NO329542B1 - 4-anilinokinazolinderivater, fremgangsmate for fremstilling av slike, farmasoytiske preparater innholdende slike, slike forbindelser for anvendelse som medikament samt anvendelse av slike forbindelser for fremstilling av medikament for behandling av sykdom - Google Patents

4-anilinokinazolinderivater, fremgangsmate for fremstilling av slike, farmasoytiske preparater innholdende slike, slike forbindelser for anvendelse som medikament samt anvendelse av slike forbindelser for fremstilling av medikament for behandling av sykdom Download PDF

Info

Publication number: NO329542B1
Authority: NO; Norway
Prior art keywords: chloro; fluoroanilino; methoxy; quinazoline; methoxyquinazoline
Prior art date: 2002-03-28

Application number

NO20044325A

Other languages

English (en)

Norwegian (no)

Other versions

NO20044325L (no

Inventor

Robert Hugh Bradbury

Jason Grant Kettle

Laurent Francois Andre Hennequin

Original Assignee

Astrazeneca Ab

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2002-03-28

Filing date

2004-10-12

Publication date

2010-11-08

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=28678580&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=NO329542(B1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2002-03-28 Priority claimed from GB0207323A external-priority patent/GB0207323D0/en

2002-12-24 Priority claimed from GB0230086A external-priority patent/GB0230086D0/en

2003-01-28 Priority claimed from GB0301916A external-priority patent/GB0301916D0/en

