HRP20050058A2 - Azaindole kinase inhibitors - Google Patents
Azaindole kinase inhibitorsInfo
- Publication number
- HRP20050058A2 HRP20050058A2 HR20050058A HRP20050058A HRP20050058A2 HR P20050058 A2 HRP20050058 A2 HR P20050058A2 HR 20050058 A HR20050058 A HR 20050058A HR P20050058 A HRP20050058 A HR P20050058A HR P20050058 A2 HRP20050058 A2 HR P20050058A2
- Authority
- HR
- Croatia
- Prior art keywords
- pyrrolo
- methyl
- substituted
- yloxy
- pyridin
- Prior art date
Links
- 229940043355 kinase inhibitor Drugs 0.000 title claims description 5
- 239000003757 phosphotransferase inhibitor Substances 0.000 title claims description 5
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
- 206010028980 Neoplasm Diseases 0.000 claims description 27
- 125000000217 alkyl group Chemical group 0.000 claims description 26
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- 230000000694 effects Effects 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 19
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- 125000001072 heteroaryl group Chemical group 0.000 claims description 17
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Description
Područje izuma
Ovaj izum se odnosi na spojeve koji inhibiraju aktivnost tirozin kinaze na receptorima faktora rasta kao što su VEGFR-2 i FGFR-1, i na taj način ih čini korisnim kao antikarcinomna sredstva. Ovi spojevi su također korisni za liječenje drugih bolesti osim raka povezanih sa putevima prenošenja signala koji djeluju preko receptora faktora rasta i receptora anti-angiogeneze, kao što je VEGFR-2.
Pozadina izuma
Normalna angiogeneza igra važnu ulogu u različitim procesima uključujući razvoj embriona, zarastanje rana, gojaznost i nekoliko komponenti reproduktivne funkcije žena. Neželjena ili patološka angiogeneza se povezuje sa bolesnim stanjima uključujući dijabetičku retinopatiju, psorijazu, reumatoidni artritis, aterom, Kaposi sarkom i hemangiom, astmu, karcinom i metastatičke bolesti (Fan et al, 1995, Trend Pharmacol. Sci. 16: 57-66; Folkman, 1995,. Nature Medicine 1: 27-31). Za promjenu vaskularne permeabilnosti se smatra da igra ulogu i u normalnim i patofiziološkim procesima (Cullinan-Bove et al, 1993,, Endocrinology 133: 829-837; Senger et al, 1993 Cancer and Metastasis Reviews, 12: 303-324).
Receptori tirozin kinaza (RTKs) su važni u transmisiji biokemijskih signala kroz citoplazmatsku membranu stanica. Ove transmembranske molekule karakteristično se sastoje od jedne ekstracelularne domene za vezanje liganda povezane preko segmenta u citoplazmatskoj membrani s intracelularnom domenom tirozin kinaze. Vezivanje liganda na receptore dovodi do stimulacije aktivnosti tirozin kinaze povezane s receptorom koja vodi do fosforilacije tirozina na receptoru kao i na drugim intracelularnim proteinima što dovodi do različitih celularnih odgovora. Do danas identificirano je barem devetnaest različitih RTK potporodica definiranih prema homologiji sekvence aminokiselina. Jedna od ovih potporodica trenutno obuhvaća receptore tirozin kinaze slične fms, Flt ili Fltl (VEGFR-1), receptor koji sadrži domenu inserta kinaze, KDR (također poznat kao Flk-1 ili VEGFR-2), i druge receptore tirozin kinaze slične fms, Flt4 (VEGFR-3). Za dva od ovih srodnih RTKs, Fit i KDR, pokazano je da vezuju vaskularni endotelijalni faktor rasta (VEGF) velikim afinitetom (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophy y s. Res. Comm. 1992,187: 1579-1586). Vezivanje VEGF za ove receptore s ekspresijom u heterolognim stanicama povezano je s promjenama u statusu fosforiliranja tirozina kod celularnih proteina i protokom kalcija. VEGF, zajedno sa kiselim i baznim faktorom rasta fibroblasta (aFGF & bFGF) je identificiran da in vitro posjeduje aktivnost poticanja rasta endotelijalnih stanica. Zapaženo je da se aFGF i bFGF vezuju i aktiviraju receptor tirozin kinaze nazvan FGFR-1. Uslijed restriktivne ekspresije njegovih receptora, aktivnost faktora rasta VEGF, nasuprot one FGFs, je relativno specifična u odnosu na endotelijalne stanice. Noviji dokazi ukazuju da je VEGF važan stimulator normalnih kao i patoloških angiogeneza (Jakeman et al, 1993, Endocrinology, 133: 848-859; Kolch et al, 1995, Breast Cancer Research and Treatment, 36:139-155) i vaskularne permeabilnosti (Connolly et al, 1989, J. Biol. Chem. 264: 20017-20024).
Kod odraslih endotelijalne stanice imaju nizak indeks proliferacije, osim u slučajevima prepravljanja tkiva, kao što je liječenje rana i reproduktivni ciklus kod žena, i adipogeneze. Međutim, u patološkim stanjima kao što je karcinom, nasljedne vaskularne bolesti, endometrioza, psorijaza, artritis, retinopatije i ateroskleroza, endotelijalne stanice aktivno proliferiraju i organiziraju se u žile. Pri izlaganju angiogenim stimulatorima sa faktorima rasta kao što su VEGF i bFGF, endotelijalne stanice, ponovo ulaze u stanični ciklus, umnožavaju se, migriraju i organiziraju u trodimenzionalnu mrežu. Sada je široko prihvaćeno da je sposobnost tumora da se širi i metastazira u zavisnosti od formiranja vaskularne mreže.
Vezivanje VEGF ili bFGF za njihove odgovarajuće receptore dovodi do dimerizacije, autofosforilacije na tirozinu i aktivacije enzima. Ovi fosfotirozinski ostaci služe kao "pristanišna" mjesta za specifične molekule nizvodne signalizacije i enzimatska aktivnost dovodi do aktivacije EC. Prekid ovih puteva trebao bi inhibirati aktivaciju endotelijalnih stanica. Prekid FGFR-1 puta trebao bi, također, utjecati na proliferaciju stanica tumora, s obzirom da se ova kinaza aktivira u mnogim vrstama tumora dodatno uz proliferacije endotelijalnih stanica. Konačno, suvremeni dokazi također sugeriraju da prekid signaliziranja VEGF inhibira migraciju endotelijalnih stanica, ključan proces u formiranju vaskularne mreže.
Prekomjerna ekspresija i aktiviranje VEGFR-2 i FGFR-1 u vaskularnoj mreži koja je povezana sa tumorom, sugerira ulogu ovih molekula u angiogenezi tumora. Angiogeneza i posljedični rast tumora se inhibira antitjelima usmjerenim protiv VEGF liganada i VEGF receptora, i pomoću skraćenih (nedostaje jedna transmembranska sekvenca i domena citoplazmatske kinaze) topljivih VEGFR-2 receptora. Dominantne mutacije uvedene u VEGFR-2 ili FGFR-1 koje dovode do gubitka enzimatske aktivnosti inhibiraju rast tumora in vivo. Antisense ciljanje ovih receptora ili njihovih srodnih liganada također inhibira angiogenezu i rast tumora. Najnoviji dokazi su rasvijetlili, djelomično, privremene zahtjeve ovih receptora za rast tumora. Pokazuje se da je VEGF signaliziranje kritično za rani rast tumora a bFGF je važnije u kasnijem periodu koji je povezan sa ekspanzijom tumora.
Detaljan opis izuma
U skladu s predmetnim izumom, spojevi formule I,
[image]
njihovi enantiomeri, dijastereomeri i farmaceutski prihvatljive soli, prekursori i njihovi solvati, inhibiraju tirozin kinaznu aktivnost receptora faktora rasta, kao što je VEGFR-2. U formuli I i kroz specifikaciju, gornji simboli se definiraju kako slijedi:
Z se izabere od O, S, N, OH, ili Cl, pod uvjetom da kada Z je O ili S, R41 je odsutno i kada Z je OH ili Cl, i R41 i R42 su odsutni;
X i Y se nezavisno izaberu od O, OCO, S, SO, SO2, CO, CO2, NR10, NR11CO, NR12CONR13, NR14CO2, NR15SO2, NR16SO2NR17, SO2NR18, CONR19, halogena, nitro, cijano, ili X ili Y su odsutni;
R1 je vodik, CH3, OH, OCH3, SH, SCH3, OCOR21, SOR22, SO2R23, SO2m24R25, CO2R26, CONR27R28, NH2, NR29SO2NR30R31, NR32SO2R33S NR34COR35, NR36CO2R37, NR38CONR39R40, halogen, nitro, ili cijano;
R2 i R3 su nezavisno vodik, alkil , supstituirani alkil, alkenil, supstituirani alkenil, alkinil, supstituirani alkinil, aril, supstituirani aril, heterociklo, supstituirani heterociklo, aralkil, supstituirani aralkil, heteroaril supstituirani heteroaril, heterocikloalkil ili , supstituirani heterocikloalkil; pod uvjetom da kada X je halo, nitro ili cijano, R je odsutno, i kada Y je halo, nitro ili cijano, R je odsutno;
R6 je H, alkil , supstituirani alkil, aril, supstituirani aril, heterociklo , supstituirani heterociklo, NR7R8, OR9 ili halogen;
R7,R8,R9,R10,R11,R12,R13,R14,R15,R16,R17,R18,R19,R20,R21,R22,R23,R24,R25,R26,R27, R28, R29, R30, R31, R32, R34, R35, R36, R38, R39 i R40 se nezavisno izaberu iz grupe koja se sastoji od vodika, alkila , supstituiranog alkila, arila, supstituiranog arila, heteroarila, supstituiranog heteroarila, heterocikla, ili supstituiranog heterocikla;
R22, R23, R33 i R37 se nezavisno izaberu iz grupe koja se sastoji od alkila , supstituiranog alkila, arila, supstituiranog arila, heteroarila , supstituiranog heteroarila, heterocikla, ili, supstituiranog heterocikla;
R42 je
[image]
(R43)n gdje je n jednako 0, 1 ili 2 i svaki R43 se nezavisno izaberu iz grupe koja se sastoji od vodika, fluora, klora i metila; i
R44 je metil, ili vodik,
s daljim uvjetima da:
a. R2 ne mora biti vodik ako X je SO, SO2, NRI3CO2, ili NR14SO2; i
b. R3 ne mora biti vodik ako Y je SO, SO2, NR13CO2, ili NR14SO2.
U preferiranoj izvedbi R1 je vodik ili metil; R6 je vodik ; R3 je niži alkil; i Z je kisik ili dušik.
U drugoj preferiranoj izvedbi R1 je vodik ; R3 je niži alkil; Y je odsutan; X je kisik ili dušik; R43 je fluor ili vodik; i R44 je vodik ili metil.
U još jednoj preferiranoj izvedbi X je kisik; R2 je jedan supstituirani alkil i R43 je fluor.
U još jednoj preferiranoj izvedbi X je odsutan; R2 je supstituirani heterociklo, supstituirani heterociklo, heteroaril, supstituirani heteroaril, i Z je dušik.
Preferirani spojevi izuma uključuju
4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazin-6-ol,
(R)-1-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f] [1,2,4]triazin-6-iloksi ]-propan-2-ol,
(S)-1-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f] [1,2,4] triazin-6-iloksi] -propan-2-ol,
(R)-1-[4-(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazin-6-iloksi] -propan-2-ol,
(R)-2-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-1-metiletilamin,
(R)-2-[4-(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4] triazin-6-iloksi]-1 -metil-etilamin,
2-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-etilamin,
(4-Fluor-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin,
(4-Fluor-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin,
(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirol[2,1-f][1,2,4]triazin-4-il]-amin, i
[5-Izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-(2-metil-1H-pirolo[2,3-b]piridin-5-il)-amin.
Izum također pruža farmaceutsku kompoziciju koja obuhvaća spoj formule I ili II i farmaceutski prihvatljivi nosač.
Izum također pruža farmaceutsku kompoziciju koja obuhvaća spoj formule I ili II u kombinaciji sa farmaceutski prihvatljivim nosačem i jednim anti-karcinomnim ili citotoksičkim sredstvom. U preferiranoj izvedbi navedeno antikarcinogeno ili citotoksično sredstvo se izabere iz grupe koja se sastoji od niza linomid; inhibitori integrin ανβ3 funkcije; angiostatin; razoksan; tamoksifen; toremifen; raloksifen; droloksifen; jodoksifen; megestrol acetat; anastrozol; letrozol; borazol; eksemestan; flutamid; nilutamid; bikalutamid; ciproteron acetat; goserelin acetat; leuprolid; finasterid; inhibitori metaloproteinaze; inhibitori funkcije receptora aktivatora urokinaza plazminogena; antitijela faktora rasta; antitijela receptora faktora rasta kao što su Avastin® (bevacizumab) i Erbitux® (cetuksimab); inhibitori tirozin kinaza; inhibitori serin/treonin kinaze; metotreksat; 5-fluoruracil; purin; analozi adenozina; citozin arabinozid; doksorubicin; daunomicin; epirubicin; idarubicin; mitomicin-C; daktinomicin; mitramicin; cisplatin; karboplatin; dušikov mustard; melfalan; klorambucil; busulfan; ciklofosfamid; ifosfamid nitrozouree; tiotepa; vinkristin; Taxol® (paklitaksel); Taxotere® (docetaksel); epotilon analozi; diskodermolid analozi; sleuterobin analozi; etopozid; tenipozid; amsakrin; topotekan; flavopiridoli; modifikatori biološkog odgovora i inhibitori proteazoma kao što je Velcade® (bortezomib).
Ovaj izum također pruža metodu inhibicije aktivnosti protein kinaze receptora faktora rasta koja obuhvaća davanje sisavcima kojima je potrebno terapeutski efektivne količine spoja formule I koja inhibira aktivnost protein kinaze.
Dodatno, objavljena je metoda za inhibiciju aktivnosti tirozin kinaze najmanje jedang receptora faktora rasta koja obuhvaća davanje vrsti sisavca kojima je potrebno terapeutski efektivne količine spoja formule I ili II. U preferiranoj izvedbi navedeni receptor faktora rasta se bira iz grupe koja se sastoji od VEGFR-2 i FGFR-1.
Konačno, iznesena je metoda za liječenje proliferativnih bolesti koja obuhvaća davanje sisavcima kojima je potrebno terapeutski efektivne količine spoja formule I. U preferiranoj izvedbi proliferativna bolest je karcinom.
Slijede definicije termina koji se mogu koristiti u predmetnoj specifikaciji. Početna definicija daje se za grupu ili termin ovdje u tekstu odnosi se na tu grupu ili izraz kroz predmetnu specifikaciju individualno ili kao dio druge grupe, osim ukoliko nije drugačije naznačeno.
Izraz «alkil" odnosi se na ravan ili razgranat lanac nesupstituiranih ugljikovodičnih grupa od 1 do 20 atoma ugljika, preferirano od 1 do 7 atoma ugljika. Izraz "niži alkil" odnosi se na nesupstituirane alkil grupe od 1 do 4 atoma ugljika.
Izraz «supstituirani alkil" odnosi se na alkil grupu koja je supstituirana sa, na primjer, jednim do četiri supstituenta kao što su halo, hidroksi skupina, alkoksi skupina, okso skupina, alkanoil, ariloksi skupina, alkanoiloksi skupina, amino skupina, alkilamino skupina, arilamino skupina, aralkilamino skupina, disupstituirani amini kod kojih su dva amino supstituenta se izaberea iz alkila, arila ili aralkila; alkanoilamino, aroilamino, aralkanoilamino, supstituirani alkanoilamino, supstituirani arilamino, supstituirani aralkanoilamino, tiol, alkiltio, ariltio, aralkiltio, alkltiono, ariltiono, aralkiltiono, alkilsulfonil, arilsulfonil, aralkilsulfonil, sulfonamido,na primjer SO2NH2, supstituirani sulfonamido, nitro, cijano, karboksi, karbamil, na primjer CONH2, supstituirani karbamil na primjer CONHalkil, CONHaril, CONHaralkil ili slučajevi gdje ima dva supstituenta na dušiku se izaberea od alkila, arila ili aralkila; alkoksikarbonil, aril, supstituirani aril, guanidino i heterociklo, kao što su, indolil, imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil i slično. Gdje je gore naznačeno da je supstituent dalje supstituiran, to će biti alkilom, alkoksi skupinom, arilom ili aralkilom.
