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 method for treating neurological disorders in a warm-blooded animal in need thereof, comprising administering to the animal an effective amount of a compound having the following structure (I):
or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof,
wherein:
X is —O— or —S—;
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 and R 3 are the same or different and independently substituted or unsubstituted heterocyclyl, or substituted or unsubstituted aryl; and
R 4 and R 5 are the same or different and independently 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,
wherein the neurological disorder is Parkinson's disease, Huntington's disease, schizophrenia, or obsessive-compulsive disorder.
2. The method of claim 1 wherein the neurological disorder is schizophrenia.
3. The method of claim 1 wherein the neurological disorder is Huntington's disease.
4. The method of claim 1 wherein the compound has the following structure (II):
5. The method of claim 4 wherein R 4 and R 5 are the same or different and independently hydrogen or C 1-6 alkyl.
6. The method of claim 4 wherein R 4 and R 5 are hydrogen.
7. The method of claim 4 wherein R 1 is C 1-6 alkyl.
8. The method of claim 7 wherein R 1 is methyl.
9. The method of claim 7 wherein R 1 is ethyl.
10. The method of claim 7 wherein R 1 is isopropyl.
11. The method of claim 4 wherein R 3 is substituted phenyl.
12. The method of claim 11 wherein R 3 is 3,4,5-trimethoxyphenyl.
13. The method of claim 11 wherein R 3 is 4-bromo-3,5-dimethoxyphenyl.
14. The method of claim 4 wherein R 2 is substituted or unsubstituted phenyl.
15. The method of claim 14 wherein R 2 is 4-morpholinophenyl.
16. The method of claim 14 wherein R 2 is 4-(1H-pyrazol-1-yl)phenyl.
17. The method of claim 4 wherein R 2 is substituted or unsubstituted naphthyl.
18. The method of claim 4 wherein R 2 is substituted or unsubstituted heteroaryl.
19. The method of claim 1 wherein the compound has the following structure (III):
20. The method of claim 19 wherein R 4 and R 5 are the same or different and independently hydrogen or C 1-6 alkyl.
21. The method of claim 19 wherein R 4 and R 5 are hydrogen.
22. The method of claim 19 wherein R 1 is C 1-6 alkyl.
23. The method of claim 22 wherein R 1 is methyl.
24. The method of claim 22 wherein R 1 is ethyl.
25. The method of claim 22 wherein R 1 is isopropyl.
26. The method of claim 19 wherein R 3 is substituted phenyl.
27. The method of claim 26 wherein R 3 is 3,4,5-trimethoxyphenyl.
28. The method of claim 26 wherein R 3 is 4-bromo-3,5-dimethoxyphenyl.
29. The method of claim 19 wherein R 2 is substituted or unsubstituted phenyl.
30. The method of claim 29 wherein R 2 is 4-morpholinophenyl.
31. The method of claim 29 wherein R 2 is 4-(1H-pyrazol-1-yl)phenyl.
32. The method of claim 19 wherein R 2 is substituted or unsubstituted naphthyl.
33. The method of claim 19 wherein R 2 is substituted or unsubstituted heteroaryl.