【WO2019211878A1】式I的类肽、药物组合物及其制备方法【专利】

) ((51)International Patent Classification:OM,PA,PE,PG,PH,PL,PT,QA,RO,RS,RU,RW,SA,A61K38/00(2006.01)C07K14/47(2006.01)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. (21)International Application Number:PCT/IN2019/050358(84)Designated States(unless otherwise indicated,for everykind o f regional protection available).ARIPO(BW,GH, (22)International Filing Date:GM,KE,LR,LS,MW,MZ,NA,RW,SD,SL,ST,SZ,TZ,03May2019(03.05.2019)UG,ZM,ZW),Eurasian(AM,AZ,BY,KG,KZ,RU,TJ, (25)Filing Language:English 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, (26)Publication Language:English MC,MK,MT,NL,NO,PL,PT,RO,RS,SE,SI,SK,SM, (30)Priority Data:TR),OAPI(BF,BJ,CF,CG,Cl,CM,GA,GN,GQ,GW,20181101687404May2018(04.05.2018)IN KM,ML,MR,NE,SN,TD,TG).(71)Applicant:COUNCIL OF SCIENTIFIC AND IN¬Declarations under Rule4.17:DUSTRIAL RESEARCH,AN INDIAN REGISTERED—as to applicant's entitlement to apply for and be granted a BODY INCORPORATED UNDER THE REGIS¬patent(Rule4.17(H))TRATION OF SOCIETIES ACT(ACT XXI OF1860)—o f inventorship(Rule4.17(iv))[IN/IN];Anusandhan Bhawan,2Rafi Marg,New Delhi,Delhi110001(IN).Published:—with international search report(Art.21(3))(72)Inventors:GHOSH,Surajit;Indian Institute of Chemi¬—with amended claims(Art.19(1)) cal Biology,4,Raja S.C.Mullick Road,Jadavpur,Kolkata,West Bengal700032(IN).PRADHAN,Krishnangsu;In¬dian Institute of Chemical Biology,4,Raja S.C.MullickRoad,Jadavpur,Kolkata,West Bengal700032(IN).DAS,Gaurav;Indian Institute of Chemical Biology,4,Raja S.C.Mullick Road,Jadavpur,Kolkata,West Bengal700032(IN).MONDAL,Prasenjit;Indian Institute of ChemicalBiology,4,Raja S.C.Mullick Road,Jadavpur,Kolkata,West Bengal700032(IN).BARMAN,Surajit;Indian In¬stitute of Chemical Biology,4,Raja S.C.Mullick Road,Ja¬davpur,Kolkata,WestBengal700032(IN).GHOSH,Sub-hajit;Indian Institute of Chemical Biology,4,Raja S.C.Mullick Road,Jadavpur,Kolkata,West Bengal700032(IN).(74)Agent:REMFRY&SAGAR;Remfry House At The Mil¬lennium Plaza,Sector27,Gurgaon,Haryana122009(IN).(81)Designated States(unless otherwise indicated,for everykind o f national protection available):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,(54)Title:ΡΕΡΤΟΠOF FORMULA I,PHARMACEUTICAL COMPOSITIONS AND METHOD FOR PREPARATION THEREOF (57)Abstract:Alzheimer's disease(AD)is a complex multifactorial syndrome disease.In AD,two proteins play main role i,e,Αβ42 peptide and hyperphosphorylated microtubule associated protein(Tau)aggregation cause severe damages inboth neuron cell membrane and key signal processing.There are other factors like loss of acetylcholine function,destabilization of microtubule also responsible for this disease.Therefore,the main challenge of the field is the multifactor property of this disease.Our main target is to develop a molecule which will target maximum factors of AD.Various attempts have been devoted towards this direction but clinical outcome is very less. Thus,the present invention provides a peptide of formula I,method of preparing the same and its pharmaceutical composition thereof.PEPTOID OF FORMULA I,PHARMACEUTICAL COMPOSITIONS ANDMETHOD FOR PREPARATION THEREOFFIELD OF THE INVENTION:Alzheimer’s disease(AD)is one of the most neurodegenerative dementia around the globe nowadays(1.Bertram,L.,and Tanzi,R.E.(2008)Thirty years of Alzheimer’s disease genetics: the implications of systematic meta-analyses.Nat.Rev.Neurosci.9,768-778).More than five million people in the world are suffering from AD.The present invention relates to a novel peptoid designed and synthesized to be used as a“multi-target-directed ligand”(MTDL) against this multifactorial complex disease.This peptoid targets most of the factors of AD like inhibition ofΑβfibrillations,stabilization of microtubule,inhibition of AChE activity and also reduction of the intracellular reactive oxygen species(ROS).Moreover,peptoids are Oligomers of N-substituted glycine which overcomes the metabolic instability,so it has increased bioavailability.BACKGROUND OF THE INVENTION:Soto et al showed that LPFFD Peptide decreases neurotoxicity and fibrillation of Ap42(Sigurdsson EM.,Permanne B.,Soto C.,Wisniewski T.,and FrangioneB.,(2000)In Vivo Reversal of Amyloid-βLesions in Rat Brain J.Neuropathol.Exp.Neurol.59,11-17and Soto C.,Sigurdsson EM.,Morelli L.,R.Kumar A.,Castano EM.and Frangione B.(1998)β-sheet breaker peptides inhibit fibrillogenesis in a rat brain model of amyloidosis:Implications for Alzheimer's therapy,Nat.Med.4,822-826.)The objective of adding lysine side chain at the C-terminal of the peptoid was to disrupt the salt bridge between Asp23and Lys28which is present in the amyloid fiber structure(Lu hrs*T.,Ritter*C.,Adrian†M.,Riek-Loher* D., Bohrmann;!;B.,belli H.,Schubert* D.and Riek*R.(2005)3D structure of Alzheimer’s amyloid-(l-42)fibrils PNAS.102,17342-17347).But the common drawback of peptides composed of natural amino acids is metabolic instability(Prades R.,Oller-Salvia B., Schwarzmaier SM.,Selva J.,Moros M.,Balbi M.,Grazffl V.,Fuente J.M.,Egea G.,Plesnila N.,Teixidy M.and Giralt E.(2015)Applying the Retro-Enantio Approach to obtain a Peptide Capable of Overcoming the Blood-Brain Barrier Angew.Chem.54,3967-3972).Usually a serum protease digests peptide bonds within seconds or few minutes and thus they have very low half-life(i.e.bioavailability)in serum.Therefore peptides are considered as poor。