HRP20020989A2 - Farnesyl transferase inhibiting 1,2-annelated quinoline enantiomer - Google Patents
Farnesyl transferase inhibiting 1,2-annelated quinoline enantiomer Download PDFInfo
- Publication number
- HRP20020989A2 HRP20020989A2 HR20020989A HRP20020989A HRP20020989A2 HR P20020989 A2 HRP20020989 A2 HR P20020989A2 HR 20020989 A HR20020989 A HR 20020989A HR P20020989 A HRP20020989 A HR P20020989A HR P20020989 A2 HRP20020989 A2 HR P20020989A2
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- Croatia
- Prior art keywords
- compound
- chlorophenyl
- pharmaceutically acceptable
- pharmaceutical preparation
- acid
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Description
Predloženi izum razmatra novi 1,2-anelirani enantiomer kinazolina, njegovu pripravu, farmaceutske pripravke koji sadrže spomenuti novi spoj te na uporabu tog spoja kao lijeka kao i na metode liječenja davanjem spomenutog spoja.
Onkogeni često kodiraju proteinske komponente koje preoblikovanjem signala dovode do rasta stanice i mitogeneze. Pojava onkogena u uzgojenim stanicama dovodi do stanične promjene karakterizirane sposobnošću rasta stanice u uzgajalištu i rasta stanica kao gustih žarišta bez kontaktne inhibicije kakvu pokazuju nepromijenjene stanice. Mutacija i/ili prekomjerena ekspresija određenih onkogena često je u vezi s pojavom humanog karcinoma. Posebna grupa onkogena poznata kao ras dokazana je u sisavaca, ptica, kukaca, mekušaca, biljaka, gljiva i kvasa. Skupina ras onkogena u sisavaca sastoji se od tri glavna člana ("izoforme"): H-ras, K-ras i N-ras onkogeni. Ti ras onkogeni služe kao kôd za usko povezane proteine poznatije kao p21ras. Jednom kada se veže uz staničnu membranu, mutant ili onkogenski oblik p21ras proizvest će signal za transformaciju i nekontrolirani rast malignih stanica tumora. Kako bi postigao taj potencijal za transformaciju, prekurzor onkoproteina p21ras mora proći kroz enzimima kataliziranu farnezilaciju rezidua cisteina lociranog u karboksil-terminalnom dijelu tetrapeptida. Zbog toga, inhibitori enzima koji katalizira tu modifikaciju, tj. farnezil transferaza, spriječit će priljubljivanje membrane s p21 ras i zaustaviti neprirodni rast ras-preoblikovanih tumora. Nadalje, općenito je prihvaćeno da inhibitori farnezil protein transferaze mogu biti vrlo korisni kao antikancerogena sredstva u onih tumora čijoj transformaciji doprinosi ras.
Budući su ras mutirani onkogeni oblici uočena uočeni u mnogim humanim karcinomima, posebno u više od 50% karcinoma debelog crijeva i karcinomu pankreasa (Kohl et al., Science, sv. 260, 1834-1837, 1993), ukazano je da inhibitori farnezil transferaze mogu biti vrlo korisni protiv tih tipova karcinoma.
U WO 97/16443, WO 97/21701, WO 98/40383 i WO 98/49157 opisani su derivati 2-kinolina koji imaju svojstva inhibiranja farnezil transferaze. Ostali spojevi kinolona koji djeluju kao inhibitori farnezil transferaze opisani su u WO 00/12498, 00/12499 i 00/47574. WO 00/39082 opisuje razred novih spojeva 1,2-aneliranih kinolina i kinazolina, koji imaju dušikom i ugljikom povezan imidazol, koji imaju svojstva inhibiranja farnezil transferaze. Među spojevima opisanim u posljednje spomenutoj patentnoj prijavi je (±)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanamin koji je dobiven u obliku enantiomerne smjese. Sada smo odvojili smjesu i pronašli da (-) enantiomer ima posebno povoljna farmakološka svojstva u usporedbi s enantiomernom smjesom.
Prema tome, predloženi izum razmatra (-)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il) tetrazolo[1,5-a]kinazolin-7-metanamin i njegove farmaceutski prihvatljive kiselinske adicijske soli.
Gornji (-) enantiomer se dalje uzima kao spoj u skladu s izumom.
