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7,8-Dihydroxyflavone and 7,8-Substituted Flavone

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7,8-Dihydroxyflavone and 7,8-Substituted Flavone (19) TZZ __T (11) EP 2 914 585 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 311/30 (2006.01) C07D 311/28 (2006.01) 07.03.2018 Bulletin 2018/10 A61K 31/353 (2006.01) A61P 25/00 (2006.01) C07D 311/38 (2006.01) C07D 311/36 (2006.01) (21) Application number: 13851584.6 (86) International application number: (22) Date of filing: 01.11.2013 PCT/US2013/067972 (87) International publication number: WO 2014/071134 (08.05.2014 Gazette 2014/19) (54) 7,8-DIHYDROXYFLAVONE AND 7,8-SUBSTITUTED FLAVONE DERIVATIVES, COMPOSITIONS, AND METHODS RELATED THERETO 7,8-DIHYDROXYFLAVON UND 7,8-SUBSTITUIERTE FLAVONDERIVATE, ZUSAMMENSETZUNGEN UND ZUGEHÖRIGE VERFAHREN 7,8-DIHYDROXYFLAVONE ET DÉRIVÉS DE FLAVONE 7,8-SUBSTITUÉE, COMPOSITIONS ET MÉTHODES ASSOCIÉES (84) Designated Contracting States: WO-A2-2011/156479 AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • CHEN, S. ET AL.: MOLECULAR PL PT RO RS SE SI SK SM TR PHARMACOLOGY, vol. 47, 1995, pages 419-424, XP002753952, (30) Priority: 05.11.2012 US 201261722339 P • S.-W. JANG ET AL: "A selective TrkB agonist with 12.07.2013 US 201361845399 P potent neurotrophic activities by 7,8-dihydroxyflavone", PROCEEDINGS OF THE (43) Date of publication of application: NATIONAL ACADEMY OF SCIENCES, vol. 107, 09.09.2015 Bulletin 2015/37 no. 6, 9 February 2010 (2010-02-09), pages 2687-2692, XP055084207, ISSN: 0027-8424, DOI: (73) Proprietor: Emory University 10.1073/pnas.0913572107 Atlanta, GA 30322 (US) • JANG,S-W. ET AL.: ’A selectiveTrkB agonist with potent neurotrophic activities by (72) Inventor: YE, Keqiang 7,8-dihydroxyflavone.’ PNAS. vol. 107, no. 6, Lilburn, Georgia 30047 (US) February 2010, pages 2687 - 2692, XP055084207 • MALIK, I.: ’Synthesis of Substituted (74) Representative: Coles, Andrea Birgit et al Dibenzothiophenes, Pyrazines, Quinoxalines, Kilburn & Strode LLP Flavones, Pyrimidines and Furans by Lacon London Regioselective Palladium (0)-Catalyzed 84 Theobalds Road Cross-CouplingReactions.’ DISSERTATION (DR. London WC1X 8NL (GB) RER. NAT.). September 2010, UNIVERSITAT ROSTOCK, XP055244175 (56) References cited: • REDDY, S. S. ET AL.: ’A convenient synthesis of WO-A1-2011/033265 WO-A2-2011/156479 ethyl furo[2,3-h]flavone/ chromone-8-carboxylates.’INDIAN JOURNAL OF CHEMISTRY. vol. 50B, November 2011, pages 1671 - 1676, XP055244176 Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 914 585 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 914 585 B1 Description ACKNOWLEDGEMENTS 5 [0001] This invention was made with government support under Grant No. RO1DC010204 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD 10 [0002] 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, synthesis uses related thereto. In certain embodiments, the disclosure relates to the pharmaceutical compositions comprising compounds disclosed herein for use in 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, 15 and Alzheimer’s disease in a subject. In certain embodiments, it is contemplated that the 7,8-substituted flavone deriv- atives disclosed herein are prodrugs of 7,8-dihydoxyflavone and analogs. BACKGROUND 20 [0003] Neurotrophins are growth factors regulate the development and maintenance of the peripheral and the central nervous system. Brain-derived neutrotrophic factor (BDNF) is a member of the neurotrophin family, which includes nerve growth factor (NGF), NT-3 and NT-4/5. BDNF binding to its cognate receptor, TrkB, triggers its dimerization through conformational changes and autophosphorylation of tyrosine residues, resulting in activation of the three major signaling pathways - mitogen-activated protein (MAPK), phosphatidylinositol 3-kinase (PI3K) and phospholipase C-γ1 (PLC-γ1). 