Izraz «halogen" ili "halo" odnosi se na fluor, klor, brom i jod.
Izraz «aril" odnosi se na monocikličnu ili bicikličnu aromatičnu grupu ugljikovodika koja ima 6 do 12 atoma ugljika u obliku prstena, kao što su fenil, naftil, bifenil i difenil grupe, od kojih se svaka može supstituirati.
Izraz «aralkil" odnosi se na aril grupu vezanu direktno preko jedne alkil grupe, kao što je benzil.
Izraz «supstituirani aril" odnosi se na aril grupu supstituiranu, na primjer, jednim do četiri supstituenta kao što su alkil, supstituirani alkil, halo skupina, trifluormetoksi skupina, trifluormetil, hidroksi skupina, alkoksi skupina, alkanoil skupina, alkanoiloksi skupina, amino skupina, alkilamino skupina, aralkilamino skupina, dialkilamino skupina, alkanoilamino skupina, tiol, alkiltio skupina, ureido skupina, nitro skupina, cijano skupina, karboksi skupina, karboksialkil, karbamil, alkoksikarbonil, alkiltiono skupina, ariltiono skupina, arilsulfonilamin skupina, sumporna kiselina, alkisulfonil, sulfonamido skupina, ariloksi skupina i slične. Ovaj supstituent se može dalje supstituirati hidroksi skupinom, alkilom, alkoksi skupinom, arilom, supstituiranim arilom, supstituiranim alkilom ili aralkilom.
Izraz « heteroaril" odnosi se na opciono supstituiranu, aromatičnu grupu, na primjer, 4- ili 7-člani monociklični, 7- do 11-člani biciklični, ili 10- do 15-člani triciklični sistem, koja sadrži bar jedan heteroatom u najmanje jedanm prstenu sa ugljikovim atomima, na primjer, piridin, tetrazol, indazol, indol.
Izraz «alkenil" odnosi se na ravne ili razgranate lance ugljikovodičnih grupa sa od 2 do 20 atoma ugljika, preferirano 2 do 15 atoma ugljika, a najviše preferirano 2 do 8 atoma ugljika , koji imaju jednu do četiri duple veze.
Izraz “supstituirani alkenil" odnosi se na jednu alkenil grupu koja je supstituirana, na primjer, jednim do dva supstituenta, kao što su, halo, hidroksi skupina, alkoksi skupina, alkanoil, alkanoiloksi skupina, amino skupina, alkilamino skupina, dialkilamino skupina, alkanoilamino skupina, tiol, alkltio skupina, alkltiono skupina, alklsulfonil, sulfonamido skupina, nitro skupina, cijano skupina, karboksi skupina, karbamil, supstituirani karbamil, guanidino skupina, indolil, imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil i slično.
Izraz “alkinil" odnosi se na ravne ili razgranate lance ugljikovodičnih grupa sa od 2 do 20 atoma ugljika, preferirano 2 do 15 atoma ugljika,a više preferirano od 2 do 8 ugljikovih atoma, koji imaju jednu do četri trostruke veze.
Izraz “supstituirani alkinil" odnosi se na alkinil grupu supstituiranu, na primjer, supstituentom, kao što je, halo, hidroksi skupina, alkoksi skupina, alkanoil, alkanoiloksi skupina, amino skupina, alkilamino skupina, dialkilamino skupina, alkanoilamino skupina, tiol, alkltio skupina, alkiltiono skupina, alkilsulfonil, sulfonamido skupina, nitro skupina, cijano skupina, karboksi skupina, karbamil, supstituirani karbamil, guanidino i heterociklo skupina, na primjer imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil i slično. Izraz “cikloalkil" odnosi se na opciono supstituirani, zasićeni ugljikovodični prsten sistem, preferirano sadrži 1 do 3 prstena i 3 do 7 ugljikovih atoma po prstenu koji dalje mogu biti kondenzirani sa nezasićenim C3-C7 karbocikličnim prstenom. Primjeri grupa uključuju ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, cikloktil, ciklodecil, ciklododecil, i adamantil. Primjeri supstituenata obuhvaćaju jednu ili više alkil grupa , kao što je opisano gore, ili jednu ili više grupa, koje su gore opisane kao alkilni supstituenti.
Izrazi “heterocikl", "heterociklični" i "heterociklo" odnose se na jednu ili više opciono supstituiranu, potpuno zasićenu ili nezasićenu, aromatičnu ili nearomatičnu cikličnu grupu, na primjer, 4- do 7- člani monociklični , 7- do 11- člani biciklični, ili 10- do 15- člani triciklični sistem, koji ima najmanje jedan heteroatom u najmanje jedanm prstenu sa ugljikovim atomima. Svaki prsten heterociklične grupe koja sadrži heteroatom može imati 1, 2 ili 3 heteroatoma odabranih između dušikovih atoma, atoma kisika i sumpora, gdje heteroatomi dušika i sumpora mogu također biti opciono oksidirani i heteroatomi dušika mogu također opciono biti kvaternizirani. Heterociklična grupa se može vezati za bilo koji heteroatom ili atom ugljika. Primjeri monocikličnih heterocikličnih grupa uključuju pirolidinil, pirolil, pirazolil, oksetanil, pirazolinil, imidazolil, imidazolinil, imidazolidinil, oksazolil, oksazolidinil, izoksazolinil, izoksazolil, tiazolil, tiadiazolil, tiazolidinil, izotiazolil, izotiazolidinil, furil, tetrahidrofuril, tienil, oksadiazolil, piperidinil, piperazinil, 2-oksopiperazinil, 2-oksopiperidinil, 2-oksopirolidinil, 2-oksazepinil, azepinil, 4-piperidonil, piridil, N-okso-piridil, pirazinil, pirimidinil, piridazinil, tetrahidropiranil, morfolinil, tiamorfolinil, tiamorfolinilsulfoksid, tiamorfolinilsulfon, 1,3-dioksolan i tetrahidro-1, 1-dioksotienil, dioksanil, izotiazolidinl, tietanil, tiiranyl, triazinil, i triazolil, i slično.
Primjeri bicikličnih heterocikličnih grupa uključuju 2,3-dihidro-2-okso-1H-indolil skupinu, benzotiazolil skupinu, benzoksazolil, benzotienil, kvinuklidinil, kvinolinil, kvinolinil-N-oksid, tetrahidroizokvinolinil, izokvinolinil, benzimidazolil, benzopiranil, indolizinil, benzofuril, hromonil, kumarinil, cinolinil, kvinoksalinil, indazolil, pirolpiridil, furopiridinil (kao što su [2,3-c]piridinil, furo[3,l-b]piridinil] ili furo[2,3-b]piridinil), dihidroizoindolil, dihidrokvinazolinil (kao što je 3,4-dihidro-4-okso-kvinazolinil), benzizotiazolil, benzizoksiazolil, benzodiazinil, benzimidazolil, benzofurazanil, benzotiopiranil, benzotriazolil, benzopirazolil, dihidrobenzofuril, dihidrobenzotienil, dihidrobenzotiopiranil, dihidrobenzotiopiranil sulfon, dihidrobenzopiranil, indolinil, indolil, izokromanil, izoindolinil, naftiridinil, ftalazinil, piperonil, purinil, piridopiridil, kvinazolinil, tetrahidrokvinolinil, tienofuril, tienopiridil, tienotienil, i slično.
Primjeri supstituenata obuhvaćaju jednu ili više alkil ili aralkil grupa kao što je gore opisano ili jednu ili više grupa gore opisanih kao alkil supstituenti. Također su obuhvaćeni manji heterocikli, kao što su, epoksidi i aziridini.
Izraz “heteroatomi" uključuje kisik, sumpor i dušik.
Spojevi formule I mogu tvoriti soli koji su također u okviru ovog izuma. Farmaceutski prihvatljive (to jest. netoksične, fiziološki prihvatljive) soli su više preferirane, mada su i druge soli također korisne, na primjer, kod izoliranja ili pročišćavanja spojeva ovog izuma.
Spojevi formule I mogu tvoriti soli s alkalnim metalima kao što je natrij, kalij i litij, sa zemnoalkalnim metalima kao što su kalcij i magnezij, s organskim bazama kao što su dicikloheksilamin, tributilamin, piridin i aminokiseline kao što je arginin, lizin i slično. Takve soli mogu nastati kao što je poznato stručnjacima u području.
Spojevi formule I mogu tvoriti soli sa različitim organskim i anorganskim kiselinama. Takve soli uključuju one formirane sa klorovodikom, bromovodikom, metansulfonskom kiselinom, sumpornom kiselinom, octenom kiselinom, trifluoroctenom kiselinom, oksalnom kiselinom, maleinskom kiselinom, benzensulfonskom kiselinom, toluenesulfonskom kiselinom i različite druge (na primjer, nitrate, fosfate, borate, tartrate, citrate, sukcinate, benzoate, askorbate, salicilate i slično). Takve soli mogu nastati kao što je poznato stručnjacima u području.
Dodatno, mogu se tvoriti zwitterioni (cviterioni) ("unutrašnje soli”).
Svi stereoizomeri spojevia trenutnog izuma se razmatraju , ili kao smjese ili u čistoj ili temeljno čistoj formi. Definicija spojeva prema izumu zahvaća sve moguće stereoizomere i njihove mješavine. Posebno zahvaća racemične oblike i izolirane optičke izomere koji imaju specifičnu aktivnost. Racemični oblici se mogu razlučiti fizičkim postupcima, kao što je, na primjer, frakciona kristalizacija, separacija ili kristalizacija dijastereoizomernih derivata ili odvajanje pomoću kromatografije sa kiralnom kolonom. Individualni optički izomeri se mogu dobiti od racemata konvencionalnim metodama, kao što je, na primjer, stvaranje soli s optički aktivnom kiselinom praćena kristalizacijom.
Spojevi formule I mogu također imati forme predlijekova. Bilo koji spoj koji će biti izmijenjen in vivo da bi se dobilo bioaktivno sredstvo (tj., spoj za formulu I) je predlijek unutar dometa i duha izuma.
Različite forme predlijekova su poznate u struci. Za primjere takvih derivata predlijekova, vidi:
Design of Prodrugs, izdavač H. Bundgaard, (Elsevier, 1985) i Methods in Enzymology. Vol. 42, p. 309-396, izdavač K. Widder, et al. (Acamedic Press, 1985);
A Textbook of Drug Design and Development, izdavač Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs," by H.Bundgaard, p. 113-191 (1991);
H. Bundgaard, Advanced Drug Delivery Reviews. 8, 1-38 (1992);
Dalje treba shvatiti da solvati (npr. hidrati) spojeva I su također u opsegu predmetnog izuma. Metode otapanja su općenito poznate u struci.
Primjena i korisnost
Predmetni izum se zasniva na otkriću da su izvjesni pirolotriazini inhibitori protein kinaza. Još određenije, oni inhibiraju efekte VEGF, što je vrijedno svojstvo u liječenju bolesnih stanja povezanih sa angiogenezom i/ili povećanom vaskularnom permeabilnošču kao što je karcinom. Izum se odnosi na farmaceutsku kompoziciju spoja formule I ili njegove farmaceutski prihvatljive soli i hidrate, i farmaceutski prihvatljivog nosača u liječenju hiperproliferativnih poremećaja kod sisavca. Preciznije, od navedene farmaceutske kompozicije se očekuje da inhibira rast onih primarnih i rekurentnih čvrstih tumora koji su povezani sa VEGF, posebno onih tumora koji u značajnoj mjeri zavise od VEGF u pogledu rasta i širenja, uključujući, na primjer, karcinome prostate, skvamoznih stanica, glave, kolorektalne, ezofagne, ginekološke (kao što je karcinom jajnika), pankreasa, dojke, prostate, pluća, vulve, kože, mozga, genitourinarnog trakta, limfnog sistema (kao što je tiroidni karcinom), želuca, grkljana i pluća. U drugoj izvedbi, spojevi predmetnog izuma su također korisni u liječenju nekarcinomnih poremećaja kao što je dijabetes, dijabetska retinopatija, psorijaza, reumatoidni artritis, gojaznost, Kaposi sarkom, hemangiom, akutne i kronične nefropatije (uključujući proliferativni glomerulonefritis i dijabetesom uzrokovane renalne bolesti), aterom, arterijski restenozis, autoimune bolesti, akutna inflamacija, očne bolesti sa proliferacijom krvnih sudova retine, dijabetskom retinopatijem, retinopatijem prematuralne i makularne degeneracije. Izum se također odnosi na implantaciju blastocita kod sisavca, liječenje ateroskleroze, ekcema, sklerodema, hemangioma. Spojevi izuma o kojima je ovdje riječ imaju dobru aktivnost protiv VEGF receptora s aktivnošću tirozin kinaze, dok posjeduju izvjesnu aktivnost protiv drugih tirozin kinaza.
Tako prema daljem aspektu izuma, omogućeno je korištenje spoja formule I ili njegove farmaceutski prihvatljive soli u proizvodnji lijeka za upotrebu u postizanju antiangiogenog efekta i/ili efekta smanjivanja vaskularne permeabilnosti kod sisavca kao što je ljudsko biće.
Prema daljnim osobinama izuma, postoji metoda za postizanje antiangiogenog efekta i/ili efekta smanjivanja vaskularne permeabilnosti kod sisavca kao što je ljudsko biće, kojem je potrebno takvo liječenje, koja obuhvaća davanje navedenoj životinji efektivne količine spoja formule I ili njegove farmaceutski prihvatljive soli kao što je prije ovdje definirano.
Spojevi koji su ovdje opisani također inhibiraju druge receptore tirozin kinaze uključujući HER1 i HER2 i stoga su korisni u liječenju proliferativnih poremećaja kao što su psorijaza i karcinom. HER1 receptor kinaza je prikazan kao izražen i aktivan kod mnogih čvrstih tumora uključujući rak pluća “non-small” (nealveolarnih) stanica, kolorektalni i tumor dojke. Slično, za HER2 receptor kinaze pokazalo se da dolazi do preekspresije kod karcinoma dojke, jajnika, pluća i želuca. Monoklonalna antitijela koja smanjuju obilnost ( količinu ) HER2 receptora ili inhibiraju signaliziranje pomoću HER1 receptora pokazala su antitumorsku efikasnost u predkliničkim i kliničkim studijama. Stoga se očekuje da inhibitori HER1 i HER2 kinaze budu efikasni u liječenju tumora koji ovise o signalima jednog ili drugog receptora. Sposobnost ovih spojeva da inhibiraju HER1 dalje doprinosi njihovoj primjeni kao antiangiogenska sredstva. Pogledajte sljedeće dokumente i reference koji su o tome naveli citate: Cobleigh, M. A., Vogel, C. L., Tripathy, D., Robert, N. J., Scholl, S., Fehrenbacher, L., Wolter, J. M., Paton, V., Shak, S., Lieberman, G., i Slamon, D. J., "Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease", /. ofClin. Oncol. 17(9), p. 2639-2648 (1999); Baselga, J., Pfister, D., Cooper, M. R., Cohen, R., Burtness, B., Bos, M., D'Andrea, G., Seidman, A, Norton, L., Gunnett, K., Falcey, J., Anderson, V., Waksal, H and Mendelsohn, J., "Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin", /. Clin. Oncol. 18(4), p. 904-914 (2000).
