NO324866B1 - Bicykliske heterocykler, medikamenter inneholdende disse, deres anvendelse for fremstilling av legemidler for behandling av sykdommer og fremgangsmater for fremstilling derav - Google Patents
Bicykliske heterocykler, medikamenter inneholdende disse, deres anvendelse for fremstilling av legemidler for behandling av sykdommer og fremgangsmater for fremstilling derav Download PDFInfo
- Publication number
- NO324866B1 NO324866B1 NO20030870A NO20030870A NO324866B1 NO 324866 B1 NO324866 B1 NO 324866B1 NO 20030870 A NO20030870 A NO 20030870A NO 20030870 A NO20030870 A NO 20030870A NO 324866 B1 NO324866 B1 NO 324866B1
- Authority
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- Norway
- Prior art keywords
- amino
- phenyl
- oxo
- chloro
- fluoro
- Prior art date
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- 238000004519 manufacturing process Methods 0.000 title claims description 21
- 238000011282 treatment Methods 0.000 title claims description 17
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims description 11
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- 229940079593 drug Drugs 0.000 title claims description 7
- 238000002360 preparation method Methods 0.000 title claims description 4
- 238000000034 method Methods 0.000 title description 7
- 125000002618 bicyclic heterocycle group Chemical group 0.000 title description 2
- -1 methoxy- Chemical class 0.000 claims description 171
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 101
- 150000001875 compounds Chemical class 0.000 claims description 74
- 238000006243 chemical reaction Methods 0.000 claims description 54
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 32
- 239000011541 reaction mixture Substances 0.000 claims description 31
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- 125000003118 aryl group Chemical group 0.000 claims description 11
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- RWAHVEYSYXHNAL-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-cyclopentyloxyquinazolin-7-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCOC1=CC2=NC=NC(NC=3C=C(Cl)C(F)=CC=3)=C2C=C1OC1CCCC1 RWAHVEYSYXHNAL-UHFFFAOYSA-N 0.000 claims description 7
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- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 claims description 6
- SNVKZKSVYQHPOI-UHFFFAOYSA-N 4-[3-[4-(3-chloro-4-fluoroanilino)-7-(cyclopropylmethoxy)quinazolin-6-yl]oxypropyl]-6,6-dimethylmorpholin-2-one Chemical compound C1C(=O)OC(C)(C)CN1CCCOC(C(=CC1=NC=N2)OCC3CC3)=CC1=C2NC1=CC=C(F)C(Cl)=C1 SNVKZKSVYQHPOI-UHFFFAOYSA-N 0.000 claims description 6
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- 239000000126 substance Substances 0.000 claims description 5
- BWYJJZBRYSADRP-UHFFFAOYSA-N 2-methoxyquinazoline Chemical compound C1=CC=CC2=NC(OC)=NC=C21 BWYJJZBRYSADRP-UHFFFAOYSA-N 0.000 claims description 4
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- JSLMOUXQBQDGLP-UHFFFAOYSA-N 4-[2-[4-(3-bromoanilino)-7-methoxyquinazolin-6-yl]oxyethyl]-6,6-dimethylmorpholin-2-one Chemical compound C=12C=C(OCCN3CC(C)(C)OC(=O)C3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Br)=C1 JSLMOUXQBQDGLP-UHFFFAOYSA-N 0.000 claims description 4
- XILCDKHRLVBGRM-UHFFFAOYSA-N 4-[2-[4-(3-chloro-4-fluoroanilino)-6-(cyclopropylmethoxy)quinazolin-7-yl]oxyethyl-methylamino]oxolan-2-one Chemical compound C1OC(=O)CC1N(C)CCOC(C(=CC1=2)OCC3CC3)=CC1=NC=NC=2NC1=CC=C(F)C(Cl)=C1 XILCDKHRLVBGRM-UHFFFAOYSA-N 0.000 claims description 4
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- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
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- A61P11/06—Antiasthmatics
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Description
Gjenstanden for foreliggende oppfinnelse er bicykliske heterocykler med den generelle formel
deres tautomere, deres stereoisomere og deres salter, spesielt deres fysiologisk akseptable salter med uorganiske eller organiske syrer eller baser, hvilke har verdifulle farmakologiske egenskaper, særlig en hemmende virkning på den med tyrosinkinasen formidlete signaltransduksjon, deres anvendelse for fremstilling av medikamneter for behandling av sykdommer, særlig av tumorsykdommer, av sykdommer i lungene og luftveiene, og deres fremstilling.
I den ovennevnte generelle formel I betyr
Ra betyr en 1-fenyletylgruppe eller en med restene Ri og R2substituert fenylgruppe, hvorunder
Ri er et fluor-, klor- eller bromatom og
R2et hydrogen- eller fluoratom,
én av restene Rbeller Rcer en R3-(CH2)m-0-gruppe og den andre av restene Rbeller Rcer en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy-, cyklobutylmetoksy-, cyklopentylmetoksy-, tetrahydrofuran-3-yloksy-, tetrahydropyran-3-yloksy-, tetrahydropyran-4-yloksy-, tetrahydrofuranylmetoksy- eller tetrahydropyranylmetoksygruppe, hvorunder
R3betyr en N-(2-okso-tetrahydrofuran-4-yl)-metylaminogruppe eller en med én eller to metylgrupper substituert 2-okso-morfolin-4-yl-gruppe og
m er tallet 2, 3 eller 4,
med det forbehold at forbindelsene
4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksyj-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy}-7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(3-metyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(5,5-dimetyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklobutyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopropylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl]amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-{2-[N-(2-okso-tetrahydrofuran-4-y0 etoksy} -7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino] etoksy} -7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-{2-[N-(^^ etoksy} -7-cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arruno]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arm^o]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-6-[3-(6,6-dim cyklopentylmetoksy-kinazolin,
(R)-4-[(l-fenyl-etyl)arnino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arruno]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-m^ kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklobutyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopropylmetoksy-kinazolin,
4-[(3-kJor-4-fluor-fenyl]amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6 cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-{2-[N-(2-okso-tetrahy etoksy} -6-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amin^ etoksy} -6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-arrun etoksy} -6-cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arm^o]-7-[3-(6,6-dimetyl-2-okso-rnorfolin-4-yl)-propyloksy]-6-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arruno]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propylok^ cyklopentylmetoksy-kinazolin og
(R)-4-[(l-fenyl-etyl)amino]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-6-cyklopentyloksy-kinazolin
er utelukket,
deres tautomere, deres stereoisomere og deres salter.
Foretrukne forbindelser med den ovennevnte generelle formel I er de, hvori
Ra betyr en 1-fenyletyl-, 3-bromfenyl- eller 3-klor-4-fluorfenylgruppe,
Rben R3-(CH2)m-0-gruppe, i hvilken
R3er en med én eller to metylgrupper substituert 2-okso-morfolin-4-yl-gruppe og m er tallet 2 eller 3,
og Rcbetyr en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy, tetrahydrofuran-3-yloksy- eller tetrahydrofuranylmetoksygruppe med det forbehold at forbindelsene
4-[(3-brom-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4- [(3-brom-fenyl)amino] -6- [2-(3 -metyl-2-okso-morfolin-4-yl)etoksy] -7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(5,5-dimetyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklobutyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopropylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-6-[3-cyklopentyloksy-kinazolin og
(R)-4-[(l-fenyl-etyl)arru^o]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin
er utelukket,
deres tautomere, deres stereoisomere og deres salter.
Foretrukne forbindelser er de med den generelle formel I er de i hvilke
Ra betyr en 3-klor-4-fluor-fenylgruppe,
Rben cyklopentyloksy-, cyklopropylmetoksy-, cyklopentylmetoksy-, tetrahydrofuran-3-yloksy- eller tetrahydrofuranylmetoksygruppe og
Rcen R3-(CH2)m-0-gruppe, i hvilken
R3er en med én eller to metylgrupper substituert 2-okso-morfolin-4-yl-gruppe og
m tallet 2,
med det forbehold at forbindelsene
4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy] -kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy] cyklopropylmetoksy-kinazolin og
4-[(3-klor-4-fluor-fenyl]armno]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentylmetoksy-kinazolin
er utelukket,
deres tautomere, deres stereoisomere og deres salter.
Som helt spesielt foretrukne forbindelser er eksempelvis de følgende nevnt: (1) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentylmetoksy-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy]-kinazolin, (2) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -kinazolin, (3) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy] -kinazolin, (4) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklobutyloksy-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy]-kinazolin, (5) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopropylmetoksy-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy]-kinazolin, (6) 4- [(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7- {2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy}-kinazolin, (7) 4-[(3-brom-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin, (8) 4-[(3-brom-fenyl)arruno]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-m kinazolin, (9) 4-t(3-klor-4-fluor-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin, (10) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin, (11) 4-[(/?)-(l-fenyl-etyl)amino]-6-[3-((S)-6-metyl^ metoksy-kinazolin, (12) 4-[(/?)-(l-fenyl-etyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-meto^^ kinazolin og (13) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
deres tautomere, deres stereoisomere og deres salter.
Forbindelsene med den generelle formel I lar seg eksempelvis fremstille etter den følgende fremgangsmåte:
a) omsetning av en forbindelse med den generelle formel
hvori
Ra er definert som innledningsvis nevnt,
en av restene Rb' eller Rc' er en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy-, cyklobutylmetoksy- eller cyklopentylmetoksygruppe og den andre av restene Rb' eller Rc' er en Zi-(CH2)m-0-gruppe, i hvilken
m er definert som innledningsvis nevnt og
Zi betyr en avgangsgruppe så som et halogenatom eller en sulfonyloksygruppe så som et klor- eller bromatom, en metansulfonyloksy- eller p-toluensulfonyloksygruppe,
med en forbindelse med den generelle formel
i hvilken
R3er definert som innledningsvis nevnt.
Omsetningen blir eventuelt utført i et løsningsmiddel eller en løsningsmiddelblanding som metylenklorid, acetonitril, dimetylformamid, dimetylsulfoksyd, sulfolan, benzen, toluen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran eller dioksan, hensiktsmessig i nærvær en tertiær organisk base så som trietylamin eller N-etyl-diisopropylamin, hvorunder disse organiske baser samtidig kan tjene også som løsningsmiddel, eller i nærvær en uorganisk base så som natriumkarbonat eller kaliumkarbonat, hensiktsmessig ved temperaturer mellom -20 og 200°C, fortrinnsvis ved temperaturer mellom 0 og 150°C,.
b) cyklisering av en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel
i hvilken
Ra er definert som innledningsvis nevnt, en av restene Rb" eller Rc" er en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy-, cyklobutylmetoksy- eller cyklopentylmetoksygruppe og den andre av restene Rb" eller Rc" er en R3'-(CH2)m-0-gruppe, i hvilken
m er definert som innledningsvis nevnt og
R31 betyr en på metylengruppene med en eller to metyl- eller etylgrupper substituert R4-0-CO-CH2-N-CH2CH2-OH-gruppe, i hvilken
R4er et hydrogenatom eller en C|.4-alkylgruppe.
Omsetningen blir eventuelt utført i et løsningsmiddel eller en løsningsmiddelblanding som metylenklorid, acetonitril, dimetylformamid, dimetylsulfoksyd, sulfolan, benzen, toluen, klorbenzen, tetrahydrofuran, benzen/tetrahydrofuran eller dioksan, hensiktsmessig i nærvær en vannfri syre som trifluoreddiksyre, metansulfonsyre eller svovelsyre eller i nærvær av et vannuttrekkende middel, f.eks. i nærvær av klormaursyreisobutylester, tionylklorid, trimetylklorsilan, fosfortriklorid, fosforpentoksyd, N,N'-dicykloheksylkarbodiimid, N,N'-dicykloheksylkarbodiimid/N-hydroksysuccinimid eller 1 -hydroksy-benztriazol, N,N'-karbonyldiimidazol eller trifenylfosfin/tetraklorkarbon, ved temperaturer mellom -20 og 200°C, fortrinnsvis likevel ved temperaturer mellom -10 og 160°C.
Ved den forut beskrevne omsetningen kan eventuelt tilstedeværende reaktive grupper som hydroksy-, karboksy- eller iminogrupper beskyttes under omsetningen med vanlige beskyttelsegrupper, hvilke etter omsetningen igjen blir avspaltet.
Eksempelvis kommer som beskyttelsesrest for en hydroksygruppe trimetylsilyl-, acetyl-, benzoyl-, metyl-, etyl-, tert.butyl-, trityl-, benzyl- eller tetrahydropyranylgruppen,
som beskyttelsesrester for en karboksygruppe trimetylsilyl-, metyl-, etyl-, tert.butyl-, benzyl-eller tetrahydropyranylgruppen og
som beskyttelserester for en iminogruppe formyl-, acetyl-, trifluoracetyl-, etoksykarbonyl-, tert.butoksykarbonyl-, benzyloksykarbonyl-, benzyl-, metoksybenzyl- eller 2,4-dimetoksybenzylgruppen i betraktning.