2004-10-12 Application filed by Astrazeneca Ab filed Critical Astrazeneca Ab

2004-12-16 Publication of NO20044325L publication Critical patent/NO20044325L/no

2010-11-08 Publication of NO329542B1 publication Critical patent/NO329542B1/no

Links

150000001875 compounds Chemical class 0.000 title claims description 160
238000000034 method Methods 0.000 title claims description 111
238000002360 preparation method Methods 0.000 title claims description 45
239000003814 drug Substances 0.000 title claims description 15
239000000825 pharmaceutical preparation Substances 0.000 title claims description 6
238000011282 treatment Methods 0.000 title description 28
208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title description 11
201000010099 disease Diseases 0.000 title description 5
229940079593 drug Drugs 0.000 title description 5
MTSNDBYBIZSILH-UHFFFAOYSA-N n-phenylquinazolin-4-amine Chemical class N=1C=NC2=CC=CC=C2C=1NC1=CC=CC=C1 MTSNDBYBIZSILH-UHFFFAOYSA-N 0.000 title description 5
238000006243 chemical reaction Methods 0.000 claims description 59
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 58
230000008569 process Effects 0.000 claims description 54
150000003246 quinazolines Chemical class 0.000 claims description 52
150000003839 salts Chemical class 0.000 claims description 52
-1 methylenedioxypyrrolidinyl Chemical group 0.000 claims description 47
125000000217 alkyl group Chemical group 0.000 claims description 43
125000006239 protecting group Chemical group 0.000 claims description 34
125000001424 substituent group Chemical group 0.000 claims description 25
125000004485 2-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])C1([H])* 0.000 claims description 24
125000000524 functional group Chemical group 0.000 claims description 22
238000007796 conventional method Methods 0.000 claims description 20
239000002253 acid Substances 0.000 claims description 19
125000003545 alkoxy group Chemical group 0.000 claims description 15
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
238000003776 cleavage reaction Methods 0.000 claims description 14
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 14
125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 14
ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 13
239000000460 chlorine Substances 0.000 claims description 13
229910052801 chlorine Inorganic materials 0.000 claims description 13
IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
230000001028 anti-proliverative effect Effects 0.000 claims description 12
125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 12
229910052757 nitrogen Inorganic materials 0.000 claims description 12
125000003282 alkyl amino group Chemical group 0.000 claims description 11
238000004519 manufacturing process Methods 0.000 claims description 11
JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 11
125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 10
125000001589 carboacyl group Chemical group 0.000 claims description 10
229910052736 halogen Inorganic materials 0.000 claims description 9
150000002367 halogens Chemical class 0.000 claims description 9
230000007017 scission Effects 0.000 claims description 9
125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 8
125000004448 alkyl carbonyl group Chemical group 0.000 claims description 8
239000001257 hydrogen Substances 0.000 claims description 8
229910052739 hydrogen Inorganic materials 0.000 claims description 8
241001465754 Metazoa Species 0.000 claims description 7
MORFQDRARBOZSN-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-piperidin-3-yloxyquinazolin-4-amine Chemical compound C=12C=C(OC3CNCCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F MORFQDRARBOZSN-UHFFFAOYSA-N 0.000 claims description 7
DFNJBNWBONZOQL-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-piperidin-4-yloxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCNCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DFNJBNWBONZOQL-UHFFFAOYSA-N 0.000 claims description 7
125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 claims description 7
238000005859 coupling reaction Methods 0.000 claims description 6
RHHAVUPVXRAMLR-ZDUSSCGKSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3s)-1-methylsulfonylpiperidin-3-yl]oxyquinazolin-4-amine Chemical compound C=12C=C(O[C@@H]3CN(CCC3)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F RHHAVUPVXRAMLR-ZDUSSCGKSA-N 0.000 claims description 6
125000000719 pyrrolidinyl group Chemical group 0.000 claims description 6
PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 5
UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 5
125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 5
239000003085 diluting agent Substances 0.000 claims description 5
229910052731 fluorine Inorganic materials 0.000 claims description 5
239000011737 fluorine Substances 0.000 claims description 5
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
238000012986 modification Methods 0.000 claims description 5
230000004048 modification Effects 0.000 claims description 5
SSOOQSBWLHGSCL-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(piperidin-4-ylmethoxy)quinazolin-4-amine Chemical compound C=12C=C(OCC3CCNCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F SSOOQSBWLHGSCL-UHFFFAOYSA-N 0.000 claims description 5
PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 4
PQNRFGOXGMDMSI-UHFFFAOYSA-N [2-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-oxoethyl] acetate Chemical compound C=12C=C(OC3CN(CCC3)C(=O)COC(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F PQNRFGOXGMDMSI-UHFFFAOYSA-N 0.000 claims description 4
125000005236 alkanoylamino group Chemical group 0.000 claims description 4
125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 4
125000004414 alkyl thio group Chemical group 0.000 claims description 4
125000000623 heterocyclic group Chemical group 0.000 claims description 4
125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
DABOZAKYWAXTGO-ZDUSSCGKSA-N 1-[(2s)-2-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]pyrrolidin-1-yl]-2-hydroxyethanone Chemical compound C=12C=C(OC[C@H]3N(CCC3)C(=O)CO)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DABOZAKYWAXTGO-ZDUSSCGKSA-N 0.000 claims description 3
QEBRMJTUPMNDKF-HNNXBMFYSA-N 1-[(3s)-3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-(dimethylamino)ethanone Chemical compound C=12C=C(O[C@@H]3CN(CCC3)C(=O)CN(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F QEBRMJTUPMNDKF-HNNXBMFYSA-N 0.000 claims description 3
SIKHQLKPCASMEL-UHFFFAOYSA-N 1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-hydroxyethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CO)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F SIKHQLKPCASMEL-UHFFFAOYSA-N 0.000 claims description 3
BGJVGJZKZPYAMV-UHFFFAOYSA-N 1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-pyrrolidin-1-ylethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CN3CCCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F BGJVGJZKZPYAMV-UHFFFAOYSA-N 0.000 claims description 3
FPPIVLMSIGJKPX-UHFFFAOYSA-N 1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]ethanone Chemical compound C=12C=C(OC3CN(CCC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F FPPIVLMSIGJKPX-UHFFFAOYSA-N 0.000 claims description 3
