HRP20040422A2 - C-5 modified indazolylpyrrolotriazines - Google Patents
C-5 modified indazolylpyrrolotriazines Download PDFInfo
- Publication number
- HRP20040422A2 HRP20040422A2 HR20040422A HRP20040422A HRP20040422A2 HR P20040422 A2 HRP20040422 A2 HR P20040422A2 HR 20040422 A HR20040422 A HR 20040422A HR P20040422 A HRP20040422 A HR P20040422A HR P20040422 A2 HRP20040422 A2 HR P20040422A2
- Authority
- HR
- Croatia
- Prior art keywords
- pyrrolo
- indazol
- triazin
- fluorobenzyl
- ylmethyl
- Prior art date
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- -1 C-5 modified indazolylpyrrolotriazines Chemical class 0.000 title claims description 51
- 150000001875 compounds Chemical class 0.000 claims description 124
- 239000000203 mixture Substances 0.000 claims description 41
- 238000011282 treatment Methods 0.000 claims description 36
- 102000001301 EGF receptor Human genes 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 206010028980 Neoplasm Diseases 0.000 claims description 23
- 125000000217 alkyl group Chemical group 0.000 claims description 22
- 125000003118 aryl group Chemical group 0.000 claims description 22
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 claims description 21
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 claims description 21
- 150000003839 salts Chemical class 0.000 claims description 21
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 claims description 18
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 claims description 18
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 claims description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 16
- 230000000694 effects Effects 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- 201000010099 disease Diseases 0.000 claims description 14
- 125000000623 heterocyclic group Chemical group 0.000 claims description 13
- 125000003107 substituted aryl group Chemical group 0.000 claims description 13
- 229940002612 prodrug Drugs 0.000 claims description 12
- 239000000651 prodrug Substances 0.000 claims description 12
- 102000005962 receptors Human genes 0.000 claims description 12
- 108020003175 receptors Proteins 0.000 claims description 12
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- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 7
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
- C04B41/009—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone characterised by the material treated
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B41/00—After-treatment of mortars, concrete, artificial stone or ceramics; Treatment of natural stone
- C04B41/45—Coating or impregnating, e.g. injection in masonry, partial coating of green or fired ceramics, organic coating compositions for adhering together two concrete elements
- C04B41/4584—Coating or impregnating of particulate or fibrous ceramic material
-
- C—CHEMISTRY; METALLURGY
- C04—CEMENTS; CONCRETE; ARTIFICIAL STONE; CERAMICS; REFRACTORIES
- C04B—LIME, MAGNESIA; SLAG; CEMENTS; COMPOSITIONS THEREOF, e.g. MORTARS, CONCRETE OR LIKE BUILDING MATERIALS; ARTIFICIAL STONE; CERAMICS; REFRACTORIES; TREATMENT OF NATURAL STONE
- C04B2111/00—Mortars, concrete or artificial stone or mixtures to prepare them, characterised by specific function, property or use
- C04B2111/00474—Uses not provided for elsewhere in C04B2111/00
- C04B2111/00793—Uses not provided for elsewhere in C04B2111/00 as filters or diaphragms
Description
Područje izuma
Ovaj izum se odnosi na spojeve koji inhibiraju aktivnost tirozin kinaze receptora faktora rasta, kao što su HER1, HER2 i HER4, čime postaju korisni kao anti-tumorska sredstva. Spojevi su, također, korisni u liječenju bolesti, različitih od raka, koje su povezane sa putevima signalne transdukcije koja djeluje preko receptora faktora rasta, kao što su HER1, HER2 i HER4.
Pozadina izuma
Receptome tirozin kinaze (RTKs) su važne u prijenosu bikemijskih signala kroz plazmatske membrane stanica. Ove transmembranske molekule se karakteristično sastoje od vanstaničnih domena vezivanja liganda povezanih kroz segment plazma membrane za unutarstaničnu domen tirozin kinaze.
Porodica humanog receptora epidermalnog faktora rasta (HER) se sastoji od četiri posebne receptorne tirozin kinaze, koje su označene kao KER1, HER2, HER3 i HER4. Ove kinaze su, također, označene i kao erbB1, erbB2 itd. HER1 se, isto tako, uobičajeno odnosi na receptor epidermalnog faktora rasta (E6F). Osim HER3, ovi receptori imaju unutrašnju aktivnost protein kinaze koja je specifična za tirozinske ostatke fosfoakceptornih proteina. HER kinaze se ekspresiraju u većini epitelnih stanica, kao i u stanicama tumora epitelnog porijekla. Također, često su ekspresirane u stanicama tumora mezenhimnog porijekla, kao to su sarkomi ili rabdomiosarkomi. RTKs, kao što su HER1 i HER2 su uključene u proliferaciju stanica i u vezi su sa bolestima, kao što su psorijaza i rak. Prekid signalne transdukcije inhibicijom ovih kinaza imati će antiproliferativni i terapeutski efekt.
Enzimska aktivnost receptornih tirozin kinaza može biti stimulirana prekomjernom ekspresijom ili dimerizacijom posredovanom ligandima. Formiranje homodimera, kao i heterodimera, demonstrirano je za porodicu HER receptora. Primjer homodimerizacije je dimerizacija HER1 (EGF receptor) jednim od liganda EGF porodice (koja obuhvaća EGF, transformirajući faktor rasta alfa, betacelulin, heparin-vezujući EGF i epiregulin). Heterodimerizacija između četiri HER receptorne kinaze može biti potaknuta vezivanjem za članove heregulin (također, odnosi se na neunegulin) porodice liganada. Takva heterodimerizacija, kako uključuje HER2 i HER3 ili HER3/HER4 kombinaciju, dovodi do značajne stimulacije aktivnosti tirozin kinaze receptornih dimera čak iako je jedan od receptora (HER3) enzimski inertan. Pokazalo se da se aktivnost kinaze HER2, također, aktivira djelovanjem prekomjerne ekspresije samog receptora u raznim tipovima stanica. Aktivacija receptornih homodimera i heterodimera dovodi do fosforilacije tirozinskih ostataka na receptorima i drugim unutarstaničnim proteinima. Ovo je praćeno aktivacijom unutarstaničnih signalnih puteva, kao što su oni, koji uključuju protein kinazu povezanu sa mikrotubulima (MAP kinaza) i fosfatidilinozitol 3-kinazu (PI3 kinaza). Pokazalo se da aktiviranje ovih puteva dovodi do stanične proliferacije i inhibicije apoptoze. Pokazalo se da se inhibicijom signaliziranja HER kinaze inhibira stanična proliferacija i preživljavanje.
Sažetak
Spojevi izuma inhibiraju aktivnost tirozin kinaze receptora faktora rasta, kao što su HER1, HER2 i HER4 i kao takvi, mogu se upotrijebiti za liječenje bolesti koje su povezane sa putevima signalne transdukcije, a koji se ostvaruju preko receptora faktora rasta. Na primjer, spojevi ovog izuma se mogu koristiti kao antiproliferativna i antitumorska sredstva. Preciznije, izum obuhvaća spoj formule I
[image]
njegove enantiomere, dijastereomere i njegove farmaceutski prihvatljive soli, prolijekove i solvate, u kojima je R odabran iz grupe, koja se sastoji od: SR2, SOR2, SO2R2, OR2 i NR3R4; R1 je odabran iz grupe, koju čine: aril, supstituirani aril, heterociklo i supstituirani heterociklo; R2 je odabran iz grupe, koju čine: vodik, alkil, supstituirani alkil, aril, supstituirani aril, aralkil, heterociklo i supstituirani heterociklo; R3 i R4 su nezavisno odabrani iz grupe, koja se sastoji od: vodika, alkila, supstituiranog alkila, arila, supstituiranog arila, heterociklo i supstituiranog heterociklo; ili R2 i R3 mogu zajedno tvoriti po izboru supstituirani monociklični, zasićeni ili nezasićeni, karbociklični ili heterociklični prsten sa 4-8 članova ili po izboru supstituirani biciklični, zasićeni ili nezasićeni, karbociklični ili heterociklični prsten sa 7-12 članova.
Također, omogućen je i postupak za liječenje proliferativnih bolesti, koji obuhvaća primjenjivanje toplokrvnim vrstama, kojima je to potrebno, terapeutski djelotvorne količine spoja formule I.
Opis
Ovaj izum osigurava spojeve formule I, farmaceutske smjese koje sadrže te spojeve i postupke za upotrebu takvih smjesa. U skladu sa ovim izumom, spojevi sa formulom I:
[image]
njihovi enantiomeri, dijastereomeri i njihove farmaceutski prihvatljive soli, prolijekovi i solvati inhibiraju aktivnost tirozin kinaze receptora faktora rasta, kao što je HER2. U formuli I, kroz cijeli opis patenta, gornji simboli su definirani, kao što slijedi:
R je odabran od: SR2, SOR2, SO2R2, OR2, NR3R4;
R1 je: aril, supstituirani aril, heterociklo, supstituirani heterociklo;
R2 je: vodik, alkil, supstituirani alkil, aril, supstituirani aril, aralkil, heterociklo i supstituirani heterociklo;
R3 i R4 su, nezavisno: vodik, alkil, supstituirani alkil, aril, supstituirani aril, heterociklo i supstituirani heterociklo ili R2 i R3 mogu zajedno tvoriti po izbom supstituirani monociklični, zasćeni ili nezasićeni, karbociktični ili heterodkličnl prsten sa 4-8 članova ili po izboru supstituirani biciklični zasićeni ili nezasićeni, karbociklični ili heterociklični prsten sa 7-12 članova.
Ispod su navedene definicije raznih izraza, koji su korišteni za opis ovog izuma. Ove definicije se primjenjuju na izraze kako su korišteni kroz ovaj opis patenta osim, ukoliko nije drugačije ograničeno u posebnim slučajevima, bilo pojedinačno ili kao dio veće grupe.
Izraz "alkil" se odnosi na pravi ili razgranati lanac nesupstituiranih ugljikovodičnih grupa od 1 do 20 ugljikovih atoma, poželjno, 1 do 7 atoma ugljika. Izraz "niži alkil" se odnosi na nesupstituirane alkilne grupe od 1 do 4 atoma ugljika.
Izraz "supstituirani alkil" se odnosi na alkilnu grupu, supstituiranu sa, na primjer, jednim do četiri supstituenta, kao što su: halo, hidroksi, alkoksi, okso, alkanoil, ariloksi, alkanoiloksi, amino, alkilamino, arilamino, aralkilamino, disupstituirani amini u kojima su 2 amino supstituenta odabrana od: alkila, arila ili aralkila; alkanoilamino, aroilamino, aralkanoilamino, supstituirani alkanoilamino, supstituirani arilamino, supstituirani aralkanoilamino, tiol, alkiltio, ariltio, aralkiltio, alkiltiono, ariltiono, aralkiltiono, alkilsulfonil, arilsulfonil, aralkilsulfonil, sulfonamido, npr. SO2NH2, supstituirani sulfonamido, nitro, cijano, karboksi, karbamil, npr. CONH2, supstituirani karbamil, npr. CONHalkil, CONH aril, CONH aralkil ili slučajevi u kojima postoje dva supstituenta na dušiku, odabrana od: alkila, arila ili aralkila; alkoksikarbonil, aril, supstituirani aril, gvanidino, heterociklo, npr. indolil, imldazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil, pirolidinil, pipeidinil, morfolinil, piperazinil, homopiperazinil i sl. i supstituirani heterociklo. Gdje je gore napomenuto, gdje je supstituent dalje supstituiran, to će biti sa: alkilom, alkoksi, arilom ili aralkilom.
Izraz "halogen" ili "halo" se odnosi na fluor, klor, brom i jod.
Izraz "aril" se odnosi na monociklične ili biciklične aromatične ugljikovodične grupe koje imaju 6 do 12 atoma ugljika u udjelu prstena, kao što su: fenil, naftil, bifenil i difenil grupe, od kojih svaka može biti supstituirana.
Izraz "aralkil" se odnosi na aril ili supstituiranu aril grupu, vezanu direktno preko alkil grupe kao što je benzil.
Izraz "supstituirani aril" se odnosi na arilnu grupu, supstituiranu sa, na primjer, jednim do četiri supstituenta, kao što su: alkil, alkenil, supstituirani alkenil, alkinil, supstituirani alkinil, aril, supstituirani aril, aralkil, halo, trifluorometoksi, trifluorometil, hidroksi, alkoksi, alkanoil, akanoitoksi, ariloksi, aralkiloksi, amino, alkilamino, arilamino, aralkilamino, dialkilamino, alkanoilamino, tiol, alkiltio, ureido, nitro, cijano, karboksi, karboksiatkil, karbamil, alkoksikarbonil, alkiltiono, ariltiono, arilsulfonilamin, sulfonska kiselina, alkilsulfonil, sulfonamido, ariloksi i sl. Supstituent može dalje biti supstituiran sa: hidroksi, halo, alkil, alkoksi, alkenil, alkinil, aril ili aralkil.
Izraz "heteroaril" se odnosi na po izboru supstituiranu, aromatičnu grupu, na primjer, koja je monociklični sa 4 do 7 članova, biciklični sa 7 do 11 članova ili triciklični sa 10 do 15 članova sustav prstena, koji u prstenu ima najmanje jedan heteroatom i najmanje jedan atom ugljika, na primjer, piridin, tetrazol, indazol.
Izraz "alkenil" se odnosi na ravni ili razgranati lanac ugljikovodičnih grupa od 2 do 20 atoma ugljika, poželjno, 2 do 15 atoma ugljika i najveću prednost imaju sa 2 do 8 ugljikovih atoma, a koji ima jednu do četiri dvostruke veze.
Izraz "supstituirani alkenil" se odnosi na alkenil grupu, supstituiranu sa, na primjer, jednim do dva supstituenta, kao što je: halo, hidroksi, alkoksi, alkanoil, alkanoiloksi, amino, alkilamino, dialkilamino, alkanoilamino, tiol, alkiltio, alkiltiono, alkilsulfonil, sulfonamido, nitro, cijano, karboksi, karbamit, supstituirani karbamil, gvanidino, indolil, imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil i slični.
Izraz "alkinil" se odnosi na ravni ili razgranati lanac ugljikovodičnih grupa od 2 do 20 atoma ugljika, poželjno, 2 do 15 atoma ugljika i najveću prednost imaju sa 2 do 8 ugljikovih atoma, a koji ima jednu do četiri trostruke veze.
Izraz "supstituirani alkinil" se odnosi na alkinu grupu, supstituiranu sa, na primjer, supstituentom, kao što je: halo, hidroksi, alkoksi, alkanoil, alkanoiloksi, amino, alkilamino, dialkilamino, alkanoilamino, tiol, alkiltio, alkiltiono, alkilsulfinil, sulfonamido, nitro, cijano, karboksi, karbamil, supstituirani karbamil, gvanidino i heterociklo, npr., imidazolil, furil, tienil, tiazolil, pirolidil, piridil, pirimidil i slični.
Izraz "cikloalkil" se odnesi na po izboru supstituirane, zasićene ciklične ugljikovodične sustave prstena, koji poželjno sadrže 1 do 3 prstena i 3 do 7 ugljika po prstenu, koji može dalje biti spojen sa nezasićenim C3-C7 karbocikličnim prstenom. Grupe, kao primjeri, obuhvaćaju: ciklopropil, ciklobutil, ciklopentil, cikloheksil, cikloheptil, ciklooktil, ciklodecil, ciklododecil i adamantil. Supstituenti, kao primjeri, uključuju jednu ili više alkil grupa, kao što su gore opisane ili jednu ili više grupa, opisanih gore kao alkil supstituenti.
Izrazi "heterocikl", "heterociklični" i "heterociklo" se odnose na po izboru supstituiranu, potpuno zasićenu ili nezasićenu, aromatičnu ili nearomatičnu cikličnu grupu, na primjer, koja je monociklični sa 4 do 7 članova, biciklični sa 7 do 11 članova ili triciklični sa 10 do 15 članova sustav prstena, koji u prstenu ima najmanje jedan heteroatom i najmanje jedan atom ugljika. Svaki prsten heterociklične grupe, koji sadrži heteroatom može imati 1, 2 ili 3 heteroatoma, odabrana od atoma dušika, atoma kisika i atoma sumpora, gdje heteroatomi dušika i sumpora mogu također, po izboru biti oksidirani, a heteroatomi dušika mogu, isto tako, po izboru bili kvatemizirani. Heterociklična grupa može biti vezana na bilo kojem heteroatomu ili atomu ugljika.
Monociklične heterociklične grupe, kao primjeri, obuhvaćaju: pirolidinil, pirolil, indolil, pirazolil, oksetanil, pirazolinil, imidazolil, imidazolinil, imidazolidinil, oksazolil, oksazolidinil, izoksazolinil, izoksazolil, tiazolil, tiadiazolit, tiazolidinil, izotiazolil, izotiazolidinil, furil, tetrahidrofuril, tienil, oksadiazolil, piperidinil, piperazinil, 2-oksopiperazinil, 2-oksopiperidinil, homopiperazinil, 2-oksohomopiperazinil, 2-oksopirolidinil, 2-oksazepinil, azepinil, 4-piperidonil, piridil, N-okso-piridil, pirazinil, pirimidinil, piridazinil, tetrahidropiranil, morfolinil, tiamorfolinit, tiamorfolinil sulfoksid, tiamorfolinil sulfon, 1,3-dioksolan i tetrahidro-1,1-dioksotienil, dioksanil, izotiazolidinil, tietanil, tiiranil, triazinil i triazolil i slične.
