US 20190262353A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2019 /0262353 A1 YONG et al. (43 ) Pub . Date : Aug . 29 , 2019 ( 54 ) TREATMENT FOR PROGRESSIVE Publication Classification MULTIPLE SCLEROSIS (51 ) Int. Cl. (71 ) Applicant : UTI LIMITED PARTNERSHIP , A61K 31 / 55 ( 2006 . 01 ) Calgary (CA ) A61K 31 / 404 ( 2006 .01 ) (72 ) Inventors : Voon Wee YONG , Calgary (CA ) ; A61P 25 / 28 (2006 .01 ) Simon FAISSNER , Bochum (DE ) ; ( 52 ) U .S . CI. Marcus KOCH , Calgary (CA ); Nathan CPC . .. .. .. A61K 31/ 55 ( 2013. 01 ) ; A61P 25 / 28 James MICHAELS, Kamloops (CA ) ( 2018 .01 ) ; A61K 31 /404 ( 2013 .01 ) (21 ) Appl. No. : 16 / 343, 818 (22 ) PCT Filed : Oct. 24 , 2017 (57 ) ABSTRACT ( 86 ) PCT No. : PCT/ CA2017 /051269 In one aspect , there is provided a method of treating , $ 371 ( C ) ( 1 ) , prophylaxis , or amelioration of a neurological disease by ( 2 ) Date : Apr. 22 , 2019 administering to a subject in need thereof one or more Related U . S . Application Data compounds described herein . In a specific example , the ( 60 ) Provisional application No . 62 /412 ,534 , filed on Oct . neurological disease is multiple sclerosis (also referred to as 25 , 2016 . “ MS ” ) . Patent Application Publication Aug. 29, 2019 Sheet 1 of 23 US 2019 / 0262353 A1 3000 Iron mediated neurotoxicity * * * * * * * * * * * Neurons 1000 fitini TTTTTTTToitain | 1 | ControlFeSO4DMSO 50 WMAtenolol PimozideFosfomycinKetoprofen MefloquineQuinapril Liothyronine'5-Chloroindole Ranitidine Bumetanide TolfenamicTranexamic acid acid ketoprofenDequaliniumPyridostigmineCyclosporine Paromomycin Labetalol Tenoxicam Mitoxanthrone Trazodone FeSO450 PM Control Fes0 , 50 PM FeSO , 50 UM + Indapam Control Feso , 50 UM FeSO , 50 UM + Indapam SA FIGURE 1 Patent Application Publication Aug. 29, 2019 Sheet 2 of 23 US 2019 / 0262353 A1 ??? - iron Antiaggregation Antihypertensive Antipsychotic Tricyclic . Antibiotic antidepressant : .. .. %survivingneurons(ofcontrols) . * * * * * * * * * 14. wow. trsiti or . B mmmmmm . ... Comece : :. DDDDDDDDDDDDD . .1 . A . v DipyridamoleClopidogrelClarithromycinCefaclor vErythromycin RifampinLoperamide* Ketoconazole Labeta?ol Methyldopa Metoprolol Atenolol Carvedilol IndapamideMefloquine Primaquine Mitoxanthrone LevodopaTrimeprazine Chlorpromazine Clozapine Periciazine DimenhydrinateFlunarizineDiphenhydramine PromethazinePhenazopyridine Yohimbine MemantineLiothyronine Clomipramine Desipramine Doxepin ImipramineTrimipramine X Live cell imaging neurotoxicity Legend : FeSO4 %Plpositiveneurons en Indapamide + Feso : * terowaniaintegrirana erDet Desipramine + FeSOA - .. .. wwerwe . www . Boswwwwwwwwwwwww 0 1 2 3 4 5 6 7 8 9 10 11 12 Time th ] FIGURE 2 Patent Application Publication Aug. 29 , 2019 Sheet 3 of 23 US 2019 / 0262353 A1 Rotenone mediated neurotoxicity C Drug * Rotenone Antipsychotic Antihypertensive Tricyclic antidepressant * * * * ???? www %controlneurons cmcm. FinW.WWW . ways . DipyridamoleClopidogrelCefaclor Labetalot Methyldopa Metoprolol Indapamide Mefloquine PrimaquineMitoxantrone Trimeprazine Chlorpromazine Clozapine Periciazine FlunarizinePromethazine MemantineLiothyronine Clomipramine Desipramine Imipramine Trimipramine