Antiproliferativni, antiangiogeni i /ili tretman za smanjivanje vaskularne permeabilnosti koji je ovdje ranije naveden, može se primijeniti kao jedinstvena terapija ili može uključiti, kao dodatak spoju izuma, jednu ili više drugih supstanci i /ili tretmana. Takvo objedinjeno liječenje može se postići pomoću simultanog, u slijedu ili odvojenog davanja pojedinačnih komponenti u ovom liječenju. Spojevi ovog izuma također mogu biti korisni u kombinaciji sa poznatim antikarcinomnim i citotoksičnim sredstvima i tretmanima, uključujući zračenje. Ako je formulirana kao fiksna doza, takva kombinacija produkata korisit spojeve ovog izuma u rasponu doze koja je dolje opisana i druga farmaceutska aktivna sredstva u okviru odobrenog raspona doze. Spojevi formule I se mogu koristiti jedan za drugim s poznatim antikarcinomnim ili citotoksičkim sredstvima i tretmanima, uključujući zračenje, kada je kombinacija formulacije neodgovarajuća.
U polju medicinske onkologije normalna je praksa da se koristi kombinacija različitih formi liječenja kod svakog pacijenta sa karcinomom. U medicinskoj onkologiji druga komponenta(e) takvog kombiniranog liječenja dodatno uz antiproliferativno, antiangiogeno i / ili liječenje za smanjivanje vaskularne permeabilnosti koje je ovdje ranije definirano može biti: operacija, radioterapija ili kemoterapija. Takva kemoterapija može da pokrije tri glavne kategorije terapeutskog sredstva:
(i) antiangiogena sredstva koja djeluju mehanizmima različitim od onih koji su ovdje ranije navedeni (na primjer, linomid, inhibitori integrin ανβ3 funkcije, angiostatin, razoksan);
(ii) citostatička sredstva kao što su antiestrogeni (na primjer, tamoksifen, toremifen, raloksifen, droloksifen, jodoksifen), progestogeni (na primjer, megestrol acetat), inhibitori aromataze (na primjer, anastrozol, letrozol, borazol, eksemestan), antihormoni, antiprogestogeni, antiandrogeni (na primjer, flutamid, nilutamid, bikalutamid, ciproteron acetat), LHRH agonisti i antagonisti (na primjer, goserelin acetat, leuprolid), inhibitori testosteron 5α-dihidroreduktaze (na primjer, finasterid), inhibitori farneziltransferaze, anti-invazivna sredstva (na primjer, inhibitori metaloproteinaze slični marimastatu i inhibitori urokinaze receptorne funkcije aktivatora plazminogena) i inhibitori funkcije faktora rasta, (takvi faktori rasta obuhvaćaju na primjer, EGF, FGF, faktor rasta dobijen iz trombocita i faktor rasta hepatocita , takvi inhibitori obuhvaćaju antitijela na faktore rasta , antitijela na receptore faktora rasta kao što su Avastin® (bevacizumab) i Erbitux® (cetuksimab); inhibitor tirozin kinaze i inhibitori serin/treonin kinaze ); i
(iii) antiproliferativni/antineoplastični lijekovi i njihove konbinacije, kako je korišteno u medicinskoj onkologiji, kao što su antimetabolici (na primjer, antifolati kao što su metotreksat, fluoropirimidini kao što je 5-fluoruracil, analozi purina i adenozina, citozin arabinozid); Interkalatorni antitumor antibiotici (na primjer, antraciklini kao što je doksorubicin, daunomicin, epirubicin i idarubicin, mitomicin-C, dactinomicin, mitramicin); derivati platine (na primjer, cisplatin, karboplatin); alkilirajuća sredstva (na primjer, dušik mustard, melfalan, klorambucil, busulfan, ciklofosfamid, ifosfamid, nitrozouree, tiotepa; antimitotična sredstva (na primjer, vinca alkaloidi kao što je vinkristin i taksoidi kao što je Taxol® (paklitaksel), Taxotere® (docetaksel) i noviji mikrobtubulna sredstva kao što su analozi epotilona, analozi diskodermolida i eleuterobin analozi); inhibitori topoizomeraze (na primjer,epipodofilotoxini kao što su etopozid i tenipozid, amsakrin, topotekan); inhibitori staničnog ciklusa (na primjer, flavopiridoli); modifikatori biološkog odgovora i inhibitori proteazoma kao što je Velcade® (bortezomib).
Kao što je gore navedeno, spojevi formule I predmetnog izuma su od značaja zbog svog antiangiogenog i/ili efekta redukcije vaskularne permeabilnosti. Za takve spojeve ovog izuma se očekuje da budu korisni kod širokog spektra bolesnih stanja uključujući karcinom, dijabetes, psorijazu, reumatoidni artritis, Kaposi sarkom, hemangiom, gojaznost, akutne ili kronične nefropatije, aterom, arterijalna restenoza, autoimune bolesti, akutne inflamacije i okularne bolesti koje su povezane sa proliferacijom krvnih žila retine, kao što je dijabetska retinopatija.
Još određenije, spojevi formule I su korisni u liječenju različitih karcinoma, uključujući (ali ne ograničavajući se na) sljedeće:
-karcinomi, uključujući one na prostati, dojci, debelom crijevu, bubregu, jetri, plućima, uključujući karcinom “small cells”(alveolarnih) stanica pluća, jednjaku, žučnom mjehuru, jajnicima, pankreasu, želucu, cervixu, tiroidi, prostati, i koži ,uključujući karcinom skvamoznih stanica;
-hematopetski tumori limfnog porijekla, uključujući leukemiju, akutnu limfocitnu limfocitnu leukemiju, akutnu limfoblastnu leukemiju, limfom B-stanica, limfom T-stanica, Hočkingov limfom, ne-Hodkingov limfom, limfom stanica dlake i Burkettov limfom;
-hematopetski tumori mijeloidnog porekla, uključujući akutne i kronične mijelogenozne leukemije, mijelodisplastični sindrom i promijelocitnu leukemiju;
-tumori mezenhimalnog porijekla, uključujući fibrosarkom i rabdomiosarkom;
- tumori centralnog i perifernog nervnog sistema, uključujući astrocitom, neuroblastom, gliom i švanom; i
-drugi tumori, uključujući melanom, seminom, teratocarcinom, osteosarkom, ksenoderom pigmentozum, keratoktantom, tiroidni folikularni karcinom i Kaposi sarkom.
Zbog ključne uloge kinaza u regulaciji proliferacije stanica općenito, inhibitori mogu djelovati kao reverzibilna citostatska sredstva koja mogu biti korisna u tretmanu bilo kog bolesnog procesa koji uključuje abnormalnu staničnu proliferaciju, na primjer benigna hiperplazija prostate, porodična adenomatoza polipoza, neuro-fibromatoza, ateroskleroza, plućna fibroza, artritis, psorijaza, glomerulonefritis, restenoza praćena angioplastnom ili vaskularnom kirurgijom, hipertrofijska formacija ožiljka, bolest inflamacije crijeva, transplantaciono odbacivanje, endotoksični šok i gljivična infekcija.
Spojevi formule I mogu inducirati ili inhibirati apoptozu. Apoptotička reakcija je neprirodna kod raznih vrsta bolesti koje pogađaju ljude. Spojevi formule I, kao modulatori apoptoze, biti će korisni u liječenju karcinoma (uključujući ali ne ograničavajući se na gore spomenute vrste), viralnih infekcija (uključujući ali ne ograničavajući se na herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus i adenovirus), prevenciji razvoja AIDS kod HIV-zaraženih pojedinaca, autoimunih bolesti (uključujući ali ne ograničavajući se na sistemski lupus, eritematozu, autoimuno izazvani glomerulonefritis, reumatoidni artritis, psorijazu, inflamatorne bolesti crijeva, i autoimuni diabetes melitus), neurodegenerativnih poremećaja (uključujući ali ne ograničavajući se na Alzheimerovu bolest , demenciju uzrokovanu AIDS-om, Parkinsonovu bolest, amyotrophic lateral sklerozu, retinitis pigmentozu, kičmeno mišićnu atrofiju i cerebelarnu degeneraciju), mijelodisplastičnih sindroma, aplastične anemije, ishemijskih povreda koje su povezane sa infarktima miokarda, moždanim udarom i reperfuzijom povreda, aritmije, ateroskleroze, bolesti jetre koje su izazvane toksinima ili alkoholom, hematoloških bolesti (uključujući ali ne ograničavajući se na kroničnu anemiju i aplastičnu anemiju), degenerativnih bolesti muskulo-skeletnog sistema (uključujući ali ne ograničavajući se na osteoporozu i artritis), rinosinusitisa osetljivih na aspirin, cistične fibroze, multiple skleroze, bolesti bubrega i bolova prouzrokovanih karcinomom.
Spojevi formule I su posebno korisni u liječenju tumora koji imaju visoku incidencu aktivnosti tirozin kinaze, kao što je tumor debelog crijeva, pluća, i tumori pankreasa. Davanjem sastava (ili kombinacije) spojevi ovog izuma, smanjuje se razvoj tumora kod mnogih sisavca.
Spojevi formule I mogu također biti korisni u liječenju drugih bolesti osim karcinoma, a koje mogu biti povezane sa putevima prijenosa signala koji djeluju preko receptora faktora rasta kao što su VEGFR-2 i FGFR-1.
Spojevi ovog izuma mogu se formulirati sa farmaceutskim prijenosnim sredstvima ili razrjeđivačima za oralno, intravenozno ili subkutano davanje. Farmaceutska kompozicija se može formulirati na klasičan način korištenjem čvrstih ili tekućih prijenosnih sredstava, otapala i aditiva koji su odgovarajući za željeni način davanja. Oralno, spojevi se mogu davati u formi tableta, kapsula, granula, praška i slično. Spojevi se također mogu davati kao suspenzije, korištenjem nosača koji su odgovarajući za ovaj način davanja. Ovi spojevi se mogu davati u dozama koje se kreću u rasponu od oko 0.05 do 800 mg/kg na dan, preferirano manje od 500 mg/kg na dan, u pojedinačnoj dozi ili u 2 do 4 podijeljene doze.
Biološke probe
VEGFR-2 i FGFR-1 kinaza analize:
Reagensi Konačna koncentracija
Standardna otopina VEGFR-2 FGFR-1
Tris pH 7.0 20 mM 20 mM
BSA10 mg/ml 25 µg/ml 25 µg/ml
MnCl2 (1M) 1.5 mM 0.5 mM
MgCl2 (1M) ---- 0.5 mM
DTT(IM) 0.5 mM 0.5 mM
Otopina enzima u 10%
glicerola (1 mg/ml) 7.5 ng/rxn 30 ng/rxn
Poli glu/tyr (10 mg/ml) 75 µg/ml 30 µg/ml
ATP(lmM) 2.5 µM 1.0 µM
γ-ATP (10µCi/µl) 0.5 µCi/ml 0.5 µCi/ml
Inkubaciona smjesa koja je korištena za VEGFR-2 ili FGFR-1 analizu sadrži sintetički supstrat poli glu/tir, (4:1), ATP, ATP-y-33P i pufer koji sadrži Mn++ i/ili Mg++, DTT, BSA, i Tris pufer. Reakcija se započinje dodavanjem enzima i nakon 60 minuta na sobnoj temperaturi prekida se dodavanjem 30% TCA do konačne koncentraciji od 15% TCA. Inhibitori se dovode do lOmM u 100% DMSO. Analize se pripremaju u formatu 96 jažica četvorostruko. Spojevi se razrjeđuju u odnosu 1:500 u 100% DMSO a zatim 1:10 u vodi za konačnu DMSO koncentraciju od 10%. 10 µL se dodaju redovima B-H u formatu 96 jažica od 10% DMSO. 20 µl spoja se dodaje redu A u koncentraciji 5 puta većoj od tekućih uvjeta. Deset µL se prenosi na svaki red, zatim slijede šest serijskih razrjeđivanja sa miješanjem, i u redu F odbacuje se 10 µL. Red G je kontrolni bez spoja a red H je kontrolni bez spoja i bez enzima. Enzim i supstrat se isporučuju korištenjem Tomtec Quadra stanice.
Pločice se pokrivaju ljepljivim poklopcima, inkubiraju na 27°C 60 minuta, a zatim se kiselina taloži sa TCA 20 minuta na ledu. Talog se prenosi na UniFilter-96, GF/C mikropločice korištenjem ili Tomtec ili Packard FilterMate skupljača. Aktivnost se određuje kvantitativnim određivanjem ugrađene radioaktivnosti pomoću Packard TopCount Microplate scintilacijskog brojača nako čega slijedi dodavanje Microscint-20 mješavine u svaku osušenu jažicu na UniFilter mikropločicama.
Instantni spojevi inhibiraju VEGFR-2 i FGFR-1 kinaze sa IC50 vrijednostima između 0.001 do 10 µM. Preferirani spojevi imaju IC50 vrijednosti manje od 0.3 µM naprama VEGFR-2.
Ovi spojevi su selektivni prema VEGFR-2 i FGFR-1 kinaza enzimima. Oni pokazuju minimum aktivnosti u odnosu na HER-2, CDK kinaze, LCK i Src kinaze.
Metode pripreme
Izvjesni spojevi formule I mogu se pripremiti prema sljedećim shemama i iskustvima stručnjaka u području.
Sve temperature su u stupnjevima Celzijusa (°C) ukoliko nije drugačije naznačeno.
Pročišćavanja preparativnom reverznom fazom (RP) HPLC provedena su na: Premisphere C-18-HC 21 x 100 mm kolona sa sistemom otapala (1) ili (2). Sistem otapala (1): Otapalo A: 10% acetonitril-90% voda + 5mM NH4OAc; Otapalo B: 90% acetonitril-10% voda + 5mM NH4OAc. Sistem otapala (2): Otapalo A: 10% acetonitril-90% voda + 0.05% TFA; Otapalo B: 90% acetonitril-10% voda + 0.05% TFA. Gradijent je od 20% B do 100% B. Za LC/MS uvjeti koji su korišteni su bili sistem otapala (1) ili (2), sa gradijentom od 0% B do 100% B u 2 minuta. Kolona: Premisphere C18-HC 4.6 x 30 mm, na 220 nM. Brzina protoka = 4 mL/min).
Za analitičku HPLC uvjeti koji su korišteni su bili (Otapalo A: 10% acetonitril-90% voda + 5mM NH4OAc; otapalo B: 90% acetonitril-10% voda + 5mM NH4OAc, sa gradijentom od 0% B do 100% B u 30 minuta. Kolona YMC ODS-A CIS, 6.0 X 150 mm, na 220 nM. Brzine protoka = 4 mL/min.). Svi sintetizirani spojevi su bili okarakterizirani najmanje pomoću protonske NMR i LC/MS (Micromass ZMD 2000, ESI). Za vrijeme razrađivanja reakcije, organski ekstrakti su osušeni iznad bezvodnog natrij sulfata (Na2SO4), ukoliko nije drugačije naznačeno.
Sljedeće kratice se koriste za uobičajeno korištene reagense. NMM; N-metilmorfolin, DIBAL; diizobutilaluminij hidrid, BOP reagens; benzotriazol-1-iloksi-tris(trimetilamino)fosfonij heksafluorfosfat , DCE; dikloretan, K2CO3; kalij karbonat, KOH; kalij hidroksid, DCC; dicikloheksil karbodiimid, EDCI; l-(dimetilaminopropil)-3-etilkarbodiimid hidroklorid, RT; sobna temperatura, HOBt; hidroksibenzotriazol, DCM; diklormetan, CbzCl; klorbenzoil klorid, mCPBA; meta-klorperbenzojeva kiselina, NaHCO3; natrij bikarbonat, HCl; kloridna kiselina, TFA; trifluoroctena kiselina, NH4C1; amonij klorid, DIPEA; diizopropilamin, Et3N; trietilamin. Na2SO4 natrij sulfat, DEAD; dietil azodikarboksilat, DPPA; difenilfosforilazid, DMF; dimetil formamid, THF; tetrahidrofuran, DBU; 1,8-diazabiciklo[5.4.0]undec-7-en, RT; sobna temperatura, min; minuti, h; sati
Shema 1
[image]
L = halogen
Korak 1
Ovaj korak se postiže reakcijom dva ekvivalenta opciono supstituiranog aldehida (1) kao što je izobutiraldehid s alkil izocijanatom u prisustvu blage baze kao što je DBU da bi se dobio spoj 3.