Biciklične heterociklične grupe, kao primjeri, obuhvaćaju: 2,3-dihidro-2-okso-1H-indolil, benzotiazolil, benzoksazolil, benzotienil, kinuklidinil, kinolinil, kinolinil-N-oksid, tetrahidroizokinolinil, izokinolinil, benzimidazolil, benzopiranil, indolizinil, benzofuril, kromonil, kumarinil, cinolinil, kinoksalinil, indazolil, pirolopiridil, furopiridinil (kao što je furo[2,3-c]piridinil, furo[3,1-b]piridinil ili furo[2,3-b]piridinil), dihidroizoindolil, dihidrokinazolinil (kao što je 3,4-dihidro-4-okso-kinazolinil), benzizotiazolil, benzizoksazolil, benzodiazinil, benzofurazanil, benzotiopiranil, benzotriazolil, benzpirazolil, dihidrobenzofuril, dihidrobenzotienil, dihidrobenzotiopiranil, dihidrobenzotiopiranil sulfon, dihidrobenzopiranil, indolinil, indazolil, izokromanil, izoindolinil, naftiridinil, ftalazinil, piperonil, purinil, piridopiridil, kinazolinil, tetrahidrokinolinil, tienofuril, tienopiridil, tienotienil i slične.
Supstituenti, kad primjeri uključuju jednu ili više alkil ili aralkil grupa, kao što su gore opisane ili jednu ili više grupa, opisanih gore kao alkil supstituenti. Također, uključeni su i manji heterociklo, kao što su epoksidi i aziridini.
Izraz "karbociklični prsten" se odnosi na stabilne, zasićene ili djelomično nezasićene, monociklične ugljikovodične prstenove sa od 3 do 7 atoma ugljika, kao što su: ciklopropil, ciklobutil, ciklopentil, cikloheksil i cikloheptil. Izraz "po izboru supstituiran", kada se odnosi na "karbociklični prsten", ovdje označava da karbociklični prsten može biti supstituiran na jednom ili više pogodnih položaja prstena, sa jednom ili više grupa, koje su nezavisno odabrane od: alkila (prednost ima niži alkil), alkoksi (prednost ima niži alkoksi), nitro, monoalkilamino (prednost ima niži alkilamino), dialkilamino (prednost ima di[niži]alkilamino), cijano, halo, haloalkila (prednost ima trifluorometil), alkanoila, aminokarbonila, monoalkilaminokarbonila, dialkilaminokarbonila, alkil amido (prednost ima niži alkil amido), alkoksialkila (prednost ima niži alkoksi[niži]alkil), alkoksikarbonila (prednost ima niži alkoksikarbonil), alkilkarboniloksi (prednost ima niži alkilkarboniloksi) i arila (prednost ima fenil), navedeni aril je po izboru supstituiran sa: halo, nižim alkil i nižim alkoksi grupama.
Izraz "heteroatom" će obuhvatiti: kisik, sumpor i dušik.
Spojevi formule I mogu tvoriti soli, koje su, također, u okviru cilja ovog izuma. Prednost imaju farmaceutski prihvatljive (tj. neotrovne, fiziološki prihvatljive) soli, iako su i druge soli isto tako korisne, npr. u izoliranju ili pročišćavanju spojeva ovog izuma.
Spojevi formule I mogu tvoriti soli sa alkalnim metalima, kao što su: natrij, kalij i litij, sa zemno-alkalnim metalima, kao što su kalcij i magnezij, sa organskim bazama, kao što su: dicikloheksilamin, tributilamin, piridin i aminokiseline, kao arginin, lizin i slične. Takve soli se mogu tvoriti kao što je poznato stručnjacima u ovom području.
Spojevi formule I mogu tvoriti soli sa raznolikim organskim i anorganskim kiselinama. Takve soli uključuju one, koje nastaju sa: vodik kloridom, vodik bromktom, metansuffbnskom kiselinom, sumpornom kiselinom, octenom kiselinom, trifluorooctenom kiselinom, oksalnom kiselinom, mateinskom kiselinom, benzensulfonskom kiselinom, toluensulfonskom kiselinom i brojnim drugim (npr. nitrati, fosfati, borati, tartarati, citrati, sukcinati, benzoati, askorbati, salidlati i slično). Takve soli se mogu tvoriti, kao što je poznato stručnjacima u ovom području.
Osim toga, mogu se formirati zwitterioni ("unutrašnje" soli).
Svi stereoizomeri spojeva ovog izuma su razmotreni bilo u pomiješanoj ili u čistoj ili u biti čistoj formi. Definicija spojeva u skladu sa pronalskom obuhvaća sve moguće stereoizomere i njihove smjese. Veoma iscrpno obuhvaća racemične oblike i izdvojene optičke izomere koji imaju specifičnu aktivnost. Racemični oblici se mogu razdvojiti fizičkim postupcima, kao što su, na primjer, frakcijska kristalizacija, razdvajanje ili kristalizacija dijastereomernih derivata ili razdvajanje kiralnom kromatografijom na koloni. Pojedinačni optički izomeri se mogu dobiti iz racemata konvencionalnim postupcima, kao što su, na primjer, stvaranje soli sa optički aktivnom kiselinom, a odmah zatim, kristalizacija.
Spojevi formule I mogu, isto tako, imati prolijek oblike. Svaki spoj koji će biti preveden in vivo u bioaktivno sredstvo (tj. spoj za formule I) je prolijek u okviru cilja i smisla izuma.
Raznovrsni oblici prolijekova su dobro poznati u struci. Za primjere takvih prolijek derivata, vidi:
a) Desian of Prodrugs. edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymoloay. Vol.42, p.309-396, edited by K. Widder, et al. (Academic Press, 1985);
b) A Textbook of Drug Desian and Development. edited by Krosgaard-Larsen and H. Bundgaard, Chapter 5, "Design and Application of Prodrugs", byH. Bundgaard, p.113-191 (1991);
c) H. Bundgaard, Advanced Drug Delivery Reviews. 8.1-38 (1992);
Treba dalje razumjeti da su, isto tako i solvati (npr. hidrati) spojeva formule I u okviru cilja ovog izuma. Postupci solvatacije su općenito poznati u struci.
U ostvarenju koje ima prednost, izum obuhvaća spoj formule II,
[image]
njegove enantiomere, dijastereomere i njihove farmaceutski prihvatljive soli, prolijekove i solvate, u kojima je R isto, kao što je prethodno gore definirano.
U još jednom ostvarenju koje ima prednost, izum obuhvaća spoj formule III
[image]
njegove enantiomere, dijastereomere i njihove farmaceutski prihvatljive soli, prolijekove i solvate, u kojima je R isto, kao što je prethodno gore definirano.
U opet drugom ostvarenju, izum obuhvaća spoj formule IV,
[image]
njegove enantiomere, dijastereomere i njihove farmaceutski prihvatljive soli, prolijekove i solvate, u kojima je R isto, kao što je prethodno gore definirano.
Primjena i upotreba
Ovaj izum je zasnovan na otkriću da su izvjesni pirolotriazini inhibitori protein kinaza. Preciznije, pirolotriazini, kao što su oni opisani u ovom izumu, inhibiraju aktivnost tirozin kinaze proteina dlanova HER porodice receptora. Ovi inhibitori će biti korisni u liječenju proliferativnih bolesti, koje zavise od signaliziranja jednog ili više ovih receptora. Takve bolesti obuhvaćaju: psorijazu, reumatoidni artritis i solidne tumore pluća, glave i vrata, grudi, kolona, ovarija i prostate. Izum se odnosi na farmaceutsku smjesu spoja formule I ili njegove farmaceutski prihvatljive soli ili hidrata i farmaceutski prihvatljivog nosača u liječenju hiperproliferativnog poremećaja kod sisavca. Opširnije, od navedene farmaceutske smjese se očekuje da inhibira rast onih primarnih i rekurentnih solidnih tumora, koji su u vezi sa HER1 (EGF receptor) i HER2 posebno, onih tumora koji značajno u svom rastu i širenju zavise od HER1 ili HER2, uključujući, na primjer, tumore: mokraćnog mjehura, skvamoznih stanica, glave, kolorektalne, ezofagealne, ginekološke (kao što su ovarijalni), pankreasne, dojki, prostate, vulve, kože, mozga, genitourinarnog trakta, limfatičnog sustava (kao što je tiroidea) želuca, larinksa i pluća. U drugom ostvarenju, spojevi ovog izuma su, također, korisni za liječenje netumoroznih poremećaja, kao što je psorijaza i reumatoidni artritis.
Tako je u skladu sa slijedećim aspektom izuma omogućena upotreba spoja formule I ili njegove farmaceutski prihvatljive soli u proizvodnji lijeka, koji se koristi za proizvodnju antiproliferativnog učinka kod toplokrvnih životinja, kao što je ljudsko biće.
U skladu sa slijedećim obilježjem izuma, omogućen je postupak za proizvodnju antiproliferativnog učinka kod toplokrvnih životinja, kao što je ljudsko biće, kojima je takvo liječenje potrebno, a koji obuhvaća primjenu navedenim životinjama djelotvorne količine spoja formule I ili njegove farmaceutski prihvatljive soli, kao što je ovdje prethodno definirana.
Na osnovu njihove sposobnosti da inhibiraju HER1, HER2 i HER4 kinaze, spojevi ovog izuma se mogu koristiti za liječenje proliferativnih bolesti, uključujući psorijazu i tumor. Pokazalo se da se kinaza HER1 receptora ekspresira i aktivira u mnogim solidnim tumorima, uključujući tumor: glave i vrata, prostate, ne-mikrocelularni pluća, kolorektalni i tumor dojki.
Slično, pokazalo se da se kinaza HER2 receptora prekomjerno ekspresira u tumoru dojki, ovarija, pluća i želuca. Monoktonska antitijela, koja nishodno reguliraju obilje HER2 receptora ili inhibiraju signaliziranje HER1 receptora, pokazala su anti-tumorsko djelovanje u prekliničkim i kliničkim ispitivanjima. Zbog toga se očekuje da će inhibitori HER1 i HER2 kinaza imati učinka u liječenju tumora koji zavise od signaliziranje bilo kojeg od dva receptora. Osim toga, ovi spojevi će imati djelovanje u inhibiranju tumora koji se oslanjaju na signaliziranje heterodimera HER receptora. Od ovih spojeva se očekuje da budu djelotvorni bilo kao pojedinačno sredstvo, bilo u kombinaciji (istovremeno ili postepeno) sa drugim kemoterapeutskim sredstvima, kao što su Taxol, adriamicin i cisplatin. Kako je pokazano da signaliziranje HER1 i HER2 regulira ekspresiju angiogenih faktora, kao što su vaskularni endotelni faktor rasta (VEGF) i interleukin 8 (IL8), od ovih spojeva se očekuje da imaju antitumorsko djelovanje proizašlo iz inhibicije angiogeneze pored inhibicije proliferacije stanica tumora i preživljavanja. Pokazano je da je HER2 receptor uključen u hiperproliferaciju sinovijalnih stanica u reumatoidnom artritisu i da može doprinijeti angiogenoj komponenti tog stanja upalne bolesti. Od inhibitora, opisanih u ovom izumu se, zbog toga, očekuje da budu djelotvorni u liječenju reumatoldnog artritisa. Sposobnost ovih spojeva da inhibiraju HER1 dalje povećava njihovu upotrebljivost kao anti-angiogenih sredstava. Vidi slijedeće dokumente i reference, koji su ovdje citirani: Schlessinger J., "Cell signaling by receptor tvrosine kinases", Cell. 103(2), p.211-225(2000); Cobteigh, M.A., Vogel, C.L., Tripathy, D., Robert, NJ., Scholl, S., Fehrenbacher, L., Wolter, J.M., Paton, V. Shak, S., Lieberman, G., and Slamon, D.J., "Multinational study of the efficacy and safety of humanized anti-HER2 monodonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease", J. of Ctin. 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 t studies of anti-epidermal growth factor receptor chimeric antibody C225 atone and in combination with cisplatin", J. din, Oncol. 18(4), p.904-914(2000); Satoh, K., Kikuchi, S., Sekimata, M., Kabuyama, Y„ Homma, M.K., and Homma Y. -Involvement of ErbB-2 in rheumatoid synovial cell growth", Arthritis Rheum. 44(2), p.260-265(2001).
Antiproliferativni tretman, koji je ovdje prethodno definiran, može se primijeniti kao samostalna terapija ili može uključiti, osim spoja izuma, jednu ili više supstanci i/Hi tretmana. Takav združeni tretman se može postići istovremenom, sekvencijalnom ili zasebnom primjenom pojedinačnih komponenti tretmana. Spojevi ovog izuma mogu, također, biti korisni u kombinaciji sa poznatim anti-tumorskim i citotoksičnim sredstvima i tretmanima, uključujući zračenje. Ukoliko su formulirani kao fiksna doza, takvi kombinirani proizvodi obuhvaćaju spojeve ovog izuma u okviru doznog opsega opisanog ispod, kao i drugo farmaceutski prihvatljivo sredstvo u okviru svog odobrenog doznog raspona. Kada je kombinirana formulacija neodgovarajuća, spojevi formule I se mogu koristiti u nizu sa poznatim antitumorskim ili citotoksičnim sredstvima i tretmanom, uključujući zračenje.
U području medicinske onkotogije, normalna je praksa u liječenju svakog pacijenta oboljelog od raka, upotreba kombinacije različitih oblika tretmana, U medicinskoj ontologiji, druga komponenta(e) takvog združenog tretmana, osim antiproltferativnog tretmana koji je prethodno ovdje definiran, može biti: kirurgija, radioterapija ili kemoterapija. Takva kemoterapija može obuhvatiti tri glavne kategorije terapeutskog sredstva:
(i) antiangiogena sredstva koja djeluju različitim mehanizmima od onih, koja su ovdje prethodno definirana (na primjer, linomid, inhibitori funkcije integrina αvβ3, angiostatin, razoksin);
(ii) citostatska sredstva, kao što su: antiestrogeni (na primjer, tamoksifen, toremifen, raloksifen, dioloksifen, jodoksifen), progestogeni (na primjer, megestrol acetat), inhibitori aromataze (na primjer, anastrozol, letrazol, borazol, egzemestan), anti-neoplastična hormonska sredstva, antiprogestogeni, antiandrogeni (na primjer, flutamid, nilutamid, bikalutamid, ciproteron acetat), LHRH agonisti i antagonisti (na primjer, gozerelin acetat, luprolid), inhibitori testosteron 5α-dihidroreduktaze (na primjer, finasterid), inhibitori farneziltransferaze, anti-invazijska sredstva (na primjer, inhibitori metaloproteinaze, kao marimastat i inhibitori funkcije receptom urokinaze aktivatora plazminogena) i inhibitori funkcije drugih faktora rasta (takvi faktori rasta uključuju, na primjer, FGF, faktor rasta iz trombocita i hepatocitni faktor rasta, takvi inhibitori obuhvaćaju antitijela na faktore rasta, antitijela na roceptore faktora rasta, inhibitore tirozin kinaze i inhibitore serin/treonin kinaze); i
(iii) antlproliferativne/antineoplasttčne lijekove i njihove kombinacije, kako se koriste u medicinskoj ontologiji, kao što su: antimetaboliti (na primjer, antifolati, kao metotreksat, fluoropirimidini, kao 5-fluorouracil, anatozi purina i adenozina, citozin arabinozid); interkalirajući antitumorski antibiotici (na primjer, antraciklinl, kao doksorubicin, daunomicin, eprrubictn i idarubtcln, mitomkan-C, daktinomicin, mitramitin); derivati platine (na primjer, cisplatin, karboplatin); alkilirajuća sredstva (na primjer, dušikov iperit, melfalan, klorambucil, busulfan, ciklofosfamid, ifosfamid nitrozourea, tiotefan); antimtiotička sredstva (na primjer, vinka atkatoidi, kao vinkristin i taksoidi, kao taksol, taksoter i novija mikrotubulska sredstva, kao što su analozi epotilona, diskodermolida i eleuterobrna); inhibltori topoizomeraze (na primjer, epipodofilotoksini, kao etopozid i tenipozid, amsakrin, topotekan); inhibitori staničnog ciklusa (na primjer, flavopiridoli); i sredstva koja mijenjaju biološki odgovor.
Kao što je gore navedeno, spojevi formule I ovog izuma su od značaja zbog njihovih antiproliferativnih učinaka. Od takvih spojeva izuma se očekuje da budu korisni za širok raspon stanja bolesti, koje obuhvaćaju: rak, psorijazu i reumatoidni artritis.
Preciznije; spojevi formule I su korisni u liječenju raznovrsnih tumora, koji uključuju (ali nisu njima ograničeni) slijedeće:
- karcinom, koji obuhvaća karcinom: mokraćnog mjehura, dojki, kolona, bubrega, jetre, pluća, uključujući mikrocelularni karcinom pluća, jednjaka, žučne vrećice, ovarija, pankreasa, želuca, cerviksa, tireoldeje, prostate, kože, uključujući karcinom skvamoznih stanica;
- tumore mezenhimnog porijekla, uključujući fibrosarkom i rabdomiosarkom;
- tumore centralnog i perifernog nervnog sustava, uključujući astrocitom, neuroblastom, gliom i schwannom; i
- druge tumore, uključujući metanom, seminom, teratokarcinom i osteosarkom.
