Methods of use and compositions of bisbenzylisoquinolines for the treatment of malignancies

Abstract

The present disclosed invention provides pharmaceutical compositions and methods of use for bisbenzylisoquinolines such as 6,6',7,12-tetramethoxy-2,2'-dimethyl-berbaman, and analogs, derivatives, isomers, and modified forms such as crystalline, salt forms, or a salt of this compound with a pharmaceutically acceptable acid or in combination with other agents to treat acute, chronic and pre-leukemic conditions as well as lymphomas and solid tumors. These include preneoplastic and neoplastic diseases and solid tumors including but not limited to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), atypical chronic myeloid leukemia (aCML), and acute myeloid leukemia (AML), polycythemia vera (PV), chronic lymphoblastic leukemia (CLL), myeloproliferative syndrome (MPS), myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPN), myelofibrosis (MF), and polycythemia vera (PV).

Description

TRANSLATION OF ABSTRACT AND TITLE Request to Record Designated Patent Application No. EP24775415.3 (Publication No. EP4680229) in Hong Kong Our Ref.: P4769HK00 54) Title: Methods and Compositions for the Use of Bisbenzylidene Isoquinoline Drugs in the Treatment of Malignant Tumors 57) Abstract: This invention discloses bisbenzylidene isoquinoline compounds, such as 6,6',7,12-tetramethoxy-2,2'-dimethyl-berbaman, and analogs, derivatives, isomers and modified forms, such as crystalline forms, salt forms, or pharmaceutical compositions and methods of use of the compound with a pharmaceutically acceptable acid salt, or in combination with other drugs, for the treatment of acute and chronic leukemia and lymphoma and solid diseases. These diseases include precancerous lesions and neoplastic diseases, as well as solid tumors, including but not limited to acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), atypical chronic myeloid leukemia (aCML), acute myeloid leukemia (AML), polycythemia vera (PV), chronic lymphocytic leukemia (CLL), myelodysplastic disorder (MPS), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), myelofibrosis (MF), and polycythemia vera (PV). Abstract