Korak 2
Produkt 3 iz ove sheme reagira sa jednim aminirajućim resredstvom, kao što je hidroksilamin-O-sulfonska kiselina ili O-2,4-dinitrofenilhidroksamat u prisustvu baze kao što je KOH ili natrij hidrid da nastane spoj 4.
Korak 3
Spoj 4 iz ove sheme je je cikliziran tretmanom sa formamidom u prisusutvu baze kao što je natrij metoksid u MeOH uz zagrijavanje da bi se dobio spoj 5.
Korak 4
Spoj 5 iz ove sheme je je halogeniran, na primjer fosfornim oksikloridom pri povećanoj temperaturi, da bi se dobio spoj 6.
Korak 5
Spoj 6 reagira s aminom kao što je anilin ili sa fenolom u organskom otapalu, kao što je acetonitril ili DMF, da bi se dobio spoj 7.
Shema 2
[image]
X1 = Cl, SMe, SO2Me
R=niži alkil
Korak 1
Pirolotriazin ester se može tretirati sa N-hidroksiacetamidinom da se dobije spoj 1.
Korak 2
Spoj 2 iz ove sheme može se tretirati halogenirajućim sredstvom kao što je fosfor oksiklorid, da se dobike intermedijer klorimidat.
Korak 3
Gore dobijeni klorimidat se dalje može tretirati odgovarajućim anilinom ili fenolom da se dobije spoj 3 iz ove sheme kao što je opisano u shemi 1.
[image]
[image]
Shema 3
G = supstituirani metil ili metilen ili supstituirani dušik ili supstituirani sumpor itd.
Korak 1
Pirolotriazin ester se tretira hidrazin hidratom da se dobije spoj 1.
Korak 2
Spoj 1 se može pretvoriti u spoj 2 kao što je opisano u shemi 1.
Shema 4
[image]
X = 0,N3,NH2
R = zaštitna grupa amina
P = Zaštitna grupa
Korak l
Ova faza se završava reakcijom 4-klor-7-azaindola s aminom kao što je alil amin, u prisustvu katalizatora kao što je paladij (0), čemu slijedi uklanjanje zaštite anilina, da se dobije spoj 1 gdje je R proton.
Korak 2
Spoj 1 ove sheme reagira sa natrij nitritom da bi se dobila diazonijeva sol koja se može ukloniti pomoću fluora da nastane spoj 2.
Korak 3
Spoj 3 ove sheme se zatim zaštiti, na primjer silil zaštitnom grupom da nastane spoj 3 sheme 4.
Korak 4
Spoj 3 ove sheme se obradi litijem, na primjer, sa sek-butil litijem na niskoj temperaturi, slijedi obrađivanje elektrofilom, kao što je azid ili oksiran, da nastane spoj 4 iz sheme 4. Pri korištenju azida spoj se dalje može obraditi paladijem na ugljiku u prisustvu vodika da se dobije anilin.
Korak 5
Sa spoja 4 se uklanja zaštita da nastane spoj 5 iz sheme 4.
Shema 5
[image]
X=0, N3, NH2
P = Zaštitna grupa
Korak l
Ovaj korak je postignut reakcijom 7-azaindol-N-oksida sa bromirajućim sredstvom, kao što je tetrametilamonij bromid, u prisustvu anhidrida metansulfonske kiseline, da se dobije spoj 1.
Korak 2
Spoj 1 iz ove sheme se zaštićuje zaštitnom grupom kao što je triizopropil silan da se dobije spoj 2 iz ove sheme.
Korak 3
Spoj 2 iz ove sheme je zatim obrađen litijem izmjenom halogena nakon čega slijedi obrada fluorirajućim sredstvom kao što je N-fluorbenzensulfonimid da se dobije spoj 3 iz sheme 5.
Korak 4
Spoj 3 iz ove sheme može se dalje pretvoriti u spoj 4 kao što je opisano u shemi 4.
Shema 6
[image]
Korak l
Ovaj korak se postiže djelovanjem litija na položaju 5 u 4-klor-7-azaindolu sa, na primjer, sek-butil litijem na niskoj temperaturi, što je praćeno prekidanjem pomoću azida, kao što je 4-azido toluen, da se dobije spoj 1.
Korak 2
Spoj 1 iz ove sheme se reducira sa vodikom uz prisustvo paladijevog katalizatora, preferirano paladija na ugljiku, da se dobije spoj 2 iz ove sheme.
Korak 3
Spoj 2 iz ove sheme se može dalje reducirati dehalogenirajućim sredstvom, kao što je cink u prahu, u prisustvu acetatne kiseline da se dobije spoj 3 iz ove sheme.
Shema 7
[image]
Korak l
4-fluor-7-azaindol se štiti odgovarajućom zaštitnom grupom kao što je fenil sulfonamid da bi se dobio spoj 1 sheme 7.
Korak 2
Spoj 1 ove sheme se obrađuje litijem, na primjer sa n-butil litijem na niskoj temperaturi, čemu slijedi obrada elektrofilom, kao što je jodmetan, da se dobije spoj 2 sheme 7.
Korak 3
Sa spoja 2 ove sheme se zatim ukloni zaštita reagensom kao što je tetrabutilamonij fluorid da se dobije spoj 3 sheme 7.
Korak 4
Spoj 3 ove sheme može biti pretvoren u spoj 4 kao što je prethodno opisano.
Dodatno, drugi spojevi formule I mogu biti pripremljeni korištenjem procedura opće poznatih stručnjacima u području. Posebno, primjeri koji slijede pružaju dodatne metode za pripremu spojeva ovog izuma.
Izum će sada biti dalje opisan pomoću radnih primjera koji slijede, a koji su preferirane izvedbe izuma. Ovi primjeri su više ilustrativni nego ograničavajući i treba razumjeti da mogu postojati druge izvedbe u koja se uklapaju u princip i opseg izuma kao što je definirano u pridruženim patentnim zahtjevima.
Primjer 1
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Etil ester 5-etil-4-(1H-pirolo[2,3-b]piridin-5-iloksi)-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline
Na 0°C natrij hidrid (14 mg, 0.36 mmol, 60% u ulju) se dodaje otopini 5-hidroksi-7-azaindola (48 mg, 0.36 mmol) u DMF (1.5 mL) 4-klor-5-metilpirolo[2,1-f][1,2,4]triazin-6-karboksilna kiselina etil ester (76 mg, 0.32 mmol, WO 0071129) se dodaje i smjesa miješa na RT 16 h, prekida sa zasićenom otopinom amonij klorida (20 mL) i ekstrahira etil acetatom (3 x 25 mL). Kombinirani organski slojevi se isperu slanom vodom (50 mL), suše, filtriraju i koncentriraju. Ostatak se pročišćava preparativnom HPLC (Retenciono vrijeme = 7.12 min). 1H NMR (400 MHz, CDC13) δ 8.10(1H, s), 7.91 (1H, br. s), 7.82 (1H, s), 7.31 (1H, s), 6.85 (1H, br. s) 4.31 (2H, q, J = 7.3 Hz), 2.79 (3H, s), 1.33 (3H, t, J = 7.3 Hz), m/z 338 (M+H)+, 379 (M + AcCN)+.
Indolni intermedijer, 5-hidroksi-7-azaindol, se priprema kao što slijedi.
[image]
Pod argonom u boci pokrivenoj aluminijskom folijom otopina 5-metoksi-7-azaindola (60 mg, 0.4 mmol, za pripremu vidjeti Heterocyd.es 1999, 50(2), 1065-1080) u diklormetanu je dodana otopini bor tribromida (890 µL, 1M) u diklormetanu na 78°C. Smjesa je ostavljena da se zagrije na RT i miješana dodatna 2 h. 10% otopina natrij bikarbonata se zatim dodaje i izdvojeni vodeni sloj se ekstrahira diklormetanom (3 x 25 mL). Kombinirani organski slojevi se isperu sa slanom vodom (30 mL), suše, filtriraju i koncentriraju da se dobije 50 mg ulja koje se direktno koristi bez daljeg pročišćavanja, m/z 135 (M+H)+.
Primjer 2
[image]
5-Metil-4-(2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-pirolo[2,1-f][1,2,4]triazin-6-karboksilna kiselina etil ester
Gore opisana procedura pripreme primjera 1 se primjenjuje korištenjem intermedijera 5-hidroksi-2-metil-7-azaindola. 1H NMR (400 MHz, CDC13) δ 1.87 (1H, br. s), 8.09 (1H, s), 8.06 (1H, br. s), 7.82 (1H, s), 7.60 (1H, br. s), 6.14 (1H, br. s), 4.31 (2H, q, J = 7.0 Hz), 2.79 (3H, s), 2.43 (3H, s), 1.33 (3H, t, J = 7.0 Hz). LC/MS ; (M+H)+ = 352, (M + AcCN)= 393.
Intermedijer, 5-hidroksi-2-metil-7-azaindol se priprema kako slijedi.
[image]
A. Otopini 5-metoksi-7-azaindola (240 mg, 1.62 mmol) u THF(10 mL) se dodaje 60% suspenzija natrij hidrida u ulju (71 mg, 1.78 mmol) na RT pod argonom. Smjesa se miješa na RT 5 minuta i dodaje se fenilsulfonil klorid (250 fiL, 1.95 mmol) i smjesa se miješa 16 h, prekida zasićenom otopinom amonij klorida (20 mL) i ekstrahira etil acetatom (3 x 25 mL). Kombinirani organski slojevi se isperu slanom vodom (50 mL), suše, filtriraju i koncentriraju. Ostatak se pročišćava “flash” kromatografijom (1% MeOH u diklormetanu + 0.5% trietilamina) da se dobije N-fenilsulfonil-5-metoksi-7-azaindol (325 mg, 70%) u čvrstom obliku. 1H NMR (400 MHz, CDC13) δ 8.12 (3H, m), 7.65 (1H, dd, J = 3.8), 7.54 (1H, m), 7.45 (2H, m), 7.28 (1H, d, J = 2.8 Hz), 6.51 (1H, d, J = 3.8 Hz), 3.82 (3H, s). (M+H) + = 289.
B. Otopina (2.7M) n-butilitija u heksanu (0.48 mL, 1.30 mmol) se dodaje otopini N-fenilsulfonil-5-metoksi-7-azaindola (220 mg, 0.76mmol) u THF (7.0 mL) na -78°C pod argonom. Nastala otopina se miješa na -78°C 1 h i dodaje se metil jodid (120 µL, 1.91 mmol). Nastala smjesa se miješa na -78°C 2 h, reakcija prekida zasićenom otopinom amonij klorida (20mL) i ekstrahira etil acetatom (3 x 25 mL). Kombinirani organski slojevi se isperu sa slanom vodom (50 mL), suše, filtriraju i koncentriraju. Ostatak se pročišćava “flash” kromatografijom (1% MeOH u diklormetanu + 0.1% trietilamina) da se dobije (170 mg, 73%) (5:1) smjese N-fenilsulfonil-5-metoksi-2-metil-7-azaindola, m/z 303 (M+H+), analitička HPLC retenciono vrijeme = 1.83 min i N-tolilsulfonil-5-metoksi-2-metil-7-azaindola, m/z 317, retenciono vrijeme = 1.97 min.
C. Otopini gornje smjese spojeva u smjesi (3:1) THF-metanol (4 mL) se dodaje 10% otopina natrij hidroksida u vodi (3 mL) na sobnoj temperaturi.
Smjesa se zagrijava na 65°C 1 h, hladi na sobnu temperaturu, neutralizira do pH 7 zasićenom otopinom amonij klorida i ekstrahira etil acetatom (3x 15 mL). Kombinirani organski slojevi se isperu slanom vodom (50 mL), suše (Na2SO4), filtriraju i koncentriraju. Ostatak se pročišćava “flash” kromatografijom na koloni sa silikagelom (1% MeOH u diklormetanu + 0.1% trietilamina) da se dobije 5-metoksi-2-metil-7-azaindol (35 mg, 66%). (M+H)+= 163.
D. Gore opisana procedura pripreme hidroksiindola iz metoksiindola u primjeru 1 se primjenjuje na 5-metoksi-2-metil-7-azaindol (35 mg, 0.2 mmol) da se dobije 5-hidroksi-2-metil-7-azaindol (32 nig, 100%) koji se direktno koristi bez daljeg pročišćavanja. LC/MS; (M+H)+ = 135.
Primjer 3
[image]
6-Benziloksi-5-metil-4-(2-metil-1H-pirolo [2,3b]piridin-5-iloksi)-pirolo [2,1-f][1,2,4]triazin
5-Hidroksi-2-metil-7-azaindol se obrađuje 6-benziloksi-4-klor-5-metil-pirolo[2,1-f][1,2,4]triazinom (vidjeti WO 0071129) metodom sličnom pripremi iz primjera 1. 1H NMR (400 MHz, DMSO-d6) δ 8.02 (1H, br. s), 7.85 (1H, s), 7.83 (1H, s), 7.70 (1H, br. s), 7.41 (6H, m), 6.15 (1H, br. s), 5.12 (2H, s), 2.92 (3H, s), 2.42 (3H, s). m/z 386 (M+H)+, 427 (M+ + AcCN).
Primjer 4
[image]
6-Benziloksi-4-(4-fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metiI-pirolo[2,1-f][1,2,4]triazin
Otopini 4-fluor-1H-pirolo[2,3-b]piridin-5-ola (53.5 mg, 0.35 mmol) u DMF (2 mL) na -78°C dodaje se natrij hidrid (60 % u ulju, 14 mg, 0.35 mmol) i smjesa se zagrijava na 0°C. Nakon 30 minuta tikvica se hladi na -78°C, dodaje se 6-benziloksi-4-klor-5-metil-pirolo[2,1-f][1,2,4]triazin (80 mg, 0.29 mmol) i smjesa se ostavlja da dostigne RT 30 min. Otopina zasićenog amonij klorida se dodaje, otopina se ekstrahira etil acetatom (3X15 mL), kombinirani organski slojevi se isperu sa vodom (30 mL), slanom vodom (30 mL), suše, i koncentriraju u vakuumu. Sirovi materijal se pročišćava trituracijom s acetonitrilom da se dobije naslovni spoj (90 mg, 80 %) u obliku prljavo-bijele krutine. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.30 (1H, d, J = 9.6 Hz), 8.00 (1H, s), 7.94 (1H, s), 7.61 (1H, t, J = 3.0 Hz), 7.49 (2H, d, J = 7.1 Hz), 7.41 (2H, t, J = 7.1 Hz), 7.34 (1H, t, J = 7.3 Hz), 6.59 (1H, dd, J = 2.0, 3.5 Hz), 5.16 (2H, s), 2.43 (3H, s). LC/MS ; (M+H)+ = m/z 390.
Intermedijer, 4-fluor-1H-pirolo[2,3-b]piridin-5-ol, se priprema kao što slijedi.