Den eventuelt påfølgende avspaltning av en anvendt beskyttelserest foregår eksempelvis hydrolytisk i et vandig løsningsmiddel, f.eks. i vann, isopropanol/vann, eddiksyre/vann, tetrahydrofuran/vann eller dioksan/vann, i nærvær av en syre så som trifluoreddiksyre, saltsyre eller svovelsyre eller i nærvær av en alkalibase så som natriumhydroksyd eller kaliumhydroksyd eller aprotisk, f.eks. i nærvær av iodtrimetylsilan, ved temperaturer mellom 0 og 120°C, fortrinnsvis ved temperaturer mellom 10 og 100°C.
Avspaltning av en benzyl-, metoksybenzyl- eller benzyloksykarbonylrest skjer imidlertid eksempelvis hydrogenolytisk, f.eks. med hydrogen i nærvær av en katalysator så som palladium/karbon i et egnet løsningsmiddel som metanol, etanol, eddiksyreetylester eller iseddik, eventuelt under tilsetning av en syre som saltsyre ved temperaturer mellom 0 og 100°C, fortrinnsvis imidlertid ved romtemperaturen mellom 20 og 60°C, og ved et hydrogentrykk på 1 til 7 bar, fortrinnsvis imidlertid fra 3 til 5 bar. Avspaltning av en 2,4-dimetoksybenzylrest skjer imidlertid fortrinnsvis i trifluoreddiksyre i nærvær av anisol.
Avspaltning av en tert.butyl- eller tert.butyloksykarbonylrest skjer fortrinnsvis ved behandling med en syre som trifluoreddiksyre eller saltsyre eller ved behandling med jodtrimetylsilan, eventuelt under anvendelse av et løsningsmiddels som metylenklorid, dioksan, metanol eller dietyleter.
Avspaltning av en trifluoracetylrest skjer fortrinnsvis ved behandling med en syre så som saltsyre, eventuelt i nærvær av et løsningsmiddel som eddiksyre ved temperaturer mellom 50 og 120°C eller ved behandling med natronlut, eventuelt i nærvær av et løsningsmiddel så som tetrahydrofuran ved temperaturer mellom 0 og 50°C.
Videre kan de oppnådde forbindelser med den generelle formel I, som allerede innledningsvis nevnt, spaltes i sine enantiomere og/eller diastereomere. Således kan eksempelvis cis-/trans-blandinger spaltes i sine cis- og trans-isomere, og forbindelser med minst ett optisk aktivt karbonatom spaltes i sine enantiomere.
Således lar eksempelvis de oppnådde cis-/trans-blandinger seg spalte ved kromatografi i sine cis- og trans-isomere, de oppnådde forbindelser med den generelle formel I, hvilke opptrer som racematenr, ved i og for seg kjente metoder (se Allinger N. L. og Eliel E. L. i "Topics in Stereochemistry", bd. 6, Wiley Interscience, 1971)) i sine optiske antipoder, og forbindelser med den generelle formel I med minst 2 asymmetriske karbonatomer på grunn av sine fysikalisk-kjemiske forskjeller oppspalte ved i og for seg kjente metoder, f.eks. ved kromatografi og/eller fraksjonert krystallisasjon, i sine diastereomere, som, hvis de dannes i racemisk form, så skilles som ovenfor nevnt i de enantiomere.
Enantiomereseparasjonen skjer fortrinnsvis ved søyleseparasjon på chirale faser eller ved omkrystallisering fra et optisk aktivt løsningsmiddel eller ved omsetning med en optisk aktiv substans som med den racemiske forbindelse danner salter eller derivater som f.eks. estere eller amider, særlig syrer og deres aktiverte derivater eller alkoholer, og separasjon av denne således oppnådde diastereomere saltblanding eller derivatet, f.eks. på grunn av forskjellige løseligheter, hvorunder de frie antipoder kan frigjøres ved innvirkning med et egnet middel frigjort fra de rene diastereomere salter eller derivater, særlig vanlige optisk aktive syrer er f.eks. D- og L-formene av vinsyre eller dibenzoylvinsyre, di-o-tolylvinsyre, eplesyre, mandelsyre, kamfersulfonsyre, glutaminsyre, asparaginsyre eller chinasyre. Som optisk aktiv alkohol kommer eksempelvis (+)- eller (-)-mentol og som optisk aktiv acylrest i amider eksempelvis (+)-eller (-)-menthyloksykarbonyl i betraktning.
Dertil kan de oppnådde forbindelser med formelen I overføres i sine salter, særlig for den farmasøytiske anvendelse i sine fysiologisk fordragelige salter med uorganiske eller organiske syrer. Som syrer kommer for dette eksempelvis saltsyre, bromhydrogensyre, svovelsyre, metansulfonsyre, fosforsyre, fumarsyre, ravsyre, melkesyre, sitronsyre, vinsyre eller malein-syre i betraktning.
Dessuten lar de derved oppnådde nye forbindelser med formelen I, hvis disse innholder en karboksy-, hydroksyfosforyl-, sulfo- eller 5-tetrazolylgruppe, seg om ønsket derpå overføre i sine salter med uorganiske eller organiske baser, særlig for den farmasøytiske anvendelse i sine fysiologisk fordragelige salter,. Som baser kommer herunder eksempelvis natriumhydroksyd, kaliumhydroksyd, arginin, cykloheksylamin, etanolamin, dietanolamin og trietanolamin i betraktning.
De som utgangsstoffer anvendte forbindelser med de generelle formler II til IV er delvis kjente fra litteraturen eller man oppnår dem ved en fra litteraturen i og for seg kjent fremgangsmåte (se eksempeler I til XIV).
Som allerede innledningsvis nevnt, viser forbindelsene ifølge oppfinnelsen med den generelle formel I og deres fysiologisk fordragelige salter verdifulle farmakologiske egenskaper, særlig en hemmende virkning på den med den Epidermal Growth Factor-reseptor (EGF-R) fremkalte signaltransduksjon, hvorunder denne eksempelvis selv kan bevirke en inhibering av ligandebindingen, reseptordimeriseringen eller tyrosinkinaser. Dertil er det mulig at signaloverføringen til videre nedstrømsliggende komponenter blokkeres.
De biologiske egenskapene til de nye forbindelser ble testet som følger:
Hemningen av den EGF-R-formidlete signaloverføringen kan f.eks. påvises med celler, som eksprimerer humant EGF-R og hvis overlevelse og proliferasjon avhenger av stimulering med EGF hhv. TGF-alfa. Her ble en interleukin-3-(IL-3) avhengig cellelinje av murin opprinnelse anvendt, som ble slik genetisk forandret at den eksprimerer funksjonelt humant EGF-R. Proliferasjonen til disse nevnte F/L-HERc celler kan derfor enten stimuleres med murint IL-3 eller med EGF (se von Riiden, T. et al. i EMBO J. 7,2749-2756 (1988) og Pierce, J. H. et al. i Science 239, 628-631 (1988)).
Som utgangsmaterial for F/L-HERc-cellene tjente cellelinjen FDC-Pi, hvis fremstilling var beskrevet av Dexter, T. M. et al. i J. Exp. Med. 152^1036-1047 (1980). Alternativ kan imidlertid også andre vekstfaktor-avhengige celler anvendes (se eksempelvis Pierce, J. H. et al. i Science 239, 628-631 (1988), Shibuya, H. et al. i Cell 70, 57-67 (1992) og Alexander, W. S. et al. i EMBO J. 10, 3683-3691 (1991)). For ekspresjon av humant EGF-R cDNA (se Ullrich, A. et al. i Nature 309.418-425 (1984)) ble rekombinante retrovirus anvendt, som beskrevet av Riiden, T. et al., EMBO J. 7,2749-2756 (1988), med den forskjell at for ekspresjon av EGF-R cDNA ble den retrovirale vektor LXSN (se Miller, A. D. et al. i BioTechniques 7,980-990 (1989)) anvendt, og som pakningscelle tjente linjen GP+E86 (se Markowitz, D. et al. i J. Virol. 62,1120-1124 (1988)).
Testen ble utført som følger:
F/L-HERc-celler ble dyrket i RPMI/1640 Medium (BioWhittaker), supplementert med 10 % føtalt storfeserum (FCS, Boehringer Mannheim), 2 mM glutamin (BioWhittaker), standardantibiotika og 20 ng/ml humant EGF (Promega), ved 37°C og 5% CO2. For å
undersøke den inhiberende aktiviteten av forbindelsene ifølge oppfinnelsen ble 1,5 x 10^ celler per brønn in triplo i 96-hullersplater dyrket i mediet ovenfor (200[xl), hvorunder proliferasjonen av cellene enten ble stimulert med EGF (20 ng/ml) eller murint IL-3. Som kilde for IL-3 tjente kultursupernanteanter av cellelinien X63/0 mIL-3 (se Karasuyama, H. et al.i Eur. J. Immunol. 18, 97-104 (1988)). Forbindelsene ifølge oppfinnelsen ble løst i 100% dimetylsulfoksyd (DMSO) og tilsatt kulturene i forskjellige fortynninger, hvorunder den maksimale DMSO-konsentrasjon var 1%. Kulturene ble inkubert i 48 timer ved 37°C.
For bestemmelse av den inhibitoriske aktivitet av forbindelsene ifølge oppfinnelsen ble det relative celletall målt med Cell Titer 96^M AQue0usNon-Radioactive Cell proliferasjon Assay (promega) i O.D. enheter. Det relative celletall ble beregnet i prosent av kontroller (F/LHERc-celler uten inhibitor) og virkestoffkonsentrasjon som hemmer proliferasjonen av cellene med 50% hemmer (IC50) utledet. Herunder ble følgende resultater oppnådd: Oppfinnlense omhandler også fysiologisk akseptable salter av forbindelsene over med uorganiske eller organiske syrer eller baser.
Oppfinnlense omhandler også forbindelse over eller et fysiologisk akseptabelt salt som nevnt over ved siden av eventuelt en eller flere inerte bærere og/eller fortynningsmidler.
Forbindelsene ifølge oppfinnelsen med den generelle formel I hemmer dermed signaltransduksjonen med tyrosinkinaser, som det for eksempel ble vist av den humane EGF-reseptoren, og er derfor nyttig for fremstilling av medikamenter for behandling av patofysiologiske prosesser som fremkalles ved overfunksjon av tyrosinkinaser. Det er f.eks. benigne eller maligne tumorer, særlig tumorer av epithelial og neuroepithelial opprinnelse, metastase samt den abnorme proliferasjon av vaskulære endothelceller (neoangiogenese).
Forbindelsene ifølge oppfinnelsen er også nyttige for fremstilling av medikamenter for profylakse og behandling av sykdommer i luftveiene og lungene, som henger sammen med enøket eller forandret slimproduksjon, som fremkalles ved stimulering av tyrosinkinaser, som f.eks. ved betennelsessykdommer i luftveiene så som kronisk bronkitt, kronisk obstruktiv bronkitt, astma, bronchiektasier, allergisk eller ikke-allergisk snue eller sinusitt, cystisk fibrose, al-antitrypsin-mangel, eller ved huste, lunge-emfysem, lungefibrose og hyperreaktive luftveier.
Forbindelsene er også egnet for fremstilling av medikamenter for behandling av sykdommer i mage-tarm-kanalen og gallengangene og -blæren, som henger sammen med en forstyrret aktivitet av tyrosinkinasene, slik som de som f.eks. finnes ved kroniske betennelsesendringer, som kolecystitt, M. Krohn, Colitis ulcerosa, og svulster i mage-tarm-kanalen eller som de forekommer ved sykdommer i mage-tarm-kanalen, som henger sammen med enøket sekresjon, som M. Ménétrier, sezernerende adenom og proteintapsyndromer,
dertil for behandling av nesepolypper samt av polypper i den gastrointestinale kanalen med forskjellig genese som f.eks. filløse eller adenomatøse polypper i tykktarmen, men også av polypper ved familiær Polyposis coli, ved tarmpolypper ved Gardner-syndromet, ved
polypper i hele mage-tarm-kanalen ved Peutz-Jeghers-syndrom, ved betente pseudopolypper, ved juvenile polypper, ved Colitis cystica profunda og ved Pneumatosis cystoides intestinales.