25 Various studies have shown links between BDNF and TrkB to conditions such as depression, schizophrenia, obsessive- compulsive disorder, Alzheimer’s disease, Huntington’s disease, Rett syndrome, and dementia, as well as anorexia nervosa and bulimianervosa. See Dwivedi, NeutopsychiatricDisease and Treatment, 2009,5: 433-49; Xiu etal., Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2009, 33(8):1508-12; Maina et al., Journal of Affective Disor- ders, 2010, 122(1-2):174-8; Zuccato et al., Nature Reviews Neurology, 2009, 5(6):311-22; Zajac et al., 2010, Hippoc- 30 ampus 20 (5): 621-36; Zeev et al., Neurology, 2009, 72 (14): 1242-7; Arancio et al., 2007, Current Opinion in Neurobiology, 17 (3): 325-30; Mercader et al, Neuropsychobiology , 2007, 56 (4): 185-90; Kaplan et al., International Journal of Eating Disorders, 2008 41 (1): 22-8. Epigenetic enhancement of BDNF signaling rescues synaptic plasticity in aging. See Zeng et al., J. Neuroscience, 2011, 31(49):17800 -17810. 7,8-dihydroxyflavone reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer’s disease. See Devi & Ohno, Neuropsychopharmacology, 2012, 37(2):434-44. 35 [0004] It has been reported that certain 7,8-dihydroxyflavone derivatives promote neurogenesis and exhibits potent antidepressant effects. See Liu et al., J Med Chem, 2010, 53 (23), pp 8274-8286. See also WO/2010/011836, WO/2010/107866, and WO 2011/156479. As 7,8-dihydroxyflavone derivatives are catechol and phenyl containing com- pounds, they areprone to be cleared in thecirculatory system following oxidation,glucuronidation, sulfation ormethylation. Thus, there is a need to identify improved flavone derivatives with improved pharmacokinetic properties. 40 [0005] The health benefits of flavonoid compounds have been reported in a number of references, including neuro- protective and anti-cancer properties. See Chiruta et al., 2012, Journal of Medicinal Chemistry, 55, 378-89; Sousa et al., 2012, European Journal of Organic Chemistry, 1, 132-43; Sivakumar et al., PCT Appl. No. US 2010/0179210. Derivatives of 3-hydroxyquinolone compounds have also been previously synthesized with reports of their fluorescence and biological activities disclosed. See Yushchenko et al., 2006, Tetrahedron Letters, 47, 905-8; Krejci et al., PCT Appl. 45 No. US 2010/0022587. [0006] A prodrug is a pharmacological substance that is administered and is subsequently converted to an active pharmacological agent through normal metabolic processes. Enzymes are involved in the bioconversion of ester-based prodrugs. See Liederer &, Borchardt, J Pharm Sci, 2006, 95(6):1177-95. [0007] The references cited hereby are not an admission of prior art. 50 SUMMARY [0008] 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 uses related thereto. In certain 55 embodiments, the disclosure relates to pharmaceutical compositions comprising compounds disclosed herein for use in treating or preventing diseases or conditions related to BDNF and TrkB activity, such as psychiatric disorders, de- pression, post-traumatic stress disorder, and autism spectrum disorders, stroke, Rett syndrome, Parkinson’s disease, and Alzheimer’s disease in a subject. In certain embodiments, it is contemplated that the 7,8-substituted flavone deriv- 2 EP 2 914 585 B1 atives disclosed herein are prodrugs of 7,8-dihydoxyflavone and analogs. [0009] In certain embodiments, the disclosure related to a compound comprising Formula I: 5 10 15 or salts thereof wherein X is O; U and Y are each O, S, NH, Nalkyl, or CH 2; Z is hydrogen, amino, diaminoalkyl, or heterocyclyl such as pyrrolidinyl optionally substituted with one or more, the 20 same or different, R15; R1 is independently selected from alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, 1 alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R is optionally substituted with one or more, the same or different, R 15; R2 is alkyl, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, 25 2 (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R is optionally sub- stituted with one or more, the same or different, R 15; R3, R4, R5, R6, R7, R8, and R9 are each individually and independently hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl)2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R3, R4, R5, R6, R7, R8, and R9 are optionally 30 substituted with one or more, the same or different, R 15; R15 is independently selected alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, 15 alkoxy, alkylthio, alkylamino, (alkyl) 2amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, or aryl, wherein R is optionally
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