhydroxy; R 7 is hydrogen, C 1 -C 5 alkyl, C 1 -C 4 dialkoxy, or C 1 -C 5 alkoxy; or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
25. The 3-(1H-indol-2-ylmethylene)-anabaseine of claim 24 , wherein n is 1-3.
26. The 3-(1H-indol-2-ylmethylene)-anabaseine of claim 25 , wherein R 2 is methyl.
27. The 3-(1H-indol-2-ylmethylene)-anabaseine of claim 24 , wherein the anabaseine is a α7 nicotinic receptor agonist.
28. The 3-(1H-indol-2-ylmethylene)-anabaseine of claim 24 wherein the anabaseine is a α7 nicotinic receptor antagonist.
29. A 3-arylidene-anabaseine of the formula:
or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
30. A 3-arylidene-anabaseine derivative selected from the group consisting of 3-(3,4-(ethylenedioxy)benzylidene)-anabaseine, 3-(3,4-(methylenedioxy)benzylidene)-anabaseine, 3-((6-methoxynaphth-2-yl)methylene)-anabaseine and 3-((benzofuran-2-yl)methylene)-anabaseine.
31. A 3-benzylidene-glucuronide-anabaseine of the formula:
where R 1 is, independently, acetoxy, acetamido, amino, dimethylcarbamoyl, diethylcarbamoyl, methylcarbamoyl, ethylcarbamoyl, difluoromethoxy, dimethylaminopropoxy, trimethylammoniumpropoxy, trimethylammoniumpentoxy, C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, hydroxyl, C 1 -C 3 alkoxy, trifluoromethoxy, methylamino, acylated glucuronidyl, or thiomethoxy and n is 0-4; R 2 is independently C 1 -C 3 alkyl and n′ is 0-3; R 3 is independently C 1 -C 3 alkyl, C 1 -C 3 alkylhydroxy, C 1 -C 3 alkoxy, cyano, halo, phenoxy, phenyl, pyridyl or benzyl and n″ is 0-4; R 4 is hydrogen, C 1 -C 3 alkyl or C 1 -C 3 alkylhydroxy; or a pharmaceutically acceptable salt, clathrate, stereoisomer, enantiomer, or combination thereof.
32. The 3-benzylidene-glucuronide-anabaseine of claim 31 , wherein the anabaseine is a α7 nicotinic receptor agonist.
33. The 3-benzylidene-glucuronide-anabaseine of claim 31 wherein the anabaseine is a α7 nicotinic receptor antagonist.
34. The 3-benzylidene-anabaseine of claim 8 , wherein the anabaseine is (R)-4-methyl-DMXBA.
35. The 3-benzylidene-anabaseine of claim 1 , wherein the anabaseine is (S)-6-methyl-DMXBA.
36. A method of selectively stimulating alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-benzylidene-anabaseine of claim 9 to an individual in need thereof.
37. A method of selectively stimulating alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-benzylidene-anabaseine of claim 12 to an individual in need thereof.
38. A method of selectively stimulating alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-cinnamylidene-anabaseine of claim 17 to an individual in need thereof.
39. A method of selectively stimulating alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-(benzofuran-2-ylmethylene)-anabaseine of claim 22 to an individual in need thereof.
40. A method of selectively stimulating alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-(1H-indol-2-ylmethylene)-anabaseine of claim 27 to an individual in need thereof.
41. A method of selectively stimulating alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a benzylidene-glucuronide-anabaseine of claim 32 to an individual in need thereof.
42. A method of selectively inhibiting alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-benzylidene-anabaseine of claim 10 to an individual in need thereof.
43. A method of selectively inhibiting alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-benzylidene-anabaseine of claim 13 to an individual in need thereof.
44. A method of selectively inhibiting alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-cinnamylidene-anabaseine of claim 18 to an individual in need thereof.
45. A method of selectively inhibiting alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-(benzofuran-2-ylmethylene)-anabaseine of claim 23 to an individual in need thereof.
46. A method of selectively inhibiting alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a 3-(1H-indol-2-ylmethylene)-anabaseine of claim 28 to an individual in need thereof.
47. A method of selectively inhibiting alpha7 nicotinic receptors, comprising the step (a) administering a therapeutically effective amount of a benzylidene-glucuronide-anabaseine of claim 33 to an individual in need thereof.
48. A pharmaceutically acceptable composition comprising at least one of the 3-benzylidene anabaseines of claim 1 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers or preservatives.
49. A pharmaceutically acceptable composition comprising at least one of the 3-cinnamylidene- anabaseines of claim 14 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers or preservatives.
50. A pharmaceutically acceptable composition comprising at least one of the 3-(1 H-indol-2-ylmethylene)-anabaseines of claim 24 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers or preservatives.
51. A pharmaceutically acceptable composition comprising at least one of the 3-(benzofuran-2-ylmethylene)-anabaseines of claim 19 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers or preservatives.
52. A pharmaceutically acceptable composition comprising at least one of the 3-benzylidene-glucuronide-anabaseine of claim 31 and one or more pharmaceutically acceptable carriers, excipients, diluents, stabilizers or preservatives.