PDE10 inhibitors and related compositions and methods
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 compound having the following structure (I-E):
or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotope thereof,
wherein:
R 1 is C 1-6 alkyl;
R 2 is phenyl substituted with morpholino, pyrazolyl, triazolyl, pyridinyl, or pyrazinyl; and
R 3 is aryl substituted with at least one halogen, alkyl, hydroxy, alkoxy, or cyano.
2. The compound of claim 1 , wherein R 1 is methyl, ethyl, or propyl.
3. The compound of claim 1 , wherein R 3 is phenyl substituted with at least one halogen, alkyl, hydroxy, alkoxy, or cyano.
4. The compound of claim 3 , wherein R 3 is phenyl substituted with at least one halogen and at least one alkoxy.
5. The compound of claim 3 , wherein R 3 is 4-bromo-3,5-dimethoxyphenyl, 4-chloro-3,5-dimethoxyphenyl, 4-fluoro-3,5-dimethoxyphenyl, 3-bromo-4,5-dimethoxyphenyl, 3-chloro-4,5-dimethoxyphenyl, 3-fluoro-4,5-dimethoxyphenyl, 4-cyano-3,5-dimethoxyphenyl, 3-cyano-4,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-hydroxy-3,5-dimethoxyphenyl, or 4-methyl-3,5-dimethoxyphenyl.
6. The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotope thereof.
7. The compound of claim 1 , wherein the compound is an isotope having one or more atoms replaced by the same atom having a different atomic mass.
8. The isotope of claim 7 , wherein one or more H atoms is replaced by 2 H.
9. The isotope of claim 7 , wherein one or more H atoms is replaced by 3 H.
10. The isotope of claim 7 , wherein one or more C atoms is replaced by 14 C.
11. A pharmaceutical composition comprising a compound of claim 1 or 7 and a pharmaceutically acceptable carrier or diluent.
12. A compound having the following structure:
or a pharmaceutically acceptable salt, stereoisomer, solvate, or isotope thereof.