Zahvaljujući ključnoj ulozi kinaza u regulaciji proliferacije stanica općenito, inhibitori mogu djelovati kao reverzibilna citostatska sredstva, koja mogu biti korisna u tretmanu bilo kojeg procesa bolesti koji se odlikuje nenormalnom proliferacijom stanica, npr. benigna hiperplazija prostate, obiteljska adenomatozna polipoza, neuro-fibromatoza, fibroza pluća, artritis, psorijaza, glomerulonelitis, restenoza po angioplastici ili vaskularnoj kirurškoj intervenciji, stvaranje hipertrofičnog ožiljka i inflamatorna bolest crijeva.
Spojevi formule I su osobito korisni u tretmanu tumora, koji imaju visoku incidenciju aktivnosti tinozin kinaze, kao što su tumori kolona, pluća i pankreasa. Primjenjivanjem smjese (ili kombinacije) spojeva ovog izuma, razvoj tumora kod domaćina sisavca je smanjen.
Spojevi formule I mogu, isto tako, biti korisni u tretmanu bolesti koje nisu rak, a mogu biti povezane sa putevima signalne transdukcije koja se ostvaruje preko receptora faktora rasta, kao što su HER1 (EGF receptor), HER2 ili HER4.
Spojevi ovog izuma se mogu oblikovati sa farmaceutskim nosačem ili punilom za oralno, intravensko ili subkutano primjenjivanje. Farmaceutska smjesa se može oblikovati na klasičan način upotrebom čvrstih ili tekućih nosača, punila i aditiva, koji su odgovarajući za željeni način primjene. Oralno, spojevi se mogu primijeniti u obliku tableta, kapsula, granula, praškova i slično. Spojevi se mogu primijeniti u opsegu doza od oko 0.05 do 200 mg/kg/dan, prednost ima manje od 100 mg/kg/dan u jednoj dozi ili u 2 do 4 podijeljene doze.
Biološki testovi
Testovi HER1, HER2 ILI HER4 kinaze:
Spojevi od značaja su testirani u puferu kinaze, koji je sadržavao 20 mM Tris.HCl,pH 7.5, 10 mM MnCl2, 0.5 mM ditlotrertola, goveđeg serum albumina u 0.1 mg/ml, poli(glu/tyr, 4:1) u 0.1 mg/ml, 1μM ATP-a i 4 μCi/ml [γ-33P]ATP. Poli(glu/Ayr,4:1) je sintetički polimer koji služi kao akceptor fosforite i nabavljen je od Sigma Chemicals. Reakcija kinaze Je otpočeta dodatkom enzima, a reakcijske smjese su inkubirane na 26°C u toku 1 h. Reakcija je završena dodatkom EDTA do 50 mM, a dodatkom triktoroctene kiseline do 5% su istaloženi proteini, (staloženi proteini su obnovljeni filtracijom na Packard Unifilter pločama i količina ugrađene radioaktivnosti je izmerena u Topcount scintilacijskom brojaču.
Za izradu rekombinantnih HER1 i HER4, izvršena je ekspresija citoplazmatskih sekvenci receptora u stanicama insekta, kao GST fuzijskih proteina, koji su pročišćeni afinitetnom kromatografijom. Citoplazmatska sekvenca HER2 je subklonirana u bakulovirusni ekspresijski vektor pBlueBac4 (Invitrogen) i ekspresirana kao neobilježeni protein u stanicama insekta. Rekombinantni protein je djelomično pročišćen iono-izmjenjivačkom kromatografijom.
Sadašnji spojevi inhibiraju HER1, HER2 i HER4 kinaze sa vrijednostima IC50 između 0.001 –25μM. Spojevi koja imaju prednost imaju vrijednosti IC50 između 0.001-5.0 μM. Još poželjniji spojevi imaju vrijednosti IC50 između 0.001-1.0 μM. Najveću prednost imaju spojevi sa vrijednostima IC50 između 0.001-0.1 μM.
Da bi se ispitali spojevi na HERG aktivnost (vidi Caballero R, et al., Direct Effects of Candesartan and Eprosartan on Human Cloned Potasslum Channels Invotved in Cardiac Repolarization, Molecular Pharmacology, Vol. 59, No., 4, pp. 825-36, 2001) može se upotrijebiti test HERG kalij kanala. Prema tome, spojevi koji imaju prednost, imaju nižu aktivnost HERG testa.
Postupci izrade
Neki spojevi formule I mogu općenito biti pripremljeni u skladu sa slijedećim shemama i znanjem stručnjaka u. ovom području. Dodatna proizvodna informacija se, isto tako, može naći u US patentnoj prijavi, koja je zajedno u postupku, serijski broj 09/573,829, podnesenoj 18. svibnja 2000. i međunarodnoj prijavi, objavljenoj pod Patent Cooperation Treaty (PCT), International Publication Number WO00/71129, obje su ovdje obuhvaćene kao reference.
Shema 1
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Korak 1
Prvi korak iz Sheme 1 se izvodi obradom estera 3-metil-1H-pirol-2-karboksilne kiseline i (T.D. Lash et al., J. Heterocyclic Chem., 1991,28,1671} sa bazom kao što je kalij t-butoksid ili natrij hidrid u bezvodnom otapalu, kao što je THF ili DMF, a poslije toga sa reagensom za aminaciju, kao što je 0-(2,4-dinitro-fenil)-hidroksilamin (T. Sheradsky, J. Heterocyclic Chem., 1967, 4, 413) ili kloramin (I.P. Sword, J. Chem. Soc. C, 1971, 820), kako bi se dobio pirolilamin ii.
Korak 2
Pirolilamin ii se zagrijava sa viškom formamida da bi se dobio pirolotriazinon iii.
Korak 3
Spoj iii se prevodi u 4-halo-pirolotriazin iv zagrijavanjem sa pogodnim fosfornim oksihalidom, npr. 4-kloro-pirolotriazin se dobije zagrijavanjem spoja iii sa fosfornim oksikloridom.
Korak 4
Halogeniranje 5-metil grupe spoja iv se izvodi obradom sa sredstvom za halogeniranje, kao što je N-bromosukcinimid ili sulfuril klorid. Reakcija se izvodi pod inertnom atmosferom, kao što je Na, u prisustvu katalizatora, kao što je dibenzoil peroksid ili 2,2'-azobisizobutironitril ili zračenja i daje 4-halo-5-halometil-pirolotriazin v.
Korak 5
Obrada spoja v sa tiolom, tiokarboksilnom kiselinom, vodom, alkoholom, karboksilnom kiselinom, primarnim ili sekundarnim aminom, u prisustvu baze, kao što je NaHCO3 ili trietilamin, u otapalu, kao što je acetonitril, proizvodi intermedijer vi u Shemi 1.
Korak 6
Obrada spoja vi sa 5-amino-indazol derivatom, na sobnoj temperaturi, u prisustvu baze, kao što je NaHCO3 ili trietilamin, u otapalu, kao što je acetonitril, daje konačni proizvod vii. Zagrijavanje spoja vi sa 5-amino-indazol derivatom, u odsustvu baze, također proizvodi spoj vii.
Shema 2
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Korak 1
Spoj vii (R=SR2) iz Sheme 1 se može oksidirati u sulfoksid, spoj i (n=1) ili sulfon, spoj l (n=2) iz Sheme 2, obradom sa odgovarajućom količinom oksidacijskog sredstva, kao što je m-kloroperbenzojeva kiselina.
Korak 2
5-aminometil derivat ii se dobije zagrijavanjem sulfoksida i (n=1) ili sulfona (n=2) u prisustvu viška alkohola ili primarnog ili sekundarnog amina.
Shema 3
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Korak 1
Alkoholna grupa u spoju vii (R=OH) iz Sheme 1 se može prevesti u odlazeću grupu, kao u spoju i iz Sheme 3. Mogu se uvesti raznolike odlazeće grupe, npr. obradom sa tionil kloridom dobije se klorid i (L=Cl), obradom sa metansulfonskim anhidridom i diizopropiletilaminom dobije se metansulfonat i (L=OSO2Me), esterifikacijom sa octenim anhidridom, u prisustvu diizopropiletilamina dobije se acetat i (L=OAc).
Korak 2
Za veoma reaktivne odlazeće grupe, kao što je klorid ili sulfonat, spoj i se prevodi direktno u spoj H iz Sheme 3 reakcijom sa alkoholom ili primarnim ili sekundarnim aminom, u prisustvu baze, kao što je diizopropiletilamin bez izoliranja spoja i. Za manje reaktivne odlazeće grupe, kao što su karboksilati, spoj i se zagrijava sa alkoholima ili primarnim ili sekundarnim aminima, u prisustvu baze, kao sto je diizopropiletilamin, da bi se dobio spoj ii.
Shema 4
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Korak 1
Ester 5-metil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline i (vidi WO 00/71129, koja je ovdje uključena kao referenca) se može saponificirati obradom sa bazom, kao što je vodena otopina LiOH, a zatim zakiseliti obradom sa kiselinom, kao što je HCl, kako bi se dobila karboksilna kiselina ii iz Sheme 4.
Korak 2
Karboksilna kiselina ii se dekarboksilira kako bi se dobio 6H-pirolotriazin-4-on iii. Ovo se može izvesti pod raznolikim uvjetima, na primjer, zagrijavanjem mješavine spoja ii u 85% H3PO4, na 110°C.
Korak 3
Ester i se može direktno prevesti u spoj iii, na primjer, zagrijavanjem mješavine spoja i u 85% H3PO4, na 110°C.
Korak 4
6H-pirolotriazin-4-on ili može se prevesti u spoj iv, kao što je prikazano u Shemi 1.
Shema 5
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Korak 1
Halogeniranje 5-metil grupe estera 4-halo-5-metil-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline i (vidi WO 00/71129, koja je ovdje uključena kao referenca) može se izvršiti obradom spoja l sa sredstvom za halogeniranje, kao što je N-bromosukcinimid ili sulfuril klorid. Reakcija se izvodi pod inertnom atmosferom, kao na primjer N2, u prisustvu katalizatora, kao što je dibenzoil peroksid ili 2,2'-azobisizobutironitril ili zračenja i daje 4-halo-5-halometil-pirolotriazin H iz Sheme 5.
Korak 2
Obrada spoja ii sa tiolom, alkoholom, primarnim ili sekundarnim aminom, u prisustvu baze, kao što je NaHCO3 ili trietilamin, u otapalu, kao što je acetonitril, proizvodi intermedijer iii.
Korak 3
Obrada spoja iii sa supstituiranim derivatom 5-amino-indazola, u prisustvu baze, kao što je NaHCO3 ili trietilamin, u otapalu, kao što je acetonitril, daje spoj iv.
Korak 4
Ester iv može se saponificirati obradom sa bazom, kao što je vodena otopina LiOH, a zatim zakiseli obradom sa kiselinom, kao što je HCl, kako bi se dobila karboksilna kiselina v iz Sheme 5.
Korak 5
Karboksilna kiselina v iz Sheme 5 se dekarboksilira zagrijavanjem da bi se dobio konačni proizvod vi.
Pored toga, drugi spojevi sa formulom I mogu se pripremiti upotrebom postupaka, koji su općenito poznati stručnjacima u ovom području. Posebno, slijedeći primjeri omogućuju dodatne postupke za izradu spojeva ovog izuma.
Izum će sada biti dalje opisan slijedećim radnim primjerom (primjerima) koji su poželjna ostvarenja izuma. Sve temperature su u stupnjevima Celzijusa (°C), ukoliko nije drugačije određeno. "HPLC Ret Time" je vrijeme zadržavanja na HPLC-u, koje je dobiveno pod slijedećim uvjetima: tip i dužina kolone, gradijentno vrijeme [ukoliko nije drugačije naznačeno, svi gradijenti startaju sa 100% otapala A (10% MeOH, 90% H2O, 0.1% TFA) i završavaju sa 100% otapala B (90% MeOH, 10% H2O, 0.1% TFA)], brzina protoka (ml/min). UV detekcija je uvijek Izvođena na 220 nM. Ovi primjeri su prije ilustrativni nego ograničavajući i treba razumjeti da mogu postojati druga ostvarenja, koja ulaze unutar cilja i okvira izuma, kako je definiran ovdje priključenim patentnim zahtjevima.
Primjer 1
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(5-benzensulfinmetil-pirolo[2,1-f][1,2,4]triazin-4-il)[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin
A. Izrada 5-metil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin-8-karboksilne kiseline
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Otopina LiOH (25 gm, 10 ekvivalenata) u vodi (416 mL) je dodana otopini metil estera 5-metil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline (23.0 gm, 0.104 mol) u mješavini THF (1.2 L) i MeOH (0.4 L). Ovo je zagrijavano na 65°C tijekom 20 h, a zatim je ukoncentrirano u vakuumu do oko 200 mL Dodana je voda (400 mL) i pH je doveden do 4 upotrebom konc. vodene HCl. Talog je sakupljen, ispran vodom i osušen kako bi se dobila kiselina (18.2 gm, 90%). 1H NMR (MeOH-D4) δ 2.67 (s, 3H), 7.63 (s, 1H), 7.84 (s, 1H). HPLC Ret Time: 0.97 min (YMC C18 S5, 4.6 x 50 mm kolona, 3 min gradijent, 4 mL/min).
B. Izrada 5-metil-3H-pirolo[2,1-f](1,2,4)triazin-4-ona
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Postupak I: Suspenzija 5-metil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline (18.1 gm, 93.7 mmol) u 85% vodenoj H3PO4 (250 mL) je zagrijavana na 110°C tijekom 3.5 h. Po hlađenju do RT, dodana je ledena voda (500 mL) i talog je sakupljen, ispran vodom i osušen. Ovo daje 5.8 gm proizvoda u obliku smeđe čvrste mase. Dodatnih 4.1 gm (ukupno 9.9 gm, 71%) proizvoda je dobiveno ekstrakcijom filtrata sa DCM-om (4 x 500 mL), sušenjem (Na2SO4) i ukianjanjem otapala. 1H NMR (CDC3) δ 2.54 (s, 3H), 6.35 (d, 1H, J=3 Hz), 7.31 (d, 1H, J=3 Hz), 7.42 (s, 1H), 9.52 (br s, 1H); HPLC Ret Time: 1.17 min (YMC C18 S5, 4.6 x 50 mm kolona, 3 min gradijent, 4 mL/min).
Postupak II: Suspenzija metil estera 5-metil-4-okso-3,4-dihidro-pirolo[2,1-f][1,2,4]triazin-6-karboksilne kiseline (5.81 gm, 0.028 mol) u 85% vodenoj H3PO4 (60 mL) Je zagrijavana na 110°C tijekom 6 h. Po hlađenju do RT, dodat je led (120 gm) i talog je sakupljen, ispran vodom i osušen da bi se dobio proizvod (3.47 gm, 83%).
Postupak III: Otopina metil estera 3-metil-1H-pirol-2-karboksilne kiseline (4.59 gm, 33 mmol) u suhom DMF-u (100 mL) dodana je polako u ledeno ohlađenu suspenziju NaH (1.72 gm, 60% disperzija u ulju, 1.3 ekvivalenta) u suhom DMF (300 mL). Poslije 30 minuta odjednom je dodan 0-(2,4-dinitro-fenil)-hidroksilamin (1.53 gm, 1.1 ekvivalent) i reakcijska mješavina je ostavljena da se miješa u ledenoj kupelji tijekom 1 h. Poslije 0.5 h, reakcijska mješavina je uklonjena iz kupelji i razrijeđena slanom otopinom. Izvedena je ekstrakcija sa EtOAc (3 puta), sjedinjeni ekstrakti su osušeni (Na2SO4), a otapala su odstranjena. Ostatak je podvrgnut kromatografiji na koloni silika gela (gradijent eluacije sa heksanom, koji sadrži 5 do 20% EtOAc), da bi se dobio metil ester 1-amino-3-metil-1H-pirol-2-karboksilne kiseline (2.96 gm, 58%) u obliku žute čvrste mase. 1H NMR (MeOH-D4) δ 2.25 (s, 3H), 3.81 (s, 3H), 5.83 (d, 1H, J=2 Hz), 6.82 (d, 1H, J=2 Hz); MS: 155 (M+H)+; HPLC Ret Time: 0.97 min (YMC Exterra ODS S7 3.0 x 50 mm, 2 min gradijent, 5 mL/min). Mješavina ovog 1-amino-pirola (2.96 gm, 19.2 mmol) u formamidu (30 mL) je zagrijavana na 165°C tijekom 10 h. Po hlađenju do RT, mješavina je razrijeđena hladnom vodom, a talog je sakupljen i ispran hladnom vodom, a zatim mješavinom EtaO i Mekšana (6:4). Ovo daje 5-metil-3H-pirolo[2,1-f][1,2,4]triazin-4-on (1.83 gm, 64%) u obliku smeđe čvrste mase.