[image]
A. Praćena je procedura opisana u J. Org. Chem., 2000, 65, 1158-1174. Tikvica od 350 mL osušena u sušioniku, zatvorena gumenom dijafragmom, je ispražnjena i napunjena argonom. Tikvica je napunjena 4-klor-1H-pirolo[2,3-b]piridinom [20 g, 131 mmol, za pripremu vidjeti Benoit, S.; Gingras, S. Processes for the preparation of antiviral 7-azaindole derivatives. U.S. Provisional Patent 60/367,401, 2003], natrij terc-butoksidom (35.2 g, 367 mmol), Pd(OAc)2 (589 mg, 2.62 mmol), (o-bifenil)PCy2 (1.83 g, 5.24 mmol) i isisan je zrak te je napunjena argonom. Dodaju se 1,4-dioksan (0.25 L) i N-alilamin (29 mL, 393 mmol) i argon je propuštan kroz smjesu 20 minuta. Dijafragma se zamjenjuje Teflon poklopcem sa zavrtnjem, tikvica se zatvara i smjesa grije na 100°C 16 h. Smjesa se hladi na sobnu temperaturu, razblažuje sa eterom (0.5 L), filtrira kroz Celite i koncentrira u vakuumu. Rezultirajuce ulje se otopi u diklormetanu (0.25 L), dva puta ispere sa vodom , suši, filtrira i koncentrira u vakuumu da se dobije alil-(1H-pirolo[2,3-b]piridin-4-il)-amin u obliku smeđe gume. 1H NMR (400 MHz, DMSO-d6) δ 11.10 (1H, br. s), 7.78 (1H, d, J = 5.3 Hz), 7.03 (1H, s), 6.73 (1H, t, J = 5.8 Hz), 6.53 (1H, d, J = 2.5 Hz), 6.04 (1H, t, J = 5.5 Hz), 5.96-5.87 (1H, m), 5.22 (1H, ddd, J = 1.8, 3.4,17.2 Hz), 5.11 (1H, ddd, J = 0.7,1.8,10.4 Hz), 3.86 (2H, m). LC/MS : m/z 174 (M+H)+.
B. Koristi se procedura opisana u Tetrahedron Letters, 1998,39,1313-1316. Okrugla tikvica od 0.5L osušena u sušioniku i opremljena hladilom se evakuira i napuni argonom. Tikvica se puni sa alil-(1H-pirolo[2,3-b]piridin-4-il)-aminom (22.69 g, 131 mmol), etanolom (262 mL), 10 % paladijem na ugljiku (15 g) i metansulfonskom kiselinom (8.5 mL, 131 mmol). Smjesa se zagrijava na 105°C 72 h. Smjesa se hladi na sobnu temperaturu, filtrira kroz Celite i koncentrira u vakuumu. Rezultirajuće ulje se pomoću SCX-silika kolone (300 g)uz eluiranje metanolom (3 X 500 mL) praćeno otopinom 2M amonijaka u metanolu (3 X 500 mL) da se dobije 1H-pirolo[2,3-b]piridin-4-ilamin (13.15 g, 75 % kroz dva koraka) u obliku žutog ulja. 1H NMR (400 MHz, DMSO-d6) δ 11.02 (1H, br. s), 7.69 (1H, d, J = 5.3 Hz), 7.01 (1H, d, J = 3.3 Hz), 6.46 (1H, d, J = 3.3 Hz), 6.10 (1H, d, J = 5.3 Hz), 6.07 (2H, s). LC/MS m/z 134 (M+H) +
C. lH-Pirolo[2,3-b]piridin-4-ilamin (10.3 g, 77 mmol) se otapa u 48 tež.% otopinu tetrafluorborne kiseline u vodi (155 mL). Smjesa se hladi na 0°C i u kapima se dodaje natrij nitrit (5.87 g, 85.1 mmol) u vodi (15 mL). Smjesa se ostavljena da dostigne RT i miješana 22 h. Etil acetat se dodaje (500 mL), smjesa se hladi na 0°C, neutralizira čvrstim natrij vodik karbonatom i slojevi se razdvajaju. Vodeni sloj se ekstrahira sa etil acetatom (2 x 300mL), organski slojevi se kombiniraju i koncentriraju u vakuumu. Nastala krutina se triturira sa 250 mL etil acetata, filtrira i filtrat se ispere 1N otopinom natrij hidroksida (2 X 200 mL). Organski slojevi se suše, filtriraju i koncentriraju u vakuumu da se dobije 4-fluor-1H-pirolo[2,3-b]piridin (4.67 g, 44 %) u obliku čvrste smeđe mase. 1H NMR (400 MHz, DMSO-d6) δ 12.00 (1H, br. s), 8.20 (1H, dd, J = 5.3, 8.4 Hz), 7.51 (1H, t, J = 3.1 Hz), 6.94 (1H, dd, J =5.3,10.4 Hz), 6.51 (1H, dd, J = 2.1, 3.6 Hz), 6.07 (2H, s). LCMS': m/z 134 (M+H)+.
D. 4-Fluor-1H-pirolo[2,3-b]piridin (2 g, 14.7 mmol) je otopljen u THF (50 mL) i dodan je u malim porcijama natrij hidrid (60 % u ulju, 881 mg, 22.0 mmol). Poslije 30 minuta, dodan je klorotriizopropilsilan (4.71 mL, 22.0 mmol ) i miješano je na 65°C 16 h. Dodan je etil acetat (100 mL), smjesa je rashlađena na 0°C, neutralizirana zasićenom otopinom amonij klorida i slojevi su odvojeni. Vodeni sloj je dva puta ekstrahiran etil acetatom (2 x l00 mL) i kombinirani su organski slojevi, isprani vodom (150 mL), slanom vodom (150 mL), osušeni i koncentrirani u vakuumu. Sirovi materijal je pročišćen “flash” kromatografijom eluiranjem sa 1 % etil acetatom u heksanu da bi se dobio 4-fluor-1-triizopropilsilanil-1H-pirolo [2,3-b] piridin (2.16 g, 50 %) kao bezbojno ulje.
1H NMR (400 MHz, DMSO-d6) δ 8.22 (1H, dd, J = 5.6, 8.3 Hz), 7.51 (1H, d, J = 3.6 Hz), 6.98 (1H, dd, J = 4.1, 10.1 Hz), 6.69 (1H, d, J = 3.5 Hz), 1.86 (3H, m), 1.06 (9H, s), 1.04 (9H, s). LC/MS: m/z 293 (M+H)+.
E. Procedura opisana u J. Med. Chem., 1997,40,2674 je modificirana.
4-Fluor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin (213 mg, 0.73 mmol) je otopljen u THF (4.9 mL) i smjesa je rashlađena do -78°C. Ukapavana je otopina Sek-Butillitija (1.10 M u THF, 1.46 mL, 1.61 mmol) i nakon 30 minuta brzo je dodan (R)-kamforsulfonil oksaziridin (418 mg, 1.82 mmol) u tetrahidrofuranu (2.5 mL). Posle 25 min dodana je zasićena otopina amonij klorida i smjesa je puštena da dostigne sobnu temperaturu. Otopina je ekstrahirana etil acetatom (3 x 15 mL) i kombinirani organski slojevi su isprani sa vodom (30 mL), slanom vodom (30 mL), osušeni i koncentrirani u vakuumu. Sirovi materijal je pročišćen pomoću “flash” kromatografije eluiranjem smjesom 5 % etil acetata u toluenu da bi se dobio traženi produkt. LC/MS: m/z 309 (M+H)+.
Dodani su 4-fluor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ol (207 mg, 0.67 mmol), THF (3.4 mL) i otopina tetrabutilamonij fluorida (1.0 M u THF, 1.01 mL, 1.01 mmol) i smjesa je miješana 90 min. Dodana je otopina zasićenog amonij klorida i smjesa je ekstrahirana etil acetatom (3 X 15 mL), kombinirani organski slojevi su isprani sa vodom (30 mL), slanom vodom (30 mL), osušeni, i koncentrirani u vakuumu. Sirovi materijal je pročišćen pomoću “flash” kromatografije eluiranjem smjesom od 1 % NH4OH: 7 % metanola: 92 % diklormetana da bi se dobio 4-fluor-1H-pirolo[2,3-b]piridin-5-ol (60 mg, 59 %) kao svijetlo žut a krutina. 1H NMR (400 MHz, DMSO-d6) δ 11.62 (1H, s), 9.34 (1H, s), 7.95 (1H, d, J = 10.3 Hz), 7.39 (1H, d, J = 2.8 Hz), 6.38 (1H, dd, J = 2.0,3.2 Hz). LC/MS: m/z l53(M+H)+.
Primjer 5
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4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazin-6-ol
U otopinu primjera 4 (84 mg, 0.22 mmol) u DMF (1.1 mL), dodani su 10 % Pd u drvenom ugljenu (10 mg) i amonij formijat (68 mg, 1.08 mmol). Smjesa je miješana na sobnoj temperaturi 20 h, zatim je filtrirana kroz Celite i koncentrirana u u vakuumu. Nastala krutina je otopljena u metanolu i pročišćena pomoću SCX-silika kolone (18 g) ispiranjem pomoću metanola (2 x 8 mL) i zatim eluiranjem 2M otopinom amonijaka u metanolu (2x8 mL) da bi se dobio nazivni spoj (60 mg, 93 %) u obliku čvrste bež mase. 1H NMR (400 MHz, DMSO-d6) δ 12.16 (1H, s), 9.53 (1H, s), 8.29 (1H, d, J = 9.6 Hz), 7.88 (1H, s), 7.61 (1H, t, J = 3.0 Hz), 7.55 (1H, s), 6.59 (1H, dd, J = 2.0, 3.5 Hz), 2.40 (3H, s). LC/MS = m/z 300 (M+H)+.
Primjer 6
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(R)-1-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin -6-iloksi] propan-2-ol
U sušioniku osušena zapečaćena epruveta, napunjena je sa 4-(4-fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-fj[1,2,4]triazin-6-olom (Primjer 5) (7.5 mg, 0.025 mmol), t-BuOH (0.25 mL), 0.5M otopinom trietilamina u t-BuOH (5 µL, 0.0025 mmol) i R-(+)-propilen oksidom (21 µL, 0.300 mmol). Epruveta je zapečaćena i smjesa je miješana na 80°C 1 h. Reakciona smjesa je rashlađena i koncentrirana u vakuumu. Sirovi materijal je pročišćen preparativnom HPLC da se dobije nazivni spoj (5 mg, 56 %) u obliku prljavo-bijele krutine. 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J= 9.6 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.61 (1H, t, J = 3.0 Hz), 6.59 (1H, dd, J = 1.9, 3.4 Hz), 4.91 (1H, d, J = 4.8 Hz), 4.02-3.94 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J = 6.3 Hz). LC/MS: (M+H)+ = 358, (M-H)- = 356.
Primjer 7
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(S)-1-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazin-6-iloksi]-propan-2-ol
A. Epruveta od 150 mL se puni sa 5-metil-4-fenoksi-pirolo[2,1-f][1,2,4]triazin-6-olom (5.93 g, 24.6 mmol), THF (2 mL) i natrij metantiolom (5.17 mg, 73.7 mmol). Epruveta je zapečaćena i smjesa je zagrijavana na 80°C 4 h. Smjesa je rashlađena do sobne temperature, dodana je voda (100 mL) i otopina je ekstrahirana etil acetatom (3 X 100 mL). Kombinirani organski slojevi su isprani vodom (200 mL), vodenom otopinom natrij hidroksida (2 x 200 mL), slanom vodom (200 mL), osušeni i koncentrirani u vakuumu da se dobije (3.2 g, 67 %) 5-metil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin-6-ola u obliku bež krutine. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (1H, s), 8.11 (1H, s), 7.39 (1H, s), 2.58 (3H, s), 2.34 (1H, s). m/z 196 (M+H+).
B. Epruveta od 10 mL napunjena je 5-metil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin-6-olom (75 mg, 0.38 mmol), terc-butilalkoholom (2 mL), (S)-propilen oksidom (0.134 mL, 1.92 mmol) i trietilaminom (5 µL, 0.04 mmol). Epruveta je zapečaćena i smjesa se zagrijava na 80°C 17 h. Smjesa se hladi na RT i koncentrira u vakuumu. Sirovi materijal se pročišćava pomoću “flash” kromatografije eluiranjem smjesom od 50 % etil acetata u heksanu da se dobije (56 mg, 58 %) (S)-1-(5-metil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin-6-iloksi)-propan-2-ol u obliku bijele krutine. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (1H, s), 7.78 (1H, s), 4.88 (1H, m), 3.95 (m, 1H), 3.82 (2H, m), 2.59 (3H, s), 2.36 (3H, s), 1.13 (3H, d, J = 6.3 Hz), m/z 254 (M+H+).
C. U otopinu (S)-5-metil-4-metilsulfanil-pirolo[2,1-f][1,2,4]triazin-6- ola (20 mg, 0.08 mmol) u kloroformu (1.0 mL) na 0°C, dodaje se otopina peroctene kiseline u octenoj kiselini (51 µL, 0.24 mmol, 32 tež.% otopina). Smjesa je puštena da dostigne RT i miješana dodatnih 2.0 h. Dodaje se zasićena otopina amonij klorida i slojevi se razdvajaju. Vodeni sloj se ekstrahira sa etil acetatom (2 X 50 mL), organski slojevi se kombiniraju, ispiru vodom (100 mL), slanom vodom (100 mL), suše i koncentriraju u vakuumu. Rezultirajući sulfon je korišten bez daljeg pročišćavanja.
D. Na -78°C, natrij hidrid (60% u ulju, 1 mg, 0.08 mmol) se dodaje otopini 4-fluor-1H-pirolo[2,3-b]piridin-5-ola (13 mg, 0.09 mmol, vidi primjer 4) u dimetil formamidu (1 mL). Smjesa se miješa na 0°C 30 min. i ponovo hladi na -78°C. Zatim se dodaje (S)-1-(4-metansulfonil-5-metilpirolo[2,1-f][1,2,4] triazin-6-iloksi)-propan-2-ol (22 mg, 0.08 mmol) i smjesa se miješa na RT 2h, reakcijsa prekida zasićenom otopinom amonij klorida (20mL) i ekstrahira etilacetatom (3 x 25 mL). Kombinirani organski slojevi su isprani slanom vodom (50 mL), sušeni (MgSO4), filtrirani i upareni. Ostatak se pročišćava preparativnom HPLC da se dobije (10 mg, 36%) naslovnog spoja. 1H NMR (400MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J = 9.3 Hz), 7.95 (1H, s), 7.93 (1H, s), 7.61 (1H, t, J = 3.1 Hz), 6.59 (1H, dd, J = 1.98,3.3 Hz),, 4.01-3.97 (1H, m), 3.92-3.83 (2H, m), 2.42 (3H, s), 1.16 (3H, d, J = 6.3 Hz), m/z 358 (M+H+).
Azaindolni intermedijer 4-Fluor-1H-pirolo[2,3-b]piridin-5-ol se priprema kao što slijedi.
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E. lH-Pirolo[2,3-b]piridin-7-oksid (50 g, 1 ekv.) i tetrametilamonij bromid (86 g, 1.5 ekv.) su postavljeni u DMF (500 mL). Smjesa se hladi na 0°C i u malim porcijama se dodaje anhidrid metansulfonske kiseline (130 g, 2 ekv.) . Pušta se da suspenzija dostigne 23°C i miješa se 4 h. Smjesa se sipa u vodu (1L) i otopina se neutralizira 50 %-tnim vodenom otopinom natrij hidroksida (pH = 7). Voda (2L) se dodaje i smjesa se hladi na 10°C 30 min.Formirani talog se filtrira i ispira hladnom vodom (1L). Talog se otapa u smjesi diklormetan / metanol (4:1), suši preko MgSO4, koncentrira u vakuumu da bi se dobio 4-brom-1H-pirolo[2,3-b] piridin (40 g, 54%). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (1H, br. s), 8.08 (1H, d, J = 5.3 Hz), 7.59 (1H,m), 7.33 (1H, d, J = 5.05 Hz), 6.41 (1H, d, J = 3.5 Hz). LC/MS ; m/z 197 (M+H)+.