Dertil kan forbindelsene med den generelle formel I og deres fysiologisk fordragelige salter anvendes for fremstilling av medikamenter for behandling av nyresykdommer, særlig ved cystiske endringer som ved cystennering, for behandling av nyrecyster, som kan være av idiopatisk genese eller opptre innenfor rammen av syndromer som f.eks. ved tuberøs sklerose, ved von-Hippel-Lindau-syndromet, ved Nefronoftisis og Markschwammnyre samt andre sykdommer, som forårsakes med aberrant funksjon av tyrosinkinaser, som f.eks. epidermal hyperproliferasjon (Psoriasis), inflammatoriske prosesser, sykdommer i immunsystemet, hyperproliferasjon av hematopoetiske celler etc.
På grunn av deres biologiske egenskaper kan forbindelsene ifølge oppfinnelsen anvendes alene eller i kombinasjon med andre farmakologisk virksomme forbindelser, eksempelvis i tumorterapi ved monoterapi eller i kombinasjon med andre anti-tumor-terapeutika, eksempelvis i kombinasjon med topoisomerase-inhibitorer (f.eks. etoposide), mitoseinhibitorer (f.eks. vinblastin), forbindelser som interagerer med nukleinsyrer (f.eks. cis-platina, cyklofosfamid, adriamycin), hormon-antagonister (f.eks. tamoksyfen), inhibitorer av metaboliske prosesser (f.eks. 5-FTJ etc), cytokiner (f.eks. interferoner), antistoffer etc. For behandling av luftveissykdommer kan disse forbindelser anvendes alene eller i kombinasjon med andre luftveisterapeutika, som f.eks. sekretolytisk, broncholytisk og/eller betennelseshemmende substanser. For fremstilling av medimaneter for behandling av sykdommer i området mage-tarm-kanalen kan disse forbindelser likeledes gis alene eller i kombinasjon med motilitets- eller sekresjons-påvirkende eller betennelseshemmende substanser. Disse kombinasjonener kan enten administreres simultant eller i rekkefølge.
Anvendelsen av disse forbindelser enten alene eller i kombinasjon med andre virkestoffer kan skje intravenøst, subkutant, intramuskulært, intrarektalt, intraperitonealt, intranasalt, ved inhalasjon eller transdermalt, hvorunder særlig aerosolformuleringen er egnet for inhalasjon.
Ved den farmasøytiske anvendelse blir forbindelsene ifølge oppfinnelsen som regel ved varmblodige virveldyr, særlig ved mennesker, anvendt i doseringen på 0,01-100 mg/kg legemsvekt, fortrinnsvis ved 0,1-15 mg/kg. For administrering blir disse formulert med en eller flere vanlige inerte bærere og/eller fortynningsmidler, f.eks. med maisstivelse, melkesukker, rørsukker, mikrokrystallinsk cellulose, magnesiumstearat, polyvinylpyrrolidon, sitronsyre, vinsyre, vann, vann/etanol, vann/glyserol, vann/sorbitol, vann/polyetylenglykol, propylenglykol, stearylalkohol, karboksymetylcellulose eller fettholdige substanser som hart fett eller deres egnete blandinger i vanlige galeniske preparater som tabletter, dragéer, kapsler, pulvere, suspensjoner, løsninger, sprays eller suppositorier.
De etterfølgende eksempler skal anskueliggjøre den foreliggende oppfinnelse nærmere:
Fremstilling av utgangsforbindelser:
Eksempel I
4- r( 3- klor- 4- fluor- fenyl') amino1- 6- cvklopentylmetoksy- 7-(' 2- brom- etoksv)- kinazol Til 3.50 g 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentylmetoksy-7-hydroksy-kinazolin og 6.89 ml 1,2-dibrometan i 40 ml N,N-dimetylformamid settes 4.84 g kaliumkarbonat. Reaksjonsblandingen blir rørt under nitrogen-atmosfere 1,5 timer ved 80°C. Etter avkjøling til romtemperatur blir reaksjonsblandingen filtrert og filtratet inndampet i vakuum. Den oljeaktige, brune resten blir avkjølt i isbad og gnidd med litt metanol, hvorunder et gulaktig fast stoff utkrystalliserer. Fellingen blir frafiltrert, med ettervasket kald metanol og i tørket vakuumeksikator.
Utbytte: 2.60 g (58 % av teoretisk),
Rrverdi: 0.82 (silikagel, metylenklorid/metanol 9:1)
Massespektrum(ESf): m/z = 494,496,498 [M+H]<+>
Analogt Eksempel I blir følgende forbindelser oppnådd: (1) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(2-brom-etoksy)-kinazolin
(reaksjonen blir utført i acetonitril som løsningsmiddel)
Rr-verdi: 0.72 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 464,466,468 [M-H]"
(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-(2-brom-etoksy)-kinazolin Rr-verdi: 0.65 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 478,480,482 [M-H]"
(3) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklobutyloksy-6-(3-brom-propyloksy)-kinazolin
(reaksjonen blir utført i acetonitril som løsningsmiddel)
Rrverdi: 0.62 (silikagel, metylenklorid/metanol 9:1)
Massespektrum(ESr): m/z = 478,480,482 [M-H]"
(4) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopropylmetoksy-6-(3-brom-propyloksy)-kinazolin
(reaksjonen blir utført i acetonitril som løsningsmiddel)
Rrverdi: 0.74 (silikagel, metylenklorid/metanol 9:1)
Massespektrum(ESI'): m/z = 478,480,482 [M-H]"
(5) 4-[(3-brom-fenyl)amino]-6-(2-brom-etoksy)-7-metoksy-kinazolin smeltepunkt: 244°C
Massespektrum(ESf"): m/z = 452,454, 456 [M+H]<+>
(6) 4-[(/?)-(l-fenyl-etyl)amino]-6-(3-brom-propyloksy)-7-metoksy-kinazolin (reaksjonen blir utført med kalium-terf.butylat som base)
Rrverdi: 0.60 (silikagel, eddikester/metanol 9:1)
(7) 4-[(Æ)-(l-fenyl-etyl)amino]-6-(2-brom-etoksy)-7-metoksy-kinazolin (reaksjonen blir utført med kalium-tetr.butylat som base)
smeltepunkt: 255°C
Massespektrum(ESr): m/z = 402,404 [M+H]<+>
(8) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-hydroksy-propyloksy)-7-cyklobutyloksy-kinazolin Rrverdi: 0.50 (silikagel, metylenklorid/metanol = 90:10) Massespektrum(ESf): m/z = 418,420 [M+H]<+>(9) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-hydroksy-propyloksy)-7-cyklopropylmetoksy-kinazolin
Rrverdi: 0.21 (silikagel, metylenklorid/metanol = 95:5)
Massespektrum(ESI<+>): m/z = 418,420 [M+H]<+>
(10) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-brom-etoksy)-7-cyklopentyloksy-kinazolin Rrverdi: 0.67 (silikagel, metylenklorid/metanol = 90:10) Massespektrum(ESr): m/z = 480,482,484 [M+H]<+>(11) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-brom-etoksy)-7-cyklopropylmetoksy-kinazolin Rrverdi: 0.68 (silikagel, metylenklorid/metanol = 90:10) Massespektrum(ESf): m/z = 466, 468, 470 [M+H]<+>(12) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(3-hydroksy-propyloksy)-kinazolin
Rrverdi: 0.53 (silikagel, metylenklorid/metanol = 90:10)
Massespektrum(ESr): m/z = 418,420 [M+H]<+>(13) 4-[(3-klor-4-fluor-fenyl)amino]-6-(4-hydroksy-butyloksy)-7-cyklopentyloksy-kinazolin Rrverdi: 0.46 (silikagel, eddikester) (14) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-brom-etoksy)-7-((/?)-tetrahydrofuran-3-yloksy)-kinazolin
Rrverdi: 0.37 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESI"): m/z = 480,482,484 [M-H]"
(15) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-brom-etoksy)-7-[(/?)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Massespektrum(ESr): m/z = 494,496,498 [M-H]"
(16) 4-[(3-kJor-4-fluor-fenyl)amino]-7-(2-brom-etoksy)-6-[(5)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Massespektrum(ESr): m/z = 494,496,498 [M-H]"
Eksempel II
4-[( 3- klor- 4- fluor- fenvl") amino1- 6- cyklopentylmetoksv- 7- hvdroksy- kinazolin 4.99 g 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentylmetoksy-7-metylkarbonyloksy-kinazolin blir opppslemmet i 80 ml metanol og blandet med 1.80 ml konsentrert, vandig ammoniakk-løsning. Reaksjonsblandingen blir rørt natten over ved romtemperatur. For opparbeiding blir reaksjonsblandingen fortynnet med 500 ml metylenklorid, vasket med vann og mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet. Man får 4.30 g av et brunaktig fast stoff. Råproduktet blir rørt med ferf.butylmetyleter, frafiltrert, ettervasket med litt terr.butylmetyleter og ved romtemperatur i vakuum tørket.
Utbytte: 3.59 g (80% av teoretisk),
Rrverdi: 0.48 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 388, 340 [M+H]<+>
Analogt Eksempel II blir følgende forbindelser oppnådd:
(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-hydroksy-kinazolin Rrverdi: 0.56 (silikagel, metylenklorid/metanol 9:1)
Massespektrum(ESr): m/z = 358, 360 [M-H]"
(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-hydroksy-kinazolin Rrverdi: 0.53 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 374,376 [M+H]<+>(3) 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-hydroksy-kinazolin Rrverdi: 0.54 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 396, 398 [M+H]<+>
(4) 4-[(3-brom-fenyl)amino]-6-hydroksy-7-metoksy-kinazolin (reaksjonen blir med Natronlut i etanol som løsningsmiddel utført)
Rrverdi: 0.23 (silikagel, eddikester)
Massespektrum(ESf): m/z = 346, 348 [M+H]<+>
(5) 4-[(3-klor-4-fluor-fenyl)amino]-7-hydroksy-6-((5)-tetrahydrofuran-3-yloksy)-kinazolin Rrverdi: 0.57 (silikagel, metylenklorid/metanol = 9:1) Massespektrum(ESf): m/z = 376, 378 [M+H]<+>(6) 4-[(3-klor-4-fluor-fenyl)amino]-7-hydroksy-6-[(5)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Rrverdi: 0.42 (silikagel, metylenklorid/metanol = 9:1)
Eksempel III
4- r( 3- klor- 4- fluor- fenvl) amino1- 6- cvklopentvlmetoksy- 7- metvlkarbonyloksv- kinazolin 4.03 g 4-klor-6-cyklopentylmetoksy-7-metylkarbonyloksy-kinazolin blir oppslemmet i 70 ml isopropanol og blandet med 1.95 g 3-klor-4-fluor-anilin. Reaksjonsblandingen blir tilbakeløpskokt to timer under nitrogen-atmosfære. Etter avkjøling til romtemperatur blir den dannede lyse fellingen frafiltrert, ettervasket med lite isopropanol og tørket i luft.
Utbytte: 4.99 g (92 % av teoretisk),
Rrverdi: 0.80 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESf): m/z = 430,432 [M+H]<+>
Analogt Eksempel II blir følgende forbindelser oppnådd:
(1) 4-[(3 -klor-4-fluor-fenyl)amino] -6-cyklopropy lmetoksy-7 -mety lkarbony loksy-kinazolin Rf-verdi: 0.86 (silikagel, metylenklorid/metanol = 9:1) Massespektrum(ESf): m/z = 402,404 [M+H]<+>(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-metylkarbonyloksy-kinazolin Rf verdi: 0.73 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 416,418 [M+H]<+>
(3) 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-metylkarbonyloksy-kinazolin Rf verdi: 0.76 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1) Massespektrum(ESr): m/z = 438,440 [M+H]<+>(4) 4-[(3-brom-fenyl)amino]-6-metylkarbonyloksy-7-metoksy-kinazolin Rf verdi: 0.50 (silikagel, eddikester) Massespektrum(ESf): m/z = 388, 390 [M+H]<+>(5) 4-[(/?)-(l-fenyl-etyl)amino]-6-hydroksy-7-metoksy-kinazolin (acetoksy-beskyttelsesgruppen blir allerede avspaltet under reaksjonsbetingelsene)
Rf verdi: 0.46 (silikagel, eddikester)
Massespektrum(ESr): m/z = 296 [M+H]<+>
(6) 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopentyloksy-kinazolin
(Pyridin blir tilsatt som hjelpebase)
Rf verdi: 0.51 (silikagel, metylenklorid/metanol = 95:5)
Massespektrum(ESf): m/z = 464,466 [M+H]<+>(7) 4-[(3-klor-4-fluor-fenyl)amino]-7-metylkarbonyloksy-6-((5)-tetrahydrofuran-3-yloksy)-kinazolin
Rf verdi: 0.67 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 416,418 [M-H]"
(8) 4-[(3-klor-4-fluor-fenyl)amno]-7-m yl)metoksy] -kinazolin-hydroklorid
smeltepunkt: 274-276°C
Massespektrum(ESr): m/z = 432,434 [M+H]<+>
Eksempel IV
4- klor- 6- cvklopentvlmetoksv- 7- metvlkarbonvloksv- kinazolin
3.80 g 4-hydroksy-6-cyklopentylmetoksy-7-metylkarbonyloksy-kinazolin blir oppslemmet i 90 ml tionylklorid og oppvarmet under nitrogen-atmosfære til koking. Etter tilsetning av fire dråper N,N-dimetylformamid blir reaksjonsblandingen oppvarmet enda to timer under tilbakeløp. Etter avkjøling til romtemperatur blir overskudd av tionylklorid avdestillert i vannstrålevakuum. Der brune resten blir rørt med 30 ml toluen. Løsningsmiddelet blir avdestillert og det blir 4.30 g av et gråbrunt fast stoff tilbake, hvilket omsettes videre uten ytterligere rensing.
