Compounds and compositions for cognition-enhancement, methods of making, and methods of treating
Disclosed are muscarinic agonist compounds including oxadiazole derivatives, compositions and preparations thereof. Also disclosed are methods of synthesizing such oxadiazole compounds. Further disclosed are methods for treating a subject with said muscarinic agonists or a pharmaceutically suitable form thereof to enhance cognitive function.
1. A compound of Formula XI:
wherein
R 1 is selected from the group consisting of —CR 2 R 3 R 4 ,
R 2 , R 3 and R 4 are independently selected from D or F; and
R 5 , R 6 , R 7 , R 8 , and R 10 are independently selected from H, D, F or a methyl group;
provided that not more than one of R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is a methyl group;
and pharmaceutically acceptable salts or stereoisomers thereof.
2. A compound of Formula I, IA, LB, X, XA or XB, or stereoisomers of I, IA, IB, X, XA or XB, or pharmaceutically acceptable salts thereof, wherein the compounds have the structures:
and wherein
X is O or S;
R 1 is NH 2 , or methyl, optionally substituted with 1-3 deuterium atoms; or, when X is S, R 1 can also be H;
R 2 is H, F, a substituted or unsubstituted C1-4 alkyl group, OH or OR wherein R is a substituted or unsubstituted C1-4 alkyl group
R 3 is H:
R 4 is F at each occurrence;
n is 0, 1 or 2; and wherein when n is 0, the pyrrolidone ring is optionally substituted at the 4 position with a substituted or unsubstituted C 1-6 , alkyl;
m is 1 or 2; and
p is 0, 1 or 2.
3. A compound of claim 2 wherein X is O.
4. A compound of a claim 2 , wherein R 1 is CH 3 or CD 3 .
5. A compound of claim 2 , wherein the compound is of Formula X.
6. A compound of claim 2 , wherein the compound is of Formula XA.
7. A compound of claim 2 , wherein the compound is of Formula XB.
8. A compound of claim 2 selected from the group consisting of 3-(methyl)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (R)-3-(methyl)-5-(piperidin-3-yl)-1,2,4-oxadiazole, (S)-3-(methyl)-5-(piperidin-3-yl)-1,2,4-oxadiazole, 5-(3-azabicyclo[3.1.0]hexan-1-yl)-3-(methyl)-1,2,4-oxadiazole, 5-((1S)-3-azabicyclo[3.1.0]hexan-1-yl)-3-(methyl)-1,2,4-oxadiazole, 5-((1R)-3-azabicyclo[3.1.0]hexan-1-yl)-3-(methyl)-1,2,4-oxadiazol, 5-(3-azabicyclo[3.1.0]heptan-1-yl)-3-(methyl)-1,2,4-oxadiazole, 5-((1S)-3-azabicyclo[3.1.0]heptan-1-yl)-3-(methyl)-1,2,4-oxadiazole, 5-((1R)-3 azabicyclo[3.1.0]heptan-1-yl)-3-(methyl)-1,2,4-oxadiazole, 3-methyl-5-(4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-methyl-5-((3S,4S)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-methyl-5-((3R,4R)-4-methylpyrrolidin-3-yl)-1,2,4-oxadiazole, 3-methyl-5-piperidin-3-yl)-1,2,4-oxadiazole, (S)-3-methyl-5-(piperidin-3-yl)-1,2,4-oxadiazole, (R)-3-methyl-5-(piperidin-3-yl)-1,2,4-oxadiazole, 5-(3-fluoropiperidin-3-yl)-3-methyl-1,2,4-oxadiazole, (R)-5-(3-fluoropiperidin-3-yl)-3-methyl-1,2,4-oxadiazole, (S)-5-(3-fluoropiperidin-3-yl)-3-methyl-1,2,4-oxadiazole, 3-methyl-5-(piperidin-3-yl)-1,2,4-thidiazole, (S)-3-methyl-5-(piperidin-3-yl)-1,2,4-thiadiazole, (R)-3-methyl-5-(piperidin-3-yl)-1,2,4-thiadiazole, 3-methyl-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, (S)-3-methyl-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole, and (R)-3-methyl-5-(pyrrolidin-3-yl)-1,2,4-oxadiazole.
9. A compound of claim 4 , wherein the compound is of Formula XB.
10. A method comprising treating a compound of Formula II or a salt thereof
with a formate ester equivalent to provide a compound of Formula XI or a salt thereof
wherein
R 1 is selected from the group consisting of —CR 2 R 3 R 4 ,
R 2 , R 3 , R 4 are independently selected from H, D or F; and
R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently selected from H, D F or a methyl group;
provided that not more than one of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is a methyl group.
11. A compound of claim 3 , wherein R 1 is CH 3 or CD 3 .
12. A compound of claim 11 , wherein the compound is of Formula X.
13. A compound of claim 11 , wherein the compound is of Formula XA.
14. A compound of claim 11 , wherein the compound is of Formula XB.
15. A compound of claim 3 , wherein the compound is of Formula X.
16. A compound of claim 3 , wherein the compound is of Formula XA.
17. A compound of claim 3 , wherein the compound is of Formula XB.
18. A compound of claim 4 , wherein the compound is of Formula X.
19. A compound of claim 4 , wherein the compound is of Formula XA.
20. A pharmaceutically acceptable composition comprising a compound of any one of claims 2 - 3 , 4 , 5 - 8 and 11 - 9 and a pharmaceutically acceptable carrier.