M ethods of treating epilepsy and related disorders with potent and selective potassium channel activators

Abstract

Disclosed is a method of administering a Kv7 channel activator or a pharmaceutically acceptable salt thereof to a person without producing an adverse event that is commonly associated with an antiseizure medication in that person. Also disclosed is a method of treating a medical condition in a patient without producing an adverse event that is commonly associated with an antiseizure medication, the method including administering to the patient in need of such treatment a therapeutically effective amount of a Kv7 channel activator or a pharmaceutically acceptable salt thereof.

Description

[0001] mecaone wresennvenon reaeso meos orean meca con ons w an an-sezure ees w aoouas asuvemrse evens. ecca,eresennvenon reaeso a meo orean evensa are common v aossoacea cean wne a acnv-saeozrurev me cacnaneon asc.vaor wouroucn averse neurooocaasssuomr ceras.nneow aecvevar,o ezrso eamenree a ans oromers mnoe cacuneaesorrean ees an oer averse evens s ca o ansezure mecaons snscunns s coamssnaveeenoseme aomnaan,aancesorer,zzness,eaace,rra , anxe, a mooence, nausea,marmen, sensor sura o cane, memor ere remans a neencne n, seec sorer. sae wouroucn averse eevwen ansn seeacevnes.oassum canne acvaorsa cou eose roucne aresennvenonsreceorean an revenn meca con ons wou n anv eemrseo evmenens,aro avree asssoc aa mee wo ansezure mecaons. armaceuca acceae sa ereoo aers oon a wmnosuerrno av canne acvaor or a common assoc ucn an averse even as n ae w an ansezure mecaonnaerson. ncun a anmonesre ermnoomeena,eroves a meo orean a meca con onn aaen, v canne acvaor or a armacenun nee o sucreamen aeraeuca eecve amoun o a resun an averse evenneaenc.a acceae sa ereo, werenereamenoes no - - oowneessecr anoonr o oeer a esmeocsm wense,coameen an caoren an more rea arecaerome wc: nuncon we accomannrawnsn res .- areras oowerm2mz versusreuencz sown secraowern omno-usnae-ms.oasneeresn. seacran roewerers oen vasr cousreuences aasenea -ue an .s aaram sownomoun eeocns onencenoervas. ncreases mosromnen a wer secrum.soueower ecreases asasma concenra aona,ecereaa,s aens.oamamareuences aer aomoun -mose an eerencenowern eacanoreomou ansoue-moweorseu arnre eoesse o,menax w, aas cacuae as comareoasene.max,meo maxmaru con n aours .s ara oreuencan versus seccreanraowoen. eenen eecs oomoun r caneromasene sownose- secraowe on secraanower.aneromasenea -n ,, anr mre.ueonxcoane acseem men om mumax,ma reesrcoennseeo, moewn a sneose oomoun maxmum. an, ercene, an resennveenooonw.nxemeaaeescronsroveo aose sene arnraccne emomens are on exemr earm, aonmeensr weseneresncaosuerrees nescrenea.owever,ese e scoe oe aene cams.ose o omeereou raersene varaonsne emo ornar sne ar ma mae mocaons an resen mensescreeren wouearnrome sr or scoe oe scemes,cscc ooo ersu xnre. an, asee ecms oomeenresse anre meesrceroensc.rse useeower,en, reeerrenrm "oa snruocru"res an an a comnaons o one or more oe assoca ncues an xressons s eseems.eerm "or" means "anor." eemens anuco n aso "a moeas onee on,"v wuean eeremceenns o ase os e.emens, mo e enres o -- erec wn coen uance wrsooe oae wr eenem anen ee omrennersve renenrre eemoe ansse mna "oen"r anoer