Rrverdi: 0.89 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Analogt Eksempel IV blir følgende forbindelser oppnådd:
(1) 4-klor-6-cyklopropylmetoksy-7-metylkarbonyloksy-kinazolin
Rrverdi: 0.84 (silikagel, metylenklorid/metanol = 9:1)
(2) 4-klor-6-cyklopentyloksy-7-metylkarbonyloksy-kinazolin
Rrverdi: 0.69 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
(3) 6-benzyloksy-4-klor-7-metylkarbonyloksy-kinazolin
Rrverdi: 0.77 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
(4) 6-benzyloksy-4-klor-7-cyklopentyloksy-kinazolin
Rf-verdi: 0.91 (silikagel, metylenklorid/metanol = 9:1) (5) 4-klor-7-metylkarbonyloksy-6-((5)-tetrahydrofuran-3-yloksy)-kinazolin Rf-verdi: 0.83 (silikagel, eddikester/metanol = 9:1) (6) 4-klor-7-metylkarbonyloksy-6-[(5)-(tetrahydrofuran-2-yl)metoksy]-kinazolin Rf-verdi: 0.48 (silikagel, cykloheksan/eddikester =1:1)
Eksempel V
4- hydroksy- 6- cvklopentvlmetoksv- 7- metvlkarbonyloksv- kinazolin
4.30 g 4,7-dihydroksy-6-cyklopentylmetoksy-kinazolin i 100 ml pyridin blir oppvarmet under nitrogen-atmosfære til 80 °C. Til den mørkebrune suspensjonen settes 1,80 ml eddiksyreanhydrid. Reaksjonsblandingen blir rørt tre timer ved 80°C, hvorunder en fullstendig løsning oppstår. Etter avkjøling til romtemperatur blir reaksjonsblandingen hellet på ca. 800 ml isvann. Den dannede felling blir frafiltrert og ettervasket grundig med vann. Det lysegrå faststoff blir tørket i vakuumeksikator.
Utbytte: 3.82 g (77% av teoretisk),
Rf-verdi: 0.49 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 301 [M-H]"
Analogt Eksempel V blir følgende forbindelser oppnådd:
(1) 4-hydroksy-6-cyklopropylmetoksy-7-metylkarbonyloksy-kinazolin Rf-verdi: 0.53 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 273 [M-H]"
(2) 4-hydroksy-6-cyklopentyloksy-7-metylkarbonyloksy-kinazolin
smeltepunkt: 209-212 °C
Massespektrum(ESr): m/z = 287 [M-H]"
(3) 6-benzyloksy-4-hydroksy-7-metylkarbonyloksy-kinazolin
Rf-verdi: 0.48 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 309 [M-H]"
(4) 4-hydroksy-7-metylkarbonyloksy-6-((S)-tetrahydrofuran-3-yloksy)-kinazolin Rf-verdi: 0.62 (Revers fase DC-ferdigplate (E. Merck), acetonitril/vann/trifluoreddiksyre = 50:50:1)
Massespektrum(ESr): m/z = 291 [M+H]<+>(5) 4-hydroksy-7-metylkarbonyloksy-6-[(5)-(tetrahydrofuran-2-yl)metoksy]-kinazolin Rf-verdi: 0.50 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESf"): m/z = 305 [M+H]<+>
Eksempel VI
4. 7- dihvdroksy- 6- cvklopentylmetoksy- kinazolin
5.76 g 2-amino-5-cyklopentylmetoksy-4-hydroksy-benzosyre og 6.52 g formamidinacetat i 140 ml etanol blir oppvarmet ca. tre timer under tilbakeløp. For opparbeiding blir reaksjonsblandingen inndampet til ca. 100 ml og med 300 ml blandet isvann, hvorunder en grå felling utfelles. Fellingen blir frafiltrert, ettervasket med vann og i tørket vakuumeksikator.
Utbytte: 4.57 g (77 % av teoretisk),
Rrverdi: 0.25 (silikagel, metylenklorid/metanol = 95:5)
Massespektrum(ESI"): m/z = 259 [M-H]"
Analogt Eksempel VI blir følgende forbindelser oppnådd:
(1) 4,7-dihydroksy-6-cyklopropylmetoksy-kinazolin
Rrverdi: 0.45 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 231 [M-H]"
(2) 4,7-dihydroksy-6-cyklopentyloksy-kinazolin
Rrverdi: 0.42 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(EI): m/z = 246 [M]<+>
(3) 6-benzyloksy-4,7-dihydroksy-kinazolin
Rrverdi: 0.44 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESI"): m/z = 267 [M-H]'
(4) 6-benzyloksy-7-cyklopentyloksy-4-hydroksy-kinazolin
smeltepunkt: 221 -223°C
Massespektrum(ESr): m/z = 337 [M+H]<+>
(5) 4,7-dihydroksy-6-((S)-tetrahydrofuran-3-yloksy)-kinazolin
Rrverdi: 0.69 (Revers-fase TLC-ferdigplate (E. Merck), acetonitril/vann/trifluoreddiksyre = 50:50:1)
Massespektrum(ESr): m/z = 247 [M-H]'
(6) 4,7-dihydroksy-6-[(5)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Rrverdi: 0.56 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 261 [M-H]'
Eksempel VII
2- amino- 5- cvklopentvlmetoksv- 4- hvdroksv- benzosvre
6.50 g 5-cyklopentylmetoksy-4-hydroksy-2-nitro-benzosyre blir løst i 130 ml metanol, blandet med 2.00 g Raney-Nickel og hydrogenen under et hydrogentrykk på 3,4 atm. i ca. tre timer ved romtemperatur til den beregnete mengde hydrogen er opptatt. Katalysatoren blir frafiltrert og ettervasket med varm metanol. Filtratet blir inndampet i vakuum. Det blir et brunaktig fast stoff tilbake, hvilket omsettes videre uten ytterligere rensing.
Utbytte: 5.79 g (100 % av teoretisk),
Rrverdi: 0.67 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESI): m/z = 250 [M-H]'
Analogt Eksempel VII blir følgende forbindelser oppnådd:
(1) 2-amino-5-cyklopropylmetoksy-4-hydroksy-benzosyre
Rrverdi: 0.51 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESr): m/z = 222 [M-H]"
(2) 2-amino-5-cyklopentyloksy-4-hydroksy-benzosyre
Rrverdi: 0.38 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESf): m/z = 238 [M+H]<+>
(3) 2-amino-5-benzyloksy-4-hydroksy-benzosyre
Rrverdi: 0.52 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESI"): m/z = 258 [M-H]"
(4) 2-amino-5-benzyloksy-4-cyklopentyloksy-benzosyre-cyklopentylester
(reaksjonen blir i einem 1:1 -blanding av metanol og tetrahydrofuran utført)
Rrverdi: 0.84 (silikagel, eddikester/cykloheksan =1:1)
Massespektrum(ESf): m/z = 396 [M+H]<+>(5) 2-amino-4-hydroksy-5-((5)-tetrahydrofuran-3-yloksy)-benzosyre Rrverdi: 0.70 (Revers-fase TLC-ferdigplate (E. Merck), acetonitril/vann/trifluoreddiksyre = 50:50:1)
Massespektrum(ESr): m/z = 238 [M-H]"
(6) 2-amino-4-hydroksy-5-[(5)-(tetrahydrofuran-2-yl)metoksy]-benzosyre Rrverdi: 0.59 (Revers-fase TLC-ferdigplate (E. Merck), acetonitril/vann/trifluoreddiksyre = 50:50:1)
Massespektrum(ESr): m/z = 252 [M-H]"
Eksempel VIII
5- cvklopentvlmetoksv- 4- hvdroksv- 2- nitro- benzosyre
15.37 g 4,5-metylendioksy-2-nitro-benzosyre og 51.84 ml cyklopentylmetanol blir løst i 100 ml dimetylsulfoksyd og avkjølt under nitrogen-atmosfære i isbad. Nå blir porsjonsvis 3.90 g natrium tilsatt. Reaksjonsblandingen blir rørt 30 minutter under isbad-kjøling, deretter kort oppvarmet ved 35-40°C og deretter rørt ytterligere tre timer under isbad-kjøling. Derpå blir isbadet fjernet og reaksjonsblandingen rørt natten over ved romtemperatur. Den mørkerødbrune reaksjonsløsningen blir hellet i ca. 800 ml aceton, hvorunder en mørkebrun felling utfelles. Fellingen blir frafiltrert, ettervasket med aceton, løst i 300-400 ml vann og
innstilt med 60 ml 2N saltsyre på ca. pH 2. Den vandige løsningen blir ekstrahert flere ganger med metylenklorid. De samlete ekstrakter blir vasket med mettet natriumklorid-løsning, tørket over natriumsulfat og inndampet. Der mørkebrune, oljeaktige resten i kolben blir løst i 800 ml metylenklorid og renset over en silikagelkolonne med metylenklorid/metanol (9:1). Man får
en brun olje, hvilken ved røring med vann under isbad-kjøling bringes til krystallisasjon. Den dannede brunaktige fellingen blir frafiltrert, ettervasket med litt vann og tørket i vakuumeksikator.
Utbytte: 9.55 g (47 % av teoretisk),
Rrverdi: 0.67 (silikagel, toluen/dioksan/etanol/iseddik = 90:10:10:6)
Massespektrum(ESr): m/z = 280 [M-H]"
Analogt Eksempel Vin blir følgende forbindelser oppnådd:
(1) 5-cyklopropylmetoksy-4-hydroksy-2-nitro-benzosyre
Rrverdi: 0.61 (silikagel, toluen/dioksan/etanol/iseddik = 90:10:10:6)
Massespektrum(ESr): m/z = 252 [M-H]"
(2) 5-cyklopentyloksy-4-hydroksy-2-nitro-benzosyre
Rrverdi: 0.62 (silikagel, toluen/dioksan/etanol/iseddik = 90:10:10:6)
Massespektrum(ESI ): m/z = 266 [M-H]"
(3) 5-benzyloksy-4-hydroksy-2-nitro-benzosyre
Smeltepunkt: 176-178°C
Massespektrum(ESr): m/z = 288 [M-H]"
(4) 4-hydroksy-2-nitro-5-((S)-tetrahydrofuran-3-yloksy)-benzosyre
Rrverdi: 0.58 (Revers-fase TLC-ferdigplate (E. Merck), acetonitril/vann/trifluoreddiksyre = 50:50:1)
Massespektrum(ESI"): m/z = 268 [M-H]" .
(5) 4-hydroksy-2-nitro-5-[(5)-(tetrahydrofuran-2-yl)metoksy]-benzosyre Rrverdi: 0.53 (Revers-fase TLC-ferdigplate (E. Merck), acetonitril/vann/trifluoreddiksyre = 50:50:1)
Massespektrum(ESr): m/z = 282 [M-H]"
Eksempel IX
( 2- hvdroksv- 2- metvl- propvlamino)- eddiksvre- etvlester
Til 50.00 g glycinetylester-hydroklorid i 100 ml mettet kaliumkarbonat-løsning settes under kjøling 100.00 g natriumkarbonat. Den dannede massen blir ekstrahert flere ganger med til sammen ca. 600 ml dietyleter. De forenede eterekstrakter blir tørket over natriumsulfat og inndampet til tørrhet. Det blir 28.60 g glycinetylester tilbake, denne blir blandet med 26,00 ml isobutylenoksyd og 40 ml absolutt etanol og oppvarmet i en Roth-bombe seks timer ved 90°C. Etter avkjøling til romtemperatur blir reaksjonsblandingen inndampet, hvorunder en tyntflytende olje blir tilbake.