Spoj iz izuma općenito je prisutan u supstancijalno čistom obliku, tj. supstancijalno čist od suprotnog (+) enantiomera, na primjer sadrži manje od 5% w/w, poželjno manje od 2% w/w, a najpovoljnije manje od 1% w/w potonjeg enantiomera.
Smatra se da farmaceutski prihvatljive kiselinske adicijske soli kako su ranije navedene obuhvaćaju terapeutski aktivne oblike netoksičnih kiselinskih adicijskih soli koje iz izuma može oblikovati. Potonji spoj može se pretvoriti u svoje farmaceutski prihvatljive kiselinske adicijske soli obradom spomenutog bazičnog oblika s odgovarajućom kiselinom. Odgovarajuće kiseline uključuju, na primjer, anorganske kiseline, kao što su halogenvodične kiseline, npr. klorovodična ili bromovodična kiselina; sulfatna, dušična i fosforna i slične kiseline; ili organske kiseline kao na primjer octena, propanska, hidroksioctena, mliječna, piruvinska, oksalna, malonska, jantarna (tj. butanodionska kiselina), malenska, fumarna, jabučna, vinska, limunska, metanosulfonska, etansulfonska, benzensulfonska, p-toluen-sulfonska, ciklaminska, salicilna, p-aminosalicilna, pamoinska i slične kiseline.
Pojam kiselinskih adicijskih soli također obuhvaća hidratne i solvatne adicijske oblike koje spoj iz izuma može oblikovati. Primjeri takvih oblika jesu npr. hidrati, alkoholati i slično.
Kada god se nadalje upotrebljava, podrazumijeva se da pojam «spoj iz izuma» također uključuje i farmaceutski prihvatljive kiselinske adicijske soli.
(-) enantiomer prema predloženom izumu može se pripraviti odvajanjem početne enantiomerne smjese opisane u gornjem WO 00/39082. Odvajanje se može izvesti na uobičajeni način, primjerice, reakcijom s odgovarajućom kiralnom kiselinom kao što je (+)-6-aminopenicilanska kiselina, D ili L aspartamska kiselina, (1S,3R) ili (1R,3S)-kamforna kiselina, (1S) ili (1R)-10-kamforsulfonska kiselina, karbobenziloksi-1-prolin, holna kiselina, dehidroholna kiselina, deoksiholna kiselina, (2S,3S) ili (2R,3R) dibenzoilvinska kiselina, (2S,3S) ili (2R,3R) diacetilvinska kiselina, (2S,3S) ili (2R,3R)-vinska kiselina, (2S,3S) ili (2R,3R) ditoluoilvinska kiselina; 2,3:4,6-di-O-izopropiliden-2-keto-1-gulonska kiselina, (+)-3,4-dihidro-2H-1-benzopiran-2-karboksilna kiselina, (R) ili (S)-4-(2-klorofenil)-2-hidroksi-5,5-dimetil-l,3,2-dioksafosforinan-2-oksid, D-glukonska kiselina, D ili L-glutaminska kiselina, D-izoaskorbinska kiselina, (S) ili (R)-2-hidroksipropan kiselina, laktobionska kiselina, D ili L-jabučna kiselina, (R) ili (S)-mandelic kiselina, L-2-((4-metoksifenil)sulfonil)-amino-pentandikiselina, L-2-((4-metilfenil)sulfonil)amino-pentan-dikiselina, (S)-6-metoksi-α-metil-2-naftalen-octena kiselina, (S)-2-(fenilkarbamoiloksi)-propan kiselina, (-)-3-pinan karboksilna kiselina, (R) ili (S)-2-pirolidon-5-karboksilna kiselina ili (R)-tiazolidin-4-karboksilna kiselina. Rezultirajući oblici soli dalje su odvojeni, primjerice, selektivnom ili frakcijskom kristalizacijom, a željeni enantiomer iz njih oslobođen pomoću alkalija.