eemen, can conras, wen an eemens reerreo asen "r esenereeween.nnervenn ee ec on" anoer eemen,ere are no wmeensresen. escre varous e unemeernsos,o comao,n aenosu, reones,eramesrs,rs an, seocron sec,onrs, ec. mae useereno reons,aers, anor secons sou no ese eemens, comonens, snus one eemen, comon eme eseerms.eseerms are on useo reon,aer, or secon.us, aerns, e reemoenn,,a coemr, oorn seenc,o rneroonm, aanoer,e orr e semen, comonen, coueerme a secon eemen, comonen, reon econscusseeow eacns oeres ,aer, or secon wouearnrome s u en emomens. "ncun" wnener ussoeonas seecermcas "ocno,m sercses" aenroerse "cnocem or ssane," oera "nucreuses" anor ses, oeraons, eemens, anor comonens, , reons,neers, more oereaures, reo uo norecueeresence or aon o one or ereo. ns,neers, ses, oeraons, eemens, comonens, anorrous as commonness un oeersrwoosee onnee o, a orecnanrca s ann sceen arcoe wrmcs useserenavee same meann ermnoo useneescronsorescrnarcuar e scosureeons.e emn. weurer unersooaeerms, sucmomens on ans noneneo conares, souenerree asavn a mea asoseenen common use conex oe reevan ar aneresensnnas conssen wer meannne overorma sense unes cosure, an w noenerreen aneaze or erms sas usaevene mse as e anncxare seosns,o erx scoee eo an wse o.eerrwesn oe. n exressroveeren, eac oeoown acaon.nnsances were aerms no s aenons are seorrououe reconze meann ose o orna eccaeneeren,aermsven an ar- resennv r s anaermn conexos usenescrne ramee anrocne.s "a" an "an" reero one oro morean one.e.,o aeas one oe eememna"c mae oanse ocne o eeme aernc oer m unoreessaen c oonnee exem ceenar.ncaes oerwse. wa o exame, "an -- o a2rous useeren, wen seccenons no oerwserove,eerm "susue" reers-, a, a ca s -ruosxu areou weuerum, aaoen-, -, -r, -, aroxrou-, an amnorou rou-, a2-, a su cscouae orro uuns,u as-ue- amnerou, a nrorou- o2ruoroarou suc as aruorome rou- ar anroue, ae, or- a c aanooxrou, ansea o aeas oneroen o a susun3rou- ona asecs we seornarou or comoun. aarenr rneescron wcoows an,nar, wenvenon aeo re sm raere ane msc coar memrao ersn. c uaseu avaora mae onr caneearremaacreeuca coosme soseonsn oe aer.resen armacneu anc eam aoccemean,er soaveereso a moe aoers oon a wmnosuerrno aucnv a cna annveer asce evvaenor ora a common assocae w an ansezure mec s n anoer emomen,rove aonnaerson. ncun amnsernoeaenn nese a o me sucor oearmeaenn a meca cononn aaen, v canne acvaor or aarmaceuca acceae saere aoeraeuca eecve amoun o a resun an averse evenneaen.e averse even man,c werenereamenoes no aomnaan,aancesorer,zzness,eaace,rra, aue somnoence, nausea,marmen, sensorsurance, seecsorer, or a comnnxe, a moo cane, memor ev canne acvaor maaveeoown cemacaonormerueoa:,us nomeereo. --

[0002] or exame,ev canne acvaor maaveeoown cemcaorm .ua: , , ,- - , , , , , aarmaceuca acceae saereo. or maaveeoown cemcaormua: -- , , n aarmaceuca acceae saereo. or maaveeoown cemcaormua: -- or a or exame,ev canne acvaor maaveeoown cemcaormua: , ,- - an , aarmaceuca acceae saereo. or maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua:-- aarmaceuca acceae saereo. or exa r maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua: aarmaceuca acceae saereo. or maaveeoown cemcaormua: -- aarmaceuca acceae saereo. neuroaec man,nammaoran,ersss-reaesorer,or exame,oca