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(12) United States Patent (10) Patent No.: US 8,203,009 B2 Ye (45) Date of Patent: Jun USOO8203 009B2 (12) United States Patent (10) Patent No.: US 8,203,009 B2 Ye (45) Date of Patent: Jun. 19, 2012 (54) NEUROTROPHIC ACTIVITY OF (56) References Cited DEOXYGEDUNN U.S. PATENT DOCUMENTS (75) Inventor: Keqiang Ye, Liburn, GA (US) 2008/0090897 A1* 4/2008 Steiner et al. ................. 514,453 (73) Assignee: Emory University, Atlanta, GA (US) OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this Jang et al. PLoS ONE, www.plosone.org Jul. 2010. 5(7), e1 1528.* patent is extended or adjusted under 35 * cited by examiner U.S.C. 154(b) by 0 days. 21) Appl. No.: 13/056,377 Primary Examiner — Nizal Chandrakumar (21) Appl. No.: 9 (74) Attorney, Agent, or Firm — James C. Mason; Susanne (22) PCT Filed: Jul. 28, 2009 Hollinger; Emory Patent Group (86). PCT No.: PCT/US2O09/051966 (57) ABSTRACT S371 (c)(1), Novel compounds and methods for activating the TrkB recep (2), (4) Date: Feb. 23, 2011 tor are provided. The methods include administering in vivo or in vitro a therapeutically effective amount of a compound (87) PCT Pub. No.: WO2010/014613 containing four six-membered rings and a substituted or PCT Pub. Date: Feb. 4, 2010 unsubstituted Cs or C. heteroaryl or hetero-cycloalkyl ring a rs and pharmaceutically acceptable salts, prodrugs, and deriva (65) Prior Publication Data tives thereof. Specifically, methods and compounds for the treatment of disorders including neurologic, neuropsychiat US 2011/014.4096 A1 Jun. 16, 2011 ric, and metabolic disorders are provided. For example, a O O method is provided of treating or reducing the risk of depres Related U.S. Application Data Sion, anxiety, or obesity in a Subject, which includes selecting (60) Provisional application No. 61/084,117, filed on Jul. a subject with or at risk of developing depression, anxiety, or 28, 2008, provisional application No. 61/118,907, obesity, and administering to the Subject a therapeutically filed on Dec. 1, 2008. effective amount of the described compounds. A further method of promoting neuroprotection in a subject is pro (51) Int. Cl. vided, which includes selecting a Subject in need of neuro CO7D 3II/00 (2006.01) protection, and administering to the Subject a therapeutically (52) U.S. Cl. ....................................................... 549/275 effective amount of the described compounds. (58) Field of Classification Search ................... 549/275 See application file for complete search history. 