Alternativni način odvajanja željenog enantiomernog oblika iz početne smjese uključuje tekućinsku kromatografiju pomoću kiralne stacionarne faze. Čisti enantiomerni oblik također se može dobiti iz odgovarajućeg čistog enantiomernog oblika odgovarajućih početnih materijala, uz uvjet da se reakcija događa stereospecifično. Čisti enantiomerni oblik također se može dobiti počevši od odgovarajućeg racemskog početnog materijala uz uvjet da se reakcija događa enantiospecifično. Čisti enantiomerni oblik može se pripraviti reakcijom početne enantiomerne smjese s jednim enantiomerom nekih kiralnih tvari kao što su kiseline ili kiselinski kloridi kako bi se dobile dijastereoizomerne smjese, odvajanjem, primjerice, selektivnom ili frakcijskom kristalizacijom ili primjenom tekućinske kromatografije, u čiste dijastereoizomere. Odgovarajući dijastereomer može se zatim cijepati u željeni enantiomer. Početna enantiomerna smjesa može se pripraviti u skladu s postupcima opisanim u WO 00/39082 ili kako je detaljnije opisano ovdje.
Spoj iz izuma i njegove farmaceutski prihvatljive kiselinske adicijske soli imaju vrijedna farmakološka svojstva u tome da djeluju kao inhibitori farnezil protein transferaze (FPT) i iznenađujuće su djelotvorni u usporedbi s početnom enantiomernom smjesom. Prema tome, potonja smjesa ima IC50 inhibicijsko djelovanje prema FPT-azi od 1.1 nM dok (-) enantiomer ima odgovarajuće djelovanje od 0.7 nM.
Izum donosi metodu inhibicije abnormalnog rasta stanica, uključujući transformirane stanice, davanjem djelotvorne količine spoja predloženog izumom. Abnormalni rast stanica odnosi se na rast kojim ne upravljaju normalni regulatori rasta (npr. gubitak kontaktne inhibicije). To uključuje abnormalni rast: (1) tumorskih stanica (tumora) koje pokazuju aktivirani ras onkogen; (2) tumorskih stanica u kojima je aktiviran ras protein kao rezultat onkogenske mutacije drugog gena; (3) benigne i maligne stanice drugih proliferacijskih oboljenja u kojima dolazi do neprirodne ras aktivacije. Ras onkogeni ne samo da doprinose rastu tumora in vivo izravnim djelovanjem na rast tumorske stanice, nego također i posredno, tj. omogućujući tumorom izazvanu angiogenezu (Rak.J. et al, Cancer Research, 55, 4575-4580, 1995). Stoga bi farmakološki ciljano mutirani ras onkogen razumljivo mogao zaustaviti rast solidnog tumora in vivo, barem djelomično inhibicijom tumorom izazvane angiogeneze.
Izum također donosi metodu inhibicije rasta tumora davanjem terapeutski djelotvorne količine spoja predloženog izumom subjektu, npr. sisavcu (posebno čovjeku) kojemu je takvo liječenje potrebno. Posebno, predloženi izum odnosi se na metodu inhibicije rasta tumora koji pokazuju aktivirani ras onkogen davanjem djelotvorne količine spoja iz izuma. Primjeri tumora koji se mogu inhibirati, ali bez ograničenja samo na njih, jesu karcinom pluća (npr. adenokarcinom i uključujući karcinom ne-malih plućnih stanica), karcinom pankreasa (npr. karcinom pankreasa kao što je egzokrini karcinom pankreasa), karcinom debelog crijeva (npr. kolorektalni karcinom, kao što je adenokarcinom debelog crijeva i adenom debelog crijeva), tumori krvnih stanica i limfnog sustava (akutna limfatička leukemija, limfom B-stanica, Burkitov limfom), mijeloidne leukemije (npr. akutna mijeloička leukemija (AML)), folikularni karcinom štitnjače, mijelodisplastični sindrom (MDS), tumori mezenhimalnog porijekla (npr. fibrosarkomi i rabdomiosarkomi), melanomi, teratokarcinomi, neuroblastomi, gliomi, benigni tumor kože (npr. keratokantom), karcinom dojke (npr. uznapredovali karcinom dojke), karcinom bubrega, karcinom jajnika, karcinom mokraćnog mjehura i karcinom kože.
Predloženi izum može također dati metodu inhibicije proliferacijskih bolesti, kako benignih tako i malignih, u kojima je neprirodna aktivacija ras proteina rezultat onkogene mutacije u genima. Sa spomenutom inhibicijom koja se postiže davanjem terapeutski djelotvorne količine ovdje opisanog spoja, subjektu kojem je takva terapija potrebna. Na primjer, benigna proliferacijska neurofibromatoza, ili tumori u kojima je ras aktiviran uslijed mutacije ili pojačane ekspresije onkogena tirozin kinaze, mogu se inhibirati spojevima predloženog izuma.