ees,an, enceaoa,reamen-ressan eesen, conane,n caanc neeruraono,coasoseorraevre wann,nnus, eec sa or eec enceaoa, severe eec enceaoaes, eecua neuroeveomenasorer w enoes o non-snrom conena enceaoa, eec sasms, eec enceao cneecuasa or eec earnane eec enceaoa wea a, earnane eec enceaoa, ereo. escomooreveomen, or a comnaon ,seru mevec mao coonsorne muaaoen aseorreesrs,veersssoerner,eorre esxsavmees,o maoreressvesorer sorer,osarumeresson,remensr rer,oar secrum , acaeresson,reamen-ressaunaesresosrocnsor,ereresso,n s aesassoocnaae ae wcve asaorer or anxe, ausmensorer weresse moo,rooneeres on ereo. sve reacon, or a comnaon amoroec maeercaa s ccoenrosos,n maoare aso nreuerro,oreacam oern ne ruersosaenen aenra mvaesorer,or exame, anxesorer,ancsorer, soca an oreresson,enera aa,s xe, moosorers, convesorers,emena, aaon,oss,ersoncaoses,soorse-rsr,aumoaacr srseosrserssorers,rra,snon,earnnsorers, memor neuroeeneravesorers,ansorers,, suera snnucreoamre,a esa,nronsooremerso,r conucsorer,ronoemoraoareeneraon,erum,zemer' aemena, convemarmenueozemer ssease, m convemarmen, m osessve-comusvesorer, sna m’suscsueaasre a,roru a, racaono,nnneraus, m, menua ree saraon, cereear aaxa, cervca sonoc meoa ceross, cronc ouree snrome, , sna cornur,erear cereear aaxa, unnon’ssease a,u ors amn s coecmrunmaosnoreerr,e soc.zorena,rae snrome,arnson'ssease, -- neuroaec maen,c nao ccocnevoen maan, oer r aaansorer,or exame, acuean, croncan, an,erss cuaran.eansorer mae mrane,nammaor eenv caan, canceran, orosoeravean. an amoun o mn,ne m ac,v oaror o mr a.aermvace cuancane a accceae saereo mae amnseren ereo mae amnserea.ev canne acvaovar oorr a or aarmaarcmeaucecuaca acc aecceae sa ereo mae amnsere ona,a, ora oereame ae sa eecroenceeaaromraacmo“nam”c s eeeccrsa ooweerv canne acvaor man.e assesse usn owe .n some exames, a caneromasenen secra ose or o aeva, ceana,n oer acamvmaaorr oer auencaans aeme o maxma resonseoown a sne maereaeran caneromasenermna sceeucrcaao awcecer oaeea sa oreereao, as evence , exames, a caneromasene reuencans.n oer m n secraower o aa,ea, anammareuencans ae accee oa meax sama reesreoon,s aes eovowen a sneose oev canne acvaor or aarmaceuca ower oea aneareuenncceans.n, m sa oeerre eaxaemraens, c a cananeromasenen secra ower oreuencans aeme o eromasenen secra acva maxma resonseoown a sneose oev canne ureor oero aw.armea scneuecaose a occeeave s caaereo, as evence ,s susana as sownn ereo mae m, m, or m. nne acvaor or aarmaceuca acceae sa envenonsurerusrae eoown non-mn exames. ove,eecvev.arm.acooasnsaummcanecnes oncvaora,raommeeorusnn,eaemonsurasesose-eenen ecve:ssesse eecs o sneoses oomoun on secraowernea aus. -- aonae cnca vo: amaouenarse a nnov ee, sma moecue, seecve acvaor ov..oassum cannes, a receor acvaon an exeeso.enn arnec-sneczaur seu eecsa,comnoeun max smaow eee mnma A wou neavemacn neuroeav crosoc sezure moe ..zoane an oer mo or or mooruncon oser , oser ca o ansezure mecaonsecuessnncsu canss soamvenoeeennceosaeomc ee a averse evenss oarescrnnormaon .n aase su . ,arrese e a. , sneoses uo m wouo ,omoun was sae an weoerae a armaconamc eecs o sneossee-sm onomosun oons eeercr.oenc.enaos sraum, we assessee owernea aus. secra uana eranuv nae ane saac nvr aeanass: rze an ose acn avev manacnenere,cennue concuaann an anaze eecrca acv o ranunco s an researcersannssno sruone,cn ar. na aneaass oss r aunmacmeranna a mcevo. usaenensn secorauanowereaveoweer, saa eeoeness an sezurerecon aneeconn e enneo reamen eca es an conve canes, awareness, an envronmnenas sc nun, neeuroos wcaeresorreerrosc.esseo remove musce an ee aracs an e sca,eanosoe. mourerr sena saourcesenncs an an raeess was aeo esmaee raa currenow a was aeo exrace secrumnrence-reeooraes. reuenc,ower aea eocs o secons.romese,eea -.z,ea.-.,z an, aea cor.re-sonz,neoaor-azn, ane caanmomnacar-euencz waenreserevea eos: ears.s w suas aecsa usneer oweenna seeu cencara conucenea au maesemaes ae- aa -,a,a ana.uencsa recev reeco srnnes woses oen,ern,a anona m- o eoemcroouen seu -- svaennaor as rseeessaseeoramseuaneo.n on maeassur,em aenns,n a ranomze seuence.na -, noose was mnueero o resn sae w coece rausrvn,exas,,ncue a- asene,re-ose ees oen an mnues o resn sae w ees cose a uanave secr,a a,n,, an os-runae.o en,eumerorme arm assusnasourerransormaon o a recornso assess sasacaco snanmcca enecse orveenrcesm.e.asmusaeer-veasse ooemrmuouanon a wneass was conuceoen ons w or assessmen o concenraon-resonse reaonsres.uane a corresonnme esus: ncreasee avenaeoawer au maes anemaes were enroe an receveomoun.omounneea a ne resn-sae oea vouneers..s eec was aso seenreuences anssocamamea wan sso.mn moennmcea a ene scee wa.s os eerevecs oneoa aneareuences, wc are correae womoun asmsuare c,onceennreaco moun on ower secrumreuenc secra wru exo nne as.a.smas coounceenorwaeornncerecraesaese ac.rosse wereomoun was weoerae a aosesese.ose-eenen eecs oomoun ower o wseerreve seennn se aecraa,oewae,r ann aamremauenacns.ansanes. w.ereaesncreasesn secrancan aoa cenra nervous s ere seen across a cannes,ounewee sem ru eec.urermore,osve correaons weren areuencn saencsr.aower anomoun asma concenraon aeme o maxma resonse oncuson n e:armaconamc acv oo reuse sncuans.osen- ane croonrce renroarson-oem neno eeu ann .ncrnea wseesernran o ee seeac era a ecoswu oesr w a aca vrso.sse amo . cn aas cnoraneca soweereaesowerncreaseneeaan,ees secraow vaor omoun were seenne aa,ea anammaans. erncreases w oserve across areuencans e canesn secraower were aneas conssen weow wncenocme ooun,se su recu acse sommnoacen ocen s seoewnenrreeuersnc-ens-ea -- uevmeaonmoemno ounomoausne sour ees anosseoren.a.oeesvee sru resus suore connue mns. an-sezure ecac wouose- aseuescennos aeouveesvemooansssruameavaonrnaeecavaeor anoera oomoun, aonae: aensese a numer o arove ansezure mecaons sorrean ees, man averse e avreen resracsor, suocr aesa sommenno aennc suerromurensome se eecsamer u. oe aneao non-aerence.us,e an an unm coen neveem exososors muroraences, neavemacua oera roes.omouns a nove eecve aens wavorae can , sma moecue, seecve acvaor ov..oassum wn eezosananee- asnaes c annacoaueevs,eomenor ees an neuroscarcsorers.n comarson was raonaesneoerenoame oonunereooenrseso. an srneccnanca sueeren srucura cass an emonsrae mnma receor acvaon an ex s,omoun moe wou neave eecAs o eoen an-sezure ecacne are enaemen oomonu nneuro.neaavora osre mo souruensceomno.nsraaeseavor su conrme oera oomoun w noose-mss mnuse. asceen onecvoese o ae sae an sae anoera oomoun acro s an sausess w caosmo aesseessoeae. eos: ea esus wereooeromaseaceo-conroe sues.ea aus ae- ,rs w, oerrenc muea, an, exaerncea-nrese waere ranomzeo oraomounmmeae reease,, uoas.ae evauaonsrouseou,e, s oures mncuae, or m maonconrn,a ccenoc,a anaorreaaeor ess, va sns,s,sca examnaons, an suca assessmens. or esus: verse ecvreonsss ocecurrn conors, oaarrccaannss a rcercoessveeoomoeounomou=n o croaocres aore=rese.nen -- waeree m. aenre r weseoreveow s raonesa oneous-r.eaeere wes no somnoence was reore.e maor os oxces.os were reore amonarcanres n roeceeavns, soemrouosuns, seve mre exse,n oreo rsee-mnn=,eesose curren uzenase sues. ease oncuso evauaeonm: oro uuno waas ssa.e anver wsee eveonesraecan m aussocea-eosease sues across aoses an convemoosurances, w oers, suc as somnoence reamen o ees an oer ne wureores noc raerocreso,r wercs. reerseesennsn aso suenoararea cm sne cncaeveomen oomoun.aens are currenen e onnue evauane ecac an sae oomounno nroen muease sues neuroscarcsorers. ca aneneraze ees as we as ae.omounosns no assocae w sca o oersnea vouneers. cemca names,-- reresene eormua23292, ansu meuaname.-uoro-,- rosounon---,-me en-,- -- ae. sccurrnn oarcansecevnomounn oors. verseeavaecne, na=ceoom=oun , , aen numrouer ooruaens aucacaoonn, v naurmouserucaons are reerence auor name anae, or ncororaener enrees ree .escosures oeseucaons areere sae oe ar asnownoo rencenos acaonn orero moreuescree eren.owever,e se seeren as oeae oenvenonescre an came a suc r caon o a reerenceeren sou noe consrue as an acnoweemen oeseer senceesnroer a arr wo reecoresennvenon. e arxee cronmseneraeono, nuem werouns eeu scvoaeen osnoze, se or nv seneec a once anrooc a aesc reue crr oea vsn ere u esscnre no m eeo orere onw.a nunc ro c euunevaens exame,armaceuca acceae sas oeranose seccasco ams.or xameseren cane emoe.urermore,snenea seneescron an or suserous oems wnarerrous oems, c seccems wnss oems, suserous oems orarerrous oem ane comne w oer seccems, enn suc a comnaon. s weer or noeres a seccscosureeren --

Claims

ereoo. aerso mn weoou o aromuncsern av canne acvaor or a armaceuca acceae sa mecaonnaerson. n an averse even as common assocae w an ansezure even a.s comm moeno ass oocraeaen w a m aen acnas ceoznureo mnenc aaaoen wouroucn an averse comr csannn aem acnvsaeorrn or aoearmaaceenunca ne nnaaen,e meo av e ac oce suacer seaameenre ao.eraeuca eecve amoun o somnoen.ce, nauseea m, aeoom ancacorann,aoanacemso orre,r w,ezzrenness,ee aaveacrsee, evrerna comrses cane, memormarmen, sensor surance, seec sorer, or a comnaon, aenrexoe., a moo aseo.own cee mmecaoo arcmcuora:no an one o ams o, werenev canne acvaor- -aseo.own cee mmecaoo arcmcuora:no an one oamso, werenev c .anne acvaor , ,, --, , , , , --aseo.own cee mmecaoo arcmcuora:no an one oamso, werenev canne acvaor , ,aseo.own o , --or aaseo.own cee mmecaoo arcmcuora:no an one oamso, werenev canne acvaor ,, --an aseo.own cemcaormua: , cvaoraarmaceuca acceae saereo.aseo.own o one oamso, werenev canne acvaor aarmaceuca acceae saereo.aseo.own o one oamso, werenev canne acvaoraarmaceuca acceae saereo.aseo.own o one oamso, werenev canne acvaor --aarmaceuca acceae saereo.aseo.own cemcaormua: one oamso, werenev canne acvaor aarmaceuca acceae saereo.aseone oamso, werenev canne acvaor aarmaceuca aseoownacceae saereo. . o one oamso, werenev canne acvaoraarmaceuca acceae saereo.aseo.own o oamso, werenev canne acvaoraarmaceuca acceae saereo. --aseo.own cee mmecaoo arcmcuora:no an one oamso, werenev canne acvaor aarmaceuca acceae saereo. aseone oamso, werenev canne acvaor aarmaceuca acceae saer ees-eo. oams-, werene meca conons an ees,.an, neuero maeoc aacncorno an oam, werene ees-reaesorersoca nnus, ,nammaoran,erssenan, canceran,osoeravean,neecu eaesac enc oer eaoeac e,ncreeamaeona-res,s seavner ee eees, cco ennceenaao neuaroeos,c casorer w neuroeveomenasorer w enoes o non-snromcneec onena enceaoa, eec sasms, eec enceaoa, earnaneua esa or eec earnane eec enceaoa weaescomooreveomeec enceaoa, ereo. n, or a comnaon eressve.soreer. meo accorno an one oams-, werene meca conons a sorer.,esr mueveo m aococorsnreouaam, wereneeressvesorers maoreressve secrumsorer,osarumeresson,ornemesonsrreura,erssseonrcesorresesrvesor,e sre,asoonaar aecve --asoareorn or an,x ae, acausemreesnson,reamen-ressaneresson ,eresson assocae w comnaonereo. sorer w eresse moo,roone eressve reacon, or a neurooc.a or neuero meeeone araccovrensoroe arn. one o ams-, werene meca con ons a sorers. amoroe mecaoer aacc socreronss,oaomars,o wreerre,nreaem neenur roeosscaan o arn ne muroeenerave enera anxe sorer,ancsorer, soca anxe, moo sorers, convesaoorreres,reesmseonn, aaon, aa ,scoses,os-raumac sresssore a, sorers, memoross,ers rs,rra ,sn on,earnn conuc sorer, neuroeeonnearavesosroreresr,s,aoarsorers,e snrome, ean sorers, emena,ronoemoraoareeneraon,ernums,orzeres,m suer'rsanusecearas,ronoemora m convemarmenueozem ase, m convemarmen, o er’ssease,ru a con,nnus, mena rearaon, cerseesesvaer-c aoamxau,svesorer, sna muscuar aro , raaonera, mu e sceross, cronc ouree snrom cee,r avucasm s sonecroumc msoeroera , sna cornur,erear cereear aaxa, unnon’ssease, or a comnaonereo,. sczorena,rae snrome,arnson'ssease, ansor.er. e meo accorno an one o ams-, werene meca con ons a neuroa.can, neo mceceove accaonr, onr raocuaamra,n w.ereneansorers acuean, croncan, an,erss.enaen m, ceancoer acacno,r ornosooaermave, wane.reneansorers mrane,nammaor armaceu.ca aecc meeaoe a scacorenreoo asn am onnes oereamns an- am, wounere one mv, c man,n oer ac mva.or or a - -armaceu.ca aecc meeaoe a scacorenreoo asn am onnes oereamas-., werenev canne acvaor or a armaceu.ca aecc meeaoe a scacorenreoo asn am onnes oeream ons-a, w,aeren, oreav c oanneere acamvaenor. or a s . e meo accorno an one o ams-, weren a caneromasenen sneceraosoew oer oe av ca,anenae, o arcavmamora orre aueanrcmacaenusc aa aeccemea oe m saaxmaer reeos,o anss eevoeonwcen a ereecureonecnceanaso.ram ,sreaeran caneromasenen secraower oea orea s . e meo accorno an one o ams-, weren a caneromasenen sneceraosoew oer oe av ca,anenae, a ancvaamorm oar areuaermncaceauncsa a acceemae oe s maaxmeare roes, aosn esveeoncoewn a ereecureonecnceanaso.ram ,sreaeran caneromasenen secraower oea an ea s . e meo accorno an one o ams-, weren a caneromasenen ceacnnr ,ea s a scow uve sar ao o nr or are auen as sacromwaa ncen nusc aae ure ac.cmeea o me saaxmae rreesoo,n asse evoeonwcen a s enecerooesnece oaeovram canne ac.vaor oer m aeaorm aaccceourcano ac acne oanee o saamesreo-s, we mre,n me s,n oreo mse. o ev - -

Images