2 Claims, 23 Drawing Sheets U.S. Patent Jun. 19, 2012 Sheet 1 of 23 US 8,203,009 B2 BDNF or 2000 compound library T48 Cell SN56 Cell TrkB receptor Treat STS (0.75 uM), 9 hours Add MR-(DEVD)2 (1OuM), 1 hour & SS4. SS SSSSSSSSSK-0 SSSSSSSSSSS S& SSSSSSSSSSSS First-round selected compounds Screening for activation of Trk B-mediated signalings in primary neurons FIG. 1 U.S. Patent Jun. 19, 2012 Sheet 2 of 23 US 8,203,009 B2 O -SO O O HO f HO O beta-dihydrogedunol alpha-dihydrogedunol 3beta-hydroxydeoxydesacetoxy (epOXy ring up) 7-Oxogedunin CsO O HO O alpha-dihydrogedunolo dihydrodeoxygedunin 3-deoxO-3beta (epoxy ring down) acetoxydeoxydihydrogedunin e HO J. 3alpha- O 3beta 3alpha hydroxydeoxgedunin acetoxydeoxydihydrogedunin acetoxydihydrodeoxygeduninO HO 36ere deoxygedunin tridesaceloxykhivorin hydroxydeoxOdihydrodeoxygedunin FIG. 2 U.S. Patent US 8,203,009 B2 (9%)O?euSISO?dodwy (Glutamate) FIG. 3 U.S. Patent Jun. 19, 2012 Sheet 5 of 23 US 8,203,009 B2 ? ? ? ? %? % (Ce,N e5ueW U.S. Patent Jun. 19, 2012 Sheet 7 of 23 US 8,203,009 B2 Deoxygedunin (500 nM) Deoxygedunin (30 min) 0 5 10 30 60 180 (min) O 50 100 250 500 (nM) Wb: anti-p-Akt (473) Wb: anti-p-Erk Wb: anti-p-Erk Wb: anti-Erk Wb: anti-Erk Hippocampal neurons FIG. 7 Wb: anti-p-TrkB Wb: anti-TrkB FIG. 8 U.S. Patent Jun. 19, 2012 Sheet 8 of 23 US 8,203,009 B2 Deoxygedunin O 1 2 4 8 hr Wb: anti-p-Trk A Wb: anti-Trk A Wb: anti-p-Trk B Wb: anti-TrkB Wb: anti-Tubulin FIG. 9 U.S. Patent Jun. 19, 2012 Sheet 9 of 23 US 8,203,009 B2 7,8-DHF Deoxyged unin O 1 2 4 8 16 hr O 1 5 10 mg/kg Wb: anti-p-TrkB Wb: anti-p-TrkB Wb: anti-TrkB Wb: anti-TrkB FIG. 10 COntrol Deoxyged unin p-TrkB Merge U.S. Patent Jun. 19, 2012 Sheet 10 of 23 US 8,203,009 B2 A 120 100 80 60 40 20 Input ECD ICD ECD CD Trk A TrkB FIG. 12A 120 100 8O 60 40 20 O Input ECD CC-1 LRM CC-2 ICD lig-1 lg-2 FIG. 12B U.S. Patent Jun. 19, 2012 Sheet 11 of 23 US 8,203,009 B2 200 Ka=1.4 x 10 100 O 5 10 15 20 (uM) (Deoxyged unin Conc.) 0. O 3 0. O 2 O.O1 O 500 1000 1500 2000 (Bound, nM) FIG. 13 U.S. Patent Jun. 19, 2012 Sheet 12 of 23 US 8,203,009 B2 OSWNCI PU DOWn: GST beads Wib: Anti-HA-HRP Wb: Anti-HA-HRP Pull Down: GST beads Wb: Anti-p-Trk B Pull DOWn: GST beads Wb: Anti-GST-HRP FIG. 14 U.S. Patent Jun. 19, 2012 Sheet 13 of 23 US 8,203,009 B2 Wb: anti-HA-HRP Pull down: GST-beads, Wb: anti-GST-HRP FIG. 15 TrkB TrkB H st ?h g H - Deoxygedunin s s s s s Wb: Anti-p-TrkB &. SS. Wb: Anti-HA-HRP U.S. Patent Jun. 19, 2012 Sheet 14 of 23 US 8,203,009 B2 Glu Glu +/- +/- -/- -/- TrkB C C C C E E 2 S 3 2 S 2 S 3 2 S o O L.L S.S is 9-a O L.T. S. E2ts o O 4L 3S. s. 9-2 O 4T. 3S. 5 Ch X df On X S df ( x S of Ch X E E S 2. Q3 E S ob. 3 SE E aS C 3B E2 E aS ob B Wb: anti-p-TrkB Wb: anti-p-TrkB Wb: anti-TrkB Wb: anti-TrkB Wb: anti-p-Trk A Wb: anti-p-Trk A Wb: anti-Trk A Wb: anti-active caspase : anti-active Caspase FIG. 17 U.S. Patent Jun. 19, 2012 Sheet 16 of 23 US 8,203,009 B2 sN NN SS Q S$ Sc. OCS K o 3 S & 9 2 S ?h N2 s 2 as2 S. 2is Wb: anti-p-Trk B Wb: anti-TrkB Wb: anti-p-Akt Wb: anti-Akt Wb: anti-p-ERK Wb: anti-ERK FIG. 19 U.S. Patent Jun. 19, 2012 Sheet 17 Of 23 US 8,203,009 B2 H . C s C - i. E N- SK9 to C O CC d d N1 O) 5 ?h h E 3R & 3,R + n & R it; 2 S.