F. Tikvica od 500-mL osušena u sušioniku, zatvorena gumenom dijafragmom se evakuira i ponovo puni argonom. Tikvica je napunjena 4-brom-1H-pirolo[2,3- b] piridinom (40 g, 1 ekv.) u THF (400mL). Smjesa je rashlađena do 0°C i u malim porcijama se dodaje natrij hidrid (60% u ulju, ispran heksanom, 8.9 g, 1 ekv.). Nakon 15 min, dodan je klor-triizopropilsilan (443.4 mL, 1 ekv.) ,epruveta ie zapečaćena i miješana na 80 0 u trajanju od 3 h. Reakciona smjesa je rashlađena, neutralizirana sa zasićenom otopinom amonij klorida (50 mL) i dva puta ekstrahirana heksanima (2 x 8OOmL). Kombinirani organski slojevi su osušeni, i koncentrirani u vakumu da se dobije 4-bromo-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin (71.1 g, 99%). 1NMR (400 MHz, DMSO-d6) δ 8.09 (1H, d, J = 5.1 Hz), 7.60 (1H, d, J = 3.5 Hz), 7.37 (1H, d, J = 5.3 Hz), 6.59 (1H, d, J = 3.5 Hz), 1.85 (3H, septu. J = 7.6 Hz), 1.04 (9H, d, J = 7.6 Hz). LC/MS ; m/z 353 (M+H+).
G. Tikvica od 250 mL osušena u sušioniku, okrugog dna se isiše i ponovo puni argonom. Tikvica se puni sa 4-bromo-1-triizopropilsilanil-1H-pirolo[2,3-b]piridinom (1.4 g, 1 ekv.), THF (25 mL) i smjesa je rashlađena do -78°C. Terc-butillitij (1.7 M u pentanu, 4.66 mL, 2ekv.) se ukapava i poslije 5 minuta, dodaje se N-fluorobenzensulfonimid (1.25 g, 1 ekv.).Posle 45 min, dodaje se zasićena otopina amonij klorida (20 mL) i smjesa se ostavlja da se zagrijava da dostigne sobnu temperaturu. Dodana je voda (40 mL) i otopina je ekstrahirana heksanima (3 X 100 mL), kombinirani organski slojevi su isprani sa vodom, osušeni preko MgSO4 i koncentrirani u vakuumu. Sirovi materijal je pročišćen pomoću “flash” kromatografije eluiranjem smjesom heksana da se dobije 4-fluor-1-triizopropilsilanil-1H-[2,3-b]piridin (970 mg, 84 %).
H. Zatim su praćene procedure koje su opisane u primjerima 4E i 4F da bi se dobio nazivni spoj .
Sljedeći primjeri su pripremljeni primjenom procedure koja je opisana za pripremu primjera 7 korištenjem odgovarajućeg hidroksiazaindola i odgovarajućeg pirolotriazina koji je, opet, pripremljen korištenjem redoslijeda u tri koraka (A-> B-> C) gore opisane sa odgovarajućom modifikacijama u fazi B. Spojevi su prikazani dolje u tablici 1.
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Tablica 1:
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4-Fluor-2-metil-5-hidroksi-1H-pirolo[2,3-b]piridin neophodan za primjere 8,10,12,14 i 17 priprema se iz 4-fluor-2-metil-1-triizopropilsilanil-1H-pirolo[2,3-b]piridina kao što je opisano u primjeru 4. Sljedeći spoj se priprema kao što slijedi.
Priprema 4-Fluor-2-metil-1-triizopropilsilanil-1H-pirolo [2,3-b]piridina
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A. U otopinu 4-fluor-1H-pirolo[2,3-b]piridina (408 mg, 3.0 mmol), u THF (5 mL) dodaje se u malim porcijama natrij hidrid (60 % u ulju, 120 mg, 3.0 mmol). Nakon 30 min, dodaje se benzensulfonil klorid (0.42 mL, 3.3 mmol) i miješa na 23°C 21 h. Dodaje se etil acetat (25 mL), smjesa se rashlađuje na 0°C, neutralizira zasićenom otopinom amonij klorida i slojevi se razdvajaju. Vodeni sloj se ekstrahira dva puta etil acetatom (2 X 25 mL), organski slojevi se kombiniraju, isperu vodom (100 mL), slanom vodom (100 mL), suše, i koncentriraju u vakuumu. Sirovi materijal se pročišćava pomoću “flash” kromatografije eluiranjem sa 25 % etil acetatom u heksanu da se dobije l-benzensulfonil-4-fluor-1H-pirolo[2,3-b]piridin (683 mg, 82 %). 1H NMR (400 MHz, DMSO-d6) δ 8.40 (1H, dd, J = 5.8, 7.8 Hz), 8.12 (2H, dd, J = 1.0,6.3 Hz), 7.98 (1H, d, J = 4.3 Hz), 7.73 (1H, tt, J = 1.3, 6.9 Hz), 7.63 (3H, t, J = 7.3 Hz), 7.25 (1H, dd, J = 5.6, 9.9 Hz), 6.93 (1H, d, J = 4.1 Hz). LCMS m/z 277 (M+H+).
B. Otopini 1-benzensulfonil-4-fluor-1H-pirolo[2,3-b]piridina (683 mg, 2.47 mmol), u THF (12.0 mL) na -78 0C, u kapima se dodaje otopina n-butillitija (2.36 M u heksanima, 2.30 mL, 5.44 mmol). Poslije 90 minuta brzo se dodaje jodmetan (0.31 mL, 4.95 mmol). Nakon 15 minuta dodaje se otopina zasićenog amonij klorida i smjesa se ostavlja da dostigne sobnu temperaturu. Otopina se ekstrahira etil acetatom (3 X 15 mL), kombinirani organski slojevi su isprani vodom (30 mL), slanom vodom (30 mL), sušeni i koncentrirani u vakuumu. Sirovi materijal je stavljen u THF (12 mL) i dodaje se otopina tetrabutilamonij fluorida (1.0 M u THF, 3.7 mL, 3.7 mmol ). Smjesa je zagrijavana na 65°C 16h. Smjesa se hladi do sobne temperature, koncentrira u vakuumu i ostatak se pročišćava preparativnom HPLC da se dobije 4-fluor-2-metil-1H-pirolo[2,3-b]piridina (300 mg, 80 %) H NMR (400 MHz,CDCl3) δ 10.70 (1H,s), 8.13 (1H,t,J=5.8 Hz),6.77 (1H,dd,J=5.3,9.6 Hz),6.25 (1H,s) 2.51 (3H,s) . LCMC ; m/z 151 (M+H+)
C. Otopini 4-fluor-2-metil-1H-pirolo[2,3-b]piridina (300 mg, 2.0 mmol), u THF (6 mL) u malim porcijama se dodaje natrij hidrid (60 % u ulju, 84 g, 2.1 mmol). Nakon 30 minuta, dodaje se klorotriizopropilsilan (0.45 mL, 2.1 mmol) i smjesa se miješa na 65°C 16h. Dodaje se etil acetat (25 mL), smjesa se hladi na 0°C, neutralizira otopinom zasićenog amonij klorida i slojevi se razdvajaju. Vodeni sloj se dva puta ekstrahira etil acetatom (2 X 25 mL), organski slojevi se kombiniraju, isperu vodom (100 mL), slanom vodom (100 mL) i koncentriraju u vakuumu. Sirovi materijal se pročišćava “flash” kromatografijom eluiranjem sa heksanima da bi se dobio 4-fluor-2-metil-triizopropilsilani-1H-pirolo[2,3-b]piridin (400 mg, 65 %) u obliku bezbojnog ulja . LCMS ; m/z 307 (M+H+).
Primjer 18
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(R)-2-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-1-metiletilamin
A. Procedure prikazane u Tetrahedron Lett, 1977, 1977, i JACS, 1999, 3637 su modificirane. Tako jedna tikvica od 10 mL je napunjena sa l-(5-metil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin-6-iloksi)-propan-2-ol (249 mg, 0.98 mmol), i tetrahidrofuranom (4.91 mL) i rashlađena do 0°C. Redom se dodaju trifenilfosfin (516 mg, 1.96 mmolola), dietil azodikarboksilat (310 µL, 1.96 mmol) i difenilfosforil azid (424 µL, 1.96 mmol). Smjesa je miješana na 23°C 15 h a zatim koncentrirana u vakuumu. Sirovi materijal je pročišćen “flash” kromatograijom eluiranjem sa smjesom 20 % etil acetata u heksanu da se dobije (156 mg, 57 %) 6-(2-azidopropoksi)-5-metil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin kao bijela krutina 1H NMR (400 MHz, DMSO-d6) δ 8.19 (1H, s), 7.85 (1H, s), 4.16 (1H, dd, J = 2.8, 9.6 Hz), 4.05-3.96 (m, 2H), 2.60 (3H, s), 2.37 (3H, s), 1.21 (3H, d, J = 6.3 Hz). LCMS m/z 254 (M+H+).
B. 6-(2-Azido-propoksi)-5-metil-4-metilsulfanil-pirolo[2,1-f][1,2,4]triazin i 4-fluor-1H-pirolo[2,3-b]piridin-5-ol su reagirali zajedno prema proceduri opisanoj u primjeru 7 da bi se dobio 6-(2-azido-propoksi)-4-(4-fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1–f] [1,2,4]triazin. Sirovi materijal je pročišćen preparativnom HPLC. 1H NMR (400 MHz, DMSO-d6) δ 12.18 (1H, s), 8.32 (1H, d, J = 9.6 Hz), 8.02 (1H, s) 7.96 (1H, s), 6.60 (1H, d, J = 3.6 Hz), 4.21 (1H, d, J = 7.0 Hz), 4.09-4.02 (2H, m), 2.42 (3H, s), 1.23 (3H, d, J= 6.3 Hz). LCMS m/z 382 (M+H+).
C. Otopina 6-(2-azidopropoksi)-4-(4-fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazina (20 mg,0.05 mmol) u etil acetatu (2.0 mL) se miješa u prisustvu vodika (14 psi) i 10 % Pd/C (10 mg) 12h. Prekomjerni vodik se uklanja i smjesa se filtrira kroz Celite i uparava. Ostatak se pročišćava preparativnom HPLC da se dobije (10 mg,54 %) naslovnog spoja. LCMC : m/z 357 (M+H+). Dihidrokloridna sol: H NMR (400 MHz,DMSO-d6) δ 12.19 (1H,s), 8.31 (1H,d,J=8.9Hz),8.16 (2H,br.s), 8.05 (1H,s), 7.97 (1H,s), 7.60 (1H,s), 6.60 (1H,s), 4.19 (2H,m), 4.03 (2H,m), 3.65 (1H,m), 1.30 (3H,d,J=6.8Hz).
Primjer 19
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(R)-2-[4-(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-5- metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-1-metil-etilamin
Spoj A iz primjera 18 se tretira 4-fluor-2-metil-1H-pirolo[2,3-b]piridin-5-olom nakon čega se provodi redukcija azida kao što je prikazano u pripremi primjera 18 da se dobije naslovni spoj. Produkt je pročišćen preparativnom HPLC. LCMS; m/z 371 (M+H+). Dihidrokloridna sol: 1H NMR (400 MHz, DMSO-d6) δ 7.97 (1H, d, J = 8.9 Hz), 7.71 (1H, s), 7.64 (1H, s), 6.20 (1H, s), 4.09 (1H, dd, J = 10.1, 3.8 Hz), 3.93 (1H, dd, J = 10.1, 3.8 Hz), 3.59 (1H, m), 3.21 (2H, m), 2.43 (3H, s), 1.81 (3H, s), 1.30 (3H, d, J = 6.8 Hz).
Primjer 20
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2-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-etilamin
A. Tikvica od 25mL je napunjena 5-metil-4-fenoksipirolo[2,1-f][1,2,4]triazin-6-olom (450 mg, 1.87 mmol, WO 0071129), (2-hidroksietil)-karbaminske kiseline terc-butil esterom (577 µL, 3.73 mmol), tetrahidrofuranom (9.3 mL) i rashlađena do 0°C. Zatim su dodani trifenilfosfin (978 mg, 3.73 mmol), dietil azodikarboksilat (310 µL,1.96 mmol). Smjesa je miješana na 23°C 15 h a zatim koncentrirana u vakuumu. Sirovi materijal je pročišćen “flash” kromatografijom eluiranjem sa smjesom od 20 % etil acetata u heksanu da bi se dobio [2-(5-metil-4-fenoksipirolo[2,1-f][1,2,4] triazin-6-iloksi)-etil] -karbaminska kiselina terc-butil ester. 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 7.93 (1H, s), 7.89 (1H, s), 7.46 (2H, t, J =4.5 Hz), 7.30 (2H, d, J = 8.4 Hz), 7.04 (1H, t, J = 5.6 Hz), 4.05-3.98 (4H, m), 2.36 (3H, s), 1.38 (9H, s). LCMS ; m/z 385 (M+H+).
B. Procedura opisana u fazi A primjera 7 je primjenjena polazeći sa (865 mg, 2.25 mmol) [2-(5-metil-4-penoksipirolo[2,1-f][1,2,4]triazin-6-iloksi)-etil]-karbaminske kiseline terc-butil esterom da bi se dobio [2-(5-metil-4-metilsulfanil-pirolo[2,1-i][1,2,4]triazin-6-iloksi)-etil]-karbaminska kiselina terc-butil ester (652.7 mg, 86 %). 1H NMR (400 MHz, DMSO-d6) δ 8.98 (1H, s), 8.17 (1H, s), 7.79 (1H, s), 7.02 (1H, t, J = 5.6 Hz), 4.02 (2H, q, J = 7.3 Hz), 3.96 (2H, t, J = 5.6Hz), 2.59 (3H, s), 2.35 (3H, s), 1.37 (9H, s). LCMS ; m/z 339 (M+H+).
C. Procedura opisana u primjeru 7 sprovedena je polazeći sa (100 mg, 0.30 mrnol) [2-(5-metil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin-6-iloksi)-etil]-karbaminske kiseline terc-butil esterom da bi se dobio{2-[4-(4-Fluor-1H-pirolo[2,3-b] piridin-5-iloksi) -5-metil-pirolo[2,1-f][1,2,4] triazin-6-iloksi]-etil}-karbaminska kiselina terc-butil ester (42 mg,73 %). 1H NMR (400 MHz, DMSO-d6) δ 12.17 (1H, s), 8.31 (1H, d, J = 9.3 Hz), 7.96 (1H, s), 7.94 (1H, s), 7.62 (1H, s), 7.05 (1H, m), 6.60 (1H, s), 4.02 (2H, m), 3.32 (2H, m), 2.40 (3H, s), 1.38 (9H, s). LCMS ; m/z 443 (M+H+).
D. U otopinu {2-[4-(4-fluor-1H-pirolo[2,3-b]piridin-5-iloksi) -5-metilpirolo [2,1-f][1,2,4]triazin-6-iloksi] -etil}-karbaminske kiseline terc-butil estera (30 mg, 0.068 mmol) u diklormetanu (1.4 mL), dodana je trifluoroctena kiselina (0,14 mL) na sobnoj temperaturi. Poslije 160 min, smjesa je koncentrirana a ostatak je pročišćen preparativnom HPLC i, nakon koncentriranja, napravljena je hidrokloridna sol korištenjem 1N vodene otopine HC1 u acetonitrilu i sol je liofilizirana da bi se dobio 2-[4-(4-fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-etilamin (14.1 mg, 53%) kao bijeli liofilizat. 1H NMR (400 MHz, DMSO-d6) δ 12.19 (1H, s), 8.31 (1H, d, J = 9.6 Hz), 8.13 (3H, broad s), 8.05 (1H, s), 7.97 (1H, s), 7.62 (1H, t, J = 3.0 Hz), 6.59 (1H, dd, J = 1.8,3.5 Hz), 4.24 (2H, t, J = 4.8 Hz), 3.26 (2H, q, J = 5.3 Hz), 2.47 (3H, s). LCMS ; m/z 343 (M+H+). HRMS izračunat za C16H15FN6O2: 343.1318, nadjeno: 343.1309.