Spoj prema izumu može se upotrijebiti za druge terapeutske svrhe, na primjer za:
a) senzitizaciju tumora prema radioterapiji davanjem spoja u skladu s izumom prije, tijekom ili nakon ozračivanja tumora radi liječenja karcinoma, na primjer kako je opisano u WO 00/01411;
b) liječenje atropatija kao što je reumatoidni artritis, osteoartritis, juvenilni artritis, giht, poliartritis, psorijatički artritis, ankilozirajući spondilitis i sistemski lupus eritematodes, primjerice kako je opisano u WO 00/01386;
c) inhibiranje proliferacije stanica glatkog mišića uključujući vaskularne proliferacijske poremećaje, aterosklerozu i restenozu, primjerice kako je opisano u WO 98/55124;
d) liječenjem upalnih stanja kao što je ulcerativni kolitis, Crohnova bolest, alergijski rinitis, bolest graft vs host, konjunktivitis, astma, ARDS, Behcetova bolest, odbijanje transplanta, utikarija, alergijski dermatitis, alopecia areata, skleroderma, egzantem, ekcem, dermatomiozitis, akne, dijabetes, sistemski lupus eritematodes, Kawasakijeva bolest, multipla skleroza, emfizem, cistična fibroza i kronični bronhitis;
e) liječenje endometrioze, materničnih fibroida, disfunkcionalnog materničnog krvarenja i endometrijske hiperplazije;
f) liječenje okularne vaskularizacije uključujući vaskulopatiju koja utječe na retinalne i koroidalne žile;
g) liječenje patoloških pojava proizašlih iz heterotrimernog vezanja G protein na membranu, uključujući bolesti povezane sa sljedećim biološkim funkcijama ili poremećajima; njuh, okus, svjetlo, percepcija, neurotransmisija, neurodegeneracija, funkcioniranje endokrinih i egzokrinih žlijezda, regulacija autokrina i parakrina, krvni tlak, embriogeneza, virusne infekcije, imunološke funkcije, dijabetes, pretilost;
h) inhibiranje virusne morfogeneze, primjerice inhibiranjem prenilacijskih ili post-prenilacijskih reakcija virusnog proteina kao što je veliki delta antigen virusa hepatitisa D; i liječenje HIV infekcija;
i) liječenje policistične bolesti bubrega;
j) potiskivanje indukcije inducibilnog dušičnog oksida uključujući poremećaje posredovane dušičnim oksidom ili citokinom, septički šok, inhibiranje apoptoze i inhibiranje citotoksičnosti dušičnog oksida.
k) liječenje malarije.
Stoga, predloženi izum iznosi spoj iz izuma za uporabu kao lijek kao i uporabu takvog spoja za izradu lijeka za liječenje jednog ili više gore navedenih stanja.
Za liječenje gornjih stanja, spoj iz izuma može se povoljno upotrijebiti u kombinaciji s jednim ili više antikancerogenih sredstava, koja se primjerice biraju između spojeva s platinom u koordinaciji, na primjer, cisplatin ili karboplatin, spojevima taksana na primjer paclitaksel ili docetaksel, kamptotekinskim spojevima, na primjer, irinotekan ili topotekan, protutumorski vinca alkaloidi, na primjer vinblastin, vinkristin ili vinorelbin, protutumorski derivati nukleozida, na primjer 5-fluoruracil, gemcitabin ili capecitabin, alkilacijska sredstva dušikovi muštardi ili nitrozourea na primjer ciklofosfamid, klorambucil, karmustin ili lomustin, protutumorski antraciklinski derivati, na primjer daunorubicin, doksorubicin ili idarubicin; protutijela HER2 na primjer trastzumab; i protutumorski podofilotoksinski derivati na primjer etopozid ili tenipozid; i protuestrogenska sredstva uključujući antagoniste receptora za estrogen ili selektivne modulatore estrogenskog receptora, poželjno tamoksifen, ili alternativno toremifen, droloksifen, faslodex i raloksifen, ili inhibitore aromataze kao što je egzemestan, anastrozol, letrazol i vorozol.
S obzirom na svoja korisna farmakološka svojstva, spoj iz izuma može se formulirati u različite farmaceutske oblike u svrhu njegove primjene.
Za pripravljanje farmaceutskih pripravaka iz ovog izuma, terapeutski djelotvorna količina spoja u obliku bazične ili kisele adicijske soli kao aktivnog sastojka, pomiješa se temeljito zajedno s farmaceutski prihvatljivim prijenosnikom koji može biti raznih oblika ovisno o obliku željenog pripravka za davanje. Ti farmaceutski pripravci su poželjni u ujednačenim oblicima doziranja naročito za oralno, rektalno, perkutano davanje ili davanje parenteralnom injekcijom. Na primjer, za pripravljanje pripravaka u obliku za oralno doziranje, u slučaju oralnih.tekućih pripravaka kao što su suspenzije, sirupi, eliksiri i otopine, može se upotrijebiti bilo koje uobičajeno farmaceutsko sredstvo, kao što je na primjer voda, glikoli, ulja, alkoholi i slično, dok se u slučaju oralnih krutih farmaceutskih pripravaka, koji uključuju praške, pilule, kapsule i tablete, mogu upotrijebiti pomoćna sredstva kao škrobovi, šećeri, kaolin, lubrikanti, veziva, sredstva za dezintegarciju i slično. Zbog njihovog lakog načina primjene, tablete i kapsule predstavljaju oblike jediničnog oralnog doziranja kojem se daje najveća prednost i u tom slučaju očigledno se upotrebljavaju kruti farmaceutski prijenosnici. Za parenteralne pripravke, prijenosnik obično uključuje sterilnu vodu, barem velikim dijelom, iako se mogu uključiti i drugi sastojci koji potpomažu topljivost. Primjeri prijenosnika za injekcijske otopine uključuju otopinu soli, otopinu glukoze ili mješavinu otopina soli i glukoze. Za pripravljanje injekcijskih suspenzija mogu se upotrijebiti prikladni tekući prijenosnici, suspenzijska sredstva i slično. U pripravcima prikladnim za perkutano davanje prijenosnik prema potrebi obuhvaća sredstvo za poboljšanje prodiranja i/ili prikladno sredstvo za kvašenje, prema potrebi u kombinaciji s prikladnim dodacima bilo koje naravi u malim udjelima, a koji dodaci ne uzrokuju nikakve štetne učinke na koži. Ti dodaci mogu olakšati aplikaciju na koži i/ili mogu biti od pomoći za pripravljanje željenih pripravaka. Ti se pripravci mogu dati na različite načine, npr. kao transdermalni flaster, kao oblog i kao mast.
Posebno povoljno je formulirati gore spomenute farmaceutske pripravke u obliku jediničnog doziranja za lako davanje i ujednačeno doziranje. Ujednačeni oblik doziranja, kako se rabi ovdje u opisu i u patentnim zahtjevima, odnosi se na fizički odvojene jedinice prikladne kao jedinično doziranje, pri čemu svaka jedinica sadrži prethodno određenu količinu aktivnog sastojka izračunatu tako da se dobije željeni terapeutski učinak, zajedno s potrebnim farmaceutskim prijenosnikom. Primjeri takvih oblika jediničnog doziranja su tablete (uključiv zarezane ili obložene tablete), kapsule, pilule, paketići praha, hostije, injekcijske otopine, ili suspenzije, čajne žličice i slično te njihovo odvojeno višestruko pakiranje.
Oni koji su vični struci mogu jednostavno odrediti terapeutski djelotvornu količinu iz dolje navedenih rezultata ispitivanja. Općenito se smatra da se povoljna količina kreće od 0.01 mg/kg do 100 mg/kg tjelesne mase, u posebnim slučajevima od 0.05 mg/kg do 10 mg/kg. Za odraslog čovjeka općenito je povoljno davati dnevnu dozu od 10 do 600 mg, poželjno 50 do 500 mg, a naročito poželjno 100 do 400 mg aktivnog sastojka, posebno su povoljne doze od 200 do 300 mg. Dnevno potrebnu dozu povoljno je podijeliti u dvije, tri, četiri ili više subdoza koje se daju u jednakim vremenskim razmacima. Te subdoze mogu se formulirati u oblike jediničnog doziranja koji sadrže na primjer 10 do 500 mg, a posebno 50 do 300 mg aktivnog sastojka po jediničnoj dozi; naročito su povoljne doze koje sadrže 50 mg, 100 mg, 200 mg ili 300 mg aktivnog sastojka.