Utbytte: 45.80 g (73 % av teoretisk),
Massespektrum(ESr): m/z = 176 [M+H]<+>
Eksempel X
4- metylamino- dihydro- furan- 2- on
2.00 g 4-(N-benzyl-N-metyl-amino)-dihydro-furan-2-on i 25 ml metanol blir hydrogenert i nærvær av 250 mg palladium (10%ig på aktivt karbon) ved et hydrogentrykk på 3,4 atm. ca. to timer ved romtemperatur til den beregnete mengde hydrogen er opptatt. For opparbeiding
blir katalysatoren frafiltrert og filtratet inndampet i vakuum. Det blir en fargeløs olje tilbake, som straks omsettes videre uten ytterligere rensing.
Utbytte: 1,20 g
Rrverdi: 0.13 (silikagel, eddikester)
Massespektrum(ESf): m/z = 116 [M+H]<+>
Eksempel XI
4-( N- benzvl- N- metyl- aminoVdihvdro- furan- 2- on
Til 15,00 g 5i/-furan-2-on i 150 ml metylenklorid settes 23.20 ml N-metylbenzylamin. Reaksjonsblandingen blir rørt ca. 48 timer ved romtemperatur. For opparbeiding blir reaksjonsblandingen inndampet og kromatografert porsjonsvis over en silikagelsøyle med eddikester/petroleter (3:1) som eluent. Detønskede produkt blir oppnådd som gulaktig olje. Utbytte: 19.77g (54 % av teoretisk),
Rrverdi: 0.67 (silikagel, eddikester)
Massespektrum(ESI+): m/z = 228 [M+Na]<+>
Eksempel XII
4- r( 3- klor- 4- fluor- fenvl) aminol- 7- cvklobutvloksv- 6- hvdroksy- kinazolin Zu 5.60 g 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-cyklobutyloksy-kinazolin dryppes under røring 10 ml trifluoreddiksyre. Reaksjonsblandingen oppvarmes derunder til ca. 40°C. Etter 20 timer røring ved romtemperatur tilsettes en gang til 3 ml trifluoreddiksyre. Etter at omsetningen også etter tre timer videre røring ved romtemperatur knapt har gått fremover, blir reaksjonsblandingen oppvarmet til 50°C. Etter fire timer er omsetningen fullstendig, og overskuddet av trifluoreddiksyre blir hovedsakelig avdestillert på rotasjonfordamper. Resten blir med vann blandet og innstilt alkalisk med konsentrert vandig ammoniakkløsning. Den dannede lysebrune felling blir frafiltrert, ettervasket med rikelig vann og tørketi eksikator. Det oppnådde produkt inneholder fortsatt trifluoreddiksyre.
Utbytte: 5.82 g
Rrverdi: 0.61 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESf): m/z = 360, 362 [M+H]<+>
Analogt Eksempel XE blir følgende forbindelser oppnådd: (1) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopropylmetoksy-6-hydroksy-kinazolin Rf-verdi: 0.65 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 360, 362 [M+H]<+>
(2) 4- [(3-klor-4-fluor-fenyl)amino] -7-cyklopentyloksy-6-hydroksy-kinazolin Rrverdi: 0.65 (silikagel, metylenklorid/metanol = 9:1) Massespektrum(ESf): m/z = 374, 376 [M+H]<+>(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-hydroksy-7-((/?)-tetrahydrofuran-3-yloksy)-kinazolin Rrverdi: 0.32 (silikagel, metylenklorid/metanol = 9:1) (4) 4-[(3-klor-4-fluor-fenyl)amino]-6-hydroksy-7-[(/?)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Massespektrum(ESr): m/z = 388, 390 [M-H]"
Eksempel XIII
6- benzvloksv- 4- r( 3- klor- 4- lfuor- fenvl) amino1- 7- cyklobutyloksy- kinazolin Til 7.00 g 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-hydroksy-kinazolin i 60 ml N,N-dimetylformamid settes 7.50 g kaliumkarbonat og 4.50 g metansulfonsyre-cyklobutylester. Reaksjonsblandingen blir rørt to timer ved 80°C. Deretter blir en gang til 2.00 g metansulfonsyre-cyklobutylester og 3.00 g kaliumkarbonat tilsatt og blandingen blir over ukeslutt rørt ved 60°C. Da omsetningen ennå ikke er fullstendig, blir på nytt 3.50 g metansulfonsyre-cyklobutylester og 5.00 g kaliumkarbonat tilsatt. Etter videre 20 timer ved 80°C er omsetningen nesten fullstendig. For opparbeiding blir reaksjonsblandingen blandet med 300 ml eddikester og vasket med vann og mettet natriumklorid-løsning. Den organiske fasen blir tørket over magnesiumsulfat og inndampet. resten blir rørt med metanol, hvorunder en brunaktig felling oppstår. Denne blir frafiltrert, ettervasket med metanol og tørket i eksikator.
Utbytte: 5.10 g (64 % av teoretisk),
Rf-verdi: 0.69 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 448,450 [M-H]"
Analogt Eksempel XIII blir følgende forbindelser oppnådd:
(1) 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopropylmetoksy-kinazolin (Det blir anvendt brommetylcyklopropan)
Rrverdi: 0.72 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESI"): m/z = 448,450 [M-H]"
(2) 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopentyloksy-kinazolin
(Det blir anvendt bromcyklopentan)
Rrverdi: 0.78 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 464,466 [M+H]<+>
Eksempel XIV
( S)-( 2- hvdroksv- propvlamino)- eddiksyre- efrt. butvlester
15.00 g (5)-(+)-l-amino-2-propanol blir løst i 100 ml N,N-dimetylformamid og blandet med 6.97 ml diisopropyletylamin. Deretter blir under isbad-kjøling 5.91 ml bromeddiksyre-terf.butylester tildryppet i løpet av 30 minutter. Kjølebadet blir fjernet og reaksjonsblandingen blir natten over rørt ved romtemperatur. For opparbeiding blir reaksjonsblandingen inndampet i vakuum. Kolberesten blir løst i 50 ml vann og mettet med 15 g natriumklorid. Den vandige løsningen blir flere ganger ekstrahert med eddikester. De sammenslåtte ekstrakter blir vasket med mettet natriumklorid-løsning, tørket over magnesiumsulfat og inndampet i vakuum, hvorunder en gulaktig olje blir tilbake.
Utbytte: 7.36 g (97 % av teoretisk),
Rrverdi: 0.46 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESr): m/z = 190 [M+H]<+>
Analogt Eksempel XIV blir følgende forbindelser oppnådd:
(1) (/?)-(2-hydroksy-propylamino)-eddiksyre-?err.butylester
Rf-verdi: 0.46 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESf): m/z = 190 [M+H]<+>
(2) (l,l-dimetyl-2-hydroksy-etylamino)-eddiksyre-tert.-butylester
Massespektrum(ESr): m/z = 204 [M+H]<+>
Rf-verdi: 0.47 (silikagel, metylenklorid/metanol/kons. vandig ammoniakkløsning = 90:10:0.1)
Eksempel XV
4- r( 3- klor- 4- fluor- fenvl) amino1- 6-( 3- metansulfonvloksy- propvloksv)- 7- cyklobutyloksv-kinazolin
Forbindelsen oppnås ved omsetning av 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-hydroksy-propyloksy)-7-cyklobutyloksy-kinazolin med metansulfonsyreklorid i metylenklorid i nærvær av diisopropyletylamin ved romtemperatur.
Rf-verdi: 0.37 (silikagel, metylenklorid/metanol = 95:5)
Massespektrum(ESI): m/z = 494,496 [M-H]"
Analogt Eksempel XV blir følgende forbindelser oppnådd: (1) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-metansulfonyloksy-propyloksy)-7-cyklopropylmetoksy-kinazolin
Rf-verdi: 0.65 (silikagel, metylenklorid/metanol = 90:10)
Massespektrum(ESI"): m/z = 494,496 [M-H]' (2) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(3-metansulfonyloksy-propyloksy)-kinazolin
Rf-verdi: 0.73 (silikagel, metylenklorid/metanol = 90:10)
Massespektrum(ESr): m/z = 496,498 [M+H]<+>(3) 4-[(3-klor-4-fluor-fenyl)arruno]-6-(4-metansulfonyloksy-butyloksy)-7-cyklopentyl^ kinazolin
Rf-verdi: 0.76 (silikagel, metylenklorid/metanol = 90:10)
Massespektrum(ESf): m/z = 524, 526 [M+H]<+>
Eksempel XVI
4- r( 3- klor- 4- fluor- fenvl) amino1- 6- hvdroksv- 7- cyklopropvlmetoksv- kinazolin Forbindelsen blir oppnådd ved hydrogenering av 6-benzyloksy-4-[(3-klor-4-fluor-fenyl)amino]-7-cylcopropylmetoksy-kinazolin i nærvær 10% Pd/C i en blanding av metylenklorid, etanol og kons. saltsyre (500:210:3.5) i en Parr-Apparatur.
Utbytte: 73 % av teoretisk
Massespektrum(ESr<f>): m/z = 360, 362 [M+H]<+>
Eksempel XVII
5- benzvloksv- 4- cvklopentvloksy- 2- nitro- benzosvre- cvklopentvlester Forbindelsen blir oppnådd ved omsetning av 5-benzyloksy-4-hydroksy-2-nitro-benzosyre med 2,2 ekvivaltenter av bromcyklopentan i nærvær av kaliumkarbonat som hjelpebase i dimetylsulfoksyd ved romtemperatur.
Utbytte: 87 % av teoretisk
Rf-verdi: 0.92 (silikagel, eddikester/cykloheksan =1:1)
Massespektrum(ESr): m/z = 426 [M+H]<+>
Eksempel XVIII
4- r( 3- klor- 4- fluor- fenvl) aminol- 6- benzyloksv- 7- f( i?')- tetrahydrofuran- 3- yloksy) kinazolin
Til en løsning av 8.00 g 4-[(3-klor-4-fluor-fenyl)amino]-6-benzyloksy-7-hydroksy-kinazolin (se WO 0055141 Al) og 2.42 ml (5)-(+)-3-hydroksy-tetrahydrofuran og 7.95 g trifenylfosfin i 160 ml tetrahydrofuran dryppes 5.03 ml azodikarboksylsyredietylester. Reaksjonsblandingen blir natten rørt over ved romtemperatur og deretter inndampet på rotasjonfordamper. Kolberesten blir renset kromatografisk over en silikagelsøyle med metylenklorid/eddikester (gradient fra 2:1 til 1:2) som eluent.
Utbytte: 7.34 g (78 % av teoretisk)
Smeltepunkt: 165-168°C
Massespektrum(ESF): m/z = 466,468 [M+H]<+>
Analogt Eksempel XVIII blir følgende forbindelser oppnådd: (1) 4-[(3-klor-4-fluor-fenyl)amino]-6-benzyloksy-7-[(/?)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Massespektrum(ESr): m/z = 480,482 [M+H]<+>
Rf-verdi: 0.38 (silikagel, metylenklorid/metanol = 15:1)
(2) 4-[(3-klor-4-fluor-fenyl)amino]-7-(2-brom-etoksy)-6-((5)-tetrahydrofuran-3-yloksy)-kinazolin
Rf-verdi: 0.35 (silikagel, metylenklorid/metanol = 20:1)
Fremstilling av sluttforbindelser:
Eksempel 1
4- r( 3- klor- 4- fluor- fenvl) aminol- 6- cvklopentvlmetoksv- 7- r2-( 2. 2- dimetvl- 6- okso- morfolin- 4-ylVetoks vi - kinazolin
250 mg 4- [(3-klor-4-fluor-fenyl)amino] -6-cyklopentylmetoksy-7-(2-brom-etoksy)-kinazolin og 341 mg (2-hydroksy-2-metyl-propylamino)-eddiksyre-etylester blir løst i 20 ml acetonitril og blandet med 50 mg natriumiodid, 275 mg kaliumkarbonat og 0.70 ml diisopropyletylamin. Reaksjonsblandingen blir oppvarmet ca. 90 timer under tilbakeløp. Etter avkjøling til romtemperatur blir reaksjonsblandingen filtrert og filtratet inndampet i vakuum. Resten i kolben blir kromatografert over en silikagelsøyle med petroleter/eddikester (50:50, senere 0:100) som eluent. Man får det cykliserte produkt som beigefarget fast stoff.