C. Izrada 4-kloro-5-metil-pirolo[2,1-f][1.2,4]triazina
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Suspenzija 5-metil-3H-pirolo[2,1-f][1,2,4]triazin-4-ona (2.57 gm, 17.2 mmol) u POCl3 (28 mL) je zagrijavana na 100°C, tijekom 40 minuta. Višak reagensa je uklonjen pod vakuumom, a ostatak je otopljen u DCM-u (300 mL). Ovo je isprano vodom i osušeno (Na2SO4), a otapalo je uklonjeno. Podvrgavanjem flash kromatografiji na silika gelu, upotrebom DCM kao eluensa, dobiven je proizvod u obliku žute čvrste mase (2.38 grn, 82%). 1H NMR (CDCl3): δ 2.63 (8, 3H), 6.74 (d, 1H, J=2 Hz), 7.74 (d, 1H, J=2 Hz), 8.05 (s, 1H).
D. Izrada 5-bromometil-4-kloro-pirolo[2,1-f][1,2,4]triazina
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Otopina 4-kloro-5-metil-pirolo[2,1-f][1,2,4]triazina (2.32 gm, 14.0 mmol) u CCl4 (140mL) je punjena sa N2, tijekom 20 minuta. Dodani su N-bromosukcinlmid (2.60 gm, 1.05 ekvivalenata) i benzoil peroksid (60 mg) i mješavina je zagrijavana pod refluksom tijekom 1 h. Poslije hlađenja do RT, sukcinimid je uklonjen filtracijom. Otapalo je uklonjeno iz filtrata, a ostatak je brzo podvrgnut kromatografiji na kratkoj koloni silika gela, upotrebom, kao eluensa, DCM. Ovo daje 5-bromometil spoj u obliku žute čvrste mase (2.49 gm, 74%). 1H NMR (CDCl3): δ 4.96 (s, 2H), 7.03 (d, 1H, J=3 Hz), 7.80 (d, 1H, J=3 Hz), 8.21 (s,1H).
E. Izrada 1-(3-fluoro-benzil)-1H-indazol-5-ilamina
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Mješavina 5-nitro-1H-indazola (8.15 gm, 50 mmol), m-fluoro-benzil klorida (7.95 gm, 1.1 ekvivalent), K2CO3 (7.59 gm, 1.1 ekvivalent) i KJ (8.47 gm, 1.02 ekvivalent) u suhom DMF (75 mL) je zagrijavana na 70°C preko noći. Po hlađenju do RT, polako je dodana voda (75 mL), kako bi se dobio talog, koji se sastoji od, oko jedan na prema jedan, mješavine izomera [HPLC Ret Time: 1.92 (1-supstituirani izomer vs. 2.03 (2-supstituirani izomer) YMC C18 S5 4.6 x 50 mm, 3 min gradijent, 4 mL/min]. Ovo je sakupljeno filtracijom i isprano vodom. Čvrsta masa je dva puta kristalizirana iz aceton/vode, da bi se dobio željeni 1-(3-fluoro-benzil)-5-nitro-1H-indazol (4.47 gm, 33%). Suspenzija ovog materijala (3.00 gm, 11.1) i 10% Pd/C (3.00 gm) u EtOH (21 mL) su držani pod atmosferom H2 (balon) tijekom 24 h. Katalizator je uklonjen filtracijom, a otapalo je upareno da bi se odvojio proizvod u obliku čvrste mase (2.4 gm, 90%). 1H NMR (CDCl3) δ: 3.61 (br s, 2H), 5.52 (s, 2H), 6.81-7.85 (m, 7H), 7.85 (s, 1H); MS: 242 (M+H)+; HPLC Ret Time: 1.03 min (YMC Xterra ODS S7,3.0 x 50 mm kolona, 2 min gradijent, 5 mL/min).
F. Izrada (5-benzensulfinilmetil-pirolo[2,1-f][1,2,4]trlazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina
N2 je uvođen u otopinu 5-bromometil-4-kloro-pirolo[2,1-f][1,2,4]triazina (850 mg, 3.46mmol)u DCM-u (30 mL) tijekom 0.5 h, a zatim je stavljen u kupelj na -20°C. Dodani su tiofenol (384 μL, 1.0 ekvivalent) i diizopropitetilamin (605 μl, 1.0 ekvivalent) i reakcijska smjesa je držana na -20°C tijekom 3 h. Poslije zagrijavanja do RT, reakcijska smjesa je isprana vodom i osušena (Na2SO4), a otapalo je uklonjeno. Ostatku su dodani 1,2-dikloroetan (10 mL), n-butanol (10 mL) i 1-(3-fluoro-benzil)-1H-indazol-5-ilamin (750 mg, 0.9 ekvivalenata) i mješavina je zagrijavana na 85°C tijekom 2.5 h. Otapala su uklonjena, a ostatak je sakupljen u DCM-u, ispran je zasićenom vodenom otopinom NaHCO3 i osušen (Na2SO4). Uklanjanjem otapala, poslije čega slijedi podvrgavanje kromatografiji na silika getu, upotrebom DCM, koji sadrži 0 do 2% MeOH, kao eluensa, dobiven je [1-(3-fluoro-benzil)-1H-indazol-5-il]-(5-fenilsulfanilmetil-pitolo[2,1-f][1,2,4]triazin-4-il)-amin (957 mg, 58%) u obliku pjene. 1H NMR (CDCl3) δ 4.48 (s, 2H), 5.59 (s, 2H), 6.53 (d, 1H, J=3 Hz), 6.8-7.0 (m, 3H), 7,2-7.6 (m, 9H), 7.95 (s, 1H), 8.06 (s, 1H), 8.15 (d, 1H, J=2 Hz), 8.88 (br s, 1H); MS: 481 (M+H)+; HPLC Ret Time: 1.87 min (YMC S7 C18, 3.0 x 50 mm kolona, 2 min gradijent, 5 mL/mtn). Ovo je otopljeno u ktoroformu (25 mL) i ohlađeno u ledenoj kupelji i dodavana je m-ktoro-perbenzojeva kiselina (500 mg, 57 do 80%, 1 ekvivalent) u malim obrocima, tijekom 15 minuta. Poslije 1 h, reakcijska mješavina je isprana sa 10% vodenom otopinom NaHSO3 i zasićenom vodenom otopinom NaHCO3 (tri puta) i osušena je (Na2SO4). Uklanjanjem otapala ostaje proizvod u obliku pjene (957 mg, 95%). 1H NMR (COCl3) δ 4.28 (d, 1H, J=14 Hz), 4.53 (d, 1H, J=14 Hz), 5.60 (s, 2H), 6.13 (d, 1H, J=3 Hz), 6.8-7.6 (m, 11H), 7.71 (dd, 1H, J=2, 9 Hz), 7.98 (s, 1H), 8.05 (s, 1H), 8.14 (d, 1H, J=2 Hz); MS: 497 (M+H)+; HPLC Ret Time: 1.67 min (YMC S7 C18, 3.0 x 50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 2
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(5-[1,4]diazepan-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin
Mješavina (S-benzensulfinilmetil-piralo[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (50 mg, 0.101 mmol) i homopiperazina (300 mg, 30 ekvivalenata) u zapečaćenoj epruveti zagrijavana je na 135°C preko noći. Reakcijska mješavina je pokupljena u DCM-u, isprana vodom i osušena (Na2SO4). Uklanjanjem otapala, a poslije toga podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, uz eluaciju sa DCM-om, koji sadrži 5% MeOH), dobiven je spoj iz nastava, u obliku pjene (39 mg, 82%). 1H NMR (CDCl3) δ 1.85 (m, 2H), 2.96 (m, 8H), 3.91 (s, 2H), 5.58 (s, 2H), 6.50 (d, 1H, J=3 Hz), 6.8-7.6 (m, 7H), 7.89 (s, 1H), 8.05 (d, 1H, J=1 Hz), 8.11 (d, 1H, J=2 Hz); MS: 471 (M+H)+; HPLC Ret Time: 1.09 min (YMC Xtema ODS S7, 3.0 x 50 mm kolona, 2 min gradijent, 5 mL/min).
Primjeri 3 do 73
Slijedeći primjeri su pripremljeni na isti način kao i Primjer 2.
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Primjer 74
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1-{4-[1-3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-pirolidin-3-on
Tetrapropilamonij penrutenat (3.2 mg, 0.1 ekvivalent) je dodan izmiješanoj suspenziji 1-{4-[1-3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(3R)-pirolidin-3-ola (42 mg, 0.092 mmol), N-metilmorfolin N-oksida (16 mg, 1.5 ekvivalent) i osušenih, naprašenih 4A molekularnih sita (100 mg), u suhom DCM-u, pod N2. Poslije 0.75 h, tamno zelena suspenzija je filtrirana kroz kratki sloj silika gela, upotrebom, kao eluensa, etil acetat. Uklanjanjem otapala iz frakcija, koje sadrže proizvod, a zatim radijalnom kromatografijom (2 mm silika gel ploča, upotrebljavajući gradijent ispiranja sa mješavinom heksana, koja sadrži 30 do 50% EtOAc) dobiven je spoj iz naslova u obliku ulja (26 mg, 61%). MS: 456 (M+H)+; HPLC Ret Time: 1.28 min (YMC Xterra ODS S7 C18, 3.0 x 50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 75
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1-{4-[1-3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-on
Otopina [5-(1,4-dioksa-8-aza-spiro[4.5]dec-8-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil}-1H-indazol-5-il]-amina (54mg, 0.105mmol) u mješavini THF (1 mL) i 1N vodene HCl (1 mL), koja sadrži 16 kapi conc. HCl, ostavljena je da se miješa na RT, tijekom 7 dana. Reakcijska smjesa je razrijeđena sa DCM i neutralizirana zasićenom vodenom otopinom NaHCO3. Po sušenju (Na2SO4), otapalo je uklonjeno, da bi se izdvojilo naslovljeni spoj u obliku ulja (19 mg, 39%). MS; 488 (M+H2O+H)+; HPLC Ret Time: 2.35 min (YMC Xterra ODS S7 C18, 3.0 x 50 mm kolona, 5 min gradijent (komponenta B je varirala od 20 do 60%), 5 mL/min).
Primjer 76
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[1-(3-fluoro-benzil)-1H-indazol-5-il]-[5-(1-okso-1λ4-tiomorfolin-4-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
Otopina [1-(3-fluoro-benzil)-1H-indazol-5il]-[5-(tiomorfolin-4-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin (46 mg, 0.096 mmol) u kloroformu (2 mL) je ohlađena u ledenoj kupelji i dodavana je, dio po dio, tijekom 12 minuta, m-kloroperbenzojeva kiselina (26mg, 65%, 1 ekvivalent). Poslije 1 h, reakcijska mješavina je zatim razrijeđena kloroformom, isprana 6% vodenom otopinom NaHSO3 i zasićenom vodenom otopinom NaHCO3 i osušena (Na2SO4). Odstranjeno je otapalo i pročišćavanjem radijalnom kromatografijom (2 mm silika gel ploča, koristeći gradijent ispiranja sa DCM-om, koji sadrži 0 do 5% MeOH) dobiven je spoj iz naslova u obliku ulja (13 mg, 27%). MS: 490 (M+H)+; HPLC Ret Time: 1.62 min (YMC S5 C18,4.60 x 50 mm kolona, 3 min gradijent, 4 mL/min).
Primjer 77
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(1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(±)-[1,4]diazepan-6-ol
Mješavina (5-benzensulfinitmetil-pirolo[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (397 mg, 0.8 mmol) i [1,4]diazepan-6-ola (417 mg, 4.5 ekvivalenata, Saari et al., J. Org. Chem., 1971, 36, 1711) u suhom DMSO (1.5 mL) u zapečaćenoj epruveti zagrijavana je na 140°C, tijekom 11 h. Razrijeđena je sa DCM (150 ml), isprana vodom i osušena (Na2SO4). Uklanjanjem otapala, a potom podvrgavanjem radijalnoj kromatografiji (4 mm silika gel ploča; gradijent ispiranja sa DCM, koji sadrži 0 do 3% 2N otopine NH3 u MeOH), dobiven je spoj iz naslova u obliku čvrste mase (242 mg, 62%). MS: 487 (M4H)*; HPLC Ret Time: 0.96 min (Xterra S7 3.0 x 50 mm S7 C18 kolona, 2 min gradijent, 5 mL/min).
Racemični materijal može biti izdvojen na Chiralpak AD 4.6 x 250 mm koloni, uz eluaciju sa 0.05% dietilaminom u EtOH, tijekom 25 minuta, sa brzinom protoka od 0.7 mL/min). S i R enantiomeri su imali vremena retencije od 16.20, odnosno 18.90 minuta. R enantiomer je sintetiziran kao što je prikazano u nastavku.
Primjer 78
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(1-{4-[1-{3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(6R)-[1,4]diazepin-6-ol
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A. Izrada N-(2-amino-etil)-2-nitro-benzensulfonamida
Otopina etilen diamina (268 mL, 20 ekvivalenata) u DCM-u (400 mL) je dodavan ledom ohlađenoj otopini o-nitrobenzen sulfonit klorida (44.4 gm, 0.2 mol) u DCM-u (200 mL) tijekom 1 h. Koncentriranjem na rotacijskom uparivaču izdvojeno je ulje, koje je raspodijeljeno između DCM-a i zasićene vodene otopine Na2CO3. Vodena faza je ponovo ekstrahirana sa DCM-om, a sjedinjene organske faze su osušene (Na2SO4). Uklanjanje otapala, poslije čega je slijedilo podvrgavanje kromatografiji na silika gelu (postepena gradijent eluacija sa DCM-om, koji sadrži 0, 5, 10, 20, 30% MeOH) proizvelo je naslovljen spoj u obliku ulja (37.2 gm, 76%). 1H NMR (CDCl3 + D2O) δ 2.82 (t, 2H, J=5.1 Hz), 3.10 (t, 2H, J=5.1 Hz), 7.73 (m, 2H), 7.83 (m, 1H), 8.11 (m, 1H); MS: 246 (M+H>+-; HPLC Ret Time: 0.39 min (YMC Xterra 3.0 x 50 mm S7 C18 kolona, 3 min gradijent, 4 mL/min).
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B. Izrada N-[2-({2S}-3-kloro-2-hidroksi-propilamino}-etil]-2-nitro-benzensulfonamida
S-(+)-epiklorohidrin (5.92 mL, 0.5 ekvivalenata) je dodan suspenziji N-{2-amino-etil)-2-nitro-benzensulfonarnida (37.2 gm, 0.152 mol) i MgSO4 (9.1 gm, 0.5 ekvivalenata) u suhom MeOH (38 mL), na RT. Nakon 8 h, čvrsta masa je uklonjena filtracijom. Filtrat je ukoncentriran i raspodijeljen između DCM-a i vode. Organska faza je izdvojena i osušena (Na2SO4), a otapalo je odstranjeno. Podvrgavanjem kromatografiji na silika gelu (postepena gradijent eluacija sa DCM-om, koji sadrži 0,1,1.5, 2, 2.5, 3% MeOH) dobiven je spoj iz naslova u obliku ulja (20.73 gmt 81%). 1H NMR (CDCl3 + D2O) δ 2.59-2.76 (m, 2H), 2.80 (t, 2H, J=5.4 Hz), 3.17 (t, 2H, J=5.4 Hz), 3.53 (d, 2H, J=5.7 Hz), 3.79 (m, 1H), 7.74 (m. 2H), 7.86 (m, 1H), 8.13 (m. 1H); MS: 338 (M+H+); HPLC Ret Time: 0.67 min (YMC Xterra 3.0 x 50 mm S7 C18 kolona, 3 min gradijent 4 mL/min).
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C. Izrada 1-(2-nitro-benzensulfonil)-(6S)-[1,4]diazepan-6-ola
Suspenzija N-[2-({2S}-3-kloro-2-hidroksi-propl!amino)-etil]-2-nitro-benzen-suttbnamida (20.73 gm, 61.4 mmol) i Cs2CO3 (73 gm, 3 ekvivalenta) u suhom acetonitrilu (600 mL), pod atmosferom N2, zagrijavana je na 60°C tijekom 6,5 h. Čvrsta masa je odstranjena putem filtracije, a zatim je otapalo uklonjeno iz flltrata. Ostatak je raspodijeljen između DCM-a (400 mL) i vode (100 mL). Organska faza je osušena (Na2SO4), a otapalo je uklonjeno. Podvrgavanjem kromatografiji na silika gelu (postepena gradijent eluacija sa DCM-om, koji sadrži: 0,1, 2, 3, 4% MeOH) dobiven je spoj iz naslova u obliku ulja (5.68 gm, 31%). 1H NMR (CDCl3 + D2O) δ 2.3 (br s, 2H), 2.85 (m, 4H), 3.09 (m, 4H), 7.68 (m, 3H), 8.00 (m, 1H); MS: 302 (M+H+); HPLC Ret Time: 0.56 min (YMC Xterra 3.0 x 50 mm S7 C18 kolona, 3 min gradijent, 4 mL/min).
