Heterocyclic flavone derivatives, compositions, and methods related thereto

Patent metadata

Field	Value
Publication number	US-10010526-B2
Application number	US-201715416964-A
Country	US
Kind code	B2
Filing date	Jan 26, 2017
Priority date	Jul 27, 2012
Publication date	Jul 3, 2018
Grant date	Jul 3, 2018

Abstract

In certain embodiments, the disclosure relates to heterocyclic flavone derivatives, such as those described by formula provided herein, pharmaceutical compositions, and methods related thereto. In certain embodiments, the disclosure relates to methods of treating or preventing diseases or conditions related to BDNF and TrkB activity, such as depression, stroke, Rett syndrome, Parkinson's disease, and Alzheimer's disease by administering effective amounts of pharmaceutical compositions comprising compounds disclosed herein.

First claim

The invention claimed is:

1. A method of treating depression a comprising the administering an effective amount of a pharmaceutical composition to a subject in need thereof,
wherein said pharmaceutical composition comprises a compound of Formula I:

or salt thereof wherein,
X is O;
A is pyrrolidinyl;
R 1 and R 2 and attached atoms form a 5 membered heterocyclic ring optionally substituted with R 15 ;
R 3 , R 4 , R 5 , R 6 , and R 8 , are hydrogen;
R 7 and R 9 are halogen;
R 15 is independently selected alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 15 is optionally substituted with one or more, the same or different, R 16 ; and
R 16 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, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

2. The method of claim 1 , wherein the pharmaceutical composition is administered in combination with an anti-depressant.

3. The method of claim 2 , wherein the anti-depressant is a selective serotonin reuptake inhibitor such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone, a serotonin-norepinephrine reuptake inhibitor such as desvenlafaxine, duloxetine, milnacipran, venlafaxine, a noradrenergic and specific serotonergic antidepressant such as mianserin and mirtazapine, a norepinephrine reuptake inhibitor such as atomoxetine, mazindol, reboxetine, viloxazine, a norepinephrine-dopamine reuptake inhibitor such as bupropion, a selective serotonin reuptake enhancer such as tianeptine and amineptine, a norepinephrine-dopamine disinhibitor such as agomelatine, a tricyclic antidepressant such as amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline, a monoamine oxidase inhibitor such as isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine.

4. The method of claim 1 , wherein the compound is selected from:
8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one,
2-chloro-8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(3H)-one, and
8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazole-2,6(1H,3H)-dione, or salts thereof.

5. A method of treating depression comprising the administering an effective amount of a pharmaceutical composition to a subject in need thereof,
wherein said pharmaceutical composition comprises a compound of Formula IA

salt thereof wherein
X is O;
A is amino, aminoalkyl, diaminoalkyl, or heterocyclyl;
Z is N or CH;
R 13 is hydroxy or alkyl optionally substituted with one or more, the same or different, R 15 ;
R 3 , R 4 , R 5 , R 6 , R 8 , and R 14 are hydrogen;
R 7 and R 9 are halogen;
R 15 is independently selected alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 15 is optionally substituted with one or more, the same or different, R 16 ; and
R 16 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, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethyl sulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

6. The method of claim 5 , wherein the pharmaceutical composition is administered in combination with an anti-depressant.

7. The method of claim 6 , wherein the anti-depressant is a selective serotonin reuptake inhibitor such as citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, or vilazodone, a serotonin-norepinephrine reuptake inhibitor such as desvenlafaxine, duloxetine, milnacipran, venlafaxine, a noradrenergic and specific serotonergic antidepressant such as mianserin and mirtazapine, a norepinephrine reuptake inhibitor such as atomoxetine, mazindol, reboxetine, viloxazine, a norepinephrine-dopamine reuptake inhibitor such as bupropion, a selective serotonin reuptake enhancer such as tianeptine and amineptine, a norepinephrine-dopamine disinhibitor such as agomelatine, a tricyclic antidepressant such as amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline, a monoamine oxidase inhibitor such as isocarboxazid, moclobemide, phenelzine, selegiline, tranylcypromine.

8. A method of enhancing memory comprising the administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein said pharmaceutical composition comprises a compound of Formula I:

or salt thereof wherein,
X is O;
A is pyrrolidinyl;
R 1 and R 2 and attached atoms form a 5 membered heterocyclic ring optionally substituted with R 15 ;
R 3 , R 4 , R 5 , R 6 , and R 8 , are hydrogen;
R 7 and R 9 are halogen;
R 15 is independently selected alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 15 is optionally substituted with one or more, the same or different, R 16 ; and
R 16 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-dim ethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methyl sulfinyl, ethyl sulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl.

9. The method of claim 8 , wherein the compound is selected from:
8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)-2-methylchromeno[7,8-d]imidazol-6(3H)-one,
2-chloro-8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(3H)-one, and
8-(3,5-difluoro-4-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazole-2,6(1H,3H)-dione, or salts thereof.

10. A method of enhancing memory comprising the administering an effective amount of a pharmaceutical compo

Assignees

• Univ Emory

Inventors

• Ye Keqiang

Classifications

• C07D491/06

  Peri-condensed systems · CPC title

• C07D311/30

  not hydrogenated in the hetero ring, e.g. flavones · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61K31/407

  condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine · CPC title

• A61K31/353

  3,4-Dihydrobenzopyrans, e.g. chroman, catechin · CPC title