TRKB agonists and methods of use
Compounds and methods related to the activation of the TrkB receptor are provided. The methods include administering a 7,8-dihydroxyflavone derivative with modified flavone or heterocyclic ring to a subject in need thereof. Methods and compounds for the treatment of disorders including neurologic disorders, neuropsychiatric disorders, and metabolic disorders (e.g., obesity) are provided.
1. A compound of Formula A,
or salts or prodrugs thereof wherein,
J is S, or NR 7 ;
X is dialkylamino, or heterocyclyl, wherein X is optionally substituted with one or more, the same or different R 8 or X is optionally R 8 ;
R 1 and R 6 and the attached atoms form a heterocyclyl optionally substituted with one or more, the same or different R 8 ;
R 2 is hydrogen, alkoxy, hydroxy, or alkanoyloxy, wherein R 2 is optionally substituted with one or more, the same or different R 8 ;
R 3 is hydrogen, alkoxy, hydroxy, dialkylamino, or alkanoyloxy, wherein R 3 is optionally substituted with one or more, the same or different R 8 ;
R 4 is hydrogen or halogen;
R 5 is hydrogen, alkoxy, hydroxy, or alkanoyloxy wherein R 5 is optionally substituted with one or more, the same or different R 8 ; and
R 7 is hydrogen, alkyl, or alkanoyl wherein R 7 is optionally substituted with one or more, the same or different R 8 ;
R 8 is alkyl, halogen, cyano, amino, mercapto, formyl, carboxy, carbamoyl, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 9 ; and
R 9 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
2. The composition of claim 1 , wherein at least one of R 4 and R 5 is a halogen.
3. A composition comprising a compound selected from:
8-(4-(dimethylamino)phenyl)chromeno[7,8-d]imidazol-6(3H)-one; and
8-(4-(dimethylamino)phenyl)-7-fluorochromeno[7,8-d]imidazol-6(3H)-one;
or salts thereof.
4. A pharmaceutical composition comprising a compound of as in claim 1 , and an excipient wherein the excipient selected from a coating, binder, salt, anti-adherent, diluent, and filler.
5. The composition of claim 4 , wherein the pharmaceutical composition is in the form of a tablet, capsule, or solution for injection.
6. The composition of claim 5 , wherein the pharmaceutical composition comprises a second therapeutic agent.
7. A compound of Formula A,
or salts or prodrugs thereof wherein,
J is O, S, or NR 7 ;
X is dialkylamino or heterocyclyl, wherein X is optionally substituted with one or more, the same or different R 8 ;
R 1 and R 6 and the attached atoms form heterocyclyl optionally substituted with one or more, the same or different R 8 ;
R 2 is hydrogen, alkoxy, hydroxy, or alkanoyloxy, wherein R 2 is optionally substituted with one or more, the same or different R 8 ;
R 3 is hydrogen, alkoxy, hydroxy, dialkylamino, or alkanoyloxy, wherein R 3 is optionally substituted with one or more, the same or different R 8 ;
R 4 is hydrogen or halogen;
R 5 is hydrogen, alkoxy, hydroxy, or alkanoyloxy wherein R 5 is optionally substituted with one or more, the same or different R 8 ; and
R 7 is hydrogen, alkyl, or alkanoyl wherein R 7 is optionally substituted with one or more, the same or different R 8 ;
R 8 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 9 ; and
R 9 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.
8. A pharmaceutical composition comprising a compound of as in claim 7 , and an excipient wherein the excipient selected from a coating, binder, salt, anti-adherent, diluent, and filler.
9. The composition of claim 8 , wherein the pharmaceutical composition is in the form of a tablet, capsule, or solution for injection.
10. The composition of claim 9 , wherein the pharmaceutical composition comprises a second therapeutic agent.
11. A compound of Formula F,
or salts or prodrugs thereof wherein,
X is hydrogen, or X is dialkylamino, or heterocyclyl, wherein X is optionally substituted with one or more, the same or different R 8 , or X is optionally R 8 ;
R 2 is hydrogen, alkoxy, hydroxy, or alkanoyloxy, wherein R 2 is optionally substituted with one or more, the same or different R 8 ;
R 3 is hydrogen, alkoxy, hydroxy, dialkylamino, or alkanoyloxy, wherein R 3 is optionally substituted with one or more, the same or different R 8 ;
R 4 is hydrogen or halogen;
R 5 is hydrogen, alkoxy, hydroxy, or alkanoyloxy wherein R 5 is optionally substituted with one or more, the same or different R 8 ; and
R 8 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 8 is optionally substituted with one or more, the same or different, R 9 ;
R 9 is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; and
R 10 and R 11 are each, the same or different hydrogen, alkyl, or alkanoyl.
12. A pharmaceutical composition comprising a compound of as in claim 11 , and an excipient wherein the excipient selected from a coating, binder, salt, anti-adherent, diluent, and filler.
13. The composition of claim 12 , wherein the pharmaceutical composition is in the form of a tablet, capsule, or solution for injection.
14. The composition of claim 13 , wherein the pharmaceutical composition comprises a second therapeutic agent.