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D. Izrada 4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetilestera octene kiseline
Otopina sirovog 5-bromometil-kloropirolo[2,1-f][1,2,4]triazina (15.3 gm, 0.062 mol) u EtOAc (300 mL) je ohlađena u ledenoj kupelji, pod atmosferom N2, i dodani su octena kiselina (17.8 mL, 5 ekvivalenata), a nakon toga diizopropiletilamin (54.3 mL, 5 ekvivalenata). Reakcijska posuda je uklonjena iz kupelji i miješana je tijekom 18 sati na RT. Talog je odvojen filtracijom, a nastati filtrat je razrijeđen heksanom (250 mL). Ispran je vodom (2 x 125 mL) i zasićenom vođenom otopinom NaCl (50 ml), osušen je (Na2SO4) i ukoncentriran u vakuumu, kako bi se dobilo viskozno smeđe uge. koje prilikom stajanja očvrsne. Uzorak čistog 4-kloro-pirolo[2,1-f][1,2,4]triazin-5-ilmetilestera octene kiseline je dobiven putem kromatografije na silika gelu (gradijent eluacija sa 0 do 30% EtOAc u heksanu) u obliku žute kristalne čvrste mase. 1H NMR (CDCl3) δ 2.09 (s, 3H), 5.48 (s, 2H), 7.00 (d, J=2.7 Hz, 1H), 7.80 (d, J^2.7 Hz, 1H), 8.18 (s, 1H), 7.80 (d, J=2.7 Hz, 1H), 7.00 (d, J=2.7 Hz, 1H), 5.48 (s, 2H), 2.09 (s, 3H). Sirovi 4-kloro-pirolo[2,1-f][1,2,4)triazin-5-ilmetil ester octene kiseline zatim je otopljen u acetonitrilu (300 mL) i obrađen je natrij bikarbonatom (26.2 gm, 5 ekvivalent) i (18.1 gm, 1.2 ekvivalenta). Poslije miješanja na RT (sob. temp.) tijekom 20 h, mješavina je ukoncentrirana u vakuumu i otopljena u DCM-u (500 mL). Isprana je sa 100 mL vode, osušena preko bezvodnog natrij sulfata, filtrirana i ukoncentrirana u vakuumu, da bi se dobila tamno obojena čvrsta- masa. Ova je iskristalizirana iz acetonitrila čime se dobilo 10 g spoja iz naslova. Matična tekućina je podvrgnuta kromatografiji na silika gelu, uz eluac^u sa 70% heksan/EtOAc da bi se dobilo još 8 gm čistog materijala (ukupan prinos, 67%): 1H NMR (CDCl3) δ 2.16 (s, 3H), 5.42 (s, 2H), 5.59 (s, 2H), 6.76 (d, J=2.5 Hz, 1 H), 6.84 (d, J=8.8 Hz, 1 H), 6.98-6.90 (bm, 2H), 7.35-7.22 (bm, 3H), 7.56 (d, J=2.6 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.96 (s, 1H), 8.06 (s, 1H), 8.17 (s, 1H), 9.42 (s, 1H); MS: 431 (M+H+); HPLC Ret Time=2.59 min (YMC Xterra 4.5 x 50 mm S7 C18 kolona, 3 min gradijent, 4mL/min).
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E. Izrada 1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-4-(2-nitro-benzensulfonil)-(6S)-[1,4]diazepan-6-ola
Mješavina 4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil estera octene kiseline (860 mg, 2 mmol), 1-(2-nitro-benzensulfonil)-(6S)-[1,4]diazepan-6-ola (602 mg, 2 mmol) i diizopropiletilamina
(0.522 mL, 3 mmol, 1.5 ekvivalenta) u suhom acetonitrilu (4 ml) u posudi pod pritiskom, zagrijavana je na 102°C, tijekom 17 sati. Poslije uklanjanja otapala, ostatak je pokupljen u DCM, ispran vodom i osušen (Na2SO4). Odstranjivanjem otapala, a zatim podvrgavanjem kromatografiji na silika gelu (gradijent eluacija sa DCM-om, koji sadrži 0 do 2% 2M NH3 u MeOH) dobiven je spoj iz naslova u obliku čvrste mase (1.14 g, 85%). 1H NMR (CDCl3) δ 2.87-3.08 (m, 5H), 3.36-3.60 (m, 4H), 3.97-4.05 (m, 3H), 5.52 (s, 2H), 6,51 (d, 1H, J-2.5 Hz), 6.82 (m, 1H), 6.91-6.96 (m, 2H), 7.21-7.25 (m, 1H), 7.25-7.31 (m, 1H), 7.44 (d, 1H, J=3.0 Hz), 7.47-7.49 (m, 1H), 7.58-7.66 (m, 3H), 7.85 (s, 1 H), 7.91 (d. 1 H, J=1.5 Hz), 7.98 (d, 1 H, J=1.0 Hz), 8.03 (d, 1 H, J=1.5 Hz), 11.02 (s, 1H). MS: 672 (M+H+); HPLC Ret Time: 1.37 min (Gradijent Vrijeme=2 min, Brzina Protoka=5 ml/min, Xterra C18 S7, 3.0 x 50 mm C18 S7 kolona).
F. Izrada 1-{4-[1-{3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(6R)-[1,4]diazepan-6-ola
Benzentiol (54 mg, 2 ekvivalenta) je dodan suspenziji 1-{4-[1-{3-fuoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(6R)-[1,4]diazepan-6-ola (164 mg, 0.244 mmol) i K2CO3 (168 mg, 1.22 mmol, 5 ekvivalenata) u 2.5 ml bezvodnog DMF-a, pod dušikom. Poslije miješanja na RT, tijekom 50 minuta, čvrsta masa je odstranjena filtracijom. Fiftrat je ukoncentriran i raspodijeljen između DCM-a i vode. Organska faza je osušena (Na2SO4), a otapalo je uklonjeno. Podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, gradijent eluacija sa O do 5% 2M NH3 u MeOH) dobiven je spoj iz naslova u obliku čvrste mase (109 mg, 92%). 1H NMR (CDCl3) δ 2.69-2.77 (m, 2H), 2.84-3.03 (m, 6H), 3.78-3.81 (m, 1H)t 3.90 (d, 1H, J=13.4 Hz), 3,96 (d, 1H, J=13.4 Hz), 5.55 (s, 2H), 6.48 (d, 1H, J=2.5 Hz), 6.86-6.88 (m, 1H), 6.92-6.98 (m, 2H), 7.23 -7,27 (m, 1H), 7.32-7.33 (m, 1H), 7,44 (d, 1H, 2.5 Hz), 7.54-7.56 (m, 1H), 7.86 (s, 1H), 8.02 (d, 1H, J=1.0 Hz), 8.04 (d, 1H, J=2.0 Hz), 11.54 (s, 1H). MS: 487 (M+H)+; HPLC Ret Time: 18.86 min (Chiralpak AD 4.6 x 250 mm kolona, uz eluaciju sa 0.05% dletilaminom u EtOH tijekom 25 minuta, sa brzinom protoka od 0.7 mL/min).
Primjer 79
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Izrada 1-{4-[1-{3-fuoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-karbonil)--amid ciklopropansulfonske kiseline
Vodeni NaOH (2.1 mL, 1.0 N) je dodan otopini metil estera 1-{4-[1-{3-fuoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-karboksilne kiseline (352 mg, 0.686 mmol) u mješavini MeOH (0.2 ml) i THF (0.2 ml), na 0°C. Poslije miješala na 0°C tijekom 1 sata, reakcijska mješavina je ostavljena da se zagrije do RT i da se miješa preko noći. Vodena HCl (2.1 ml, 1.0 N) je dodavana kap po kap, i reakcija je ekstrahirana sa DOM. Organski ekstrakti su osušeni (Na2SO4), a otapala su uklonjena, da bi zaostala 1-{4-[1-{3-fluoro-benzil)-1H-indazol-5-ilamino]pirolo[2,1-f][1,2,4] triazin-5-ilmetil}-piperidin-4-karboksilna kiselina, u obliku čvrste mase (329 mg, čistoća 84% prema LCMS-u), koja je korištena kao takva. Otopina sirove kiseline (100 mg, 0.168 mmol) u THF-u (2 ml) je dodavana kap po kap, otopini 1,1'-karbonildiimidazola (33 mg, 0.2 mmol) u THF-u (0.3 ml), a ovo je zagrijavano pod refluksom tijekom 30 minuta. Po hlađenju do RT, dodan je ciklopropilsulfonamid (82 mg, 0.67 mmol, 4 ekvivalenta), a zatim otopina DBU (50 μL, 0.336 mmol, 2 ekvivalenta) u THF-u (0.2 mi). Reakcijska smjesa je miješana tijekom 18 sati, razrijeđena sa EtOAc-om (120 ml), isprana sa puferom pH 4.0 (9 mL) i slanom otopinom (5 ml) i osušena (Na2SO4). Odstranjivanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 1 do 5% MeOH) dobiven je spoj iz naslova u obliku čvrste mase (58 mg, 57%). 1H NMR (CDCl3) δ 0.98-1.00 (m, 2H), 1.22-1.27 (m, 2H), 1.84-1.92 (m, 4H), 2.03-2.16 (m, 2H), 2.24-2.32 (m, 1 H), 2.83-2.92 (m, 1H)t 3.08-3.11 (m, 2H), 3.74 (s, 2H), 5.54 (s, 2H), 6.46 (d, 1H, J=2.5 Hz), 6.81-6.97 (m, 3H), 7.20-7.27 (m, 1H), 7.36-7.51 (m, 3H), 7.84 (s, 1H), 8,06 (s, 2H), 11.82 (bs, 1H). MS: 603.7 (M+H+): HPLC Ret Time: 1.21 min (Gradient Vrijeme=2 min, Brzina Protoka=5 ml/min, Xterra 3.0 x 50 mm S7 C18 kolona).
Primjer 80
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(1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-il)-piperazin-1-il-metanon
Mješavina sirove (1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-karboksine kiseline (75 mg, 0.15 mmol), EDC (72 mg, 0.376 mmol) i DMAP (37 mg, 0,3 mmol) u suhom DCM-u (1 mL) miješana je na RT, tijekom 0.5 h. Dodan je piperazin (104 mg, 1,2 mmol) i, poslije 64 h, reakcijska mješavina je razrijeđena sa DCM, isprana vodom i osušena (Na2SO4). Odstranjivanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (1 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 1 do 5% MeOH) dobiven je spoj iz naslova u obliku čvrste mase (11 mg, 13%), 1H NMR (CDCl3) δ 1.67-1.80 (m, 4H), 1.96-2.09 (m, 2H), 2.15-2.18 (m, 1H). 2.58-2.65 (m, 1H), 2,82-2.86 (m, 4H), 3.17-3.20 (m, 2H), 3.43-3.48 (m, 2H), 3.57-3.62 (m, 2H), 3.77 (s, 2H), 5.57 (s, 2H), 6.48 (d, 1H, J=2,5 Hz), 6.83-6.88 (m, 1H), 6.90-6.97 (m, 2H), 7.21-7.29 (m, 1H), 7.36-7.39 (m, 1H), 7.44 (d, 1H, J=2.7 Hz), 7.55-7.58 (m, 1H), 7.89 (s, 1H), 8.08 (s, 1H), 8.18 (d, 1H, J=1.5 Hz), 11.87 (br, 1H). MS: 568.67 (M+H+); HPLC Ret Time: 1.03 min (Gradijent Vrijeme 2 min, Brzina Protoka=5 ml/min, Xterra 3.0 x 50 mm S7 C18 kolona).
Primjer 81
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3-(1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-ilamino)-propionitril
Akrilonitril (0.2 mL, 30 ekvivalenata) je dodan otopini [5-(4-amino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (47 mg, 0.1 mmol) u MeOH (3 mL), na RT. Uklanjanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (1 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 0 do 2% MeOH), dobiveno je 40 mg (76%) naslovljenog spoja u obliku čvrste mase. MS: 524 (M+H)+; HPLC Ret Time: 0.99 min (Xterra 3.0 x 50 mm S7 C18 kolona, 2 min gradijent, 5 mL/min).
Primjer 82
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[1-(3-fluoro-benzil)-1-indazol-5-il]-{5-[4-(2-metansulfonil-etilamino)-piperidin-1-ilmetil]-pirolo[2,1-f][1,2,4]triazin-4-il}-amin
Metil vinil sulfon (0.011 mL, 0.1 mmol) je dodan otopini [5-(4-amino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (47 mg, 0.1 mmol) u MeOH (3 mL), na RT. Poslije miješanja preko noći, naslovljeni spoj (54 mg, 94%) je sakupljen filtracijom, ispran sa MeOH i osušen. MS: 577 (M+H)+; HPLC Ret Time: 0.98 min (Xterra 3.0 x 50 mm S7 C18 kolona, 2 min gradijent, 5 mL/min).
Primjer 83
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N-(1-{4-[1-{3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-il)-acetamid
Octeni anhidrid (25 uL, 2.3 ekvivalenta) je dodan mješavini [5-{4-amino-piperidin-1-ilmetil)-pirolo[2,1.f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (47mg, 0.1 mmol) i K2CO3 (21 mg, 0.15 mmol) u MeOH (3 mL), na 0°C, pod dušikom. Poslije 1 h, reakcija je uklonjena iz ledene kupelji, a mješavina je ostavljena da se miješa na RT, preko noći. Otapalo je odstranjeno, a ostatak je pokupljen u DCM, ispran vodom i osušen (Na2SO4). Odstranjivanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, gradijent ispiranja sa DCM, koji sadrži 0 do 3% MeOH) dobiven je spoj iz naslova u obliku čvrste mase (41 mg, 80%). MS: 513 (M+H)+; HPLC Ret Time: 1.12 min (Xterra 3.0 x 50 mm S7 C18 kolona, 2 min gradijent, 5 mL/min).
Primjer 84
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N-(1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-il)-2-hidroksi-acetamid
Acetoksiacetil klorid (46 mg, 2 ekvivalenta) je dodan, kap po kap, otopini [5-(4-amino-piperidin-1-ilmetil)-pirolo [2,1.f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (47 mg, 0.1 mmol) (80 mg, 0.17 mmol) i trietflamina (71 μL, 3 ekvivalenta) u suhom DCM-u (3 ml), na 0°C, pod dušikom. Nakon miješanja na 0°C tijekom 3 h, i na RT tijekom 1 h, razrijeđen je sa DCM-om, ispran vodom i osušen (Na2SO4). Odstranjivanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, gradijent ispiranja sa DCM, koji sadrži 0 do 2% MeOH), dobiven je (1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1.f][1,2,4]triazin-5-ilmetil}-piperidin-4-ilkarbamoil)-metil ester octene kiseline u obliku čvrste mase (73 mg, 75%). Otopina ovog estera u THF-u (0.4 ml) je obrađena vodenom NaOH (1 N, 0.38 mL, 3 ekvivalenta). Poslije 2 h na RT, razrijeđena je sa DCM-om, isprana je vodom i osušena (Na2SO4). Uklanjanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, koristeći gradijent eluaciju sa DCM-om, koji sadrži 0 do 3% MeOH) dobiven je spoj iz naslova, u obliku čvrste mase (47 mg, 70%). MS: 529 (M+H)+; HPLC Ret Time: 1.37 min (YMC Xterra ODS S7 3.0 x 50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 85
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2-(1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-ilamino}-etanol
Mješavina [5-(4-amino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol--5-il)-amina (188mg, 0.4mmol) i [1,3]dioksolan-2-ona (352 mg, 10 ekvivalenata) u zapečaćenoj epruveti je zagrijavana na 100°C tijekom 3.5 h. Spoj iz naslova je izdvojen radijalnom kromatografijom (2 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 0 do 3% MeOH) koja je proizvela spoj iz naslova u obliku čvrste mase (43 mg, 21%); MS: 515 (M+H+); HPLC Ret Time: 1.29 min (YMC Xterra ODS S7 3.0 x 50 mm kolona, 2 min gradijent, 5 ml/min).
Primjer 86
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[1-(3-fluoro-benzil)-1H-indazol-5-il]-[5-(4-metilamino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
Mješavina (5-benzensulfinilmetil-pirolo-[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (200mg, 0.4 mmol) i 4-amino-piperidina (1.2 g, 30 ekvivafenata) u bočici, stavljena je u mikrovalni reaktor (Personal Chemisty's Smith Creator) i zračena je na 150°C tijekom 20 minuta. Gornjoj mješavini je dodan etil formijat (3 ml) i zračenje je nastavljeno na 135°C, tijekom 30 minuta. Koncentriranjem reakcijske mješavine, a zatim pročišćavanjem preparativnom HPLC, dobiven je N-(1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-il)-formamid (71 mg, 36%). Otopljen je u suhom THF-u (0.3 ml) i dodan, kap po kap, izmiješanoj otopini LiAIH4 (1M u eteru, 0.57 ml, 4 ekvivalenta). Polako je dodavana voda (0.5 mL) i, poslije 20 h, spoj iz naslova (16 mg, 23%) je izoliran preparativnom HPLC. MS: 485 (M4H)+; HPLC Het Time: 1.02 min (Xterra 3.0 x 50 mm S7 C18 kolona, 2 min gradijent, 5 ml/min).
Primjer 87
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[5-(4-dimetilamino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin
Natrij cijanoborohidrid (5 mg, 2 ekvivalenta) je dodan otopini [5-(4-amino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (20 mg, 0.042 mmol), octene kiseline (3 uL) i 37% formaldehida (7 uL, 2 ekvivalenta) u DCM-u (0.3 ml), na 0°C. Poslije 0.5 h, reakcijska mješavina je izvučena iz ledene kupelji, i, poslije dodatnih 4 h, razrijeđena je sa DCM-om i prevedena u alkalnu reakciju pomoću zasićene otopine NaCO3. Organski sloj je osušen (Na2SO4), a otapalo je uklonjeno. Naslovljeni spoj (4 mg, 8%) je izoliran preparativnom HPLC. MS: 499 (M+H)+; HPLC Ret Time: 1.04 min (YMC ODS-A C18 S7 3,0 x 50 mm kolona, 2 min gradijent, 5 ml/min).
