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 method for treating schizophrenia or psychosis 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 or stereoisomer thereof,
wherein:
m, n and p are individually 0 or 1;
x is 1, 2 or 3;
A is an optionally substituted heterocycle, wherein the heterocycle is quinoline;
B is —O—, —NR 6 — or —S(O) z — where z is 0, 1 or 2;
R is hydrogen or oxo;
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 —; and
R 3 , R 4 , R 5 and R 6 are the same or different and independently hydrogen or C 1-6 alkyl.
2. The method of claim 1 wherein the compound has the following structure (II):
3. The method of claim 1 wherein the compound has the following structure (III):
4. The method of claim 1 wherein the compound has the following structure (IV):
5. The method of claim 1 wherein the compound has the following structure (V):
6. The method of claim 1 wherein the compound has the following structure (VI):
7. The method of claim 1 wherein the compound has the following structure (IVa):
8. The method of claim 7 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.
9. The method of claim 8 wherein R 2 is at each occurrence the same or different and independently, C 1-6 alkyl or —CHF 2 or —CF 3 .
10. The method of claim 7 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).
11. The method of claim 1 wherein the compound has the following structure (IVb):
12. The method of claim 1 wherein the compound has the following structure (IVc):
13. The method of claim 1 wherein the compound has the following structure (IVg):
wherein:
a is 1, 2, 3 or 4;
b is 0.1 or 2; 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.
14. The method of claim 13 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.
15. The method of claim 14 wherein R 2 is at each occurrence the same or different and independently C 1-6 alkyl, —CHF 2 or —CF 3 .
16. The method of claim 14 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 .