)
(
(51)InternationalPatentClassification:
A61K47/64(2017.01)A61P35/00(2006.01)A61P7/00(2006.01)(21)InternationalApplicationNumber:
PCT/EP2024/058226
(22)InternationalFilingDate:
02April2024(02.04.2024)
(25)FilingLanguage:(26)PublicationLanguage:(30)PriorityData:
18305390.9
03April2024(03.04.2024)
EnglishEnglish
EP
(84)DesignatedStates(unlessotherwiseindicated,forevery
kindofregionalprotectionavailable).ARIPO(BW,GH,GM,KE,LR,LS,MW,MZ,NA,RW,SD,SL,ST,SZ,TZ,UG,ZM,ZW),Eurasian(AM,AZ,BY,KG,KZ,RU,TJ,TM),European(AL,AT,BE,BG,CH,CY,CZ,DE,DK,EE,ES,FI,FR,GB,GR,HR,HU,IE,IS,IT,LT,LU,LV,MC,MK,MT,NL,NO,PL,PT,RO,RS,SE,SI,SK,SM,TR),OAPI(BF,BJ,CF,CG,Cl,CM,GA,GN,GQ,GW,KM,ML,MR,NE,SN,TD,TG).
Published:
—withinternationalsearchreport(Art.21(3))
(71)Applicant:SYNDIVIA[FR/FR];650BoulevardGonthier
d'Andernach,67400IllkirchGraffenstaden(FR).(72)Inventors:KONIEV,Oleksandr;23,mePaulEluard,
67200STRASBOURG(FR).KOLODYCH,Sergii;23,RuePaulEluard,67200STRASBOURG(FR).BON-NEFOY,Jean-Yves;4,RueduQuai,67600Ebersmunster(FR).(74)Agent:CABINETBECKERETASSOCIES;25,me
LouisleGrand,75002PARIS(FR).(81)DesignatedStates(unlessotherwiseindicated,forevery
kindofnationalprotectionavailable):AE,AG,AL,AM,AO,AT,AU,AZ,BA,BB,BG,BH,BN,BR,BW,BY,BZ,CA,CH,CL,CN,CO,CR,CU,CZ,DE,DJ,DK,DM,DO,DZ,EC,EE,EG,ES,FI,GB,GD,GE,GH,GM,GT,HN,HR,HU,ID,IL,IN,IR,IS,JO,JP,KE,KG,KH,KN,KP,KR,KW,KZ,LA,LC,LK,LR,LS,LU,LY,MA,MD,ME,MG,MK,MN,MW,MX,MY,MZ,NA,NG,NI,NO,NZ,OM,PA,PE,PG,PH,PL,PT,QA,RO,RS,RU,RW,SA,SC,SD,SE,SG,SK,SL,SM,ST,SV,SY,TH,TJ,TM,TN,TR,TT,TZ,UA,UG,US,UZ,VC,VN,ZA,ZM,ZW.
(54)Title:CONJUGATEOFCYTOTOXICDRUGANDPRODRUGFORMOFSAIDCONJUGATE
(57)Abstract:Thepresentinventionrelatestoaspecificconjugateofcytotoxicdmgsandprodmgformsofsaidconjugate,foruseintreatingcancerandinflammatorydiseases.Theconjugateisrepresentedbyformula(I)whereinArepresentsaradicalderivingfromacytotoxicchug,Gisaself-immolativemoiety,andmis0or1,andpharmaceuticallyacceptablesaltsthereof.
Conjugateofcytotoxicdrugandprodrugformofsaidconjugate
FIELDOFTHEINVENTION
Thepresentinventionrelatestoaspecificconjugateofcytotoxicdrugsandprodrugformsof
saidconjugate,foruseintreatingcancerandinflammatorydiseases.
TECHNICALBACKGROUND
Cancerandinflammatorydiseasesareamongthemostfrequentillnessesnowadays.In
particular,cancerisoneofthemostimportantcauseofdeathinindustrializedcountries,andthenumberofpeoplediagnosedwithcancercontinuestogrowatthecurrenttime.
Severaltreatmentmodeshavebeendevelopedsofar,howeverchemotherapyremainstheonlyonethatcanbeusedagainstcirculatingtumors,suchaslymphomasandleukemias,and
metastases.
Inchemotherapy,onestrategyliesininhibitingpolymerizationoftubulinandthuspreventingcelldivision(antimitotics).Thiscanbeachievedbyusingcompoundsofthedolastatinfamily,
inparticular,naturaldolastatin10,whichcanbeisolatedfromtheIndianOceanseahare
Dolabellaauriculariaandconsistsoffouramino-acids,threeofwhichbeingspecificthereto.Syntheticderivativesofdolastatin10suchasauristatinPE,auristatinEandmonomethyl
auristatinE(MMAE)alsoexistandhaveproventobeefficientinhibitors.Themajorflawofsuchcompoundsliesinthelackofselectivitytowardscancercells,resultinginthedestruction
ofhealthytissuesandthereforeintensesideeffects,suchashairlossornausea.Thedevelopmentofprotein-drugconjugatesofsuchactiveagentshasappearedasanelegantandefficientstrategytoovercomethelackofselectivity.
Protein-drugconjugatesarebyfarthefastestgrowingclassofhighlypotentactivepharmaceuticalingredients.Protein-drugconjugateconstructsgenerallyinvolveaprotein,such
asanantibody,covalentlyattachedtooneendofalinkergroup,ontheotherendofwhichisa
cytotoxin,i.e.ahighlypotentcellkillingtoxin.Theproteincomponentofthebiomolecule
providestargetspecificity.Oncetheconjugateentersthecell,thetoxinisreleased,forinstancebyactionofcellularenzymes.Mostprotein-drugconjugatesareindeeddirectedtocancertreatment.Besidesthemarketedtrastuzumabemtansine(referredtoasT-DM1orKadcyla?)andthebrentuximabvedotin(Adcetris?),anumberofprotein-drugconjugatesarecurrently
undergoingclinicaltrialsforavarietyofcancerindications.
WO2024192979A1细胞毒性药物的缀合物和所述缀合物的前药形式[专利]