Primjer 88
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[1-(3-fluoro-benzil)-1H-indazol-5-il]--{5-[(metil-piperidin-4-il-amino)-metil]-pirolo[2,1-f][1,2,4]triazin-4-il}-amin
Na sličan način, terc-butil ester 4-({4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]pirolo[2,1-f][1,2,4]triazin-5-ilmetil)}-amino)-piperidin-1-kartioksilne kiseline je preveden u terc-butil ester 4-({4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-metilamino)-piperidin-1-karboksilne kiseline, koji je obrađen sa TFA, na 0°C, tijekom 1 h, da bi se dobio spoj iz naslova u obliku čvrste mase (ukupan prinos 37%). MS: 485 (M+H)+; HPLC Ret Time: 0.95 min (YMC 3.0 x 50 mm S7 C18 kolona, 2 min gradijent, 5 ml/min).
Primjer 89
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[1-{3-fluoro-benzil)-1H-indazol-5-il]-{5-[4-{1H-tetrazol-5-il)-piperidin-1-ilmetil]-pirolo[2,1-f][1,2,4]triazin-4-il}-amin
Mješavina 1-{4-[1-{3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-fl[1,2,4]triazin-5-ilmetil)-piperidin-4-karbonitrila (145 mg, 0.3 mmol), natrij azida (59 mg, 3 ekvivalenta) i amonij klorida (48 mg, 3 ekvivalenta) u DMF-u (0.6 ml) u zapečaćenoj epruveti je miješana na 100°C tijekom 20 h. Reakcijska mješavina je ohlađena do RT, razrijeđena sa DCM-om, isprana vodom i osušena (Na2SO4). Uklanjanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 2 do 7% 2M NH3 u MeOH) dobiven je spoj iz naslova u obliku čvrste mase (38 mg, 24%); MS: 524 (M+H+); HPLC Ret Time: 1.13 min (Xterra 3.0 x 50 nnm S7 C18 kolona, 2 min gradijent, 5 ml/min).
Primjer 90
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[5-(6,6-difluoro-[1,4]diazepan-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin
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A. Izrada 6,6-difluoro-[1,4]diazepana
Tetrapropilamonij perrutenat (0.75 gm, 0,05 ekvivatenata) Je dodan izmiješanoj suspenziji 1,4-bis-(toluen-4-sulfonil)-[1,4]dlazepan-6-ola (13 gm, 30.7 mmola, Saari et al., J. Org. Chem., 1971, 36, 1711), N-metilmorfolin N-oksida (5.38 gm, 1.5 ekvivalenata) i izlomljenih 4A molekularnih sita (20 gm) u suhom DCM-u (100 mL). Poslije 1.5 h, uliven je na kratku kolonu silika gela i eluiran je mješavinom 10% EtOAc u DCM-u, da bi se dobio 1,4-bis-(toluen-4-sulfonil)-[1,4]diazepin-6-on (8.9gm, 60%) u obliku bijele čvrste mase: 1H NMR (CDCl3) δ 2.44 (s, 6H), 3.71 (s, 4H). 3.91 (s, 4H), 7.32 (d, 4H, J=8.1 Hz), 7.65 (d, 4H, J=8.1 Hz). Otopina ovog ketona (8,9 gm, 21.1 mmoi) u suhom DCM-u, ohlađena je u aceton/suhi led kupelji i dodavan je, tijekom 5 minuta, DAST (8.4 mL, 3 ekvivalenta). Reakcijska smjesa je ostavljena da se zagrije do RT i, nakon 20 h, ohlađena je u ledenoj kupelji, i dodavana je voda, kap po kap, da bi se razgradio višak reagensa. pH vodene faze je doveden na 10 sa vodenom otopinom NaOH i dodan je dodatni DCM (300 mL). Organska faza je izdvojena i osušena (Na2SO4), a otapalo je odstranjeno. Ostatak je iskristaliziran iz aceton/vode da bi se dobio 6,6-difluoro-1,4-bis-(toluen-4-sulfonil)-[1,4]diazepin (6.47gm, 69%) u obliku pahuljastih bijelih kristala: 1H NMR(CDCl3) δ 2.44(s,6H), 3.41 (s, 4H), 3.68 (t, 4H, J=12.3 Hz), 7.33 (d, 4H, J=8.0 Hz), 7.64 (d, 4H, J=8.0 Hz). Otopina dffluorida (3.41 gm, 7.75 mmol) i fenola (2.9 gm, 4 ekvivalenta) u 30%-tnoj otopini HBr u HOAc (50 mL) je zagrijavana na 60°C tijekom 6 h. Reakcijska smjesa je ukoncentrirana, a ostatak je suspendiran u etanolu, da bi se istaložila bis-HBr sa 6,6-difluoro-[1,4]diazepana, u obliku žutosmeđe čvrste mase (1.82 gm, 79%). Ova sol (600 mg, 2.04 mmol) je suspendirana u MeOH (10 mL) i dodavan je, uz miješanje, vodeni NaOH (0.41 mL, 10 N, 2 ekvivalenta). Nastala otopina je eiulrana kroz Varian Mega Bond Elut SCX spremnik, nakon čega slijedi dodavanje 10 mL MeOH. 6,6-difluoro-[1,4]diazepan je izeluiran sa SCX spremnika sa 50 mL 2N otopine NH3 u MeOH. Uklanjanjem otapala on zaostaje u obliku ulja (211 mg, 76%): 1H NMR (CDCl3) δ 2.93 (s, 4H), 3.21 (t, 4H,J=13.9Hz).
B. Izrada [5-(6,6-difluoro-[1,4]diazepan-1-ilmetil}-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(-3-fluoro-benzil)-1H-indazol-5-il]-amina
Otopina metansulfonskog anhidrida (114 mg, 3,2 ekvivalenta) u DCM-u (0.6 mL) je dodana otopini {4-[H3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-il}-metanola (78 mg, 2 mmol) u suhom DCM-u (1.4 mL), na 0°C, pod dušikom, nakon čega slijedi dodavanje trietilamina (0.140 mL, 5 ekvivalenata), -Poslije miješanja na 0°C, tijekom 1 h, dodani su 6,6-difluoro[1,4]diazepan (82 mg, 3 ekvivalenta) i 1,2-dikloroetan (2 mL). Reakcijska mješavina je prenesena u mikrovalni reaktor (Personal Chemistry's Smith Creator) i zračena je na 65°C tijekom 50 minuta. Uklanjanjem otapala, a zatim preparativnom HPLC, dobiven je spoj iz naslova u obliku čvrste mase (29 mg, 29%). MS: 507 (M+H+); HPLC Ret Time: 1.47 min (YMC Xterra ODS S7 3.0 x 50 mm kolona, 2 min gradijent 5 ml/min).
Primjer 91
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(±)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-[5-(6-fluoro-[1,4]diazepan-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
Slijedeći gornji postupak spajanja sa 6-fluoro-[1,4]diazepanom (Ziegler et al., J. Med. Chem., 1990, 33, 142) dobiven je naslovljeni spoj u obliku čvrste mase (prinos 26%). MS: 489 (M+H)+; HPLC Ret Time: 1.33 min (YMC Xterra ODS S7 3.0 x 50 mm kolona, 2 min gradijent, 5 ml/min).
Primjer 92
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1-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil]-[1,4]-diazepan-6-on
Oksidacijom terc-butil estera 4-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil)-6-hidroksi-[1,4]drazepan-1-karboksilne kiseline, kao što je opisano u Primjeru 74, dobije se terc-butil ester 4-(4-[1-{3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-6-okso-[1,4]diazepan-1-karboksilne kiseline, kome je uklonjena zaštita sa TFA, kako bi se dobio spoj iz naslova u obliku čvrste mase (ukupan prinos 61%). MS: 485 (M+H)+; HPLC Ret Time: 1.01 min (Xtena S7 3.0 x 50 mm S7 C18 kolona, 2 min gradijent 5 ml/min).
Primjer 93
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[1-(3-fluoro-benzil)-1H-indazol-5-il]-[5-(piperidin-4-iloksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
Suspenzija 5-bromometil-4-kioro-pirolo[2,1-f][1,2,4]triazina (61mg, 0.25mmol), terc-butil estera 4-hidroksi-piperidin-1-karboksilne kiseline (500 mg, 10 ekvtvatenata) i NaHCO3 (42 mg, 2 ekvivalenta) u suhom CH3CN (0.5 mL), pod N2, je ostavljena da se miješa na RT tijekom 3 dana. Dodani su 1-(3-fluoro-benzil)-1H-indazol-5-ilamin (54 mg, 0.9 ekvivalenata) i dodatni NaHCO3 (42 mg, 2 ekvivalenta) i reakcijska smjesa je ostavljena da se miješa preko noći. Reakcijska smjesa je razrijeđena sa DCM-om, Isprana vodom i osušena (Na2SO4). Uklanjanjem otapala, a zatim podvrgavanjem radijalnoj kramatograflji (2 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 0 do 3% MeOH) dobiven je terc-butil ester 4-{4-[1-(3-fluoro-benzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetoksi}-piperidin-1-karboksilne kiseline, u obliku pjene (47 mg, 33%). Ovo je obrađeno mješavinom DCM (1.5 mL) i TFA (1 mL) tijekom 40 minuta, a zatim su otapala uklonjena. Ostatak je pokupljen u DCM-u, Ispran zasićenom vodenom otopinom NaHCO3 i osušen (Na2SO4). Uklanjanjem otapala, a zatim podvrgavanjem radijalnoj kromatografiji (2 mm silika gel ploča, gradijent eluacija sa DCM-om, koji sadrži 0 do 5% MeOH) dobiven je čisti amin (11 mg, 29%) u obliku ulja. 1H NMR (CDCl3) δ 1.1-1,3 (m, 2H), 1.7-1.9 (m, 4H), 2.5-2.6 (m, 2H), 3.0-3,1 (m, 2H), 3.44 (d, 2H, J=7Hz), 4.85 (s, 2H), 5.59 (s, 2H), 6.55 (d, 1H, J=2 Hz), 6,8-7.0 (m, 3H), 7.2-7.5 (m, 4H), 7.97 (s, 1H), 8.05 (s, 1H), 8,20 (d, 1H, J=2 Hz), 9.70 (s, 1H); MS: 486 (M+H)+; HPLC Ret Time: 1.35 min (YMC S7 C18, 3.0 x 50 mm, 2 min gradijent, 5 ml/min.
Primjeri 94 do 116
Slijedeći analozi etera pripremljeni su upotrebom postupka, opisanog u Primjeru 93. Kada polazni alkohol nije nosio Boc zaštitnu grupu, korak uklanjanja zaštite je izostavljen. Alkoholi koji su nosili primarnu ili sekundarnu amino grupu, najprije su prevedeni u njihove N-Boc derivate, upotrebom di-terc-butil dikarbonata, u skladu sa općim postupcima iz literature (T. Greene and P. Wuts, Protective Groups in Organic Synthesis, 3. Izdanje).
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Primjer 117
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([1-{3-fluorobenzil)-1H-indazol-5-il]-[5-({2S}-morfolin-2-ilmetoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
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A. Izrada {4-[1-{3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-il}-metanola
Smjesa sirovog 5-bromometil-4-kloro-pirolo[2,1-f][1,2,4]triazina (3.69 gm, 0.015 mol i NaHCO3 (2,51 gm, 2 ekviv) u mješavini acetonitrila (50 mL) i vode (5 mL) je miješana pod N2 atmosferom u toku 3 dana. Ovo je obrađeno sa Na2SO4 i zatim sa 1-(3-fluorobenzil)-1H-indazol-5-ilaminom (3.24 gm, 0.90 ekviv) i NaHCO3 (1 gm) i ostavljeno da se miješa tijekom 18 h na RT. Roakcijska masa je filtrirana i filtratni sloj ispran sa DCM (100 mL). Filtrat je ukoncentriran i ostatak podvrgnut kromatografiji na sllika gelu (ispiranje sa -30% EtOAc u heksanu), koja je data naslovljeni spoj u obliku žutosmeđe čvrste mase (3.78 gm, 65% prinos): 1H NMR (CDCl3) δ 3.03 (t, J=5.9 Hz, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.56 (s, 2H), 6.76 (d, J=2,7 Hz, 1 H), 6.83 (d, J=.O Hz, 1 H), 6.98-6,90 (m, 3H). 7.43 (d, J=2.5 Hz, 1H). 7.51 (dd, J=2.1, 8.8 Hz, 1 H), 7.96 (s, 1H), 8,03 (s, 1H), 8.22 (s, 1H), 9.91 (s, 1H); MS: (M+H+); HPLC Ret Time: 2.38 min (YMC C18 S5, 3.0x50 mm, 4 min gradijent 4 ml/min.
B. Izrada ([1-(3-fluorobenzil)-1H-indazol-5-il]-[5-({2S}-morfolin-2-ilmetoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amina
Tionil ktorid (18 pL, 1.1 ekviv) je dodan u otopinu {4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-il}-metanola (80 mg, 0.205 mol) u suhom DCM (4 mL), na RT. Poslije 12 min, dodan je terc-butil ester (2S)-2-hidroksimetil-morfolin-4-karboksilne kiseline (65.3 mg. 1.5 ekviv, H. Yanagisawa et al., Heterocydes, 1993, 35, 105,), a odmah zatim i DIPEA (39.5 pL, 1.1 ekviv). Poslije 72 h na RT, otapalo je uklonjeno, a kromatografija ostatka na silika getu (gradijent ispiranja sa O do 50% EtOAc u heksanu) je dala terc-butil ester 2-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetoksimetil}-morfolin-4-karboksilne kiseline (60 mg, 50% prinos); MS: 588 (M+H)+; HPLC Ret Time: 2.69 min (Xterra C18 S5, 3.0x50 mm, 3 min gradijent, 4 mL/min, Otopina ovog materijala u DCM (2 mL) je ohlađena do 0°C i obrađena sa TFA (1 mL). Poslije 90 min, otapala su uklonjena i ostatak je otopljen u DCM. Ovo je isprano sa zasićenom NaHCO3 otopinom i organska faza je osušena (Na2SO4) i otapala uklonjena. Pročišćavanje preparativnom HPLC i zatim, radijalnom kromatografijom (1 mm ploče silika gela, gradijent ispiranja sa 0 do 3% NH3 (2N u MeOH) u DCM, dalo je naslovljeni spoj (30 mg, 60% prinos): 1H NMR (CDCl3) δ 2.84-2.58 (m, 4H), 3.65-3,35 (m, 4H), 3.65-3.35 (m, 4H), 4.87 (s, 2H), 5.58 (s, 2H), 6.54 (d, J=2.5 Hz, 1H), 6.83 (d, J=9.5 Hz, 1H), 6.98-6.90 (m, 2H), 7.32-7.20 (m, 3H), 7.48 (d, J=2.5 Hz, 1H), 7.58 (dd, J=1.8, 8.8 Hz, 1 H), 7.94 (s, 1H), 8.19 (s, 1H), 9.58 (s, 1H); MS: 488 (M+H)+; HPLC Ret Time: 1.65 min (YMC C18 S5, 3.0x50 mm, 3 min gradijent, 4 mL/min).
Primjer 118
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[trans-5-(4-amino-cikloheksiloksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin
Naslovljeni spoj je, na sličan način, pripremljen od terc-butil estera (trans-4-hidroksi-cikloheksil)-karbaminske kiseline: MS: 486 (M+H)+; HPLC Ret Time: 2.13 min (Xterra C18 S5,4.6x50 mm, 3 min gradijent, 4 ml/min).
Primjer 119
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[5-(2-amino-2-metil-propoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin
Smjesa octene kiseline 4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo [2,1-f]-[1,2,4]triazin-5-ilmetilestera (100 mg, 0.24 mmol), terc-butil estera (2-hidroksi-1,1-dimetil-etil)-karbaminske kiseline 156 mg, 3 ekviv) i DIPEA (62 μL, 1.5 ekviv) u suhom acetonitrilu (0.2 mL) u bočici je smještena u mikrovalni reaktor (Personal Chemistry's Smith Creator) i zračena tijekom 10 min na 109°C. Otapalo je uklonjeno i ostatak pokupljen u suhi DCM (3 mL), a zatim, ohlađen do 0°C. Dodan je TFA (3 mL) i poslije 1.5 h uklonjena su otapala. Ostatak je podijeljen između DCM i zasićene otopine NaHCO3. Organska faza je osušena (Na2SO4) i otapalo uklonjeno. Pročišćavanje radijalnom kromatografijom (1 mm ploča silika gela, gradijent eluiranja sa 0 do 5% MeOH u DCM) je dalo naslovljeni spoj (13 mg, 12% prinos): MS: 460 (M+H)+; HPLC Ret Time: 1.34 min, YMC Xterta ODS S7 3.0x50 mm, 2 min gradijent, 5 mL/min).
