Positive allosteric modulators of group II mGluRs
The disclosure provides compounds and compositions, and methods of using these compounds and compositions, as positive allosteric modulators of the metabotropic glutamate subtype 2 (mGlu2) receptor, and for treating CNS disorders associated with the mGlu2 receptor including schizophrenia, anxiety, addiction, e.g. cocaine addiction, nicotine addiction, and the like.
1. A compound of Formula IV:
wherein:
X and X′ are each independently absent or are each independently O;
y is 1;
q is independently an integer selected from 0, 1, 2, 3, and 4;
m is an integer selected from 0, 1, 2, and 3;
W is independently selected from CH 2 , O, S, and NCH 3 ;
R 1 is independently selected from hydrogen, halogen, cyano, nitro, unsubstituted C 1 -C 6 alkyl, perfluoroalkyl, —(CH 2 ) j OR 5 , —(CH 2 ) j C(O)OR 5 , and (CH 2 ) j C(O)NR 6 R 7 , wherein each j is 0;
R 3 is independently selected from hydrogen, branched or unbranched alkyl, cycloalkyl, phenyl, benzyl and cycloalkylalkyl, wherein benzyl is optionally substituted with perfluoroalkoxy; and
R 5 , R 6 , and R 7 are each independently selected from hydrogen branched or unbranched alkyl.
2. The compound of claim 1 , wherein the compound of Formula IV has Formula V:
3. The compound of claim 1 , wherein the compound of Formula IV is:
4. A method of treating a CNS disorder including schizophrenia, anxiety and addiction, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of claim 1 having Formula IV, thereby treating the disorder.
5. The method of claim 4 , wherein the disorder is an addictive disorder.
6. The method of claim 5 , wherein the addictive disorder is nicotine addiction, alcohol addiction, opiate addiction, amphetamine addiction, methamphetamine addiction, or cocaine addiction.
7. The method of claim 6 , wherein the addictive disorder is nicotine addiction.
8. The method of claim 6 , wherein the addictive disorder is cocaine addiction.
9. The method of claim 4 , wherein the CNS disorder is schizophrenia.
10. A method of treating a warm-blooded animal having an addictive disorder or schizophrenia, the method comprising the step of administering to the animal an effective amount of the compound of claim 1 having Formula IV, thereby treating the disorder or schizophrenia.
11. A pharmaceutical composition comprising the compound of claim 1 having Formula IV, and a pharmaceutically acceptable carrier.
12. A method of treating substance abuse, the method comprising the step of administering to a subject in need thereof, an effective amount of the compound of claim 1 having Formula IV, wherein the effective amount is sufficient to diminish, inhibit or eliminate desire for and/or consumption of the substance in the subject.
13. The method of claim 1 , wherein the substance is nicotine, alcohol, opiates, amphetamines, methamphetamines, or cocaine.
14. A method for treating an addictive disorder, the method comprising the steps of: a) administering to a subject in need thereof, an effective amount of the compound of claim 1 having Formula IV, during a first time period, wherein the first time period is a time period wherein the subject expects to be in an environment wherein, or exposed to stimuli in the presence of which, the subject habitually uses an addictive substance; and b) administering an effective amount of the compound of claim 1 having Formula IV during a second time period, wherein the second time period is a time period wherein the subject is suffering from withdrawal.
15. The compound of claim 1 , wherein R 3 is cycloalkyl.
16. The compound of claim 1 , wherein m is 2.
17. The compound of claim 1 , wherein:
m is an integer selected from 1, 2, and 3; and
at least one R 1 is halogen.