- 25 isi 2t is5 2 Wb: anti-active caspase 3 Wb: anti-p-TrkB Wb: anti-TrkB FIG. 20 Vehicle DG Vehicle DG Wb: anti-p-TrkB Wb: anti-TrkB Wo: anti-BDNF FIG. 21 U.S. Patent Jun. 19, 2012 Sheet 18 of 23 US 8,203,009 B2 Vehicle DG 60 50 40 Vestibular ganglion Cell 30 number (%) 20 10 Vehicle DG FIG. 22 U.S. Patent US 8,203,009 B2 FIG. 23A Wild-type 2OO 150 100 $o FIG. 23B Water NMPP1 TrkB F616A KnOCkin U.S. Patent Jun. 19, 2012 Sheet 20 of 23 US 8,203,009 B2 KA KA+Deoxyged unin FIG. 24 TUNEL Merge 120 100 8 O 2 O O 3 U.S. Patent Jun. 19, 2012 Sheet 21 of 23 US 8,203,009 B2 MCAO + Deoxyged unin 60 Infaction Volume 50 (%. Contralateral 40 Hemisphere) 30 20 10 O MCAO- MCAO + Veh Deoxyged unin FIG. 25 U.S. Patent Jun. 19, 2012 Sheet 22 of 23 US 8,203,009 B2 Day 1 -> Day 2 Day 3 Day 4-> Day 5 Habituation Fear Conditioning Testing for DG VS. Vehicle Cue-Dependent 1 hr before training Fear Memory 5000.0 4000.0 3OOOO 2000.0 1000.0 O.O DEOXYGEDUNIN VEHICLE 70 60 -0- 08-DG 9 50 -- DMSO 40 30 & 20 10 O TEST 1 TEST 2 FREEZING FREEZING FIG. 28 U.S. Patent Jun. 19, 2012 Sheet 23 of 23 US 8,203,009 B2 - - - - - 08-DG VEHICLE CO C-D .__-->=.*** • _-~~ )==*** • FIG. 29A - - - - - 08-DG VEHICLE CN LOO FIG. 29B US 8,203,009 B2 1. 2 NEUROTROPHIC ACTIVITY OF stituted or unsubstituted C-2 haloalkyl, Substituted or DEOXYGEDUNN unsubstituted C- alkenyl, Substituted or unsubstituted C-2 alkynyl, Substituted or unsubstituted aryl, Substituted or This application claims the benefit of U.S. Provisional unsubstituted cycloalkyl, substituted or unsubstituted het Application Ser. No. 61/084,117, filed Jul. 28, 2008, and 5 eroaryl, substituted or unsubstituted heterocycloalkyl, substi 61/118,907, filed Dec. 1, 2008. The entire disclosures of the tuted or unsubstituted arylalkyl, substituted or unsubstituted prior applications are hereby incorporated by reference. heteroarylalkyl, substituted or unsubstituted cycloalkylalkyl, This invention was made with government Support under and substituted or unsubstituted heterocycloalkylalkyl; R is Grant No. RO1-NSO45627 from the National Institutes of hydrogen, carbonyl, hydroxyl, -O-R', —O—C(=O)— Health. The government has certain rights in this invention. 10 R", or - NRR, wherein Rand R, are each independently selected from R'; R is carbonyl, R', O R', or—O C BACKGROUND (=O) R': A is a substituted or unsubstituted Cs or Chet eroaryl or Cs or Cr-r heterocycloallyl, is a single or Neurologic and neuropsychiatric disorders such as depres double bond, wherein two double bonds are not adjacent; and Sion, anxiety, amyotrophic lateral sclerosis, and central ner 15 Fis a double bond or Vous system injuries, to name a few, afflict millions of people every year resulting in a multitude of symptoms including weight change, decreased energy, headaches, digestive prob lems, chronic pain, paralysis, and in certain instances, death.
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