Doxepin Control Rotenone 10 UM + Indapamide Rotenone 10 uM We 3 . S FIGURE 3 Patent Application Publication Aug. 29 , 2019 Sheet 4 of 23 US 2019 / 0262353 A1 HORAC HORAC 15001 - Blank 1500 , + Blank www > Die schem Indapamide * Clomipramine 1000 RFU RFU 500 5007 Time (min ) Time (min ) . Tricyclic Antihypertensive Antipsychotic antidepressant VE * * * HORACGAE - cost Galicacid Clopidogrel CefaclorMethylodopa Metoprolol "Atenolot Indapamide Primaquine 4 Clozapine DoxepinImipramine Dipyridamole MitoxantroneMitoxantroneChlorpromazineTrimeprazineop PericiazineFlunarizine DimenhydrinatePromethazine MemantineLiothyronine Clomipramine Desipramine Trimipramine FIGURE 4 Patent Application Publication Aug. 29 , 2019 Sheet 5 of 23 US 2019 / 0262353 A1 T - cell proliferation 150 - Antipsychotic Tricyclic antidepressant Ž %activatedT-cells(cpm) .# . # . # # SRO ttt sk # tu * * * * * * * * X N DMSO Primaquine Clozapine Doxepin Non-activated ActivatedDipyridamole Clopidogrel Cefaclor XLabetalolMethyldopa MetoprololIndapamide Mefloquine Mitoxanthrone TrimeprazineChlorpromazine Periciazine FlunarizinePromethazine MemantineLiothyronine Clomipramine Desipramine ImipramineTrimipramine aCD3 /aCD28 activated FIGURE 5 Patent Application Publication Aug. 29, 2019 Sheet 6 of 23 US 2019 / 0262353 A1 Neuroprotection by clomipramine b Clomipramine interacts with iron Live cell imaging neurotoxicity dra 0000 - ** * * * * * * ???-?????????????????????? Neurons Neurons %Pipositiveneurons 2000 wwwwwwwwwwwwwwwwwwwww ?????????????:???- LOW ?? 100M ControlOSNO Fesod Control(wash )DMSO FeSO4 SO ClomiHIM +(washiFier *Fe oui ) 4 ( awendung Clomi(wash ,readded )+Fe . e $ o wos 2hPro -incubation Clomi *fa muco mini Clom 2 UM T - cell proliferation G1 phase S - aseud . 00000L - . * * * ** %totalcells ototalcells . 25 RSS . 100IN 500 nM Non-activated Activated DMSO Non-activated Activated Non-activated Activated" Clomipramine dwoo auwe dituoo ULJE B - cell proliferation B - cells TNF - 0 150007 0000- Lud Pgimi 2004 ControlPane Activated auguedwoo Activated BUDEJOWO Activated FIGURE 6 Patent Application Publication Aug. 29, 2019 Sheet 7 of 23 US 2019 / 0262353 A1 EAE - Delayed treatment * * * * * * * * - Vehicle * * * * + Clomipramine Clinicalscore * * * ????????????????????????? Annas on ooo N N P G A B on Days post MOG Treatment period FIGURE 7A Patent Application Publication Aug. 29, 2019 Sheet 8 of 23 US 2019 / 0262353 A1 Treatment period 100 Sumofscores VehicleClomipramine FIGURE 7B Patent Application Publication Aug. 29, 2019 Sheet 9 of 23 US 2019 / 0262353 A1 # - Corrigasmine Clinicalscore A Days post immunization Treatment period Sum of scores Weight day o Weight day 16 A huwe . S AN weight[9] Sumofscores wwwiiwiwiwilini [?]??????. CCL2 6 R ALLS LAHAHALAAMCHLULA RelativeRNAexpression RelativeRNAexpression RelativeRNAexpression WWW WA Serum Spinal cord f Clomipramine DMCL P = 0 . 7026 SpinalcordfuM 500 000 15000 50 100 150 20 Serum Inha Serum nM ) Clomipramine wwwwwwwwwwwwwwwwwwwww FIGURE 8 Patent Application Publication Aug . 29, 2019 Sheet 10 of 23 US 2019 /0262353 A1 Clomipramine LETTT m e s .comwwwwwlustrerad ibak1 ANSMOLOS|018 Microglial actlvation Axonal damage H3E 3 ax ?????????? Microglial activation / axonal damage SPT F . 