Sljedeći primjeri navode se u svrhu ilustracije.
Eksperimentalni dio
Pod dolje navedenim "THF" smatra se tetrahidrofuran, "DIPE" je diizopropileter i "EtOAc" je etilacetat.
Primjer
a) Pripravljanje[image] intermedijar (2)
Smjesa 6-(4-klorobenzoil)-4-(3-klorofenil)-2(IH)-kinazolinona (intermedijar 1)(0.0506 mol), pripravljenog kako je opisano u WO 98/49157, u POCl3 (100 ml) miješana je i refluksirana 1 sat. Otapalo je upareno do suhog. Ostatak je obrađen nekoliko puta u CH2Cl2. Otapalo je upareno do suhog. Ostatak je obrađen u CH2Cl2. Smjesa je izlivena u led/NH4OH. Organski sloj je odvojen, isušen (MgSO4), profiltriran, a otapalo upareno do suhog. Ostatak (24.2 g) je kristaliziran iz CH3CN. Talog je odfiltriran i isušen, čime je dobiveno 19.8 g intermedijara (2) (94%), tt. 152°C.
b) Pripravljanje[image] intermedijara (3)
Otopina n-butillitija u heksanu (1.6 M)(90 ml) dodana je kap po kap na -70°C u struji Na smjesi 1-metilimidazola (0.144 mol) u THF (120 ml). Smjesa je miješana na -70°C 15 minuta. Dodan je kap po kap klorotrietilsilan (0.148 mol) na -70°C te je smjesa miješana 15 minuta na toj temperaturi. Dodana je kap po kap otopina n-butillitija u heksanu (1.6 M)(80 ml). Smjesa je miješana na -70°C 15 min. Dodana je kap po kap smjesa intermedijara (2) (0.0822 mol) u THF (300 ml). Smjesa je miješana na -70°C 1 sat, hidrolizirana, ekstrahirana s EtOAc te dekantirana. Organski sloj je isušen (MgSO4), profiltriran, a otapalo upareno. Ostatak je pročišćen kolonskom kromatografijom preko silikagela. Čiste frakcije su skupljene, a otapalo upareno, čime je dobiveno 24.9 g (61%) intermedijara (3).
[image]
c) Smjesa intermedijara (3)(0.0061 mol) i natrijevog azida (0.0079 mol) u N,N-dimetilacetamidu (DMA)(20 ml) miješana je na 50°C 18 sati. Smjesa je ohlađena do sobne temperature te izlivena u ledenu vodu. Talog je odfiltriran, temeljito ispran s H2O te obrađen s CH2Cl2. Organska otopina je isušena, profiltrirana, a otapalo upareno. Ostatak je kristaliziran iz CH3CN DIPE. Talog je odfiltriran i isušen čime je dobiveno 2.3 g (75%) (±)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanola (intermedijar 4); tt 232-233°C.
d) Smjesa intermedijara (4)(0.0573 mol) i sulfoniluree (300 g) miješana je na 160°C 5 sati te ohlađena. Dodana je ledena voda, zatim metilen-klorid i smjesa profiltrirana preko dijatomejske zemlje. Organski sloj je odvojen, isušen (MgSO4), profiltriran, a otapalo upareno do suhog. Ostatak je pročišćen kolonskom kromatografijom preko silikagela. Čista frakcija je skupljena, a otapalo upareno čime je dobiveno 7.5 g (±)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanamina (intermedijar 5).
e) Intermedijar (5) razdvojen je na svoje enantiomere i pročišćen kolonskom kromatografijom preko Chiralpak AD® (eluens: heksan/EtOH 50/50; 15-35 μm). Čiste prve (A) frakcije su skupljene, a otapalo upareno čime je dobiveno 3.3 g ostatka koji je kristaliziran iz CH3CN/DIPE. Talog je odfiltriran i isušen, čime je dobiveno 2.55 g (-)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a] kinazolin-7-metanamina (spoj 1)[α]D20:= -7.16° (c= 5 mg/ml MeOH); tt= 178-180°C; 1H-NMR (DMSO, 400 MHz) δ u ppm: 8.73 (d, J = 8.6 Hz, 1H), 8.38 (dd, J = 8.6 Hz, J = 1.5 Hz, 1H); 7.74-7.67 (m, 3H); 7.64 (s, 1H); 7.62-7.56 (m, 2H); 7.40 (d, J= 8.6 Hz, 2H); 7.21 (d, J = 8.6 Hz, 2H); 5.93 (s, 1H), 3.43 (s, 3H); 3.40 (s, široki, 2H); MS (elektroraspršivanje, mod pol. OR=50V) m/z: 501-505 (M+H)+; 473-477, 391-395, 83; Anal. (C25H18C12N8) C izr. 59.89 pronađeno 59.71, H izr. 3.62 pronađeno 3.52, N izrač. 22.35 pronađeno 22.17. Ovaj spoj sadrži manje od 0.5% w/w (+) enantiomera kako je izmjereno pomoću HPLC (Chiralpak AD® 10 μm eluens heksan/etanol 50/50).
