NMDA receptor modulators and uses thereof
Disclosed are compounds having enhanced potency in the modulation of NMDA receptor activity. Such compounds are contemplated for use in the treatment of diseases and disorder such as learning, cognitive activities, and analgesia, particularly in alleviating and/or reducing neuropathic pain. Orally available formulations and other pharmaceutically acceptable delivery forms of the compounds, including intravenous formulations, are also disclosed.
1. A compound represented by
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof; wherein
R 1 is —C(O)—C 2 -C 4 alkyl, wherein C 2 -C 4 alkyl is substituted at one carbon with NH 2 or —NH-carbobenzyloxy and at a different carbon by hydroxyl; or
R 1 is
X is N;
R 5 ′ is H;
R 8 is —C(O)—C 2 -C 4 alkyl, wherein C 2 -C 4 alkyl is substituted at one carbon with NH 2 or —NH-carbobenzyloxy and at a different carbon by hydroxyl;
R 3 and R 3 ′ are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, —C 1 -C 4 alkyl, amido, amine, and —C 2 -C 4 alkenyl, wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl and phenyl are optionally substituted by one or more substituents selected from R a ;
R 2 is selected from the group consisting of H, R 7 , —S(O) 2 —C 1 -C 4 alkyl, —C 1 -C 4 alkyl, hydroxyl, and phenyl, wherein C 1 -C 4 alkyl, and phenyl are optionally substituted by one or more substituents selected from R a ;
R 5 is independently selected from the group consisting of H, halogen, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, —C 2 -C 4 alkenyl, cyano, amino, phenyl, and hydroxyl, wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl and phenyl are optionally substituted by one or more substituents selected from R a ;
R 7 is selected from the group consisting of —C(O)—C 1 -C 4 alkyl and —C(O)—O—C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by 1, 2 or 3 substituents selected from R b ;
R a is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, —C 1 -C 4 alkyl, and —C 1 -C 4 alkoxy;
R b is selected, independently for each occurrence, from the group consisting of carboxy, hydroxyl, halogen, amino, phenyl, —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, and —NH—R c ; and
R c is selected, independently for each occurrence, from the group consisting of —C(O)—O—C 1 -C 4 alkyl and —C(O)—C 1 -C 4 alkyl.
2. The compound of claim 1 , wherein R 1 is —C(O)—C 2 -C 4 alkyl, wherein C 2 -C 4 alkyl is substituted at one carbon with NH 2 or —N-carbobenzyloxy and at a different carbon by hydroxyl.
3. The compound of claim 1 , wherein R 1 is:
4. The compound of claim 1 , wherein R 3 is phenyl.
5. The compound of claim 1 , wherein R 3 is H.
6. The compound of claim 1 , wherein R 1 is —C(O)—C 2 -C 4 alkyl, substituted at one carbon with NH 2 and at a different carbon with hydroxyl.
7. The compound of claim 1 , wherein C 1 -C 4 alkyl is selected from the group consisting of methyl, ethyl, propyl, n-butyl and t-butyl, and is optionally substituted by one, two, or three substituents selected from the group consisting of F, Cl, and Br.
8. The compound of claim 1 , wherein the compound is represented by:
or a pharmaceutically acceptable salt, a stereoisomer, and/or an N-oxide thereof.
9. The compound of claim 1 , wherein R 1 is selected from the group consisting of:
10. A compound of claim 1 , which is capable of generating an enhanced single shock evoked NMDA receptor-gated single neuron conductance (I NMDA ) in hippocampal CA1 pyramidal neurons at concentrations of 100 nM to 1 μM.
11. A non-peptidyl compound selected from the group consisting of:
or a pharmaceutically acceptable salt, a stereoisomer and/or an N-oxide thereof.
12. A pharmaceutically acceptable composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
13. The composition of claim 12 , wherein the composition is suitable for oral administration to a patient.