Primjer 120
(1-benzil-1H-indazol-5-il)-[5-(2-metoksi-etokslmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
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Suspenzija 5-bromometil-4-kloro-piroto[2,1-f][1,2,4]triazina (50 mg, 0.202 mmol i NaHCO3 (75 mg, 4.4 ekviv) u 2-metoksietanolu (1.0 mL), pod N2 je ostavljena da se miješa na RT tijekom 6 h. Reakcijska masa je onda razrijeđena sa DCM, ekstrahirana vodom i osušena (Na2SO4). Uklanjanjem otapala zaostaje 4-kloro-5-(2-metoksi-etoksimetil)-pirolo [2,1-f][1,2,4]triazin (41 mg, 84%) u obliku ulja, 1H NMR (CDCl3) δ 3.40 (s, 3H), 3.67 (m, 4H), 4.96 (s, 2H), 7.05 (d, 1H, J=3Hz), 7.82 (d, 1H, J=3Hz), 8.16 (s, 1H). Suspenzija 4-kloro-5-(2-metoksi-etoksimetil)-piroto [2,1-f][1,2,4]triaztna (5 mg, 0.020 mmol), NaHCO3 (3 mg, 2 ekviv) i 1-benzil-1H-indazol-5-ilamina (4.5 mg, 1 ekviv, pripremljen na isti način kao i 1-(3-fluorobenzil)-1H-indazol-5-ilamin ali upotrebom benzil klorida) u suhom CH3CN (0.5 mL), ostavljena je da se miješa na RT tijekom 2 h. Reakcijska masa je razrijeđena sa DCM, isprana vodom i osušena (Na2SO4). Uklanjanjem otapala, a zatim, radijalnom kromatografijom (1 mm ploča silika gela, gradijent ispiranje sa DCM, koji sadrži 0 do 1% MeOH) dobiven je proizvod u obliku ulja (1.8 mg, 21%). 1H NMR (CDCl3) δ 3.16 (s, 3H), 3.63 (m, 4H), 4.83 (s, 2H), 5.53 (s, 2H), 6.48 (d, 1H, J=3Hz), 7.1-7.5 (m, 8H), 7.88 (s, 1H), 7.96 (s, 1H), 8.11 (s, 1H); 9.56 (s, 1H); MS: 429 (M+H)+; HPLC Ret Time: 2.58 min (YMC C18 S5, 4.6x50 mm, 3 min gradijent (otpočne sa 0% otapala B i završava sa 70% otapala B), 4 mL/min).
Primjer 121
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[5-{2-metoksi-etokslmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-(1-piridin-2-ilmetil-1H-indazol-5-il)-amin
Suspenzija 4-kloro-5-(2-metoksi-etoksimetil)-pirolo[2,1-f][1,2,4]triazina (24 mg, 0,099 mmol), NaHCO3 (42mg, 5 ekviv) i 1-piridin-2-ilmetil-1H-indazol-5-liamma (22mg, 1 ekviv, pripremljen na isti načinj kao i 1-(3-fluorobenzil)-1H-indazol-5-ilamin ali upotrebom 2-pikolil klorida) u suhom CH3CN (1mL), ostavljena je-da se miješa na RT tijekom 1 h. Reakcijska masa je razrijeđena sa DCM, isprana vodom i osušena (Na2SO4). Uklanjanjem otapala, a zatim, radijalnom kromatografijom (1 mm ploča silika gela, gradijent ispiranje sa i DCM, koji sadrži 0 do 1% MeOH) dobiven je proizvod u obliku ulja (4.8 mg, 11%). 1H NMR (CDCl3) δ 3.26 (s, 3H), 3.76 (m, 4IJI), 4.90 (s, 2H), 5.75 (s, 2H), 6.56 (d, 1H, Js3Hz), 6.83 (d, 1H, J=5Hz), 7.18 (m, 1H), 7,40 (d, 1H, J=5Hz), 7.49 (d, 1H, J=2Hz), 7.56 (m, 2H), 7.96 (s, 1H), 8.07 (s, 1H), 8.22 (d, 1H, J=1Hz), 8.59 (m, 1 H), 9.65 (s, 1H); MS: 429 (M+H)+; HPLC Ret Time: 1.30 min (YMC ODS-A C18 S7, 3.0x50-mm, 2 min gradijent (otpočne sa 0% otapala B 4 završava sa 70% otapala B), 5 mL/min).
Primjer 122
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{5-[(3R)-3-amino-pirolidin-1-ilmetil]-pirolo[2,1-f][1,2,4]triazin-4-il}-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin
Mješavina (5-benzensulfinilmetil pirolo[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-III-amina (100 mg, 0.20 mmol) i (3R)-3-(N-terc-butoksikarbonilamino)pirolidina; (380 mg, 10 ekviv) u zapečaćenoj epruveti je grijana na 130°C u toku 35 h. Reakcijska smjesa je pokupljena u DCM, isprana vodom i osušena (Na2SO4). Poslije uklanjanja otapala, ostatak je prenesen u DCM (1.5 ml) i dodan je TFA (1 ml). Otapala su uklonjena i ostatak otopljen u DCM, ispran vodom i osušen (Na2SO4). Po uklanjanju otapala slijedi radijalna kromatografija (2 mm ploča silika gela, upotrebljavajući gradijent ispiranje sa DCM, koji sadrži 1 do 5% MeOH) kako bi se dobilo naslovljeni spoj u obliku ulja (13 mg, 14%). 1H NMR (CDCl3) δ 1.49 (br s, 2H), 1.66 (m, 1H), 2.29 (m, 1H), 2,43 (m, 1H), 3.69 (m, 1H), 3.87 (d, 1H, J=13.5Hz), 3,96 (d, 1H, J=13.5Hz), 5.58 (s, 2H), 6.49 (d, 1H, J=3Hz), 6.8-7.6 (m, 7H), 7.92 (s, 1H), 8.04 (s, 1H), 8.26 (d, 1H, J=2Hz); MS: 457 (M+H)+; HPLC Ret Time: 1.15 min (YMC Xterra ODS 37 C18, 3.0x50 mm kolona, 2 min gradijent, 5 mL/min).
Primjeri 123 do 127
Slijedeći primjeri su pripremljeni na isti način kao Primjer 122.
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Primjer 128
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[1-(3-nuorobenzil)-1H-indazo]-5-il]-[5-(4-cijanometil-[1,4]diazepan-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
Bromoacetonitril (0.028 mL, 4 ekviv) je dodan u na ledu ohlađenoj otopini 5-[1,4]diazepan-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluorobenzil)-1H-indazo1-5-il]-amina (47 mg, 0.10 mmol) i TEA (0.055 mL, 4 ekviv) u DCM (3 mL). Ovo je ostavljeno da se miješa tijekom 1 h i onda uklonjeno iz ledene kupelji. Poslije stajanja preko noći, reakcijska masa je razrijeđena sa DCM, isprana vodom i osušena (Na2SO4). Uklanjanje otapala, a zatim, radijalna kromatografija (2 mm ploča silika gela upotrebom gradijenta ispiranja sa DCM koji sadrži 0 do 1% MeOH) su osigurali naslovljeni spoj u obliku ulja (49 mg, 95%). MS: 510 (M+H)+; HPLC Ret Time: 1.17 min (YMC S7 C18, 3.0x50 mm kolona, 2 min gradijent, 5 ml/min).
Primjer 129
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[1-(3-fluorobenzil)-1H-indazol-5-il]-{5-[4-{2-metansulfonil-etil)-[1,4]diazepan-1-ilmetil]pirolo[2,1-f]t1,2,4]triazin-4-il}-amin
Metil vinil sulfon (0.042 mL, 4 ekviv) je dodan u otopinu 5-[1,4]diazepan-1-ilmetil-pirolo[2,1f][1,2,4]triazin-4-il)-[1-(3-fluorobenzil)-1H-indazol-5-il]-amina (47 mg, 0.10 mmol) u DCM (3 mL). Poslije miješanja tijekom noći, otapalo je uklonjeno i izvršeno je pročišćavanje radijalnom kromatografijom (2 mm ploča silika gela upotrebom gradijenta ispiranja sa DCM koji sadrži 0 do 1% MeOH) koje je osiguralo naslovljeni spoj u obliku ulja (54 mg, 93%). MS: 577 (M+H)+; HPLC Ret Time: 1.08 min (YMC S7 C18, 3.0x50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 130
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[1-(3-fluorobenzil)-1H-indazol-5-il]-{5-[4-(2-cijano-etil)-[1,4]diazepan-1-ilmetil]-pirolo[2,1-f][1,2,4]triazin-4-il}-amin
Akritonitril (0.302 mL, 45 ekviv) je dodavan iz 3 dijela tijekom 2 dana u otopinu 5-[1,4]diazepan-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-ilH1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (47 mg, 0.10 mmoi) u DCM (3 mL), na RT. Otapalo je uklonjeno i izvršeno je pročišćavanje radijalnom kromatografijom (2 mm ploča silika gela upotrebom gradijente ispiranja sa DOM koji sadrži 0 do 1 % MeOH) koje je osiguralo naslovljeni spoj u obliku ulja (34 mg, 64%). MS: 524 (M+H)+; HPLC Ret Time: 1.08 min (YMC S7 C18, 3.0x50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 131
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2-(4-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-[1,4]diazepan-1-il)-etanol
Smjesa 5-[1,4]diazepan-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-ilH1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (47 mg, 0.10 mmol), 2-bromoetanola (0.019 mL, 1.5 ekviv) i K2CO3 (35 mg, 2.5 ekviv) u CH3CN (2.5 mL) je grijana pri refluksu preko noći, Reakcijska masa je zatim, razrijeđena sa DCM, isprana vodom i osušena (Na2SO4). Otapalo je uklonjeno i izvršeno je pročišćavanje radijalnom kromatografijom (2 mm ploča silika gela upotrebom gradijenta ispiranja sa DCM koji sadrži 0 do 5% MeOH) koje je osigurate naslovljeni spoj u obliku ulja (21 mg, 41%). MS: 515 (M+H)+; HPLC Ret Time: 1.15 min (YMC Xterra ODS S7 C18, 3.0x50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 132
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[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(4-metansulfonil-[1,4]diarepan-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin
Metansuffonil klorid (0.034 mL, 4 ekvrv) Je dodan u ledeno ohlađenu otopinu 5-[1,4]diazepan-1-ilmetil-pirolo[2,1f][1,2,4]triazin-4-il)-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amina (35 mg, 0.074 mmol) i TEA (0.041 mL, 4 ekviv) u DCM (2.6 mL). Ovo je ostavljeno da se miješa u toku 1 h i zatim je uklonjeno iz ledene kupelji. Poslije stajanja preko noći, reakcijska masa je razrijeđena sa DCM, isprana vodom i osušena (Na2SO4). Otapalo je uklonjeno, a zatim je izvršena radijalna kromatografija (2 mm ploča silika geta upotrebom gradijenta ispiranja sa DCM koji sadrži 0 do 2% MeOH) koja je osigurala naslovljeni spoj u obliku ulja (22 mg, 54%). MS: 549 (M+H)+; HPLC Ret Time: 1.26 min (YMC Xterra ODS S7 C18, 3.0x50 mm kolona, 2 min gradijent, 5 mL/min).
Primjer 133
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1-(4-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-[1,4]diazepan-1-H)-propan-1,2-dion
Otopina piruvatne kiseline (0.008 mL, 1 ekviv) i 5-[1,4]diazepan-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-il)-[1-{3-fluorobenzil)-1H-indazol-5-i]-amina (47 mg, 0.10 mmol) u EtOAc (3 mL) je ohlađena do -16°C i dodana je otopina diciktoheksilkarbodiimida (22 mg, 1.1 ekviv) u EtOAc (0.5 mL). Ovo je ostavljeno da se postepeno zagrije do RT i da se miješa preko noći. Reakcijska masa je filtrirana i otapalo je uklonjeno iz filtrata. Radijalna kromatografija ostatka (2 mm ploča silika gela upotrebom gradijenta ispiranja sa DCM koji sadrži 0 do 2% MeOH) je osigurala naslovljeni spoj u obliku ulja (8 mg, 14%). MS: 541 (M+H)+; HPLC Ret Time: 1.27 min (YMC Xterra ODS S7 C18, 3.0x50 mm kolona, 2 min gradijent, 5 ml/min).
Claims (16)
1. Spoj formule I
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njegovi enantiomeri, dijastereomeri i njegove farmaceutski prihvatljive soli, prolijekovi i sol vati, naznačen time, što :
R je odabran iz grupe, koja se sastoji od: SR2, SOR2, SO2R2, OR2 i NR3R4;
R1 je odabran iz grupe, koja se sastoji od: a rila, supstituiranog arila, heterociklo, supstituiranog heterociklo;
R2 je odabran iz grupe, koja se sastoji od: vodika, alkila, supstituiranog alkila, arila, supstituiranog arila, aralkila, heterociklo i supstituiranog heterociklo;
R3 i R4 su, nezavisno odabrani iz grupe, koju čine: vodik, alkil, supstituirani alkil, aril, supstituirani aril, heterociklo i supstituirani heterociklo; Ni R2 i R3 mogu zajedno tvoriti po izboru supstituirani monoclklični, zasićeni ili nezasićeni, karbociklični ili heteroctklični prsten sa 4-8 članova ili po izboru supstituirani biciklični, zasićeni ili nezasićeni, karbociklični ili heterociklični prsten sa 7-12 članova.
2. Spoj, kao u patentnom zahtjevu 1, naznačen time, što je R1 odabran iz grupe, koju čine: benzen, fluorom supstituirani benzen i piridin.
3. Spoj, kao u patentnom zahtjevu 2, naznačen time, što R1 je fluorom supstituirani benzen.
4. Spoj, kao u patentnom zahtjevu 3, naznačen time, što je R eter.
5. Spoj, kao u patentnom zahtjevu 1, naznačen time, što je odabran iz grupe, koja uključuje:
(5-[1,4]diazepan-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-il)-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
[1-(3-fluorobenzil)-1h-indazol-5-il]-(5-imidazol-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-il)-amin;
amid 1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-3-karboksilne kiseline;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(4-metil-piperazin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
2-(4-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperazin-1-il)-etanol;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(3R)-pirolidin-3-ol;
(1-{4-[1-(3-fluorobenzil)-1H-indazoi-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-il)-metanol;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-ol;
(2R)-3-({4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-amino)-propan-1,2-diol;
2-({4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-amino)-etanol;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(3S)-pirolidin-3-ol;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(4-cijanometil-cikloheksilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
[5-(3,5-dimetil-piperazin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-((3S)-3-metil-piperazin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
amid 4-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperazin-2-karboksilne kiseline;
4-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperazin-2-on;
2-({4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-amino)-2-metil-propan-1,3-diol;
2-({4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-amino)-propan-1,3-diol;
[1-(3-fluorobenzil)-1H-indazol]-5-il]-(5-piperazin-1-ilmetil-pirolo[2,1-f][1,2,4]triazin-4-il)amin;
[1-(3-fluorobenzil)-1H-indazol-5-ilH5-[4-(2-metoksi-etilamino)-piperidin-1-ilmetil]-pirolo[2,1-f][1,2,4]triazin-4-il}-amin;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-[1,4]diazepan-5-on;
[5-(4-amino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-ilH1-(3-fluoro-benzil)-1H-indazol-5-il]-amin;
(+)-[5-(cis-4-amino-3-metil-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
(+)-[5-(trans-4-amino-3-metil-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-on;
(1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(+)-[1,4]diazepan-6-ol;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-(6R)-[1,4]diazepan-6-ol;
2-(1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-piperidin-4-ilamino)-etanol;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(4-metilamino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
[5-(6,6-difluoro-[1,4]diazepan-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-ol]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
(+)-[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(6-fluoro-[1,4]diazepan-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
1-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-[1,4]diazepan-6-on;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(piperidin-4-iloksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
2-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetoksi}-etanol;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(piperidin-3-ilmetoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
3-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetoksi}-propan-1,2-diol;
[5-(4-amino-butoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
[5-(4-amino-propoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
([1-(3-fluorobenzil)-1H-indazol-5-il]-[5-({2S}-morfolin-2-ilmetoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
[trans-5-(4-amino-cikloheksiloksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
[5-(2-amino-etoksimetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
3-{4[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetoksi}-propan-1-ol;
{5-[(3R)-3-amino-pirolidin-1-ilmetil]-pirolo[2,1-f][1,2,4]triazin-4-il}-[1-(3-fluorobenzil)-1H-indazol-5-il]-amin;
[5-(4-amino-piperidin-1-ilmetil)-pirolo[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin;
[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(piperidin-4-ilaminometil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
(+)-[1-(3-fluorobenzil)-1H-indazol-5-il]-[5-(piperidin-3-ilaminometil)-pirolo[2,1-f][1,2,4]triazin-4-il]-amin;
[5-(4-aminometil-piperidin-1-ilmetil)-[2,1-f][1,2,4]triazin-4-il]-[1-(3-fluoro-benzil)-1H-indazol-5-il]-amin;
2-(4-{4-[1-(3-fluorobenzil)-1H-indazol-5-ilamino]-pirolo[2,1-f][1,2,4]triazin-5-ilmetil}-[1,4]diazepan-1-il)-etanol;
6. Farmaceutska smjesa, naznačena time, što obuhvaća spoj kao u patentnom zahtjevu 1 i farmaceutski prihvatljiv nosač.
7. Farmaceutska smjesa, naznačena time, što obuhvaća spoj kao u patentnom zahtjevu 1, a u kombinaciji sa farmaceutski prihvatljivim nosačem i najmanje jednim drugim antitumorskim ili citotoksičnim sredstvom je oblikovana kao fiksna doza.
8. Farmaceutska smjesa kao u patentnom zahtjevu 7, naznačena time, što je navedeno antitumorsko ili citotoksično sredstvo odabrano iz grupe, koja se sastoji od: tamoksifena, toremifena, raloksifena, droloksifena, jodoksifena, megestrol acetata, anastrozola, leterazola, borazola, egzemestana, flutamida, nilutamida, bikalutamida, ciproteron acetata, gozerelin acetata, luprolida, finasterida, herceptina, metotreksata, 5-fluorouracila, citozin arabinozida, doksorubicina, daunomicina, epirubicina, idarubicina, mitomicina-C, daktinomicina, mitramicina, cisplatina, karboplatina, melfalana, klorambucila, busulfana, ciklofosfamida, ifosfamida, nitrozourea, tiotefana, vinkristina, taksola, taksotera, etopozida, tenipozida, amsakrina, irinotekana, topotekana i epotilona.
9. Postupak za liječenje proliferativne bolesti, naznačen time, što obuhvaća primjenjivanje toplokrvnim vrstama kojima je to potrebno terapeutski djelotvorne količine spoja formule I.
10. Postupak kao u patentnom zahtjevu 9, naznačen time, što je proliferativna bolest izdvojena iz grupe, koja se sastoji od: tumora, psorijaze i reumatoidnog artritisa.
11. Postupak kao u patentnom zahtjevu 10, naznačen time, što je proliferativna bolest rak.
12. Postupak kao u patentnom zahtjevu 11, naznačen time, što dalje obuhvaća primjenjivanje toplokrvnim vrstama kojima je to potrebno terapeutski djelotvorne količine najmanje jednog drugog antitumorskog ili citotoksičnog sredstva u kombinaciji sa spojem formule I.
13. Postupak kao u patentnom zahtjevu 12, naznačen time, što je navedeno antitumorsko ili citotoksično sredstvo odabrano iz grupe, koja se sastoji od: tamoksifena, toremifena, raloksifena, droloksifena, jodoksifena, megestrol acetata, anastrozola, leterazola, borazola, egzemestana, flutamida, nilutamida, bikalutamida, ciproteron acetata, gozerelin acetata, luprolida, finasterida, herceptina, metotreksata, 5-fluorouracila, citozin arabinozida, doksorubicina, daunomicina, epirubicina, idarubicina, mitomicina-C, daktinomicina, mitramicina, cisplatina, karboplatina, melfatana, klorambucila, busulfana, ciklofosfamida, ifosfamida, nitrozourea, tiotefana, vintalstina, taksola, taksotera, etopozida, tenipozida, amsakrina, irinotekana, topotekana i epotilona.
14. Postupak mjenjanja aktivnosti trrozin kinaze receptora, naznačen time, što obuhvaća primjenjivanje toplokrvnim vrstama kojima je to potrebno djelotvorne količine spoja iz zahtjeva 1.
15. Postupak kao u patentnom zahtjevu 14, naznačen time, što je navedena receptorna tirozin kinaza izdvojena iz grupe, koja se sastoji od: HER1, HER2 i HER4.
16. Postupak za liječenje bolesti koje su povezane sa putevima signalne transdukcije koja se odvija preko receptora faktora rasta, naznačen time, što obuhvaća primjenjivanje toplokrvnim vrstama kojima je to potrebno djelotvorne količine spoja iz zahtjeva 1.
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US33301401P | 2001-11-14 | 2001-11-14 | |
PCT/US2002/036528 WO2003042172A2 (en) | 2001-11-14 | 2002-11-12 | C-5 modified indazolylpyrrolotriazines |
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EP (1) | EP1446401B1 (hr) |
JP (1) | JP4301440B2 (hr) |
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CN (1) | CN1615306A (hr) |
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AT (1) | ATE524462T1 (hr) |
BR (1) | BR0214112A (hr) |
CA (1) | CA2467068A1 (hr) |
ES (1) | ES2370709T3 (hr) |
HR (1) | HRP20040422A2 (hr) |
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IL (1) | IL161616A0 (hr) |
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Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6867300B2 (en) | 2000-11-17 | 2005-03-15 | Bristol-Myers Squibb Company | Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors |
US6670357B2 (en) * | 2000-11-17 | 2003-12-30 | Bristol-Myers Squibb Company | Methods of treating p38 kinase-associated conditions and pyrrolotriazine compounds useful as kinase inhibitors |
TW200300350A (en) * | 2001-11-14 | 2003-06-01 | Bristol Myers Squibb Co | C-5 modified indazolylpyrrolotriazines |
EP2289894A3 (en) * | 2002-04-23 | 2011-07-20 | Bristol-Myers Squibb Company | Pyrrolo-triazine compounds useful as kinase inhibitors |
WO2003091229A1 (en) | 2002-04-23 | 2003-11-06 | Bristol-Myers Squibb Company | Aryl ketone pyrrolo-triazine compounds useful as kinase inhibitors |
US7388009B2 (en) | 2002-04-23 | 2008-06-17 | Bristol-Myers Squibb Company | Heteroaryl-substituted pyrrolo-triazine compounds useful as kinase inhibitors |
TW200401638A (en) * | 2002-06-20 | 2004-02-01 | Bristol Myers Squibb Co | Heterocyclic inhibitors of kinases |
TWI329112B (en) * | 2002-07-19 | 2010-08-21 | Bristol Myers Squibb Co | Novel inhibitors of kinases |
JP4791183B2 (ja) | 2002-08-23 | 2011-10-12 | スローン−ケッタリング インスティトュート フォア キャンサー リサーチ | エポチロン、その中間体、類似体の合成およびその使用 |
US7649006B2 (en) | 2002-08-23 | 2010-01-19 | Sloan-Kettering Institute For Cancer Research | Synthesis of epothilones, intermediates thereto and analogues thereof |
TW200420565A (en) | 2002-12-13 | 2004-10-16 | Bristol Myers Squibb Co | C-6 modified indazolylpyrrolotriazines |
MXPA05008183A (es) | 2003-02-05 | 2005-10-05 | Bristol Myers Squibb Co | Proceso para preparar pirrolotriazina como inhibidores de cinasa. |
US20060014741A1 (en) * | 2003-12-12 | 2006-01-19 | Dimarco John D | Synthetic process, and crystalline forms of a pyrrolotriazine compound |
US7102001B2 (en) | 2003-12-12 | 2006-09-05 | Bristol-Myers Squibb Company | Process for preparing pyrrolotriazine |
US7064203B2 (en) * | 2003-12-29 | 2006-06-20 | Bristol Myers Squibb Company | Di-substituted pyrrolotriazine compounds |
MY145634A (en) * | 2003-12-29 | 2012-03-15 | Bristol Myers Squibb Co | Pyrrolotriazine compounds as kinase inhibitors |
US7459562B2 (en) | 2004-04-23 | 2008-12-02 | Bristol-Myers Squibb Company | Monocyclic heterocycles as kinase inhibitors |
TW200538453A (en) | 2004-04-26 | 2005-12-01 | Bristol Myers Squibb Co | Bicyclic heterocycles as kinase inhibitors |
US7102002B2 (en) * | 2004-06-16 | 2006-09-05 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
US7173031B2 (en) | 2004-06-28 | 2007-02-06 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
US7432373B2 (en) | 2004-06-28 | 2008-10-07 | Bristol-Meyers Squibb Company | Processes and intermediates useful for preparing fused heterocyclic kinase inhibitors |
TW200600513A (en) | 2004-06-30 | 2006-01-01 | Bristol Myers Squibb Co | A method for preparing pyrrolotriazine compounds |
US7253167B2 (en) | 2004-06-30 | 2007-08-07 | Bristol-Myers Squibb Company | Tricyclic-heteroaryl compounds useful as kinase inhibitors |
US7102003B2 (en) * | 2004-07-01 | 2006-09-05 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds |
US7504521B2 (en) | 2004-08-05 | 2009-03-17 | Bristol-Myers Squibb Co. | Methods for the preparation of pyrrolotriazine compounds |
US7148348B2 (en) | 2004-08-12 | 2006-12-12 | Bristol-Myers Squibb Company | Process for preparing pyrrolotriazine aniline compounds useful as kinase inhibitors |
US7151176B2 (en) * | 2004-10-21 | 2006-12-19 | Bristol-Myers Squibb Company | Pyrrolotriazine compounds |
TW200635927A (en) * | 2004-12-22 | 2006-10-16 | Bristol Myers Squibb Co | Synthetic process |
ES2319462T3 (es) | 2005-03-28 | 2009-05-07 | Bristol-Myers Squibb Company | Inhibidores competitivos de atp cinasas. |
US7534882B2 (en) | 2005-04-06 | 2009-05-19 | Bristol-Myers Squibb Company | Method for preparing pyrrolotriazine compounds via in situ amination of pyrroles |
US7547782B2 (en) | 2005-09-30 | 2009-06-16 | Bristol-Myers Squibb Company | Met kinase inhibitors |
US7514435B2 (en) * | 2005-11-18 | 2009-04-07 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
US7348325B2 (en) | 2005-11-30 | 2008-03-25 | Bristol-Myers Squibb Company | Pyrrolotriazine kinase inhibitors |
CN101466710B (zh) | 2005-12-02 | 2013-05-29 | 拜尔健康护理有限责任公司 | 用于治疗与血管生成有关的过度增殖性病症和疾病的取代的4-氨基-吡咯并三嗪衍生物 |
PE20070855A1 (es) * | 2005-12-02 | 2007-10-14 | Bayer Pharmaceuticals Corp | Derivados de 4-amino-pirrolotriazina sustituida como inhibidores de quinasas |
US8063208B2 (en) | 2006-02-16 | 2011-11-22 | Bristol-Myers Squibb Company | Crystalline forms of (3R,4R)-4-amino-1-[[4-[(3-methoxyphenyl)amino]pyrrolo[2,1-f][1,2,4]triazin-5-yl]methyl]piperidin-3-ol |
DE102006030479A1 (de) * | 2006-07-01 | 2008-03-20 | Merck Patent Gmbh | Indazolderivate |
US8071779B2 (en) | 2006-12-18 | 2011-12-06 | Inspire Pharmaceuticals, Inc. | Cytoskeletal active rho kinase inhibitor compounds, composition and use |
WO2010071885A1 (en) | 2008-12-19 | 2010-06-24 | Cephalon, Inc. | Pyrrolotriazines as alk and jak2 inhibitors |
US20120149902A1 (en) * | 2009-07-28 | 2012-06-14 | Ube Industries, Ltd. | Pyrrolo[2,3-d]pyrimidine derivative |
CN102627647A (zh) * | 2012-03-20 | 2012-08-08 | 南京药石药物研发有限公司 | 4-氯-5-甲基-1H-吡咯并[2,1-f][1,2,4]三嗪的合成方法 |
EP2948454B1 (en) | 2013-01-24 | 2017-05-31 | Council of Scientific & Industrial Research An Indian registered body incorporated under the Registration of Societies Act (Act XXI of 1860) | Triazine compounds and a process for preparation thereof |
JP6473146B2 (ja) | 2013-10-11 | 2019-02-20 | ブリストル−マイヤーズ スクイブ カンパニーBristol−Myers Squibb Company | ピロロトリアジンキナーゼ阻害剤 |
WO2015081783A1 (zh) * | 2013-12-06 | 2015-06-11 | 江苏奥赛康药业股份有限公司 | 吡咯并[2,1-f][1,2,4]三嗪类衍生物及其制备方法和用途 |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4908056A (en) | 1986-04-25 | 1990-03-13 | E. I. Du Pont De Nemours And Company | Heterocyclic acyl sulfonamides |
DK0778277T3 (da) | 1995-12-08 | 2003-10-27 | Pfizer | Substituerede heterocycliske derivater som CRF antagonister |
CZ68199A3 (cs) | 1996-08-28 | 1999-11-17 | Pfizer Inc. | 6,5-Heterobicyklické deriváty, farmaceutická kompozice na jejich bázi a způsob léčení chorob |
ES2328269T3 (es) * | 1999-05-21 | 2009-11-11 | Bristol-Myers Squibb Company | Pirrolotriazinas como inhibires de quinasas. |
JP4623483B2 (ja) | 1999-08-23 | 2011-02-02 | 塩野義製薬株式会社 | sPLA2阻害作用を有するピロロトリアジン誘導体 |
US6867300B2 (en) * | 2000-11-17 | 2005-03-15 | Bristol-Myers Squibb Company | Methods for the preparation of pyrrolotriazine compounds useful as kinase inhibitors |
US20040082585A1 (en) * | 2001-10-03 | 2004-04-29 | Pharmacia Corporation | Prodrugs of substituted polycyclic compounds useful for selective inhibition of the coagulation cascade |
TW200300350A (en) * | 2001-11-14 | 2003-06-01 | Bristol Myers Squibb Co | C-5 modified indazolylpyrrolotriazines |
WO2003091229A1 (en) * | 2002-04-23 | 2003-11-06 | Bristol-Myers Squibb Company | Aryl ketone pyrrolo-triazine compounds useful as kinase inhibitors |
TW200400034A (en) * | 2002-05-20 | 2004-01-01 | Bristol Myers Squibb Co | Pyrazolo-pyrimidine aniline compounds useful as kinase inhibitors |
TWI329112B (en) * | 2002-07-19 | 2010-08-21 | Bristol Myers Squibb Co | Novel inhibitors of kinases |
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2002
- 2002-11-08 TW TW091132942A patent/TW200300350A/zh unknown
- 2002-11-12 EP EP02793930A patent/EP1446401B1/en not_active Expired - Lifetime
- 2002-11-12 KR KR1020047007261A patent/KR20050044441A/ko not_active Application Discontinuation
- 2002-11-12 AT AT02793930T patent/ATE524462T1/de not_active IP Right Cessation
- 2002-11-12 NZ NZ533034A patent/NZ533034A/en unknown
- 2002-11-12 BR BR0214112-4A patent/BR0214112A/pt not_active Application Discontinuation
- 2002-11-12 HU HU0402566A patent/HUP0402566A3/hu unknown
- 2002-11-12 CA CA002467068A patent/CA2467068A1/en not_active Abandoned
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- 2002-11-12 RU RU2004117549/04A patent/RU2004117549A/ru not_active Application Discontinuation
- 2002-11-12 JP JP2003544009A patent/JP4301440B2/ja not_active Expired - Fee Related
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- 2002-11-12 WO PCT/US2002/036528 patent/WO2003042172A2/en active IP Right Grant
- 2002-11-12 CN CNA028270657A patent/CN1615306A/zh active Pending
- 2002-11-12 PL PL02368909A patent/PL368909A1/xx not_active Application Discontinuation
- 2002-11-13 AR ARP020104360A patent/AR037368A1/es not_active Application Discontinuation
- 2002-11-14 PE PE2002001102A patent/PE20030712A1/es not_active Application Discontinuation
- 2002-11-14 UY UY27540A patent/UY27540A1/es not_active Application Discontinuation
- 2002-11-14 US US10/294,281 patent/US6908916B2/en not_active Expired - Lifetime
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2004
- 2004-04-30 IS IS7243A patent/IS7243A/is unknown
- 2004-05-11 HR HR20040422A patent/HRP20040422A2/hr not_active Application Discontinuation
- 2004-05-12 MX MXPA04004492A patent/MXPA04004492A/es unknown
- 2004-05-13 NO NO20041983A patent/NO20041983L/no not_active Application Discontinuation
- 2004-05-13 ZA ZA200403694A patent/ZA200403694B/en unknown
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2005
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Also Published As
Publication number | Publication date |
---|---|
WO2003042172A3 (en) | 2004-01-29 |
WO2003042172A2 (en) | 2003-05-22 |
EP1446401A4 (en) | 2006-04-12 |
JP4301440B2 (ja) | 2009-07-22 |
NO20041983L (no) | 2004-06-24 |
CA2467068A1 (en) | 2003-05-22 |
AR037368A1 (es) | 2004-11-03 |
HUP0402566A2 (hu) | 2005-03-29 |
PE20030712A1 (es) | 2003-08-21 |
IL161616A0 (en) | 2004-09-27 |
IS7243A (is) | 2004-04-30 |
ATE524462T1 (de) | 2011-09-15 |
US20050209235A1 (en) | 2005-09-22 |
HUP0402566A3 (en) | 2009-01-28 |
JP2005509030A (ja) | 2005-04-07 |
ES2370709T3 (es) | 2011-12-22 |
PL368909A1 (en) | 2005-04-04 |
TW200300350A (en) | 2003-06-01 |
EP1446401A2 (en) | 2004-08-18 |
US6908916B2 (en) | 2005-06-21 |
KR20050044441A (ko) | 2005-05-12 |
RU2004117549A (ru) | 2006-01-10 |
CN1615306A (zh) | 2005-05-11 |
UY27540A1 (es) | 2003-07-31 |
BR0214112A (pt) | 2004-09-14 |
NZ533034A (en) | 2004-11-26 |
EP1446401B1 (en) | 2011-09-14 |
MXPA04004492A (es) | 2004-08-11 |
US20030186983A1 (en) | 2003-10-02 |
ZA200403694B (en) | 2006-06-28 |
NO20041983D0 (no) | 2004-05-13 |
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