Sljedeći primjeri su pripremljeni korištenjem procedure slične onoj koja je opisana u primjeru 7 korištenjem odgovarajućeg hidroksiazaindola. Međutim, sulfon iz primjera 7 je zamijenjen u sljedećim primjerima odgovarajućim kloroimidatom. Vidjeti primjer 25 za pripremu 5-izopropilpirolo[2,1-f]-triazina koji se traži za primjer 22.
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Tablica: 2
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Primjer 23
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(R)-1-[5-Metil-4-(2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-pirolo[2,1-f][1,2,4]triazin-6-iloksi]-propan-2-ol
Sulfon, 1-(4-metansulfonil-5-metil-pirolo[2,1-f][1,2,4]triazin-6-iloksi)-propan-2-ol, se povezuje sa 4-fluor-2-metil-1H-pirolo[2,3-b]piridin-5-olom prema proceduri opisanoj u primjeru 4 (55% iskorištenje). LCMS ;m/z 354 (M+H+), Dihidrokloridna sol: 1H NMR (400 MHz, DMSO-d6) δ 11.65 (1H, s), 8.04 (1H, s), 7.90 (1H, s), 7.87 (1H, s), 7.75 (1H, s), 6.17 (1H, s), 4.33 (1H, m), 3.98 (1H, m), 3.85 (2H, m), 2.49 (3H, s), 2.40 (3H, s), 1.16 (3H, d, J = 6.8 Hz).
Primjer 24
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(4-Fluor-1H-pirolo[2,3-b]piridin-5-il)-[5-izpropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
A. otopinu N-hidroksiacetamidina (315 mg, 4.25 mmol) u THF (10 mL) na 0 °C dodan je natrij hidrid (60% u ulju, 340 mg, 8.5 mmol) u malim porcijama i nastala smjesa je miješana 20 min. Zatim je dodan metil ester 5-izopropil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline i smjesa je zagrijavana u posudi pod tlakom na 80°C 18 h. Reakciona smjesa je rashlađena i talog je filtriran. Filtrat je razrijeđen sa etil acetatom i ispran zasićenom otopinom amonij klorida, slanom vodom (50 mL), osušen (MgSO4), filtriran i koncentriran da bi se dobio 5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-3H-pirolo[2,1-f][1,2,4]triazin-4-on (520 mg, 95%).
B. U otopinu oksadiazola iz prethodne faze ( 300 mg, 1.08 mmol) u toluenu (7 mL) su dodani fosfor oksiklorid (122 µL, 1.29 mmol) i diizopropiletilamin (150 µL, 0.86 mmol) i reakciona smjesa je zagrijavana do refluksa 3 dana. Reakciona smjesa je rashlađena i lijevana preko ledeno hladne zasićene otopine natrij bikarbonata. Razdvojeni vodeni sloj je ekstrahiran etil acetatom (2 x 25 mL) i kombinirani organski slojevi su isprani slanom vodom (50 mL), osušeni (MgSO4), filtrirani i upareni da bi se dobio sirovi 4-klor-5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazin , koji je direktno korišten u sljedećoj fazi (280 mg, 94%).
C. Diizopropiletilamin (0.1 mL, 0.5 mmol) dodan je u otopinu 4- klor-5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazina (54 mg, 0.18 mmol, vidi primjer 25) i 4-fluor-1H-pirolo[2,3-b]piridin-5- ilamina (30 mg, 0.18 mmol) u DMF (1.0 mL). Smjesa je miješana na sobnoj temperaturi 16 h, reakcija je prekinuta zasićenom otopinom amonij klorida (20 mL) i ekstrahirana etil acetatom (3 x 25 mL). Kombinirani organski slojevi su isprani slanom vodom (50 mL), osušeni, filtrirani i koncentrirani. Ostatak je pročišćen preparativnom HPLC da bi se dobio nazivni spoj (34mg, 43%). LCMS : m/z 393 (M+H)+. Monohidrokloridna sol: 1H NMR (400 MHz, DMSO-d6) δ 11.99 (1H, s), 8.12 (1H, s.), 7.89 (1H, s), 7.50 (1H, s), 6.55 (1H, br, s.), 4.16 (1H, m), 2.43 (3H, s), 1.44 (6H, d, J = 7.3 Hz).
Intermedijer, 4-Fluor-1H-pirolo[2.3-b]piridin-5-ilamin se priprema kao što slijedi:
D. Okrugla tikvica od 100 mL osušena u sušioniku je isisana i napunjena argonom. Tikvica je napunjena 4-fluor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridinom (763 mg, 2.61 mmol), THF (17.4 mL) i smjesa je rashlađena do -78°C. Otopina sek-butillitija (1.10 M in THF, 5.21 mL, 5.74 mmol) dodana je u kapima i poslije 30 minuta, brzo je dodan l-sulfonilazido-4-metilbenzen (1.29 g, 6.52 mmol) u THF (7.4 mL). Poslije 25 min, dodana je zasićena otopina amonij klorida i smjesa je puštena da dostigne sobnu temperaturu. Smjesa je ekstrahirana etil acetatom (3 X 50 mL), kombinirani organski slojevi su isprani vodom (100 mL), slanom vodom (100 mL), osušeni i koncentrirani u vakuumu. Sirovi materijal je miješan u heksanima da bi se uklonio ekscesni l-azido-4-metilbenzen a filtrat je pročišćen “flash” kromatografijom eluiranjem sa smjesom od 2.5 % etil acetatata u heksanima da se dobije 5-azido-4-fluor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin (746 mg, 86 %) u obliku bezbojnog ulja. 1H NMR (400 MHz, DMSO-d6) δ 8.16 (1H, d, J = 10.3 Hz), 7.56 (1H, d, J = 3.3 Hz), 6.71 (1H, d, J = 3.6 Hz) 1.84 (3H, m), 1.05 (9H, s), 1.03 (9H, s). LCMS : m/z 334 (M+H+),
E. Procedura koja je opisana za desililaciju u primjeru 7 primjenjena je da bi se dobio 5-azido-4-fluor-1H-pirolo[2,3-b]piridin. 1H NMR (400 MHz, DMSO-d6) δ 12.10 (1H, s), 8.14 (1H, d, J = 10.1 Hz), 7.57 (1H, t, J = 2.5 Hz), 6.53 (1H, dd, J = 1.8,3.3 Hz). LCMS ; m/z 178 (M+H).
F. Procedura za pretvaranje azido grupe u amino grupu koja je opisana u primjeru 18 primijenjena je na 5-azido-4-fluor-1H-pirolo[2,3-b]piridin korištenjem 45 p.s.i. vodika da bi se dobilo 4-fluor-1H-pirolo[2,3-b]piridin-5-ilamin (91% iskorištenje) kao čvrsta masa. 1H NMR (400 MHz, DMSO-d6) δ 11.42 (1H, s), 7.84 (1H, d, J = 10.9 Hz), 7.30 (1H, t, J = 3.0 Hz), 6.28 (1H, dd, J = 1.9, 3.6 Hz). LCMS ;m/z 152 (M+H+). HRMS proračunato na C7H6FN3: 151.0545, nađeno: 151.0549
Primjer 25
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(4-Fluor-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-3l)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
A. Etil izocijanoacetat (80 g, 0.71 molova) je otopljen u 1 L suhog tetrahidrofurana pod dušikom i u otopinu se dodaje l,8-diazabiciklo[5.4.0]undec-7-en (107.7g, 0.71 molova). Otopina izobutiraldehida (29.7g, 0.41 molova) u 1.5 L suhog tetrahidrofurana dodavan je ukapavanjem na sobnoj temperaturi preko 3 časa. Smjesa je zatim miješana na sobnoj temperaturi 16 h. Reakciona smjesa je koncentrirana u vakuumu do smeđeg ulja. Koncentrat je raspodijeljen na sobnoj temperaturi između 1.2 L etil acetata i 0.5 L vode. Organski sloj je onda ispran sa 0.4 L 0.1 N kloridne kiseline nakon čega je slijedilo dodavanje 0.3 L zasićene otopine natrij bikarbonata i zatim 0.3 L zasićene slane vode. Organski sloj je osušen (natrij sulfat), filtriran i koncentriran u vakumu do smeđeg ulja. Ostatak je otopljen u toluenu i dodan u 1600 ml (-800 g) kolone silikagela namočene sa heksanom. Proizvod je eluiran na 15 PSI dušičnom tlaku sa 4.8 L heksana a zatim sa 5 L 20% etil acetata u heksanu. Eluens koji sadrži proizvod TLC analize je kombiniran i koncentriran u vakuumu do žutog ulja. Koncentrat je uparen do suhog pod visokim vakuumom dajući produkt A, 3-(l-metiletil)pirol-2,4-dikarboksilna kiselina dietil ester (54g, 60% iskorištenje) žuto ulje koje je očvrsnulo stojeći na sobnoj temperaturi. TLC silikagel: Rf = 0.2, heksan/etil acetat (4/1) UV vizualizacija i PMA mrlja 1H NMR: (CDC13) δ 1.2-1.5 (m, 12H), 4.2-4.3 (m, 1H), 4.3-4.3 (m, 4H), 7.5 (d, 1H).
B. Suspenziji NaH (13.9 g, 34 mmol, 60% u ulju) u DMF (0.36 L) na 0°C dodana je otopina spoja A (75 g, 29 mmol) u DMF (0.4 L). Poslije miješanja 45 min u malim porcijama dodan je 2,4-dinitrohidroksilamin. Kada je dodavanje završeno, hladna kupelj je uklonjena i smjesa je puštena da se zagrijava na sobnoj temperaturi. Poslije 2 h reakciona smjesa je ulivena u vodu i ekstrahirana etil acetatom. Organski sloj je ispran zasićenim natrij bikarbonatom, 10% litij kloridom (LiCl) i slanom vodom, zatim osušen i koncentriran. Ostatak je pročišćen da bi se dobio traženi spoj 1-amino-3-(l-metiletil)pirol-2,4-dikarboksilna kiselina dietil ester, kao ulje(81 g) od 80% čistoće, koji je korišten bez daljeg pročišćavanja.
C. Spoj B (77.7 g, 0.29 M) je miješan sa formamidom (0.5 L) i zagrijavano do 160°C. Poslije 8 h smjesa je puštena da se rashladi do sobne temperature, miješana 2 dana i onda razrijeđena vodom (4L). Ovaj produkt je ekstrahiran etil acetatom. Organski sloj je koncentriran, ostatku je dodan toluen i ostatak je ponovo koncentriran. Smeđa čvrsta masa je triturirana s eterom i osušena pod visokim vakuumom da bi se dobio 5-(l-metiletil)pirolo[2,1-f][1,2,4]triazin-4(3H)-on-6-karboksilna kiselina etil ester, kao čvrsta masa svijetlo smeđe boje (45 g, 62%). LC/MS; (M+H)+ = 250.1
D. Suspenzija 5-izopropil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin- 6-karboksilna kiselina etil estera je suspendiranog u vodi (4 mL) i hidrazin hidratu (4 mL) je zagrijavana na 110°C 24 h. Reakciona smjesa je rashlađena i formirani talog je izoliran filtracijom i osušen na zraku. Talog je suspendiran u etil acetatu i dodan je acetil klorid (853 µL, 12 mmol) . Smjesa je miješana na sobnoj temperaturi 2 dana i talog je izoliran filtracijom, ispran sa etil acetatom i osušen na zraku da bi se dobio 5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-3H-pirolo[2,1-f][1,2,4]triazin-4-on (575 mg, 35%).
E. Procedura za nastajanje kloroimidata koja je opisana u primjeru 24 korištena je za pretvorbu 5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-3H-pirolo[2,1-f][1,2,4]triazin-4-on u 4-klor-5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirolo[2,1-f][1,2,4]triazin u kvantitativnom prinosu, koji je dalje korišten direktno bez ikakavog daljeg pročišćavanja.
F. Procedura koja je opisana u primjeru 24 za povezivanje anilina je korištena da reaguju 4-klor-5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirolo[2,1-f][1,2,4]triazin i 4-fluor-1H-pirolo[2,3-b]piridin-5-ilamin da bi se dobio nazivni spoj (41 % iskorištenjea). Monohidrokloridna sol: 1H NMR (400 MHz, MeOD-d4 ) δ 8.26 (1H, s.), 8.00 (1H, s), 7.50 (1H, m), 6.69 (1H, m.), 4.08 (1H, m), 2.51 (3H, s), 1.40(6H,d,J = 7.1 Hz).
Primjeri koji slijede su pripremljeni korištenjem procedure povezivanja koja je predstavljena u primjeru 24. Primjeri 26 i 27 su pripremljeni korištenjem procedure slične onoj opisanoj za pripremanje primjera 24 i 25, i jednog i drugog, korištenjem odgovarajućeg 5-aminoazaindola. Primjer 28 je načinjen na sličan način kao primjer 18.
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Tablica 3
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Primjer 32
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1-[5-Izopropil-4-(1H-pirolo[2,3-b]piridin-5-ilamino)-pirolo[2,1-f] [1,2,4]triazin-6-iloksi]-propan-2-ol
1-(5-Izopropil-4-metilsulfanilpirolo[2,1-f][1,2,4]triazin-6-iloksi)-propan-2-ol 262 mg, 0.93 mmol, koji je dobijen po primjeru 25 korištenjem procedure u fazi B primjera 7) i l-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ilamin (290 mg, 0.93mmol) su otopljeni u kloroformu i dodana je m-kloroperbenzojeva kiselina (60 %, 535 mg, 1.86 mmol). Smjesa je zagrijavana na 120°C 10 min u Personal Chemistry Smith Enrys Optimizer™ miklrovalnoj pećnici. Otopina je uparena u vakuumu i ostatak je pročišćen preparativnom HPLC. Izolirani produkt je otopljen u THF (10 mL) i dodan je TBAF (1.0 M, 0.2 mL, 0.2 mmol). Smjesa je miješana 5 min. i otapalo je pušteno da se upari u vakuumu. Ostatak je pročišćen preparativnom HPLC da bi se dobio nazivni spoj (3 mg, 1%).
Intermedijer, 1-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ilamin je pripremljen na sljedeći način:
A. 4-Klor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin (10 g, 32.5 mmol) je otopljen u THF (250 mL) i rashlađen na -78°C. Zatim je ukapavan sek-butillitij (54.8 mL, 1.3M/cikloheksan, 71.4 mmol) i otopina je miješana 20 min. Dodana je otopina tozilazid (16 g, 81.2 mmol.) u THF (100 mL) i smjesa je miješana 1h. Reakcija smjese je prekinuta zasićenom otopinom amonij klorida (50 mL) i zagrijavana do sobne temperature. Ova smjesa je ekstrahirana heksanima (2 x 200 mL) i kombinirani organski slojevi su osušeni. Organska faza je je filtrirana i koncentrirana u vakuumu. Sirovi produkt je pročišćen “flash” kromatografijom (silika gel, 100% heksani) da bi se dobilo 5-azido-4-klor-1-triizopropilsilanil-1H-pirolo[2,3-b] piridin kao smjesa sa početnim materijalom (10.2g). Ova smjesa je direktno korištena u sljedećoj fazi.
B. 5-Azido 4-klor-1-triizopropilsilanil- 1 H -pirolo [2,3-b] piridin (1.6 g, 4.6 mmol) je otopljen u etil acetatu (100 mL) i dodan je Pd/C (10%, 100 mg).
Ova suspenzija je miješana na sobnoj temperaturi pod 1 atmosferom vodika 18 h. A krutina je uklonjen filtracijom pomoću Celite® i otopina je ostavljena da se upari u vakuumu. Sirovi produkt je pročišćen “flash” kromatografijom (silika gel, 95% heksani, 5% etil acetat) da bi se dobio 4-klor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ilamin (730 mg, 43.5% , 2 faze).