Utbytte: 62 mg (23 % av teoretisk),
Rf-verdi: 0.29 (silikagel, eddikester)
Massespektrum(ESr): m/z = 541, 543 [M-H]"
Analogt Eksempel 1 blir følgende forbindelser oppnådd:
(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy]-kinazolin
Rf-verdi: 0.58 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESr): m/z = 513, 515 [M-H]"
(2) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklobutyloksy-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy] -kinazolin
Smeltepunkt: 212-214°C
Massespektrum(ESr): m/z = 527, 529 [M-H]"
(3) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopropylmetoksy-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy]-kinazolin
Smeltepunkt: 200-202°C
Massespektrum(ESr): m/z = 527, 529 [M-H]"
(4) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin
Smeltepunkt: 222-224°C
Massespektrum(ESr): m/z = 487, 489 [M-H]"
Eksempel 2
4-[( 3- klor- 4- fluor- fenvl) amino1- 6- cyklopropvlmetoksv- 7-{ 2- rN-( 2- okso- tetrahvdrofuran- 4-vD- N- metvl- aminol - etoksy} - kinazolin
300 mg 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(2-brom-etoksy)-kinazolin og 400 mg 4-metylamino-dihydro-furan-2-on i 20 ml acetonitril blir blandet med 240 mg kaliumkarbonat og 70 mg natriumiodid og oppvarmet 24 timer under tilbakeløp. Etter avkjøling til romtemperatur blir reaksjonsblandingen filtrert og filtratet inndampet i vakuum. Resten i kolben blir kromatografert over en silikagelsøyle med
metylenklorid/metanol/konsentrert vandig ammoniakkløsning (97:3:0.05) som eluent. Tittelforbindelsen blir oppnådd som lyst beigefarget fast stoff.
Utbytte: 70 mg (22 % av teoretisk),
Rf-verdi: 0.47 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1)
Massespektrum(ESf): m/z = 501,503 [M+H]<+>
Analogt Eksempel 2 blir følgende forbindelser oppnådd:
(1) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7- {2- [N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -kinazolin Rrverdi: 0.42 (silikagel, metylenklorid/metanol/konsentrert, vandig ammoniakkløsning = 90:10:0.1) Massespektrum(ESr): m/z = 515, 517 [M+H]<+>(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-{3-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-propyloksy} -7-cyklobutyloksy-kinazolin
Smeltepunkt: 147.5-151°C
Massespektrum(ESf): m/z = 515,517 [M+H]<+>
Eksempel 3
4- r( 3- brom- fenvl) aminol- 6- r2-("( 5)- 6- metyl- 2- okso- morfolin- 4- vl)- etoksvl- 7- metoksv-kinazolin
Til 380 mg 4-[(3-brom-fenyl)amino]-6-(2-{N-[(fe^.butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino}-etoksy)-7-metoksy-kinazolin i 8 ml acetonitril settes 90 u.1 metansulfonsyre. Reaksjonsblandingen blir oppvarmet ca. tre timer under tilbakeløp, deretter blir én gang til én ekvivalent metansulfonsyre tilsatt og videre oppvarmet under tilbakeløp til omsetningen er fullstendig. For opparbeiding blir reaksjonsblandingen med eddikester fortynnet og vasket med mettet natriumhydrogenkarbonat-løsning og mettet natriumklorid-løsning. Den organiske fasen blir tørket over magnesiumsulfat og inndampet i vakuum. Resten i kolben blir rørt med dietyleter og frafiltrert. Man får tittelforbindelsen som hvitt fast stoff.
Utbytte: 280 mg (85 % av teoretisk),
Smeltepunkt: 190°C
Massespektrum(ESr): m/z = 485,487 [M-H]"
Analogt Eksempel 3 blir følgende forbindelser oppnådd:
(1) 4-[(3-brom-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin
Smeltepunkt: 193°C
Massespektrum(ESr): m/z = 487,489 [M+H]<+>(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin (reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 208°C
Massespektrum(ESr): m/z = 459,461 [M-H]"
(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin (reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.33 (silikagel, eddikester)
Massespektrum(ESr): m/z = 473,475 [M-H]"
(4) 4-[(i?)-(l-fenyl-etyl)amino]-6-[3-((S)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin (reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.41 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESI"): m/z = 449 [M-H]"
(5) 4-[(/?)-(l-fenyl-etyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin (reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.49 (silikagel, eddikester/metanol/konsentrert vandig ammoniakkløsning = 9:1:0.1) Massespektrum(ESr): m/z = 435 [M-H]"
(6) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklobutyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 185.5-189.5°C
Massespektrum(ESf): m/z = 515, 517 [M+H]<+>(7) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(5,5-dimetyl-2-okso-mofrolin-4-yl)-propyloksy cyklobutyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 214-216°C
Massespektrum(ESr): m/z = 527, 529 [M-H]"
(8) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopropylmetoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 160.5-163°C
Massespektrum(ESf): m/z = 515,517 [M+H]<+>(9) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-((5)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopropylmetoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 160-162°C
Massespektrum(ESf): m/z = 515, 517 [M+H]<+>(10) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.31 (silikagel, eddikester)
Massespektrum(ESf"): m/z = 515, 517 [M+H]<+>(11) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 176-178°C
Massespektrum(ESr): m/z = 515, 517 [M+H]<+>(12) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopropylmetoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.37 (silikagel, eddikester)
Massespektrum(ESr): m/z = 501,503 [M+H]<+>(13) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoks cyklopropylmetoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rrverdi: 0.37 (silikagel, eddikester)
Massespektrum(ESf): m/z = 501, 503 [M+H]<+>(14) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy] -kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rrverdi: 0.48 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESr): m/z = 501, 503 [M+H]<+>(15) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[2-((i?)-6-metyl-2-okso-morfolin-4-yl)-etoksy] -kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Massespektrum(ESf): m/z = 501, 503 [M+H]<+>(16) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rrverdi: 0.67 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESr): m/z = 513,515 [M-H]"
(17) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[3-((5)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rrverdi: 0.67 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESr): m/z = 513, 515 [M-H]"
(18) 4-[(3-klor-4-fluor-fenyl)amino]-6-[^ cyklopentyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.56 (silikagel, eddikester)
Massespektrum(ESf): m/z = 529,531 [M+H]<+>(19) 4-[(3-klor-4-fluor-fenyl)arnino]-6-cyklopentyloksy-7-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy] -kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rrverdi: 0.60 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESf): m/z = 515, 517 [M+H]<+>(20) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Massespektrum(ESI+): m/z = 515, 517 [M+H]<+>(21) 4-[(3-klor-4-fluor-fenyl)amino]-6-[4-((5)-6-metyl-2-okso-morfolin-4-yl)-butyloksy]-7-cyklopentyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rrverdi: 0.51 (silikagel, eddikester)
Massespektrum(ESf): m/z = 543, 545 [M+H]<+>(22) 4-[(3-klor-4-fluor-fenyl)amino]-6-[4-((/?)-6-metyl-2-okso-morfolin-4-yl)-butyloksy]-7-cyklopentyloksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Massespektrum(ESf): m/z = 543, 545 [M+H]<+>(23) 4-[(3-klor-4-fluor-fenyl)arnino]-6-[3-((5)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 183-186°C
Massespektrum(ESI+): m/z = 475,477 [M+H]<+>(24) 4-[(3-klor-4-fluor-fenyl)anMo]-6-[3-(5,5-dimetyl-2-o^ metoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Rf-verdi: 0.43 (silikagel, eddikester)
Massespektrum(ESr): m/z = 487,489 [M-H]"
(25) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 212-213°C
Massespektrum(ESr): m/z = 461,463 [M+H]<+>(26) 4-[(3-klor-4-fluor-fenyl)amino]-6-{2-[N-(karboksymetyl)-N-((S)-2-hydroksy-propyl)-amino] -etoksy} -7-metoksy-kinazolin
(biprodukt ved fremstilling av 3(25))
Smeltepunkt: 187-190°C
Massespektrum(ESf): m/z = 479,481 [M+H]<+>(27) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 229-232°C
Massespektrum(ESr): m/z = 473,475 [M-H]"
(28) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy]-7-((/?)-tetrahydrofuran-3-yloksy)-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 195-196°C
Massespektrum(ESr): m/z = 531,533 [M+H]<+>(29) 4-[(3-klor-4-fluor-fenyl)armno]-6-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-eto (tetrahydrofuran-2-yl)metoksy]-kinazolin
(reaksjonen blir utført med trifluoreddiksyre i acetonitril)
Smeltepunkt: 184°C
Massespektrum(ESf): m/z = 545, 547 [M+H]<+>(30) 4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy]-6-((5)-tetrahydrofuran-3 -yloksy)-kinazolin
Smeltepunkt: 202-205°C
Massespektrum(ESr): m/z = 531,533 [M+H]<+>(31) 4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy]-6-[(5)-(tetrahydrofuran-2-yl)metoksy]-kinazolin
Smeltepunkt: 182°C
Massespektrum(ESI<+>): m/z = 545, 547 [M+H]<+>
Eksempel 4
4- r( 3- brom- fen vl) aminol- 6-( 2- f N- IYfert. butvloksvkarbonvPmetvn- N- rf 5V2- hvdroksv-propvD- amino) - etoksyl- 7- metoksv- kinazolin
Til 650 mg 4-[(3-brom-fenyl)amino]-6-(2-brom-etoksy)-7-metoksy-kinazolin og 1.10 g (5)-(2-hydroksy-propylamino)-eddiksyre-ter?.butylester i 15 ml acetonitril settes 0.25 ml diisopropyletylamin. Reaksjonsblandingen blir rørt natten over ved 50°C. Når ingen omsetning kan sees, blir reaksjonsblandingen inndampet, blandet med 20 ml N,N-dimetylformamid og rørt åtte timer ved 60°C. Derpå blir temperaturen forhøyet til 80°C. Etter åtte timer til er omsetningen fullstendig. Reaksjonsblandingen blir inndampet og kromatografert gjennom en silikagelsøyle med eddikester som eluent. Man får det ønskede produkt som hvitt fast stoff. Utbytte: 410 mg (51 % av teoretisk),
Rf-verdi: 0.27 (silikagel, eddikester)
Massespektrum(ESr): m/z = 559, 561 [M-H]"
Analogt Eksempel 4 blir følgende forbindelser oppnådd: (1) 4-[(3-brom-fenyl)arrino]-6-^ propyl)-amino} -etoksy)-7-metoksy-kinazolin
Smeltepunkt: 130°C
Massespektrum(ESr): m/z = 559,561 [M-H]"
(2) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-{N-[(tert.butyloksykarbonyl)metyl]-N-((i?)-2-hydroksy-propyl)-amino}-etoksy)-7-metoksy-kinazolin (reaksjonen blir utført i N,N-dimetylformamid)
Rf-verdi: 0.40 (silikagel, eddikester/petroleter = 4:1)
(3) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-{N-[(terf.butyloksykarbonyl)metyl]-N-((/?)-2-hydroksy-propyl)-amino}-propyloksy)-7-metoksy-kinazolin (reaksjonen blir utført i N,N-dimetylformamid)
Rf-verdi: 0.37 (silikagel, eddikester/petroleter = 4:1)
Massespektrum(ESr): m/z = 547, 549 [M-H]"
(4) 4-[(Æ)-( 1 -fenyl-etyl)amino]-6-(3- {N-[(tert.butyloksykarbonyl)metyl]-N-((S)-2-hydroksy-propyl)-amino}-propyloksy)-7-metoksy-kinazolin (reaksjonen blir utført i N,N-dimetylformamid)
Rf-verdi: 0.65 (silikagel, eddikester/metanol = 9:1)
Massespektrum(EI): m/z = 524 [M]<+>(5) 4-[(i?)-(l-fenyl-etyl)amino]-6-(2-{N-[(rer?.butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino}-etoksy)-7-metoksy-kinazolin (reaksjonen blir i N,N-dimetylformamid utført) Rf-verdi: 0.57 (silikagel, eddikester/metanol/konsentrert vandig ammoniakkløsning = 9:1:0.1) (6) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-{N-[(tert.-butyloksykarbonyl)metyl]-N-((/?)-2-hydroksy-propyl)-amino} -propyloksy)-7-cyklobutyloksy-kinazolin
Rrverdi: 0.31 (silikagel, metylenklorid/metanol = 95:5)
(7) 4-[(3-klor-4-lfuor-fenyl)arrrå^ 2-hydroksy-etyl)-amino} -propyloksy)-7-cyklobutyloksy-kinazolin
Rrverdi: 0.29 (silikagel, metylenklorid/metanol = 95:5)
Massespektrum(ESr): m/z = 603, 605 [M+H]<+>
(8) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3-{N-[(tert.-butyloksykarbonyl)metyl]-N-((Æ)-2-hydroksy-propyl)-amino}-propyloksy)-7-cyklopropylmetoksy-kinazolin Rrverdi: 0.37 (silikagel, metylenklorid/metanol = 95:5) (9) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3- {N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino}-propyloksy)-7-cyklopropylmetoksy-kinazolin Rrverdi: 0.50 (silikagel, eddikester) (10) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2- {N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino} -etoksy)-7-cyklopentyloksy-kinazolin Rrverdi: 0.54 (silikagel, eddikester/cykloheksan = 9:1) (11) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-{N-[(tert.-butyloksykarbonyl)metyl]-N-((/?)-2-hydroksy-propyl)-amino} -etoksy)-7-cyklopentyloksy-kinazolin Rrverdi: 0.66 (silikagel, eddikester) (12) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-{N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino} -etoksy)-7-cyklopropylmetoksy-kinazolin Rrverdi: 0.60 (silikagel, eddikester) (13) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-{N-[(tert.-butyloksykarbonyl)metyl]-N-((/?)-2-hydroksy-propyl)-amino} -etoksy)-7-cyklopropylmetoksy-kinazolin Rrverdi: 0.60 (silikagel, eddikester) (14) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(2-{N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino}-etoksy)-kinazolin Rrverdi: 0.30 (silikagel, eddikester) (15) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(2-{N-[(tert.-butyloksykarbonyl)metyl]-N-((i?)-2-hydroksy-propyl)-arruno}-etoksy)-kinazolin Rf-verdi: 0.30 (silikagel, eddikester) (16) 4- [(3-klor-4-fluor-fenyl)arnino]-6-cyklopropylmetoksy-7-(3- {N- [(tert.-butyloksykarbonyl)metyl]-N-((/?)-2-hydroksy-propyl)-arruno}-propyloksy)-kinazolin Rf-verdi: 0.35 (silikagel, eddikester) (17) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-(3-{N-[(tert.-butyloksykarbonyl)metyl]-N-((S)-2-hydroksy-propyl)-amino}-propyloksy])-kinazolin Rrverdi: 0.35 (silikagel, eddikester) (18) 4-[(3-klor-4-fluor-fenyl)anuno]-6-(2-{N-[(etoksykarbonyl)metyl]-N-(2-hydroksy-^ metyl-propyl)-amino} -etoksy)-7-cyklopentyloksy-kinazolin
Rrverdi: 0.64 (silikagel, metylenklorid/metanol = 9:1)
Massespektrum(ESf): m/z = 575, 577 [M+H]<+>
(19) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-(2- {N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino}-etoksy)-kinazolin Rrverdi: 0.51 (silikagel, eddikester) (20) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-(2-{N-[(tert.-butyloksykarbonyl)metyl] -N-((Æ)-2-hydroksy-propyl)-arnino} -etoksy)-kinazolin Rrverdi: 0.51 (silikagel, eddikester) (21) 4-[(3-klor-4-fluor-fenyl)amino]-6-(4-{N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino} -butyloksy)-7-cyklopentyloksy-kinazolin Rrverdi: 0.61 (silikagel, eddikester) (22) 4-[(3-klor-4-fluor-fenyl)amino]-6-(4-{N-[(tert.-butyloksykarbonyl)metyl]-N-((/?)-2-hydroksy-propyl)-amino} -butyloksy)-7-cyklopentyloksy-kinazolin Rrverdi: 0.61 (silikagel, eddikester) (23) 4-[(3-klor-4-fluor-fenyl)armno]-6-(3-{N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-^ hydroksy-propyl)-amino} -propyloksy)-7-metoksy-kinazolin
Rrverdi: 0.46 (silikagel, eddikester)
Massespektrum(ESr): m/z = 547, 549 [M-H]" (24) 4-[(3-klor-4-fluor-fenyl)amino]-6-(3- {N-[(tert.-butyloksykarbonyl)metyl]-N-( 1,1-dimetyl-2-hydroksy-etyl)-amino} -propyloksy)-7-metoksy-kinazolin Massespektrum(ESr): m/z = 563,565 [M+H]<+>(25) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2- {N-[(tert.-butyloksykarbonyl)metyl]-N-((5)-2-hydroksy-propyl)-amino} -etoksy)-7-metoksy-kinazolin
Rrverdi: 0.66 (silikagel, eddikester/metanol = 9:1)
Massespektrum(ESf): m/z = 535,537 [M+H]<+>(26) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-{N-[(etoksykarbonyl)metyl]-N-(2-hydroksy-2-metyl-propyl)-amino} -etoksy)-7-metoksy-kinazolin
(foreligger som blanding med allerede cyklisert substans)
Rrverdi: 0.44 (silikagel, eddikester)
Massespektrum(ESr): m/z = 521, 523 [M+H]<+>(27) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2-{N-[(etoksykarbonyl)metyl]-N-(2-hydroksy-2-metyl-propyl)-amino}-etoksy)-7-((/?)-tetrahydrofuran-3-yloksy)-kinazolin
(foreligger som blanding med allerede cyklisert substans)
Rrverdi: 0.30 (silikagel, metylenklorid/metanol = 9:1)
(28) 4-[(3-klor-4-fluor-fenyl)amino]-6-(2- {N-[(etoksykarbonyl)metyl]-N-(2-hydroksy-2-metyl-propyl)-amino}-etoksy)-7-[(/?)-(tetrahydrofuran-2-yl)metoksy]-kinazolin Massespektrum(ESr): m/z = 589, 591 [M-H]" (29) 4-[(3-klor-4-fluor-fenyl)amino]-7-(2- {N-[(etoksykarbonyl)metyl]-N-(2-hydroksy-2-metyl-propyl)-amino}-etoksy)-6-((5)-tetrahydrofuran-3-yloksy)-kinazolin
Rf-verdi: 0.16 (silikagel, metylenklorid/metanol = 20:1)
(30) 4-[(3-klor-4-fluor-fenyl)amino]-7-(2-{N-[(etoksykarbonyl)metyl]-N-(2-hydroksy-2-metyl-propyl)-amino}-etoksy)-6-[(S)-(tetrahydrofuran-2-yl)metoksy]-kinazolin Rf-verdi: 0.68 (silikagel, eddikester/metanol = 15:1)
Analogt med Eksemplene foran og andre kjente fremgangsmåter fra litteraturen kan følgende forbindelser fremstilles: (1) 4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-6-metoksy-kinazolin (2) 4-[(3-klor-4-fluor-fenyl)amino]-7-[3-(6-metyl-2-okso-morfolin-4-yl)-propyloksy]-6-metoksy-kinazolin (3) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin (4) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-((5)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin (5) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(5,5-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin (6) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(5,5-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin (7) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(3-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin (8) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(3-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin (9) 4-[(/?)-(l-fenyl-etyl)amino]-6-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin (10) 4-[(/?)-(l-fenyl-etyl)arruno]-6-[2-((i?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-m^ kinazolin (11) 4-[(3-klor-4-fluor-fenyl)amino]-7-[4-(6-metyl-2-okso-morfolin-4-yl)-butyloksy]-6-metoksy-kinazolin (12) 4-[(3-klor-4-fluor-fenyl)amino]-7-[3-(6-metyl-2-okso-morfolin-4-yl)-propyloksy]-6-metoksy-kinazolin (13) 4-[(3-ldor-4-fluor-fenyl)amino]-6-[4-(6-metyl-2-okso-morfolin-4-yl)-butyloksy]-7-metoksy-kinazolin (14) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-(tetrahydrofuran-3-yloksy)-kinazolin (15) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-(tetrahydropyran-3-yloksy)-kinazolin (16) 4-[(3-klor-4-fluor-fenyl)arnino]-6-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-(tetrahydropyran-4-yloksy)-kinazolin (17) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-(tetrahydrofuran-2-ylmetoksy)-kinazolin (18) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6-metyl-2-okso-rnorfolin-4-yl)-etoksy]-7-(tetrahydropyran-4-ylmetoksy)-kinazolin (19) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-(tetrahydrofuran-3-yloksy)-kinazolin (20) 4-[(3-klor-4-fluor-fenyl)arruno]-6-[3-(6,6-dimetyl-2-okso-mofrolin-4-yl)-propylok 7-(tetrahydrofuran-3-yloksy)-kinazolin (21) 4-[(3-klor-4-fluor-fenyl)amino]-6-[4-(6,6-dimetyl-2-okso-morfolin-4-yl)-but^^ 7-(tetrahydrofuran-3-yloksy)-kinazolin (22) 4-[(3-klor-4-fluor-fenyl)arru^o]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-(tetrahydrofuran-2-ylmetoksy)-kinazolin (23) 4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-(tetrahydrofuran-2-ylmetoksy)-kinazolin (24) 4-[(3-klor-4-fluor-fenyl)amino]-6-[4-(6,6-dimetyl-2-okso-morfolin-4-yl)-butyloksy]-7-(tetrahydrofuran-2-ylmetoksy)-kinazolin (25) 4-[(3-klor-4-fluor-fenyl)arruno]-7-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-6-(tetrahydrofuran-3-yloksy)-kinazolin (26) 4-[(3-klor-4-fluor-fenyl)arru^o]-7-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-6-(tetrahydropyran-3-yloksy)-kinazolin (27) 4-[(3-klor-4-fluor-fenyl)armno]-7-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-6-(tetrahydropyran-4-yloksy)-kinazolin (28) 4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-6-(tetrahydrofuran-2-ylmetoksy)-kinazolin (29) 4-[(3-klor-4-fluor-fenyl)arru^o]-7-[2-(6-metyl-2-okso-morfolin-4-yl)-etoksy]-6-(tetrahydropyran-4-ylmetoksy)-kinazolin (30) 4-[(3-klor-4-fluor-fenyl)arruno]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6 (tetrahydrofuran-3-yloksy)-kinazolin (31) 4-[(3-klor-4-fluor-fenyl)amino]-7-[3-(6,6-dimetyl-2-okso-morfolin-4^ 6-(tetrahydrofuran-3-yloksy)-kinazolin (32) 4-[(3-klor-4-fluor-fenyl)amino]-7-[4-(6,6-dimetyl-2-okso-morfolin-4-yl)-butyloksy]-6-(tetrahydrofuran-3-yloksy)-kinazolin (33) 4-[(3-klor-4-fluor-fenyl)arruno]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-(tetrahydrofuran-2-ylmetoksy)-kinazolin (34) 4-[(3-klor-4-fluor-fenyl)amino]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-6-(tetrahydrofuran-2-ylmetoksy)-kinazolin (35) 4-[(3-klor-4-fluor-fenyl)amino]-7-[4-(6,6-dimetyl-2-okso-morfolin-4-yl)-butyloksy]-6-(tetrahydrofuran-2-ylmetoksy)-kinazolin
Eksempel 5
Dragéer med 75 mg virkesubstans
Fremstilling:
Virkesubstans blir blandet med kalsiumfosfat, maisstivelse, polyvinylpyrrolidon, hydroksypropylmetylcellulose og halvparten av den angitte mengde magnesiumstearat. På en
tablettmaskin blir det fremstilt pressete produkter med et tverrsnitt på ca. 13 mm, disse blir revet på en egnet maskin med en sikt med 1,5 mm-maskevidde og blandet med restmengden av magnesiumstearat. Dette granulatet blir presset på en tablettmaskin til tabletter med den ønskete form.
Kjernevekt: 230 mg
Stempel: 9 mm, buet
Den derved fremstilte dragéekjerne blir overtrukket med en film, som i det vesentlige består av hydroksypropylmetylcellulose. De ferdige filmdragéer blir glanset med bivoks. Dragéevekt: 245 mg.
Eksempel 6
Tabletter med 100 mg virkesubstans
Sammensetning:
1 tablett inneholder:
Fremstillingsmåte:
Virkestoff, melkesukker og stivelse blir blandet og fuktet jevnt med en vandig løsning av polyvinylpyrrolidon. Etter sikting av den fuktige massen (2,0 mm-maskevidde) og tørking i Hordentørkeskap ved 50°C blir det siktet på nytt (1,5 mm-maskevidde) og smøremiddelet tilblandet. Den presseferdige blandingen blir bearbeidet til tabletter.
Tablettvekt: 220 mg
Tverrsnitt: 10 mm, biplane med facette på begge sider og rille på en side.
Eksempel 7
Tabletter med 150 mg virkesubstans
Sammensetning:
1 tablett inneholder:
Fremstilling:
Den med melkesukker, maisstivelse og kiselsyre blandete virkesubstans blir fuktet med en 20%ig vandig polyvinylpyrrolidonløsning og slått med en sikt med 1,5 mm-maskevidde. Det ved 45°C tørkete granulat blir en gang til revet med den samme sikten og blandet med den angitte mengde magnesiumstearat. Av blandingen presses tabletter.
Tablettvekt: 300 mg
Stempel: 10 mm, flatt
Eksempel 8
Hardgelatin- kapsler med 150 mg virkesubstans
1 kapsel inneholder:
Fremstilling:
Virkestoffet blir blandet med hjelpestoffene, med tilsatt en sikt på 0,75 mm-maskevidde og blandet homogent i et egnet apparat.
