NDMA 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 disorders, 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:
where
R 11 , R 12 and R 13 are each independently selected from the group consisting of H, halogen, C 1-3 alkoxy, and C 1-3 alkyl (optionally substituted by one, two or three halogens);
X 1 is OH or NH 2 ,
X 2 is H or OH;
and pharmaceutically acceptable salts, stereoisomers and hydrates thereof.
2 . The compound of claim 1 , wherein the halogen, for each occurrence, is independently selected from the group consisting of Cl, Br, and F.
3 . The compound of claim 1 or 2 , wherein the compound is substantially more efficacious when administered orally to a patient as compared to oral administration to a patient of a peptidyl compound represented by:
4 . The compound of any one of claims 1 - 3 , wherein X 2 is OH and X 1 is NH 2 .
5 . The compound of any one of claims 1 - 4 , wherein each of R 11 , R 12 , and R 13 is H.
6 . The compound of any one of claims 1 - 5 , wherein R 11 and R 13 is H, and R 12 is selected from the group consisting of F, Br, Cl, CH 3 , CF 3 , and —OCH 3 .
7 . A compound represented by:
wherein:
R 1 , R 2 , R 3 , and R 4 are each independently selected from the group consisting of hydrogen; halogen, C 1 -C 6 alkyl, and —OH;
R 5 is H or —CH 2 -phenyl (wherein the phenyl is optionally substituted by one, two, or three substituents selected from the group consisting of halogen, C 1-3 alkoxy, and C 1-3 alkyl (optionally substituted by one, two or three halogens)), provided that R 5 is —CH 2 -phenyl when R 1 and R 3 are —OH and R 2 and R 4 are methyl; and
X is selected from the group consisting of OR x and NR x R x , wherein R x is independently selected, for each occurrence, from the group consisting of hydrogen, and C 1 -C 6 alkyl; pharmaceutically acceptable salts, stereoisomers, and hydrates thereof.
8 . The compound of claim 7 represented by:
9 . The compound of claim 7 represented by:
10 . The compound of claim 7 represented by:
11 . The compound of claim 7 represented by:
12 . A pharmaceutical composition, comprising:
a therapeutically effective amount of a compound of any one of claims 1 - 11 and a pharmaceutically acceptable carrier.
13 . The pharmaceutical composition of claim 11 , suitable for injection.
14 . A method of treating depression, Alzheimer's disease, attention deficit disorder, ADHD, schizophrenia, or anxiety, in a patient in need thereof, comprising administering to said patient:
a pharmaceutically effective amount of a compound of any one of claims 1 - 12 .
15 . A method of treating depression, Alzheimer's disease, attention deficit disorder, ADHD, schizophrenia, or anxiety, in a patient in need thereof, comprising orally administering to said patient a pharmaceutically effective amount of a compound of any one of claims 1 - 6 .
16 . A method of treating depression, Alzheimer's disease, attention deficit disorder, ADHD, schizophrenia, or anxiety, in a patient in need thereof, comprising administering subcutaneously or intravenously to said patient a pharmaceutically effective amount of a compound of any one of claims 8 - 11 .