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US009737531B2 (12 ) United States Patent ( 10 ) Patent No. : US 9 , 737 ,531 B2 Javitt ( 45) Date of Patent : Aug . 22 , 2017 ( 54 ) COMPOSITION AND METHOD FOR 2008 /0194698 A1 * 8 / 2008 Hermanussen et al. .. .. 514 /662 TREATMENT OF DEPRESSION AND 2011/ 0207776 A18 / 2011 Buntinx 2011 /0306586 Al 12 / 2011 Khan PSYCHOSIS IN HUMANS 2012 /0041026 A12 / 2012 Waizumi (71 ) Applicant : Daniel C Javitt , Bardonia , NY (US ) FOREIGN PATENT DOCUMENTS ( 72 ) Inventor: Daniel C Javitt, Bardonia , NY (US ) CN 101090721 12 / 2007 KR 2007 0017136 A 2 / 2007 ( 73 ) Assignee : GLYTECH , LLC , Ft. Lee, NJ (US ) WO WO 2005 /000216 A2 1 / 2005 WO WO 2005 /065308 A2 7 / 2005 ( * ) Notice : Subject to any disclaimer , the term of this WO WO 2005 /079756 9 / 2005 patent is extended or adjusted under 35 WO 2011044089 4 / 2011 U . S . C . 154 ( b ) by 0 days . wo WO 2012 / 104852 Al 8 / 2012 ( 21 ) Appl. No. : 13 /936 , 198 OTHER PUBLICATIONS Ceglia et al. , “ The 5 -HT2A receptor antagonist M100 , 907 prevents ( 22 ) Filed : Jul. 7 , 2013 extracellular glutamate rising in response to NMDA receptor block ade in the mPFC ,” Journal of Neurochemistry , 2004 , 91 , 189 - 199 . * ((65 65 ) Prior Publication Data Mony et al. , “ Identification of a novel NR2B -selective NMDA US 2014 / 0018348 A1 Jan . 16 , 2014 receptor antagonist using a virtual screening approach , ” Bioorganic & Medicinal Chemistry Letters 20 ( 2010 ) 5552 - 5558 . * Ceglia et al ., “ The 5HT2A receptor antagonist M100 , 907 prevents Related U . S . Application Data extracellular glutamate rising in response to NMDA receptor block ( 60 ) Provisional application No . 61/ 741 , 114 , filed on Jul . ade in the mPFC ,” Journal of Neurochemistry , 2004 , 91 , 189 - 199 . * 12 , 2012 , provisional application No . 61 / 741 , 115 , Rogoz , Z . et al . “ Synergistic effect of uncompetitive NMDA recep tor antagonists and antidepressant drugs in the forced swimming test filed on Jul . 12 , 2012 . in rats ” Neuropharmacology , Pergamon Press , Oxford , GB , 42 ( 8 ) : 1024 - 1030 , XP002288820 ( Jun . 2002 ) . (51 ) Int. CI. Heresco - Levy , U . et al. “ Controlled trial of d - cycloserine adjuvant AOIN 43 / 00 ( 2006 .01 ) therapy for treatment- resistant major depressive disorder ” Journal A61K 31 /553 ( 2006 .01 ) of Affective Disorders , Elsevier Biochemical Press, Amsterdam , A61K 31 /554 ( 2006 .01 ) NL , 93 ( 1 - 3 ) : 239 - 243 , XP024997304 ( Jul. 2006 ) . A61K 31/ 496 ( 2006 .01 ) Crane , G . E . “ Cycloserine as an antidepressant agent” American A61K 31 /42 ( 2006 .01 ) journal of Psychiatry , American Psychiatric Publishing , Inc . , US , A61K 31 / 06 ( 2006 . 01 ) 115 (11 ) : 1025 - 1026 , XP009158563 (May 1 , 1959 ) . A61K 31/ 381 Oliver et al. " Quetiapine augmentation in depressed patients with (2006 .01 ) partial response to antidepressants ” Human Psychopharm Clin Exp , A61K 31 /55 ( 2006 . 01 ) 23 :653 - 660 , 2008 . A61K 31/ 138 (2006 .01 ) Poleszak et al “ A complex interaction between glycine/ NMDA A61K 45 / 06 ( 2006 .01 ) receptors and serotonergic /noradrenergic antidepressants in the A61K 31 /431 ( 2006 .01 ) forced swim test in mice " Journal of Neural Transmission , A61K 31/ 4525 (2006 .01 ) 118 : 1535 - 1546 , 2011 . A61K 31/ 519 ( 2006 . 01 ) Ishibashi et al “ Pharmacological Profile of Lurasidone , a Novel A61K 31/ 551 ( 2006 .01 ) Antipsychotic Agent with Potent 5 -Hydroxytryptamine 7 ( 5 -HT7 ) A61K 31 / 135 ( 2006 .01 ) and 5 -HT1A Receptor Activity " Journal of Pharmacology and (52 ) U . S . CI. Experimental Therapeutics , 334 : 171 - 181 , 2010 . CPC .. .. A61K 31/ 496 ( 2013 . 