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 Formula I:
and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof; wherein T is, independently for each occurrence, CR 4 R 4 ′ , and n is 0, 1, 2 or 3;
A is optionally present and is selected from the group consisting of phenyl and pyridine, wherein A is optionally substituted by one or more substituents selected from R a ;
R 1 is selected from the group consisting of H, hydroxyl, —S(O) 2 —C 1 -C 4 alkyl C 1 -C 4 alkyl, C 2 -C 4 alkenyl, phenyl, and R 7 , wherein C 1 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by one or more substituents selected from R a ;
R 3 and R 3 ′ are independently selected from the group consisting of H, halogen, hydroxyl, C 1 -C 4 alkyl, amido, amine, and C 2 -C 4 alkenyl, wherein C 1 -C 4 alkyl and C 2 -C 4 alkenyl are optionally substituted by one or more substituents selected from R a ;
R 4 and R 4 ′ are independently selected from the group consisting of H, halogen, hydroxyl, phenyl, C 1 -C 4 alkyl, amido, amine, C 1 -C 4 alkoxy, and C 2 -C 4 alkenyl, wherein C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 1 -C 4 alkoxy, 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, and C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by one or more substituents selected from R a ;
R 5 is 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 hydroxyl, halogen, amino, 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, 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 3 is H.
3. The compound of claim 1 , wherein R 2 is —C(O)—C 2 -C 4 alkyl, substituted at one carbon with NH 2 and another carbon with hydroxyl.
4. 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, wherein C 1 -C 4 alkyl is optionally substituted by one, two, or three substituents selected from the group consisting of F, Cl, and Br.
5. The compound of claim 1 , wherein R 1 is
6. The compound of claim 1 , wherein the compound is
7. A compound represented by:
and pharmaceutically acceptable salts, stereoisomers, and N-oxides thereof, wherein
R 1 is selected from the group consisting of H, hydroxyl, —S(O) 2 —C 1 -C 4 alkyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, phenyl, and R 7 , wherein C 1 -C 4 alkyl and C 2 -C 4 alkyl are optionally substituted by one or more substituents selected from R a ;
R 3 and R 3 ′ are independently selected from the group consisting of H, halogen, hydroxyl, C 1 -C 4 alkyl, amido, amine, and C 2 -C 4 alkenyl, wherein C 1 -C 4 alkyl, and C 2 -C 4 alkenyl 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, and C 1 -C 4 alkyl, wherein C 1 -C 4 alkyl is optionally substituted by one or more substituents selected from R a ;
R 5 is independently selected for each occurrence 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 group consisting of —C(O)—C 1 -C 4 alkyl or 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 hydroxyl, halogen, amino, 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, 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.
8. A compound represented by formula II:
and pharmaceutically acceptable salts, stereoisomers and N-oxides thereof; wherein
R 1 is selected from the group consisting of H, hydroxyl, C 1 -C 4 alkyl, and R 7 , wherein C 1 -C 4 alkyl is optionally substituted by one or more substituents each independently selected from halogen, hydroxyl, and amino;
R 3 and R 3 ′ are each H;
R 2 is selected from the group consisting of H and R 7 ;
R 6 is 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 1, 2 or 3 substituents selected from R a ;
R 5 is H;
R 7 is —C(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 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.
9. A non-peptidyl compound selected from the group consisting of:
or pharmaceutically acceptable salts, stereoisomers and N-oxides thereof.
10. A pharmaceutically acceptable composition comprising a compound of claim 1 , and a pharmaceutically acceptable excipient.
11. The composition of claim 10 , wherein the composition is suitable for oral administration to a patient.