Druge (B) frakcije skupljene su i uparene čime je dobiveno 3.3 g ostatka koji je kristaliziran iz CH3CN/DIPE. Talog je odfiltriran i isušen čime je dobiveno 2.6 g (+)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanamina (spoj 2)[α]D20= +5.9° (c= 5 mg/ml MeOH). Ovaj spoj sadrži 4% w/w (-) enantiomera kako je izmjereno pomoću HPLC (Chiralpak AD® 10 μm eluens heksan/etanol 50/50).
C. Farmakološki primjer
Primjer C.1: " In vitro ispitivanje na inhibiciju farnezil protein transferaze";
Ispitivanje in vitro na inhibiciju farnezil protein transferaze u biti je provedeno na način opisan u WO 98/40383, str. 33-34.
Primjer C.2: "Ispitivanje reverzije ras-transformiranih fenotipova stanice
Ispitivanje reverzije ras-transformiranih fenotipova stanice u biti je provedeno na način opisan u W0 98/40383, str. 34-36.
Primjer C.3: "Model inhibitora sekundarnog tumora s transferazom farnezil proteina "
Model inhibitora sekundarnog tumora s farnezil protein transferazom upotrijebljen je kao što je opisano u W0 98/40383, stranica 37.
D. Primjer pripravka: Film-tablete
Pripravljanje tabletne jezgre
Smjesa od 100 g spoja formule (I), 570 g laktoze i 200 g škroba dobro je pomiješana, a zatim navlažena s otopinom od 5 g natrijevog dodekil-sulfata i 10 g polivinil-pirolidona u oko 200 ml vode. Mokra smjesa praha je prosijana, isušena i ponovo prosijana. Zatim je dodano 100 g mikrokristalne celuloze i 15 g hidrogeniziranog biljnog ulja. Sve je dobro promiješano, komprimirano u tablete, čime je dobiveno 10.000 tableta od kojih svaka sadrži 10 mg spoja formule (I).
Oblaganje
Otopini od 10g metilceluloze u 75ml denaturiranog etanola dodana je otopina 5 g etilceluloze u 150 ml diklorometana. Dodano je 75ml diklorometana i 2.5 ml 1,2,3-propantriola. Rastaljeno je 10 g polietilen glikola i otopljeno u 75ml diklorometana. Ova otopina dodana je prijašnjoj, a nakon toga dodano je 2.5 g magnezijevog oktadekanoata, 5 g polivinil-pirolidona i 30 ml koncentrirane suspenzije boje i sve homogenizirano. Jezgre tableta obložene su tako dobivenom smjesom u za to predviđenom aparatu.
Claims (14)
1. Spoj, naznačen time, da je (±)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanamin i njegove farmaceutski prihvatljive soli.
2. Spoj, naznačen time, da je (-)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanamin.
3. Farmaceutski pripravak, naznačen time, da obuhvaća farmaceutski prihvatljiv prijenosnik, i kao aktivni sastojak terapeutski djelotvornu količinu spoja prema zahtjevu 1.
4. Farmaceutski pripravak prema zahtjevu 3, naznačen time, da je u njemu aktivni sastojak spoj prema zahtjevu 2.
5. Farmaceutski pripravak prema zahtjevu 3 ili zahtjevu 4, naznačen time, da je u jediničnom obliku doziranja.
6. Farmaceutski pripravak prema zahtjevu 5, naznačen time, da sadrži 50 do 300 mg aktivnog sastojka u svakoj jediničnoj dozi.
