PDE10 inhibitors and related compositions and methods
View Patent ↗Compounds that inhibit PDE10 are disclosed that have utility in the treatment of a variety of conditions, including (but not limited to) psychotic, anxiety, movement disorders and/or neurological disorders such as Parkinson's disease, Huntington's disease, Alzheimer's disease, encephalitis, phobias, epilepsy, aphasia, Bell's palsy, cerebral palsy, sleep disorders, pain, Tourette's syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders. Pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs of the compounds are also provided. Also disclosed are compositions containing a compound in combination with a pharmaceutically acceptable carrier, as well as methods relating to the use thereof for inhibiting PDE10 in a warm-blooded animal in need of the same.
1. A pharmaceutical composition comprising:
a compound of the following structure (I):
or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof,
wherein:
A is:
R 1 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 aralkyl, aryl, —(CH 2 ) n O(CH 2 ) m CH 3 or —(CH 2 ) n N(CH 3 ) 2 ;
R 2 is (i) substituted or unsubstituted aryl or (ii) substituted or unsubstituted heterocyclyl;
R 3 is substituted or unsubstituted aryl;
R 4 is hydrogen, C 1-6 alkyl or C 1-6 haloalkyl;
n is 1, 2, 3, 4, 5 or 6; and
m is 0, 1, 2, 3, 4, 5 or 6; and
a pharmaceutically acceptable carrier or diluent.
2. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-A):
3. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-B):
4. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-C):
5. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-D):
6. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-E):
7. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-F):
8. A pharmaceutical composition of claim 1 comprising a compound the following structure (I-G):
9. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-H):
10. A pharmaceutical composition of claim 1 comprising a compound of the following structure (I-I):
11. A pharmaceutical composition of claim 1 wherein R 4 is hydrogen.
12. A pharmaceutical composition of claim 1 wherein R 4 is C 1-6 alkyl.
13. A pharmaceutical composition of claim 12 wherein R 4 is methyl.
14. A pharmaceutical composition of claim 1 wherein R 1 is C 1-6 alkyl.
15. A pharmaceutical composition of claim 14 wherein R 1 is methyl.
16. A pharmaceutical composition of claim 14 wherein R 1 is ethyl.
17. A pharmaceutical composition of claim 1 wherein R 3 is substituted or unsubstituted phenyl.
18. A pharmaceutical composition of claim 17 wherein R 3 is substituted phenyl.
19. A pharmaceutical composition of claim 18 wherein R 3 is 4-bromo-3,5-dimethoxyphenyl.
20. A pharmaceutical composition of claim 18 wherein R 3 is 4-chloro-3,5-dimethoxyphenyl.
21. A pharmaceutical composition of claim 18 wherein R 3 is 3,4,5-trimethoxyphenyl.
22. A pharmaceutical composition of claim 1 wherein R 2 is substituted or unsubstituted aryl.
23. A pharmaceutical composition of claim 22 wherein R 2 is substituted or unsubstituted phenyl.
24. A pharmaceutical composition of claim 23 wherein R 2 is substituted phenyl.
25. A pharmaceutical composition of claim 24 wherein R 2 is phenyl substituted with C 1-6 alkoxy.
26. A pharmaceutical composition of claim 24 wherein R 2 is phenyl substituted with substituted or unsubstituted heterocyclyl.
27. A pharmaceutical composition of claim 26 wherein R 2 is phenyl substituted with substituted heterocyclyl.
28. A pharmaceutical composition of claim 27 wherein R 2 is 4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl.
29. A pharmaceutical composition of claim 27 wherein R 2 is 4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl.
30. A pharmaceutical composition of claim 26 wherein R 2 is phenyl substituted with unsubstituted heterocyclyl.
31. A pharmaceutical composition of claim 30 wherein R 2 is 4-morpholinophenyl.
32. A pharmaceutical composition of claim 1 wherein R 2 is substituted or unsubstituted heterocyclyl.
33. A pharmaceutical composition of claim 1 wherein the compound is:
1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone;
2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)-1-(5-(3,4,5-trimethoxyphenyl)furan-2-yl)ethanone;
1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone;
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone;
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone;
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone; or
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone.
34. A pharmaceutical composition of claim 1 wherein the compound is:
1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone.
35. A pharmaceutical composition of claim 1 wherein the compound is:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone.
36. A pharmaceutical composition of claim 1 wherein the compound is:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone.
37. A pharmaceutical composition of claim 1 wherein the compound is:
1-(5-(4-chloro-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-thiadiazol-2-yl)phenyl)ethanone.
38. A pharmaceutical composition of claim 1 wherein the compound is present in the composition in an amount from 0.1 mg to 250 mg per dosage.
39. A pharmaceutical composition of claim 34 wherein the compound is present in an amount from 1 mg to 60 mg per dosage.
40. A pharmaceutical composition of claim 1 wherein the pharmaceutical composition is a powder, granule, pill, tablet, capsule, liquid, syrup, suspension, emulsion, or aqueous injection solution.