Compound for adjusting activity of NMDA receptor, and pharmaceutical composition and use thereof
View Patent ↗Provided are a compound for adjusting the activity of an NMDA receptor, and a pharmaceutical composition and the use thereof. In particular, provided are a compound as represented by formula I, a pharmaceutically acceptable salt or ester, a stereoisomer, or a solvate thereof. The compound has the effect of enhancing the activity of the NMDA receptor, and can be used to prepare drugs for preventing/treating depression, anxiety disorder, tension, learning and cognitive defects, neuropathic pain and other diseases,
1 . A compound represented by formula I:
or a pharmaceutically acceptable salt, ester, or stereoisomer thereof wherein,
Ring A is selected from
R 1 is selected from H, C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, —CONRR′, and natural amino acid fragments;
when Ring A is
R 2 is selected from H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, —CONRR′, and natural amino acid fragments;
when Ring A is
R 2 is selected from C1-C6 alkoxycarbonyl, C2-C6 acyl, —CONRR′, and natural amino acid fragments;
R 3 is selected from H, cyano, 3- to 8-membered nitrogen-containing aliphatic heterocycle-C1-C4 acyl, C1-C6 alkoxycarbonyl, and —CONHR 4 ;
R and R′ are each independently selected from H and C1-C6 alkyl;
R 4 is selected from H, natural amino acid fragments and carboxylic acid derivatives of the said natural amino acid fragments;
optionally, the C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, C1-C6 alkoxycarbonyl, —CONRR′, —CONHR 4 , and natural amino acid fragments are each independently substituted by one or more substituents selected from: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl, and C1-C6 alkoxy; 3- to 8-membered nitrogen-containing aliphatic heterocycle-C1-C4 acyl is substituted by one or more substituents selected from: halogen, amino, hydroxyl, carboxyl, nitro, C1-C6 alkyl, and C1-C6 alkoxy;
wherein the natural amino acid fragments are selected from the carboxyl or amino residues of the following amino acids: Thr, Ser, Val, Gly, Ala, Ile, Leu, Phe, Tyr, Asp, and Gln; and, R 1 , R 2 and R 3 satisfy:
(1) R 1 , R 2 and R 3 are not H at the same time;
(2) when R 1 and R 3 are H, R 2 is not Boc;
(3) when formula I is
R 1 is
and R 3 is H, R 2 is not
(4) when formula I is
R 1 is
and R 3 is H, R 2 is not C2-C6 acyl or —CONRR′;
(5) when formula I is
R 1 and R 3 are H, R 2 is not acetyl,
(6) the compound of formula I is not
2 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein Ring A is selected from
3 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein, R 1 is selected from H, C1-C6 alkyl, phenyl-C1-C4 alkyl, C2-C6 acyl, and natural amino acid fragments.
4 . The compound according to claim 1 , or a pharmaceutically acceptable salt, stereoisomer thereof, wherein,
when Ring A is
R 2 is selected from H, C1-C6 alkyl, C1-C6 alkoxycarbonyl, C2-C6 acyl, and natural amino acid fragments;
when Ring A is
R 2 is selected from C1-C6 alkoxycarbonyl C2-C6 acyl, and natural amino acid fragments;
optionally, the C1-C6 alkyl, aryl-C1-C4 alkyl, C2-C6 acyl, and natural amino acid fragments are each independently substituted by one or more substituents selected from: halogen, amino, hydroxyl, cyano, carboxyl, nitro, C1-C6 alkyl, and C1-C6 alkoxy.
5 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein, R 3 is selected from H, cyano, 5- to 7-membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl and —CONHR 4 ; R 4 is selected from H, natural amino acid fragments, amide derivatives of the said natural amino acid fragments and cyano derivatives of the said natural amino acid fragments.
6 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein the natural amino acid fragments are selected from the carboxyl or amino residues of the following amino acids: Thr, Ser, Val, Gly, Ala, Ile, Phe, Gln and Tyr.
7 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein the compound is selected from:
8 . A pharmaceutical composition comprising an effective amount of the compound of the formula I according to claim 1 , a pharmaceutically acceptable salt, ester, or stereoisomer thereof.
9 . A method for treating depression, anxiety, stroke, Huntington's disease, Alzheimer's disease, neuralgia or schizophrenia in subjects, including administering an effective amount of the compound, pharmaceutically acceptable salt, ester, or stereoisomer of claim 1 to a subject in need thereof.
10 . A method for regulating activity of NMDA receptor in vivo or in vitro, including providing a subject, a mammalian cell or an NMDA receptor with an effective amount of the compound, pharmaceutically acceptable salt, ester, or stereoisomer of claim 1 .
11 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein R 1 is selected from H, C1-C6 alkyl, and C2-C6 acyl.
12 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein R 1 is selected from H, acetyl, methyl,
13 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein:
when Ring A is
R 2 is selected from H, C1-C4 alkoxycarbonyl, C2-C6 acyl, and carboxyl residues of the natural amino acids;
when Ring A is
R 2 is selected from C1-C4 alkoxycarbonyl, C2-C6 acyl, and carboxyl residues of the natural amino acids.
14 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein:
when Ring A is
R 2 is selected from H, methyl, ethyl, propyl, butyl, tert-butoxycarbonyl, acetyl,
when Ring A is
R 2 is selected from tert-butoxycarbonyl, acetyl,
15 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein R 3 is selected from H, cyano, 5- to 7-membered nitrogen-containing aliphatic heterocycle-C1-C3 acyl, C1-C4 alkoxycarbonyl, and —CONHR 4 ; R 4 is selected from H, natural amino acid fragments and amide derivatives of the said natural amino acid fragments.
16 . The compound according to claim 1 , or a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein R 3 is selected from H, cyano,
17 . The pharmaceutical composition according to claim 8 , wherein, the pharmaceutical composition also comprises one or more pharmaceutically acceptable excipients.
18 . The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof.