布瓦西坦专利

US20110212944Al(19)UnitedStates(12)PatentApplicationPublication(10)Pub.N0.:US2011/0212944A1Liuetal.(43)Pub.Date:Sep.1,2011(54)2-OXO-1-PYRROLIDINEDERIVATIVESA61K31/4015(2006.01)A61K31/53(2006.01)(76)Inventors:JulieLiu,Lexington,MA(US);A61K31/4166(200601)RosePersichetti,Stow,MA(US)A61P25/00(2006.01)A61P11/00(2006.01)(21)APPI-NO-I13/002,267A61P13/00(2006.01)_A61P25/04(2006.01)(22)PCTFiled:Jun.30,2009(86)PCTN0.:PCT/US09/49224(52)US.Cl..........514/217;548/550;514/424;514/242;514/391§371(00)’(2),(4)Date:May4,2011(57)ABSTRACTRelatedUS.ApplicationData____Thisinventionrelatestonovel2-oXo-1-pyrrolidines,their(60)PrOVlslOnalapphcanonNO‘61/077,349’?ledonJul‘1’derivatives,andpharmaceuticallyacceptablesaltsthereof.2008'Thisinventionalsoprovidescompositionscomprisingacom____poundofthisinventionandtheuseofsuchcompositionsinPubhcatlonClassl?catlonmethodsoftreatingdiseasesandconditionsthatarebene?(51)Int,Cl,ciallytreatedbyadministeringacompoundWiththeabilitytoA61K31/55(200601)actasasynapticvesicleprotein2A(SV2A)ligandand/oraC07D207/26(2006.01)sodiumchannelblocker.US2011/0212944A12-OXO-1-PYRROLIDINEDERIVATIVESCROSSREFERENCETORELATEDAPPLICATIONS[0001]ThisapplicationclaimsprioritytoUS.ApplicationNo.61/077,349,?ledJul.1,2008,Whichisincorporatedhereinbyreferenceinitsentirety.FIELDOFTHEINVENTION[0002]Thisinventionrelatestodeuteratedderivativesof2-oXo-1-pyrrolidines,andpharrnaceuticallyacceptablesaltsthereof.Thisinventionalsoprovidescompositionscomprisingacompoundofthisinventionandtheuseofsuchcompositionsinmethodsoftreatingdiseasesandconditionsthatarebene?ciallytreatedbyadministeringacompoundWiththeabilitytoactasasynapticvesicleprotein2A(SV2A)ligandand/orasodiumchannelblocker.BACKGROUNDOFTHEINVENTION[0003]Brivaracetam,alsoknoWnas2(S)-[2-oXo-4(R)-propylpyrrolidin-l-yl]butyramide,bindstosynapticvesicleprotein2A(SV2A)andinhibitsactivityatneuronalvoltagedependentsodiumchannelsincorrelationWithsuppressionofseiZuresduetoacquiredorgeneticepilepsy(vonRosenstiel,P.,Neurotherapeutics,2007,Jan.,4(1):84-7).[0004]BrivaracetamiscurrentlyundergoingclinicaltrialsforthetreatmentofepilepsyinrefractorypatientsWithpartialonsetseizures,forUnverricht-LundborgDisease(ULD)alsoknoWnasprogressivemyoclonicepilepsyType1(EPMl)andfortremor.BrivaracetamhasreceivedorphandrugstatusintheUSandEUforthetreatmentofsymptomaticmyoclonicepilepsies.[0005]TreatmentemergentadverseeventsrelatedtobrivaracetamWeremildtomoderateinseverityandprimarilyCNS-related.Theseeventsinclude,butarenotlimitedto,diZZiness,somnolence,headache,euphoricmood,throatirritation,fatigue/nauseaandblurredvision/feelingdrunk/agitation/hypotension,allofWhichsubsidedWithin24hoursofdrugadministration.(Rola,P.etal.,Epilepsia,2004,45(suppl7):abstract2.365).[0006]Despitethebene?cialactivitiesofbrivaracetam,thereisacontinuingneedforneWcompoundstotreattheaforementioneddiseasesandconditions.SUMMARYOFTHEINVENTION[0007]TheinventionprovidesacompoundofFormulaI:0Z10RN“.N.,NH2,orapharrnaceuticallyacceptablesaltthereof,WhereineachZisindependentlyselectedfromhydrogenanddeuterium,R1isann-propylgrouphavingZerotosevendeuteriumatoms,R2isanethylgrouphavingZeroto?vedeuteriumatoms;andWheneachRhasZerodeuteriumatoms,atleastoneZisdeuterium.Sep.1,2011[0008]Inanembodimentoftheinvention,R1isselectedfromCD3CH2CH2i,CD3CD2CH2i,CD3CH2CD2-,CH3CH2CD2-,CH3CD2CD2-,CD3CD2CD2-andCH3CH2CH2i.[0009]Inanotherembodimentoftheinvention,R2isselectedfromCH3CH2i,CD3CH2i,CH3CD2-,andCD3CD2-.[0010]Inanotherembodimentoftheinvention,R1isCD3CH2CH2i,orCD3CD2CH2i,andR2isCH3CH2i,CD3CH2i,CH3CD2-,orCD3CD2-.[0011]Inparticularembodimentsoftheinvention,thecompoundisCompound100DDoD\“WN;NHZ;DDDi_DDD30’IDCompound101ODDoD\“WN:NHLDHD3C=DH3C/Compound102ODHoD\“WN;NHZ;orDH5D3CEDH3C/Compound103OHO.NH/éDHE2'D3C=DH3C/[0012]Accordingtotheinvention,incompoundsofFormulaI,anyatomnotdesignatedasdeuteriumispresentatitsnaturalisotopicabundance.[0013]TheinventionfurtherprovidesacompositioncomprisingacompoundofFormulaIandanacceptablecarrier.Inanembodimentoftheinvention,thecompositionispyrogenfree.Whenthecompoundisformulatedforpharmaceuticaladministration,thecarrierisapharrnaceuticallyacceptablecarrier.[0014]ThecompositioncomprisingFormulaIcanfurtherincludeasecondtherapeuticagentusefulinthetreatmentofapatientsufferingfromorsusceptibletoadiseaseorconditionselectedfromepilepsy,epileptogenesis,seiZuredisorders,convulsions,bipolardisorders,mania,depression,anxiety,migraine,trigeminalandotherneuralgia,chronicpain,neuropathicpain,cerebralischemia,cardiacarrhythmia,myotonia,cocaineabuse,stroke,myoclonus,essentialtremorandothermovementdisorders,neonatalcerebralhemorrhage,amyotrophiclateralsclerosis,spasticity,Parkinson’sUS2011/0212944A1diseaseandotherdegenerativediseases,bronchialasthma,asthmaticstatusandallergicbronchitis,asthmaticsyndrome,bronchialhyperreactivity,bronchospasticsyndromes,allergicandvasomotorrhinitis,rhinoconjunctivitis,loWerurinarytractdysfunctionincludingurinaryincontinenceandoveractivebladder,fecalincontinence,conditionsofloWerurinarytractdysfunctionrelatedtobenignprostatic