C. 4-Klor-1-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ilamin (10.2 g, 31.5 mmol) je razrijeđen etil acetatom (200 mL) i acetatnom kiselinom (100 mL). Cinkov prah(50 g, 0.8 mol.) dodan je u malim porcijama na sobnoj temperaturi. Nakon miješanja suspenzije na sobnoj temperaturi 4 h, smjesa se filtrira kroz Celite i filtrat je polagano neutraliziran pomoću zasićene otopine natrij bikarbonata i ekstrahiran etil acetatom (2 x 300 mL). Kombinirani organski slojevi su osušeni, filtrirani i upareni u vakkumu. Sirovi proizvod je pročišćen “flash” kromatografijom (silikagel, 5% etil acetata u heksanima) da bi se dobio l-triizopropilsilanil-1H-pirolo[23-b]piridin-5-ilamin (6.38 g).
Primjeri 33-35 su pripremljeni na sljedeći način: Primjer 33 je sintetiziran na način sličan pripremanju primjera 32. Primjeri 34 i 35 su pripremljeni na način sličan pripremi primjera 24.
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Tablica 4
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Primjer 36
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5-Izopropil-4-[metil-(1H-pirolo[2,3-b]piridin-5-il)-amino-pirolo[2,1-f] [1,2,4] triazin-6-karboksilna kiselina metil ester
Nazivni spoj je pripremljen na način koji je sličan pripremi iz primjera 24 korištenjem metil-(1H-pirolo[2,3-b]piridin-5-il)-amina i 4-klor-5-izopropilpirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline metil estera. (25% iskorištenje). LCMS ;m/z 365 (M+H+). Monohidrokloridna sol: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.73 (1H, s), 8.22 (1H, s.), 8.00 (1H, s), 7.75 (1H. s), 7.50 (1H. s), 6.40 (1H. s.), 3.70 (3H, s), 3.26 (1H, m), 2.51 (3H, s), 0.54 (6H, d, J = 7.3 Hz).
Intermedijer, metil-(lH-pirolo[2,3-b]piridin-5-il)-amin, je pripremljen kao što slijedi:
A. 1-Triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ilamin(375mg, 1.3 mmol) i trietilamin (271 juL, 1.95 mmol) u diklormetanu (10 mL) je tretiran sa di-terc-butil dikarbonatom (340 mg, 1.5 mmol) i smjesa je miješana na sobnoj temperaturi 2.5 h prekinuta zasićenom otopinom amonij klorida (20 mL) i ekstrahirana etil acetatom (3 x 25 mL). Kombinirani organski slojevi su isprani sa slanom vodom (50 mL), osušeni (MgSO4), filtrirani i koncentrirani. Ostatak je pročišćen preparativnom HPLC.
B. l-Triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-il)-karbaminska kiselina terc-butil ester (250 mg, 0.6 mmol) je zatim tretiran sa natrij hidridom (24 mg, 60% ulje, 0.6 mmol) i metil jodidom (48 µL, 0.77 mmol) u DMF (2.0 mL). Smjesa je miješana na sobnoj temperaturi 16 h, reakcija prekinuta zasićenom otopinom amonij klorida (20 mL) i ekstrahirana etil acetatom (3 x 25 mL). Kombinirani organski slojevi su isprani slanom vodom (50 mL), osušeni (MgSO4.), filtrirani i koncentrirani. Ostatak, koji je korišten bez daljeg pročišćavanja, je zatim tretiran sa TFA (1.0 mL) u diklormetanu (4.0 mL) i smjesa je miješana na sobnoj temperaturi 10 h, koncentrirana i pročišćena preparativnom HPLC da bi se dobio metil(1H-pirolo[2,3-b]piridin-5-il)-amin (31 mg, 33%). m/z 148 (M+H)+.
Primjer 37
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Etil-[5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-(1H-pirolo[2,3-b]piridin-5-il)-amin
Korištena je gore opisana procedura u primjeru 24. Tako, kada se koriste 4-klor-5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazin (86 mg, 0.31 mmol), etil-(1H-pirolo[23-b]piridin-5-il)-amin (50 mg, 0.31 mmol) i diizopropiletilamin (162 µL, 0.93 mmol) u DMF (2.0 mL) dobija se nazivni spoj. LCMS ; m/z 403 (M+H)+. Monohidrokloridna sol: 1H NMR (400 MHz, DMSO-d6) δ 9.70 (1H, s), 8.20 (1H, s.), 8.02 (1H, s), 7.52 (1H, s), 7.29 (1H, s), 6.38 (1H, br. s.), 4.10 (2H, q, J = 6.8 Hz), 3.24(1H, m), 2.30 (3H, s), 1.19 (311, t, J = 6.8 Hz), 0.59 (6H,d, J = 7.1 Hz). (1H, m), 2.30 (3H, s), 1.19 (3H, t, J = 6.8 Hz), 0.59 (6H, d, J = 7.1 Hz).
Intermedijer, etil-pirolo[2,3-b]piridin-5-il)-amin, se priprema kao što slijedi:
A. Acetil klorid (75 µL, 1.0 mmol) dodan je u otopinu 1-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-ilamina (230 mg, 0.8 mmol) i 4-dimetilaminopiridina (5 mg) u piridinu (1.6 mL). Smjesa je miješana na sobnoj temperaturi 24 h i dodana je zasićena otopina amonij klorida (30 mL) i etil acetat (30 mL). Razdvojeni vodeni sloj je ekstrahiran etil acetatom (3 x 25 mL) i kombinirani organski slojevi su osušeni, filtrirani i koncentrirani da se dobije ulje koje je pročišćeno preparativnom HPLC da bi se dobio N(1H-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-il)-acetamid (140 mg, 53 %) u obliku ulja: LCMS ;m/z 332 (M+H+).
B. Na sobnoj temperaturi pod argonom otopini bor-dimetilsulfid kompleksa (665 µL, 6.6 mmol, 10 M) dodan je N-metil-N-(l-triizopropilsilanil-1H-pirolo[2,3-b]piridin-5-il)-acetamidu (110 mg, 0.33 mmol) u THF (3.0 mL). Smjesa je zagrijavana na 65 °C 2 h rashlađena i polako je dodan 6N otopina hidrokloridne kiseline. Smjesa je zagrijavana do 100 °C i snažno miješana 12 h rashlađena i 6 N otopina natrij hidroksida dodavan je dok nije postignut pH 7. Smjesa je ekstrahirana etil acetatom (3x15 mL) i kombinirani organski slojevi su osušeni, filtrirani i upareni da se dobije ulje koje se pročišćava preko silika-gel-SCX kolone (arilsulfonska kiselina sa ispiranjima sa metanolom i 2N NH3 u metanolu) da bi se dobio etil-(1H-pirolo[2,3-b]piridin-5-il)-amin. LCMS; m/z 203 (M + AcCN), 162 (M+H)+.
Claims (20)
1. Spoj forumule (I)
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naznačen time da
Z se izabere između O, S, N, OH, i Cl, pod uvjetom da kada je Z ili O ili S, R41 je odsutno i kada je Z OH ili Cl, i R41 i R42 su odsutni;
X i Y nezavisno se izaberu između O, OCO, S, SO, SO2, CO, CO2, NR10, NR11CO, NR12CONR13, NR14CO2, NR15SO2, NR16SO2NR17, SO2NR18, CONR19, halogena, nitro, cijano, ili X ili Y su odsutni;
R1 je vodik, CH3, OH, OCH3, SH, SCH3, OCOR21, SOR22, SO2R23, SO2NR24R25, CO2R26, CONR27R28, NH2, NR29SO2NR30R31, NR32SO2R33, NR34COR35, NR36CO2R37, NR38CONR39R40, halogen, nitro, ili cijano;
R2 i R3 su nezavisno vodik, alkil, supstituirani alkil, alkenil, supstituirani alkenil, alkinil, supstituirani alkinil, aril, supstituirani aril, heterociklo skupina, supstituirana heterociklo skupina, aralkil, supstituirani aralkil, heteroaril, supstituirani heteroaril, heterocikloalkil ili supstituirani heterocikloalkil; pod uvjetom da kada je X halo skupina, nitro skupina ili cijano skupina, R je odsutan, i, kada je Y halo skupina, nitro skupina ili cijano skupina, R je odsutan;
R6 je H, alkil, supstituirani alkil, aril, supstituirani aril, heterociklo skupina, supstituirani heterociklo, NR7R8, OR9 ili halogen;
R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R21, R24, R25, R26, R27, R28, R29, R30, R31, R32, R34, R35, R36, R38, R39 i R40 nezavisno se izaberu između grupa koje sadrže vodik, alkil, supstituirani alkil, aril, supstituirani aril, heteroaril, supstituirani heteroaril, heterociklo, ili supstituirani heterociklo;
R22, R23, R33 i R37 su nezavisno se izaberu između grupa koje sadrže alkil, supstituirani alkil, aril, supstituirani aril, heteroaril, supstituirani heteroaril, heterociklo, ili supstituirana heterociklo;
R42 je
[image]
(R43)n gdje je n jednako 0, 1 ili 2 i svaki R43 se nezavisno izaberu iz grupe koja se sastoji od vodika, fluora, klora i metila; i
R44 je metil, ili vodik,
s daljim uvjetima da:
a. R2 ne mora biti vodik ako X je SO, SO2, NRI3CO2, ili NR14SO2; i
b. R3 ne mora biti vodik ako Y je SO, SO2, NR13CO2, ili NR14SO2;
ili enantiomer, dijastereomer, ili njegova farmaceutski prihvatljiva sol prekursor ili solvat.
2. Spoj A prema patentom zahtjevu 1 naznačen time da
R1 je vodik ili metil; R6 je vodik; R3 je niži alkil; i Z je kisik ili dušik.
3. Spoj A prema patentom zahtjevu 1 naznačen time da
R1 je vodik ; R3 je niži alkil ; Y nije prisutan; X je kisik ili dušik; R43 je fluor ili vodik; i R44 je vodik ili metil.
4. Spoj prema zahtjevu 1 naznačen time da je X kisik; R2 je supstituirani alkil i R43 je fluor.
5. Spoj prema zahtjevu 1 naznačen time da X nije prisutan; R2 je supstituirani hetrociklo, supstituirani heterociklo, heteroaril ili supstituirani heteroaril, i Z je dušik.
6. Spoj naznačen time da se izabere iz skupine koje se sastoj od niza
4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazin-6-ol,
(R)-1-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f] [1,2,4]triazin-6-iloksi ]-propan-2-ol,
(S)-1-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f] [1,2,4] triazin-6-iloksi] -propan-2-ol,
(R)-1-[4-(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metil-pirolo[2,1-f][1,2,4]triazin-6-iloksi]-propan-2-ol,
(R)-2-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-1-metiletilamin,
(R)-2-[4-(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4] triazin-6-iloksi]-1-metil-etilamin,
2-[4-(4-Fluor-1H-pirolo[2,3-b]piridin-5-iloksi)-5-metilpirolo[2,1-f][1,2,4]triazin-6-iloksi]-etilamin,
(4-Fluor-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(3-metil-[1,2,4]oksadiazol-5-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin,
(4-Fluor-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin,
(4-Fluor-2-metil-1H-pirolo[2,3-b]piridin-5-il)-[5-izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirol[2,1-f][1,2,4]triazin-4-il]-amin, i
[5-Izopropil-6-(5-metil-[1,3,4]oksadiazol-2-il)-pirolo[2,1-f][1,2,4]triazin-4-il]-(2-metil-1H-pirolo[2,3-b]piridin-5-il)-amin.
7. Farmaceutska kompozicija naznačen time da sadrži najmanje jedan od spojeva iz patentnog zahtjeva 1 i njihov farmaceutski prihvatljiv nosač.
8. Farmaceutska kompozicija naznačen time da sadrži najmanje jedan od spojeva iz patentnog zahtjeva 6 i njihove farmaceutski prihvatljive nosače.
9. Farmaceutska kompozicija naznačen time da sadrži najmanje jedan ili više spojeva iz pateentnog zahtjeva 1 u kombinaciji sa njihovim farmaceutski prihvatljivim nosačima i bar jedno dodatno antikarcinomno ili citotoksično sredstvo.
10. Farmaceutska kompozicija naznačen time da sadrži najmanje jedan ili više spojeva iz patentnog zahtjeva 6 u kombinaciji sa farmaceutski prihvatljivim nosačima i najmanje jedno dodatno antikarcinomno ili citotoksično sredstvo.
11. Farmaceutska kompozicija iz patentog zahtjeva 7 naznačen time da se navedeno antikarcinomno ili citotoksično sredstvo izabere iz grupe koje se sastoji od: linomida, inhibitora integrin ανβ3 funkcije, angiostatina, razoksana, tamoksifena, toremifena, raloksifena, droloksifena, jodoksifena, megestrol acetata, anastrozola, letrozola, borazola,eksemestana, flutamida, nilutamida, bikalutamida, ciproteron acetata, goserelin acetata, leuprolida, finasterida, herceptina, inhibitora metaloproteinaz, inhibitora urokinaze aktivatora funkcije receptora plazminogena, antitjela faktora rasta, antitjela receptora faktora rasta, bevacizumaba, cetuksimaba, inhibitora tirozin kinaza, inhibitora serin/treonin kinaza, metotreksata, 5-fluorouracila,analoga purina, adenozina, citozin arabinozida, doksorubicina, daunomicina, epirubicina, idarubicina, mitomicina-C, daktinomicina, mitramicina, cisplatina, carboplatina, dušik mustarda, melfalana, klorambucila, busulfana, ciklofosfamida, ifosfamida, nitrozourea, tiotepa, vinkristina, paklitaksela, docetaksela, analoga epotilona , analoga diskodermolida, analoga eleuterobina, etopozida, tenipozida, amsakrina, topotekana, irinotekana,flavopiridola, proteazom inhibitora uključujući bortezomib i modifikatore biološkog odgovora.
12. Postupak za postizanje antiangiogenog efekta naznačen time da obuhvaća davanje sisavcu kojem je to potrebno efektivne količine najmanje jednog spoja prema patentom zahtjevu 1 s antiangiogenom aktivnošću .
13. Postupak za postizanje efekta redukcije vaskularne permeabilnosti naznačen time da obuhvaća davanje sisavcu kojem je to potrebno efektivne količine najmanje jednog spoja prema patentom zahtjevu 1 s aktivnošću redukcije vaskularne permeabilnosti.
14. Postupak za inhibiciju aktivnosti protein kinaze receptora faktora rasta naznačen time da obuhvaća davanje sisavcu kojem je to potrebno efektivne količine najmanje jednog spoja prema patentom zahtjevu 1 s aktivnošću inhibicije protein kinaze.
15. Postupak za inhibiciju aktivnosti tirozin kinaze receptora faktora rasta naznačen time da obuhvaća davanje sisavcu kojem je to potrebno efektivne količine najmanje jednog spoja prema patentom zahtjevu 1 s aktivnošću inhibicije tirozin kinaze.
16. Postupak za liječenje proliferativnih bolesti naznačen time da obuhvaća davanje sisavcu kojem je to potrebno terapeutski efektivne količine kompozicije prema patentom zahtjevu 7.
17. Postupak za liječenje karcinoma naznačen time da obuhvaća davanje sisavcu kojem je to potrebno terapeutski efektivne količine kompozicije prema patentom zahtjevu 7.
18. Postupak za liječenje upale naznačen time da obuhvaća davanje sisavcu kojem je to potrebno terapeutski efektivne količine kompozicije prema patentom zahtjevu 7.
19. Postupak za liječenje autoimunih bolesti naznačen time da obuhvaća davanje sisavcu kojem je to potrebno terapeutski efektivne količine kompozicije prema patentom zahtjevu 7.
20. Postupak za liječenje bolesti povezanih s prijenosom signala putevima koji idu preko receptora faktora rasta naznačen time da obuhvaća davanje sisavcu kojem je to potrebno terapeutski efektivne količine kompozicije prema patentom zahtjevu 1.
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