7,8-dihydoxyflavone and 7,8-substituted flavone derivatives, compositions, and methods related thereto

Patent metadata

Field	Value
Publication number	US-9975868-B2
Application number	US-201715593654-A
Country	US
Kind code	B2
Filing date	May 12, 2017
Priority date	Nov 5, 2012
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

In certain embodiments, the disclosure relates to 7,8-dihydoxyflavone and 7,8-substituted 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 psychiatric disorders, depression, post-traumatic stress disorder, and autism spectrum disorders, stroke, Rett syndrome, Parkinson's disease, and Alzheimer's disease by administering effective amounts of pharmaceutical compositions comprising compounds disclosed herein to a subject in need thereof. In certain embodiments, it is contemplated that the 7,8-substituted flavone derivatives disclosed herein are prodrugs of 7,8-dihydoxyflavone and analogs.

First claim

The invention claimed is:

1. A method of treating a BDNF and TrkB related disease or condition comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a compound of Formula I:

or a salt thereof, wherein:
X is O, S, or NH;
U and Y are each O, S, NH, Nalkyl, or CH 2 ;
Z is hydrogen, amino, diaminoalkyl, or heterocyclyl optionally substituted with one or more, the same or different, R 15 ;
R 1 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R 1 is optionally substituted with one or more, the same or different, R 15 ;
R 2 is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2 is optionally substituted with one or more, the same or different, R 15 ;
R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkyl sulfonyl, aryl sulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are optionally substituted with one or more, the same or different, R 15 ;
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, methylsulfinyl, ethylsulfinyl, mesyl, ethyl sulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; and
a pharmaceutically acceptable excipient,
wherein the disease or condition is depression, schizophrenia, obsessive-compulsive disorder, anorexia nervosa, bulimia nervosa, anxiety, amyotrophic lateral sclerosis, Autism spectrum disorders, post-traumatic stress disorder, Alzheimer's disease, Huntington's disease, Rett syndrome, epilepsy, Parkinson's disease, dementia, diabetic neuropathy, peripheral neuropathy, or stroke.

2. The method of claim 1 , wherein the subject is diagnosed with, exhibiting symptoms of, or at risk of the disease or condition.

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

4. The method of claim 3 , wherein the anti-depressant is a selective serotonin reuptake inhibitor, a serotonin-norepinephrine reuptake inhibitor, a noradrenergic and specific serotonergic antidepressant, a norepinephrine reuptake inhibitor, a norepinephrine-dopamine reuptake inhibitor, a selective serotonin reuptake enhancer, a norepinephrine-dopamine disinhibitor, a tricyclic antidepressant, or a monoamine oxidase inhibitor.

5. The method of claim 1 , wherein U and Y are NH or Nalkyl.

6. The method of claim 1 , wherein U and Y are oxygen.

7. The method of claim 1 , wherein R 1 and R 2 are alkyl.

8. The method of claim 1 , wherein the compound is selected from:
4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(methylcarbamate);
4-oxo-2-phenyl-4H-chromene-7,8-diyl dipropionate;
diethyl (4-oxo-2-phenyl-4H-chromene-7,8-diyl) dicarbonate;
4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(ethylcarbamate);
4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(dimethylcarbamate); and
4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(3-methylbutanoate), or a salt thereof.

9. The method of claim 1 , wherein the disease or condition is Alzheimer's disease.

10. The method of claim 1 , wherein the disease or condition is Parkinson's disease.

11. The method of claim 1 , wherein the disease or condition is depression.

12. The method of claim 1 , wherein the disease or condition is Huntington's disease.

13. The method of claim 3 , wherein the anti-depressant is citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, vilazodone, desvenlafaxine, duloxetine, milnacipran, venlafaxine, mianserin, mirtazapine, atomoxetine, mazindol, reboxetine, viloxazine, bupropion, tianeptine, amineptine, agomelatine, amitriptyline, clomipramine, doxepin, imipramine, trimipramine, desipramine, nortriptyline, protriptyline, isocarboxazid, moclobemide, phenelzine, selegiline, or tranylcypromine.

14. A method of treating a BDNF and TrkB related disease or condition comprising administering an effective amount of a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises 4-oxo-2-phenyl-4H-chromene-7,8-diyl bis(2,2-dimethylpropanoate) and a pharmaceutically acceptable excipient,
wherein the disease or condition is depression, schizophrenia, obsessive-compulsive disorder, anorexia nervosa, bulimia nervosa, anxiety, amyotrophic lateral sclerosis, autism spectrum disorders, post-traumatic stress disorder, Alzheimer's disease, Huntington's disease, Rett syndrome, epilepsy, Parkinson's disease, dementia, diabetic neuropathy, peripheral neuropathy, or stroke.

Assignees

• Univ Emory

Inventors

• Ye Keqiang

Classifications

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P25/18

  Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title