01 ) ; A61K 31/ 06 (Continued ) ( 2013 .01 ) ; A61K 31/ 135 ( 2013 .01 ) ; A61K 31 / 138 ( 2013 .01 ) ; A61K 31/ 381 ( 2013 . 01 ) ; A61K 31/ 42 ( 2013 . 01 ) ; A61K 31/ 431 Primary Examiner — Jared D Barsky ( 2013 .01 ) ; A61K 31 /4525 (2013 .01 ) ; A61K (74 ) Attorney , Agent, or Firm — JMB Davis Ben - David 31/ 519 ( 2013 .01 ) ; A61K 31 /55 ( 2013 . 01 ) ; A61K 31 / 551 ( 2013 . 01 ) ; A61K 31 / 553 (2013 . 01 ); A61K 31 /554 (2013 .01 ) ; A61K (57 ) ABSTRACT 45/ 06 ( 2013 . 01 ) Compositions and methods tor the treatment of depression (58 ) Field of Classification Search and psychoses in humans are disclosed . More particularly , None the invention is directed to formulations containing antip See application file for complete search history. sychotic and / or antidepressant medications and also con taining an NMDAR antagonist. The present invention is also (56 ) References Cited directed to methods for the treatment of humans suffering from depression and other psychoses , including , schizophre U . S . PATENT DOCUMENTS nia , by administration of the inventive compositions in 6 ,228 ,875 B1 * 5 / 2001 Tsai et al. .. 514 /380 antidepressant and /or antipsychotic effective amounts . 2005 / 0261340 A1 11/ 2005 Weiner 2006 / 0204486 A1 * 9 / 2006 Pyke et al. .. .. .. .. 424 / 94 . 2 2008/ 0194631 A1 * 8 / 2008 Trovero et al. .. .. .. .. 514 / 325 2 Claims, 1 Drawing Sheet US 9 ,737 ,531 B2 Page 2 ( 56 ) References Cited OTHER PUBLICATIONS Marek et al, “ The Selective 5 -HT2A Receptor Antagonist M100907 Enhances Antidepressant- Like Behavioral Effects of the SSRI Fluoxetine” Neuropsychopharmacology 30 : 2205 -2215 , 2005. Letter to Dr. Daniel Javitt from Dr. Yehezkel Caine , CEO of Herzog Hospital , Apr. 12 , 2017 (redacted ) ( 1 page ) . Letter to Dr. Yehezkel Caine , CEO of Herzog Hospital from Dr. Daniel Javitt, May 15 , 2017 ( redacted ) ( 3 pages ) * cited by examiner U . S . Patent Aug . 22 , 2017 US 9 ,737 , 531 B2 los * 5MDL100907(0.3mg/kg,1P)+DCS30–DOI(21.P 60-6MDL100907(0.3mg/kg,1P)+DCS300–DOI2 6.48MDL100907(03mg/kg,1P)+DOI2 3.DCS(300mg/kg,1P)+2 807:2DCS(30mg/kg,1.P)+ :1.PTS(P)=DOI2mg/kg, . 20 ARMS OPEN IN SPENT TIME % US 9 ,737 ,531 B2 COMPOSITION AND METHOD FOR Current treatments for major depression consist primarily TREATMENT OF DEPRESSION AND of older antidepressants , such as monoamine oxidase inhibi PSYCHOSIS IN HUMANS tors (MAOI ) and tricyclic antidepressants ( TCAs ) ( e . g . imipramine , amitryptiline , desipramine , clomipramine ) that CROSS REFERENCE TO RELATED were first developed in the 1960 ' s , and newer agents such as APPLICATIONS tetracyclic antidepressants ( TeCAs) , e . g ., amoxapine, setip tiline , maprotiline , mianserin , mirtazapine ) , serotonin This application claims the benefit of provisional appli - (SSRI ) and serotonin /norephinephrine (SNRI ) reuptake cation No. 61/ 741, 114 , filed Jul. 12 , 2012 , and provisional inhibitors ( e . g ., fluoxetine, fluvoxamine , paroxetine , citalo application No . 61 /741 , 115 , filed Jul . 12 , 2012 , the contents 10 pram , escitalopram , duloxetine , venlafaxine , dapoxetine , of each of which are hereby incorporated by reference . indalpine , valzodone ) . These agents work by modulating brain levels of monoamines , in particular norepinephrine BACKGROUND OF THE INVENTION and serotonin , and /or by blocking 5 -HT2A receptors. MAOIs and TCAs are considered “ broader spectrum ” agents Schizophrenia is a clinical syndrome associated with 15 than SSRI /SNRIs that were developed subsequently . psychotic symptoms such as delusions and hallucinations , as MAOI, TCAs . TeCAs, SSRIs , and SNRIs may collectively well as a decline in function in such areas as work , social be considered traditional antidepressants . relation or self care . Antipsychotics may also be effective in treatment of Diagnosis of schizophrenia may be determined using depression . Potentially beneficial antipsychotic medications standard textbooks of the art such as the Diagnostic and 20 include but are not limited to risperidone , olanzapine, que Statistical Manual of Mental Disorders - fourth edition tiapine , aripiprazole, clozapine, lioperidone , sertindole , ( DSM -IV ) published by the American Psychiatric Associa asenapine , lurasidone , cariprazine tion Symptoms of schizophrenia are typically measured Other antipsychotics and antidepressants in development using rating scales such as the Positive and Negative Syn - include Valdoxan (agomelatine , AGO178 ) ( Servier, Novar drome Scale (PANSS ) . 25 tis ) , Lu AA21004 (Lundbeck , Takeda ). F2695 , levomil Symptoms of schizophrenia are treated with antipsychotic nacipran (Forest , Pierre Fabre; SEP -227162 (Sepracor ) . medications , which function primarily by blocking dop - LUAA24530 ( Lundbeck , Takeda ) , SEP - 225289 ( Sepracor ) , amine D2 receptors . Epivanserine (Sanofi - Aventis ), SR46349 (Sanofi - Aventis ) , Antipsychotics may be divided into typical ( e . g . chlorpro - LY12624803 , HY10275 (Lilly , Hypnion ). TIK - 301/ mazine , haloperidol, perphenazine) vs . atypical ( e . g . amisul - 30 LY156735 ( Tikvah Therapeutics) , Lonasen ( bioanserin , pride , aripiprazole , asenapine , bioanserin , bifeprunox , car Dainippon ), LU - 31 - 130 (Lundbeck ) , SLV313 (Solvay ) , Edi iprazine , clotiapine , clozapine, iloperidone , lurasidone, voxetine (LY2216684 , Lilly ) , OPC -34712 (Otsuka / Lund mosaproamine , olanzapine , paliperidone, perospirone, que - beck Vyvanse ( lisdexamfetamine , Shire ). BCI- 224 ( sacome tiapine , remoxipride , risperidone , sertindole , sulpride, zip line , BrainCells ) , BCI- 540 ( clouracetam . BrainCells ) , BMS rasidone , zotepine ) based upon receptor binding, preclinical 35 82036 (BMS / AMRI ) . effects and side effect profile . Clinically effective doses of However, current treatment approaches have severe limi antipsychotic medication typically produce >60 % occu - tations. Only 60 -65 % of patients respond to the initial pancy of
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    US007964607B2 (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest et a1. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO[3,4-D]PYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460077 9/2004 WO 02085904 10/2002 (75) Inventors: Patrick Robert Verhoest, Old Lyme, CT WO 2004037176 5/2004 (US); Caroline ProulX-Lafrance, Ledyard, CT (US) OTHER PUBLICATIONS Wunder et a1, M01. PharmacoL, v01. 28, N0. 6, (2005), pp. 1776 (73) Assignee: P?zer Inc., New York, NY (U S) 1781. van der Staay et a1, Neuropharmacology, v01. 55 (2008), pp. 908 ( * ) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 USC 154(b) by 562 days. Primary Examiner * Susanna Moore (74) Attorney, Agent, or Firm * Jennifer A. Kispert; (21) Appl.No.: 12/118,062 Michael Herman (22) Filed: May 9, 2008 (57) ABSTRACT (65) Prior Publication Data The invention provides PDE9-inhibiting compounds of For US 2009/0030003 A1 Jan. 29, 2009 mula (I), Related US. Application Data (60) Provisional application No. 60/917,333, ?led on May 11, 2007. (51) Int. Cl. C07D 48 7/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01) (52) US. Cl. ................................... .. 514/262.1; 544/262 (58) Field of Classi?cation Search ................ .. 544/262; 5 1 4/2 62 .1 See application ?le for complete search history. and pharmaceutically acceptable salts thereof, Wherein R, R1, (56) References Cited R2 and R3 are as de?ned herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S.