Claims

- - . sueeocsno nreere:aenreore cnoemorassnc a anm nneosearsncoseeas seus aenc s aoumorsn a ormuaeranrne comrsneoown srucuraormu coa:moun oa. wnceuren1a wno1u aremae soanme oreren sor cane caron-aseans s o ,3,23or an2s3or25an ca3ron3rroen,ase “”somerc conuraon ae-′ cra . w snerreonoca meeonse,a asn ,e mse seoercoeerraomve neeoroausm csonssn, oeu memeoa ansasc umors an so c. weren an eecve amoun comrses.o mm2. . me meo o cam, wereneseases seeceromerou con meeosasc snrome cronc meoeuema , ascsan cr oonc .oeuemaa , an acue meoeuema ,ocema vera.e a m.eeoor oer ceaamm, wereneaens amnsereeranrne remens, oren w arosnenasenor or oer cemoeraeuc . a reermerenas,m oernm m wmunoo munooec crose enra reeu aeunasc ces sn oror, or oer cemoeraeuc- - c. c conememooerraaneeuousc re wmense orrmosmnenasenor or oer . wereneeuemas ressaunooceraes mnma nnrnsca or exra-nrnsca anas oer ce rmesouearaesueacse re aemrenresa,men w arosnenasenor, or rosnenasenor or oer c oermso reerraacoeruco r oermaesn r.essanceo a.e a m.ereoam acecnorrnouo caemn, woereneseases aece aeas one o: sem c n orn o cancer sem ces oreuemc .rreoammee ens, roruou consesnn oono ox m,oaecu,arawasncun seece urvvn,cn,seo nea-caenn,sr,,c, c.reamenrou onn,enascn, ana , an su enon o moecuarroenaresnvovene orvvoax oe cnaansecse,r anc-e,u cema sem ces seeceromerou conssn am,a ancn-.,ea-caenn,c-,c-x-aa,. aeen mse, woe ore cna sma a,uroer comrsn amnsern an aona an-euema a na an-euema aenss seecerom exsn eureomvea areeanmesn seseocreeuroemm oan,e or an weren sa aona an- nors, nasenors, au orro mraoren oasernosneorsn,asnenors,-nase comroxnauroenas, a onwraoc orc mnoerse, c ana-raeuneem, aara a-e,nasu.norucnee orrerooxno aruca,n an. onee meo o cam, werene meo oeranrnes amnsere aeas a o.: . oraa, c. surecnuearnaeousn.uson, anor- -.eaes m oeo o cam, werenereuenc oeranrne amnsraons a a.ne .o o wr: eoursoasnuson c.. seroecreeess avne esncaaon oosnase onaenoerance e.o ermenoosose amnsraons . reseanse o aeooues,s snaes, a muease onea o amnm meuae,e soows,e asna co,n anroe..e meo o cam, werenesenzsounones amnserea..aes m oer moore o. cam, werenesenzsounones amnsereor- .aee mneno an o am coaunm o, a woeuren.e msme2nzosou mnomn2.es amnsereo sa .aes m oer moore a.ccorno cam, weren sa amnsraonswceaor seven .s ae moueo. a mccorm2noo ca mmm2w.ereneose o saesenzsounone . ame mneseore acocror-nao csa orm mo,re w.eren saesenzsounones .s ae moueo. a mccorm2noo ca mmm,2w.ereneose o saesenzsounone .em mae .oooe oc a smemn cseernranso aanaaeonn nee o meoaave cononnroro a n roceures, sa meo comrsn: o omnen osre mronr asenzsounoneo saaenroro amnsraon .ce meoaave cononn aens orroceuresncun: .usuoanosame- - v. v.a .ueaaraon aanne v.oaran, v.msae, v. crne, x.arane x.eecazaurnene. . neeooasscorsreeaasn a suec w cancer sem ce-reaereneoasc an neoasms es, c sucron asc m meeooseuasemc sanrome, aca, c mroeoroerave euemaa , acue meoeuema ,ocemnc meo momas, non-euemc soumors, a vera an suecn reco comrsne se o amnserno sa s nze nee o sareamen an eecve amoun o ereannzrnseo aunnoenrevsa suvces, ass,’,,-erameox-,’-me-eraman suc as crsane, saorms, oorm ae sras, a on ansaos,rorus, esers, moeorms acceae ac orn comnaon w oer a coemns.oun w aarmaceuca. aneo mre anaoo o, a c maome, woermre snucer aasn crrnsea ornne, saeorm o aervave,somer comoun w aarmaceuca orms, or a sa os oer aens a acceae ac orn comnaon w ars carrer anornn as aarmmancesuercea a coonm wa aerarmaceuca acceae ac, secon oer aens. ouc orn comnaon w a.me moceoorn o caomram,u wce,renm saocorrsn oceorr aensncueemuzuma, enamusneroc amuc,rzerraaumuma, uaraneosaeorue,araamneaosemaeu,zuamzava,onraumuzuucma,,uara mruvcarun,eueranoramucn,n run, nuuzuma,zacne,ecane, oznoramuc, eazurne,enaome,oxorucnnov,erseanzucrrnoex ane,eacunaorunec,n- - croocoosrea,mceo,osanme,orsea.ra.,nee,ranosa,r-eucravaacranne,oxan eruaemrozumaeosarcoosame, vonv,ecn, uomcnaunorucnrocore,arane araonuema rsencroxe,ncasar ncrsneuae,n ,rsenox osun,osun,usuan,usuexu crsneuae,osu asan,eevecmanesae, suan,aencoosame, esae,eranusuan,oncusonan rocore,man rocore,rcea ,maceaxneeesuccnae,onan aran san,nromaceaxneeesuccnae,arane eraes aen, reasaena aenos.n,orezomecae,anonosa, -.owe meer,aoe an, ca cosmueo,souns, acacocr onr moe ccaamoo, wse.rene comouns as a.see mnezoso acucnoornnes sou cca ams,, weree sceue o amnsraonor eranrne aner ’,,-erameox-,’-me-eraman or a sa os comovuanve ws,so amerasrm anace aunacoas, m acoceaeorms suc as saorms, w oer aensncues:a wee wee e ac orn comnaon weeorree wees w a- wee reseorree weeswee amnsraonae oorar o anem wneesraoro m ronermenoosose or conroe reeas n.ue wees w or anmmeae, sow,.eu meemoa coarrarceaernze a su oneccoeanvn croncase --nuce meo amnsern a e-meae eevaeea-caenn comrsn: su eraeuca eecve amoun o aea-caennnoroe naescen an aormonseer sune ac,e wraeereuncaeue emeac sveem coeses o ar aen-e.rosne. suce m ase,o’, o, c-aemram,e woexre-n,’-emeea-ca-enennors asenzsounone somers an anaos, moeorms suc as saroarmmasn, ore ara snar one asn comerovuanvess,- - a amenns.sere w aarmaceuca acceae ac orn comnaon w oer.roem meeorou acc coornno cam, werene - nasenors seece esaurn,ozaserss,nan ous:man,asan, non,osun,onan, osaurn, araecran, va,aan-,e-xavarmasornae-nrosae, nor, auroranasen essancr- roennase or, ,aen, mu-aree roennasennoorr,,-- umrourannaasseennoor,- mu-aree an- uroranasenor. r, - easn,.osee m oe aoe oa-c caaenmnn,uroer.r comrsn amnsern aeraeuca eecve.osee m oe ano os canm,oru.rer comrsn amnsern aeraeuca eecve.osee m oe ano an o- ccaanmcer,urer comrsn amnsern aeraeuca eecve nor, an an-mea aoene seeceromerou conssn o: aroen sness comnaon o anwo or m,o anre aereaon. aen, a sero,nereron aa, an a.eera meeuoc a oen ca semece, wroemreneer souuecs ressano an-cancer eecs o a non. conssn o:man,asan an.osee m oe ao o c.am,urer comrsn amnsern aeraeuca eecve.eer maeno, oeuc craavmacn, w,ereencen.norncuesus nomeo- -.osee m oe ao o- canmo,rsu.rer comrsn amnsern aeraeuca eecve.orea meeno, oo csaamurn,, a wnereesnauren,-enrnor,sunczaurnn, curenso naonm.eo. ce meo accorno cam, weren an ’ aree same or eren sor 2a esne ca -′ c3orron-ase ra2car5o an a3nssnc3u orn wroeonu,asmae “on”,som3,erc2con3ourrao ann a conssn o menocaon, an wereneseases seeceromerou ,euema aons soasucm sonrome , meoroerave neoasms mm2o mm2. rs an weren an eecve amoun comrses. .eeer meo accorno cam, weren1an1′ or2are a ac, aromac, carooxcamcce,s easeres s suass, suuear ameno,e suroenr, n,u ccareocx acc,, aneosnene,se es aers, susuens. no.orem ms.eo accorno cam, weren1an1′ or2arerorus, esers or sa. come mneeon a ac sconrenoosa ceamorm,. werene a ona an-euemc aens are.osea meeoorm. accorno cam , werene aens are comnen a sne

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