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 syndrome, schizophrenia, delusional disorders, drug-induced psychosis and panic and obsessive-compulsive disorders. The compounds have the general structure: wherein m, n, p, x, R, R 1 , R 2 , R 3 , R 4 , R 5 , A and B, are defined herein, including pharmaceutically acceptable salts, stereoisomers, solvates or prodrugs thereof. Also disclosed are compositions containing a compound of this invention 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 (IVg):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
a is 1, 2, 3 or 4;
b is 1 or 2;
x is 1, 2 or 3 with the proviso that when x is 1, R 1 is not a single methyl substituent;
R 1 represents 1 or 2 substitutents independently halogen, C 1-6 alkyl, —CHF 2 or —CF 3 ;
R 2 is at each occurrence the same or different and independently, hydrogen, C 1-6 alkyl, benzyl, —CH 2 CONH 2 , —CHF 2 , —CF 3 , or any two R 2 groups may be taken together to form a C 1-6 alkanediyl;
R 3 , R 4 and R 5 are the same or different and independently hydrogen or C 1-6 alkyl; and
R 7 and R 8 are the same or different and independently hydrogen, halogen, C 1-6 alkyl, —O(C 1-6 alkyl), C 1-6 haloalkyl or nitro.
2. The compound of claim 1 wherein R 3 , R 4 and R 5 are hydrogen.
3. The compound of claim 1 wherein R 7 is hydrogen, R 8 is —CH 3 , a is 1, b is 1 and the compound has the following structure:
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
5. A compound having the following structure (IVa):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A is
x is 3 and the —OR 2 groups are located at the 3, 4 and 5 positions;
R 1 is absent;
R 2 is at each occurrence the same or different and independently hydrogen, C 1-6 alkyl, —C(═O)(C 1-6 alkyl), benzyl, —CH 2 CONH 2 , —CHF 2 or —CF 3 ; and
R 3 , R 4 and R 5 are hydrogen.
6. The compound of claim 5 wherein R 2 is at each occurrence the same or different and independently C 1-6 alkyl or —CHF 2 or —CF 3 .
7. A pharmaceutical composition comprising a compound of claim 5 and a pharmaceutically acceptable carrier or diluent.
8. A compound having the following structure (IVa):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
A is
x is 2 or 3 and two of the —OR 2 groups are located at the 3 and 4 positions;
R 1 is absent;
R 2 is at each occurrence the same or different and independently C 1-6 alkyl, —CHF 2 or —CF 3 ;
R 3 , R 4 and R 5 are hydrogen; and
R 7 is —O(C 1-6 alkyl).
9. A pharmaceutical composition comprising a compound of claim 8 and a pharmaceutically acceptable carrier or diluent.
10. A compound having the following structure (IVg):
or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
x is 1, 2 or 3;
a is 1;
b is 0;
R 1 is absent or represents 1, 2, or 3 substituents that are the same or different and independently halogen, C 1-6 alkyl, —CHF 2 , —CF 3 , —CH 2 NH 2 , —CH 2 NH(C 1-6 alkyl) or —CH 2 N(C 1-6 alkyl) 2 ;
R 2 is at each occurrence the same or different and independently hydrogen, C 1-6 alkyl, —C(═O)(C 1-6 alkyl), benzyl, —CH 2 CONH 2 , —CHF 2 or —CF 3 ;
R 3 , R 4 and R 5 are hydrogen; and
R 7 is halogen or C 1-6 haloalkyl.
11. The compound of claim 10 wherein R 2 is at each occurrence the same or different and independently C 1-6 alkyl, —CHF 2 or —CF 3 .
12. The compound of claim 10 wherein R 1 is absent or represents 1, 2, or 3 substituents that are the same or different and independently halogen, C 1-6 alkyl, —CHF 2 or —CF 3 .
13. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier or diluent.