Sluttblandingen blir fyllt i hardgelatin-kapsler av størrelse 1.
Kapselfylling: ca. 320 mg
Kapselhylse: Hardgelatin-kapsel størrelse 1.
Eksempel 9
Suppositorier med 150 mg virkesubstans
1 suppositorie inneholder:
Fremstilling:
Etter smelting av suppositorimassen blir virkestoffet fordelt homogent deri og smeiten hellet i forut avkjølte former.
Eksempel 10
Suspensjon med 50 mg virkesubstans
100 ml suspensjon innholder:
Fremstilling:
Dest. vann blir oppvarmet til 70°C. Heri blir under røring p-hydroksybenzosyremetylester og -propylester samt glyserol og karboksymetylcellulose-natriumsalt løst. Det blir avkjølt til romtemperatur og virkestoffet tilsatt under røring og dispergert homogent. Etter tilsetning og løsing av sukkeret, sorbitløsningen og aromaen blir suspensjonen satt under vakuum for lufting under røring.
5 ml suspensjon innholder 50 mg virkestoff.
Eksempel 11
Ampuller med 10 mg virkesubstans
Sammensetning:
Fremstilling:
Virkesubstansen blir løst i den nødvendige mengde 0,01N HC1, stilt isotonisk med koksalt, sterilfiltrert og fylt i 2 ml ampuller.
Eksempel 12
Ampuller med 50 mg virkesubstans
Sammensetning:
Fremstilling:
Virkesubstansen blir løst i den nødvendige mengde 0,0IN HC1, stilt isotonisk med koksalt, sterilfiltrert og fylt i 10 ml ampuller.
Eksempel 13
Kapsler for<p>ulverinhalasjon med 5 mg virkesubstans
1 kapsel inneholder:
Fremstilling:
Virkesubstansen blir blandet med laktose for inhalasjonsformål. Blandingen blir fylt på en kapselmaskin i kapsler (vekt av tom kapsel ca. 50 mg).
Kapselvekt: 70,0 mg
Kapselstørrelse: 3
Eksempel 14
Inhalasionsløsning for håndforstøver med 2. 5 mg virkesubstans
1 støt inneholder:
Fremstilling:
Virkesubstansen og benzalkoniumkloridet blir løst i etanol/vann (50/50). pH-verdien til løsningen blir innstilt med lN-saltsyre. Den innstilte løsning blir filtrert og fylt i beholdere egnet for håndforstøver (patroner).
Fyllmasse i beholderen: 4,5 g
Claims (9)
1. Forbindelser med den generelle formel I
hvor
Ra betyr en 1-fenyletylgruppe eller en med restene Ri og R2substituert fenylgruppe, hvorunder
Ri er et fluor-, klor- eller bromatom og
R2et hydrogen- eller fluoratom,
én av restene Rbeller Rcer en R3-(CH2)m-0-gruppe og den andre av restene Rbeller Rcer en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy-, cyklobutylmetoksy-, cyklopentylmetoksy-, tetrahydrofuran-3-yloksy-, tetrahydropyran-3-yloksy-, tetrahydropyran-4-yloksy-, tetrahydrofuranylmetoksy- eller tetrahydropyranylmetoksygruppe, hvorunder
R3betyr en N-(2-okso-tetrahydrofuran-4-yl)-metylaminogruppe eller en med én eller to metylgrupper substituert 2-okso-morfolin-4-yl-gruppe og
m er tallet 2, 3 eller 4,
med det forbehold at forbindelsene 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6- {2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(3-metyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-H 4-[(3-brom-fenyl)amino]-6-[2-(5,5-dimetyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-m kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklobutyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopropylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl]amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-6-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-arnino]-etoksy} -7-cyklopentylmetoksy-kinazolin,
4-[(3-ldor-4-fluor-fenyl)arnino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl) metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentylmetoksy-kinazolin,
(R)-4-[(l-fenyl-etyl)arm^o]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)armno]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklobutyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopropylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl]arruno]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -6-metoksy-kinazolin,
4-[(3-klor-4-lfuor-fenyl)amino]-7-{2-[N-(2-okso-tetrahydro etoksy} -6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -6-cyklopentylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-6-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)arru^o]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)anu^o]-7-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-6-cyklopentylmetoksy-kinazolin og (R)-4-[(l-fenyl-etyl)amino]-7-[3-(6,6-dimetyl-2-okso-rnorfolin-4-yl)-propyloksy]-6-cyklopentyloksy-kinazolin
er utelukket,
deres tautomere, deres stereoisomere og deres salter.
2. Forbindelser med den generelle formel I ifølge krav 1, i hvilken Ra betyr en 1-fenyletyl-, 3-bromfenyl- eller 3-klor-4-fluorfenylgruppe,
Rben R3-(CH2)m-0-gruppe, i hvilken
R3er en med én eller to metylgrupper substituert 2-okso-morfolin-4-yl-gruppe og m er tallet 2 eller 3,
og Rcbetyr en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy, tetrahydrofuran-3-yloksy- eller tetrahydrofuranylmetoksygruppe med det forbehold at forbindelsene 4-[(3-brom-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4-[(3-brom-fenyl)amino]-6-[2-(3-metyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin, 4-[(3-brom-fenyl)amino]-6-[2-(5,5-dimetyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklobutyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopropylmetoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-metoksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-7-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin og (R)-4-[(l-fenyl-etyl)amino]-6-[3-(6,6-dimetyl-2-okso-morfolin-4-yl)-propyloksy]-7-cyklopentyloksy-kinazolin
er utelukket,
deres tautomere, deres stereoisomere og deres salter.
3. Forbindelser med den generelle formel I ifølge krav 1, i hvilken Ra betyr en 3-klor-4-fluor-fenylgruppe,
Rben cyklopentyloksy-, cyklopropylmetoksy-, cyklopentylmetoksy-, tetrahydrofuran-3-yloksy- eller tetrahydrofuranylmetoksygruppe og
Rcen R3-(CH2)m-0-gruppe, i hvilken
R3er en med én eller to metylgrupper substituert 2-okso-morfolin-4-yl-gruppe og m tallet 2,
med det forbehold at forbindelsene 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentyloksy-kinazolin,
4-[(3-klor-4-fluor-fenyl)amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopropylmetoksy-kinazolin og 4-[(3-klor-4-fluor-fenyl]amino]-7-[2-(6,6-dimetyl-2-okso-morfolin-4-yl)-etoksy]-6-cyklopentylmetoksy-kinazolin
er utelukket,
deres tautomere, deres stereoisomere og deres salter.
4. Følgende forbindelser med den generelle formel I ifølge krav 1: (1) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentylmetoksy-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy] -kinazolin, (2) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopentyloksy-7-{2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino] -etoksy} -kinazolin, (3) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7-[2-(2,2-dimetyl-6-okso-morfolin-4-yl)-etoksy] -kinazolin, (4) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklobutyloksy-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy]-kinazolin, (5) 4-[(3-klor-4-fluor-fenyl)amino]-7-cyklopropylmetoksy-6-[3-(2,2-dimetyl-6-okso-morfolin-4-yl)-propyloksy]-kinazolin, (6) 4-[(3-klor-4-fluor-fenyl)amino]-6-cyklopropylmetoksy-7- {2-[N-(2-okso-tetrahydrofuran-4-yl)-N-metyl-amino]-etoksy} -kinazolin, (7) 4-[(3-brom-fenyl)amino]-6-[2-((5)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin, (8) 4-[(3-brom-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin, (9) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((/?)-6-metyl-2-okso-morfolin-4-yl)-etoksy]-7-metoksy-kinazolin, (10) 4-[(3-klor-4-fluor-fenyl)arm^o]-6-[3-((/?)-6-metyl-2-okso-morfolin-4-yl)-propyloksy metoksy-kinazolin, (11) 4-[(/?)-(l-fenyl-etyl)amino]-6-[3-((5)-6-metyl-2-okso-morfolin-4-yl)-p^^ metoksy-kinazolin, (12) 4-[(Æ)-( 1 -fenyl-etyl)amino]-6-[2-((S)-6-metyl-2-okso-morfolin-4-yl)-etoksy] -7-metoksy-kinazolin og (13) 4-[(3-klor-4-fluor-fenyl)amino]-6-[2-((S)-6-metyl-2-okso-morfolin-4-yl)etoksy]-7-metoksy-kinazolin,
deres tautomere, deres stereoisomere og deres salter.
5. Fysiologisk akseptable salter av forbindelsene ifølge kravene 1 til 4 med uorganiske eller organiske syrer eller baser.
6. Legemiddel inneholdende en forbindelse ifølge kravene 1 til 4 eller et fysiologisk akseptabelt salt ifølge krav 8 ved siden av eventuelt en eller flere inerte bærere og/eller fortynningsmidler.
7. Anvendelse av en forbindelse ifølge kravene 1 til 5 for fremstilling av et legemiddel som er egnet for behandling av benigne eller maligne tumorer, for profylakse og behandling av sykdommer i luftveiene og lungene, for behandling av polypper, av sykdommer i mage-tarm-kanalen, gallegangene og -blæren samt nyrene og huden.
8. Fremgangsmåte for fremstilling av et legemiddel ifølge krav 6,karakterisertv e d at på ikke-kjemisk måte en forbindelse ifølge kravene 1 til 5 innarbeides i en eller flere inerte bærere og/eller fortynningsmidler.
9. Fremgangsmåte for fremstilling av forbindelsene med den generelle formel I ifølge kravene 1 til 5,karakterisert vedat a) en forbindelse med den generelle formel
i hvilken
Ra er definert som nevnt i kravene 1 til 4,
en av restene Rb' eller Rc' er en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy-, cyklobutylmetoksy- eller cyklopentylmetoksygruppe og den andre av restene Rb' eller Rc' er en Z|-(CH2)m-0-gruppe, i hvilken
m er definert som nevnt i kravene 1 til 4 og
Zi betyr en avgangsgruppe,
omsettes med en forbindelse med den generelle formel
H-R3,(HI)
i hvilken
R3er definert som nevnt i kravene 1 til 4, eller b) en eventuelt i reaksjonsblandingen dannet forbindelse med den generelle formel i hvilken
Ra er definert som nevnt i kravene 1 til 4,
en av restene Rb" eller Rc" er en metoksy-, cyklobutyloksy-, cyklopentyloksy-, cyklopropylmetoksy-, cyklobutylmetoksy- eller cyklopentylmetoksygruppe og den andre av restene Rb" eller Rc" er en R3'-(CH2)m-0-gruppe, i hvilken
m er definert som nevnt i kravene 1 til 4 og
R3' betyr en på metylengruppene med en eller to metyl- eller etylgrupper substituert R4-0-CO-CH2-N-CH2CH2-OH-gruppe, i hvilken
R4er et hydrogenatom eller en Ci-4-alkylgruppe,
cykliseres, og
om nødvendig en ved den forut beskrevne omsetningen anvendt beskyttelsesrest blir avspaltet igjen, og/eller
om ønsket en således oppnådd forbindelse med den generelle formel I blir spaltet i sine stereoisomere, og/eller
en således oppnådd forbindelse med den generelle formel I blir overført i sine salter, særlig for den farmasøytiske anvendelse i sine fysiologisk fordragelige salter.
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DE10042058A DE10042058A1 (de) | 2000-08-26 | 2000-08-26 | Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
PCT/EP2001/009532 WO2002018351A1 (de) | 2000-08-26 | 2001-08-18 | Bicyclische heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und vefahren zu ihrer herstellung |
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- 2001-08-18 WO PCT/EP2001/009532 patent/WO2002018351A1/de active Application Filing
- 2001-08-23 UY UY26903A patent/UY26903A1/es not_active Application Discontinuation
- 2001-08-24 TW TW090120905A patent/TWI294422B/zh not_active IP Right Cessation
- 2001-08-24 AR ARP010104041A patent/AR033562A1/es not_active Suspension/Interruption
- 2001-08-24 MY MYPI20013985A patent/MY126132A/en unknown
-
2003
- 2003-02-03 EC EC2003004464A patent/ECSP034464A/es unknown
- 2003-02-05 ZA ZA200300991A patent/ZA200300991B/en unknown
- 2003-02-14 BG BG107559A patent/BG107559A/bg active Pending
- 2003-02-24 HR HR20030138A patent/HRP20030138A2/hr not_active Application Discontinuation
- 2003-02-24 IL IL154602A patent/IL154602A/en not_active IP Right Cessation
- 2003-02-25 NO NO20030870A patent/NO324866B1/no not_active IP Right Cessation
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2004
- 2004-01-21 HK HK04100462A patent/HK1057557A1/xx not_active IP Right Cessation
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