7. Farmaceutski pripravak prema zahtjevu 5 ili zahtjevu 6, naznačen time, da je u obliku tablete.
8. Postupak pripravljanja farmaceutskog pripravka prema bilo kojem od zahtjeva 3 do 7, naznačen time, da je terapeutski djelotvorna količina aktivnog sastojka temeljito pomiješana s farmaceutski prihvatljivim prijenosnikom.
9. Spoj prema zahtjevu 1 ili zahtjevu 2, naznačen time, da je za uporabu kao lijek.
10. Uporaba spoja prema zahtjevu l ili zahtjevu 2, naznačen time, da je za proizvodnju lijeka za inhibiranje rasta tumora.
11. Metoda inhibiranja rasta tumora u subjekta, naznačena time, da obuhvaća davanje subjektu djelotvorne količine spoja prema zahtjevu 1 ili zahtjevu 2.
12. Metoda prema zahtjevu 11, naznačena time, da se spoj daje dnevno u dozi od 10 do 600 mg.
13. Metoda prema zahtjevu 12, naznačena time, da se spoj daje u dnevnoj dozi od 50 do 500 mg.
14. Postupak pripravljanja spoja prema zahtjevu 1 ili zahtjevu 2, naznačen time, da obuhvaća obradu (±)-5-(3-klorofenil)-α-(4-klorofenil)-α-(1-metil-1H-imidazol-5-il)tetrazolo[1,5-a]kinazolin-7-metanamina ili njegove farmaceutski prihvatljive kiselinske adicijske soli kako bi se razdvojili sastavni (+) i (-) enantiomeri i izdvajanje (-) enantiomera ili njegove farmaceutski prihvatljive kiselinske adicijske soli.
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| EP00202181 | 2000-06-22 | ||
| PCT/EP2001/006747 WO2001098302A1 (en) | 2000-06-22 | 2001-06-13 | Farnesyl transferase inhibiting 1,2-annelated quinoline enantiomer |
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| DE60307616T2 (de) | 2002-04-15 | 2007-10-04 | Janssen Pharmaceutica N.V. | Farnesyl transferase hemmende tricyclische quinazolinederivate substitutiert mit kohlenstoff-gebundenen imidazolen oder triazolen |
| US20050003422A1 (en) | 2003-07-01 | 2005-01-06 | Mitch Reponi | Methods for assessing and treating cancer |
| US11311519B2 (en) | 2014-05-01 | 2022-04-26 | Eiger Biopharmaceuticals, Inc. | Treatment of hepatitis delta virus infection |
| US10076512B2 (en) | 2014-05-01 | 2018-09-18 | Eiger Biopharmaceuticals, Inc. | Treatment of hepatitis delta virus infection |
| EP3226973A4 (en) * | 2014-12-04 | 2018-05-30 | Eiger Biopharmaceuticals, Inc. | Treatment of hepatitis delta virus infection |
| ES2844848T3 (es) | 2015-04-21 | 2021-07-22 | Eiger Biopharmaceuticals Inc | Composiciones farmacéuticas que comprenden Lonafarnib y Ritonavir |
| CA2985123C (en) | 2015-08-17 | 2021-04-13 | Antonio Gualberto | Methods of treating cancer patients with farnesyltransferase inhibitors |
| MY190861A (en) | 2016-11-03 | 2022-05-12 | Kura Oncology Inc | Farnesyltransferase inhibitors for use in methods of treating cancer |
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| GB1519765A (en) * | 1974-09-05 | 1978-08-02 | Ici Ltd | Pesticidal dihydrotetrazolo(1,5a) quinazolines compositions and processes |
| US4141979A (en) * | 1976-12-23 | 1979-02-27 | Pfizer Inc. | Tetrazolo[a]quinazol-5-ones antiallergy and antiulcer agents |
| GB9513577D0 (en) * | 1995-07-04 | 1995-09-06 | Brotherwood Rodney J | Improvements in passenger carrying vehicles |
| TW349948B (en) * | 1995-10-31 | 1999-01-11 | Janssen Pharmaceutica Nv | Farnesyl transferase inhibiting 2-quinolone derivatives |
| DE69620445T2 (de) * | 1995-12-08 | 2002-12-12 | Janssen Pharmaceutica N.V., Beerse | (imidazol-5-yl)methyl-2-chinolinoderivate als farnesyl protein transferase inhibitoren |
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