30 Somman * Rankordar Raskorder Axoraldomage RES randum VE ST BURA Microglial adlikako FIGURE 9 Patent Application Publication Aug . 29, 2019 Sheet 11 of 23 US 2019 /0262353 A1 Chronic EAE b treatment initiated at remission Chronic EAE - treatment from clinical onset + Vehicle * Clomipramine Score Clinicalscore olub + Clomipramine minimaal p * 0 .0175 T TTTTT Days post Immunization Days after immunization Treatment Treatment Biozzi ABH EAE * * 2 - 0 .0062 1 - Vehicle II . Clomipramine ) 144Well Clinicalscore Disability AssessiveShowVIN MOG immunization O . A First relapse Remission Chronic phase Days post immunization . .. phase . Treatment Time FIGURE 10 Patent Application Publication Aug . 29, 2019 Sheet 12 of 23 US 2019 /0262353 A1 5 -Chloroindole - Atenolol - iron 150 , drug H X %controlneurons - H# HEH HCWmo TAS HOTI RHHRI@ - IMMT It OCHT HEIM HGTH- SET oc AcetaminophenAcetylcysteine AcyclovirAllopurinol Almotriptan Altretamine Amikacin sulfate Amlodipine besylate AmoxicillinAmphotericin Antipyrine B Aspirin Atenolol 5-Chloroindole Acebutolol-2-Carboxylic hydrochloride acid Acetazolamide AmantadinehydrochlorideAmiloride AmiodaroneAmitriptylinehydrochloride hydrochloride hydrochloride FIGURE 11A Atorvastatin - Carbachol irondrug %controlneurons C# HEW nm - C DC HEM BRINA HEH! IMIMI HOCH - 0 - 0 x 1 del II COM FW 1 HMC-70 Bupropion V Captopril AtorvastatincalciumAtovaquone Azathioprine AzithromycinBenazepril BenserazideBacitracin hydrochlorideBaclofen hydrochloride Bethanechol Benztropine Brompheniramine chlorideAh Bezafibrate Bisacodyl maleate Budesonide Bumetanide Candesartan Busulfancilextil Carbachol FIGURE 11B Patent Application Publication Aug . 29, 2019 Sheet 13 of 23 US 2019 /0262353 A1 Carbamazepine - Clozapine drug XHD X XB X %controlneurons XHULIN X i EI 11HOC# BEKER H7? HEI IA FT?? CefaclorCefadroxilCephalexin Hc CimetidineCiprofloxacin Clemastine Clopirogrelsulfate Clozapine CarbamazepineCarvedilolChlorpheniraminetartrate (SChlorpromazine )maleate ChlorpropamideChlorthalidone ClindamycinClarithromycin ClomipraminehydrochlorideClonidine hydrochloride hydrochloride CloxacillinClotrimazole sodium FIGURE 11C iron Colchicine - Dipyridamole drug %controlneurons HEWA ECO Cresol HOCIO DanazolDapsone Digoxin CyclobenzaprineColchicineCromolynCyclophosphamidehydrochloride sodium hydrateCyclosporine DextromethorphanDesipramineDequalinium hydrochloridechloride hydrobromide DiclofenacDiazoxide DiltiazemsodiumDiphenhydramine Diflunisal Diphenylpyraline hydrochloride Dimenhydrinate hydrochloride hydrochloride Dipyridamole FIGURE 11D Patent Application Publication Aug . 29, 2019 Sheet 14 of 23 US 2019 /0262353 A1 Disopyramide - Fosfomycin drug X - iron H %controlneurons H HCM HCM HEN ? XHWHINE 1 HC HCHHI HOCI HH-0 Hmmun ERRIA HLEHR DisopyramideDoxepinDoxycyclinephosphate hydrochloride Doxylaminehydrochloride Edrophonium succinate EnalaprilErgonovine chloride ErythromycinEthambutol maleate maleate hydrochloride estolate Ethosuximide EtodolacDEWOEzetimibe FamciclovirFlunarizine Famotidine FluphenazineFenofibratehydrochloride Fluoxetinehydrochloride HORREO Flurbiprofen