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

• US 10,526,303 B2
• Filed: 02/26/2018
• Issued: 01/07/2020
• Est. Priority Date: 11/05/2012
• Status: Active Grant

• Current Assignee: Emory University
• Original Assignee: Emory University
• Inventors: Ye, Keqiang
• Primary Examiner(s): Solola, Taofiq A
• Application Number:
  US15/905,179
• Publication Number:
  US 20180186762A1
• Time in Patent Office: 680 Days
• Field of Search: 514456
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 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 Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 311/28 with aromatic rings attached in position 2 only
• CPC Class Codes: C07D 311/30 not hydrogenated in the hetero ring, e.g. flavones
• CPC Class Codes: C07D 311/36 not hydrogenated in the hetero ring, e.g. isoflavones
• CPC Class Codes: C07D 311/38 2,3-Dihydro derivatives, e.g. isoflavanones

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.

Claims

1. A compound having Formula I:

2. The compound of claim 1, wherein U and Y are NH or Nalkyl.

3. The compound of claim 1, wherein U and Y are oxygen.

4. A pharmaceutical composition comprising a compound of as in claim 1 and a pharmaceutically acceptable excipient.

5. The composition of claim 4, wherein the pharmaceutical composition is in the form of a tablet, capsule, pill, or solution for injection.

6. A method of preventing or treating a BDNF and TrkB related disease or condition comprising the administering an effective amount of a pharmaceutical composition of claim 4, to a subject in need thereof.

7. The method of claim 6 wherein the subject is diagnosed with, exhibiting symptoms of, or at risk of the disease or condition.

8. The method of claim 6, 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, Rhett syndrome, epilepsy, Parkinson'"'"'s disease, dementia, diabetic neuropathy, peripheral neuropathy, obesity, or stroke.

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

10. The method of claim 9, 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.