APWGONAWSQJAFF-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-morpholin-4-ylethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)CN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F APWGONAWSQJAFF-UHFFFAOYSA-N 0.000 claims description 3
FYUILKSGHOYVJD-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-2-pyrrolidin-1-ylethanone Chemical compound C=12C=C(OC3CCN(CC3)C(=O)CN3CCCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F FYUILKSGHOYVJD-UHFFFAOYSA-N 0.000 claims description 3
XLKMNDIRQXLLRJ-UHFFFAOYSA-N 1-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]ethanone Chemical compound C=12C=C(OC3CCN(CC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F XLKMNDIRQXLLRJ-UHFFFAOYSA-N 0.000 claims description 3
FEGFNGQBRZUWHV-UHFFFAOYSA-N 2-(4-acetylpiperazin-1-yl)-1-[3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]ethanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)CN3CCN(CC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F FEGFNGQBRZUWHV-UHFFFAOYSA-N 0.000 claims description 3
DIBGTMXGHUALIU-UHFFFAOYSA-N 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]acetamide Chemical compound C=12C=C(OC3CCN(CC(N)=O)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F DIBGTMXGHUALIU-UHFFFAOYSA-N 0.000 claims description 3
MCQMHAGBYHUBTA-UHFFFAOYSA-N 2-[4-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]piperidin-1-yl]acetamide Chemical compound C=12C=C(OCC3CCN(CC(N)=O)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F MCQMHAGBYHUBTA-UHFFFAOYSA-N 0.000 claims description 3
IIPZVWOEYKWBAM-IWPPFLRJSA-N [(4r)-4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxy-1-methylpyrrolidin-2-yl]-morpholin-4-ylmethanone Chemical compound C=12C=C(O[C@H]3CN(C)C(C3)C(=O)N3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F IIPZVWOEYKWBAM-IWPPFLRJSA-N 0.000 claims description 3
QTMFEEDRXUIFDA-MRNPHLECSA-N [3-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]-[(2s)-1-methylpyrrolidin-2-yl]methanone Chemical compound C=12C=C(OC3CN(CCC3)C(=O)[C@H]3N(CCC3)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F QTMFEEDRXUIFDA-MRNPHLECSA-N 0.000 claims description 3
125000004644 alkyl sulfinyl group Chemical group 0.000 claims description 3
230000029936 alkylation Effects 0.000 claims description 3
238000005804 alkylation reaction Methods 0.000 claims description 3
125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 3
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 3
125000002757 morpholinyl group Chemical group 0.000 claims description 3
PNWLNPVNZZWWEA-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-6-[1-[3-(dimethylamino)propylsulfonyl]piperidin-4-yl]oxy-7-methoxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(CC3)S(=O)(=O)CCCN(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F PNWLNPVNZZWWEA-UHFFFAOYSA-N 0.000 claims description 3
QBSXCQDYNHLCCN-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1-methylpyrrolidin-3-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F QBSXCQDYNHLCCN-UHFFFAOYSA-N 0.000 claims description 3
BDLUIKGKNQFJIO-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1-methylsulfonylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(CC3)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F BDLUIKGKNQFJIO-UHFFFAOYSA-N 0.000 claims description 3
HIOMOLUQMPMYMG-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(1-methylpiperidin-4-yl)methoxy]quinazolin-4-amine Chemical compound C=12C=C(OCC3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F HIOMOLUQMPMYMG-UHFFFAOYSA-N 0.000 claims description 3
MORFQDRARBOZSN-LBPRGKRZSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3s)-piperidin-3-yl]oxyquinazolin-4-amine Chemical compound C=12C=C(O[C@@H]3CNCCC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F MORFQDRARBOZSN-LBPRGKRZSA-N 0.000 claims description 3
SBMNEPVEDPDQNB-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[2-(1-methylpiperidin-4-yl)ethoxy]quinazolin-4-amine Chemical compound C=12C=C(OCCC3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F SBMNEPVEDPDQNB-UHFFFAOYSA-N 0.000 claims description 3
WYMUMLSWCGOSNO-CYBMUJFWSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[[(2r)-1-methylpyrrolidin-2-yl]methoxy]quinazolin-4-amine Chemical compound C=12C=C(OC[C@@H]3N(CCC3)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F WYMUMLSWCGOSNO-CYBMUJFWSA-N 0.000 claims description 3
OYWPEXPOKASXIN-CYBMUJFWSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[[(2r)-1-methylsulfonylpyrrolidin-2-yl]methoxy]quinazolin-4-amine Chemical compound C=12C=C(OC[C@@H]3N(CCC3)S(C)(=O)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F OYWPEXPOKASXIN-CYBMUJFWSA-N 0.000 claims description 3
125000004193 piperazinyl group Chemical group 0.000 claims description 3
125000003386 piperidinyl group Chemical group 0.000 claims description 3
LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
KBIXTCZEFRUUAZ-CQSZACIVSA-N 1-[(2r)-2-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]pyrrolidin-1-yl]ethanone Chemical compound C=12C=C(OC[C@@H]3N(CCC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F KBIXTCZEFRUUAZ-CQSZACIVSA-N 0.000 claims description 2
ALLCTPWIIGFMFC-HNNXBMFYSA-N 1-[(2s)-2-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]pyrrolidin-1-yl]-2-(dimethylamino)ethanone Chemical compound C=12C=C(OC[C@H]3N(CCC3)C(=O)CN(C)C)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F ALLCTPWIIGFMFC-HNNXBMFYSA-N 0.000 claims description 2
GODGDPVZOQBJJT-AWEZNQCLSA-N 1-[(2s)-2-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]pyrrolidin-1-yl]-2-(methylamino)ethanone Chemical compound CNCC(=O)N1CCC[C@H]1COC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1F GODGDPVZOQBJJT-AWEZNQCLSA-N 0.000 claims description 2
FKIGKBRONDNFSA-UHFFFAOYSA-N 2-[4-[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]acetonitrile Chemical compound C=12C=C(OC3CCN(CC#N)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F FKIGKBRONDNFSA-UHFFFAOYSA-N 0.000 claims description 2
OTPVAYXUVFDRBW-UHFFFAOYSA-N 2-[4-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]piperidin-1-yl]acetonitrile Chemical compound C=12C=C(OCC3CCN(CC#N)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F OTPVAYXUVFDRBW-UHFFFAOYSA-N 0.000 claims description 2
125000004575 3-pyrrolidinyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 2
JOANRURMBNMJHR-UHFFFAOYSA-N 4-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]piperidine-1-carbonitrile Chemical compound C=12C=C(OCC3CCN(CC3)C#N)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F JOANRURMBNMJHR-UHFFFAOYSA-N 0.000 claims description 2
230000008878 coupling Effects 0.000 claims description 2
238000010168 coupling process Methods 0.000 claims description 2
229910052740 iodine Inorganic materials 0.000 claims description 2
125000006518 morpholino carbonyl group Chemical group [H]C1([H])OC([H])([H])C([H])([H])N(C(*)=O)C1([H])[H] 0.000 claims description 2
PUGRPTFZBHHZPM-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-(1-methylpiperidin-4-yl)oxyquinazolin-4-amine Chemical compound C=12C=C(OC3CCN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F PUGRPTFZBHHZPM-UHFFFAOYSA-N 0.000 claims description 2
JPNAFMLRYCEEAB-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(1-methylpyrrolidin-3-yl)methoxy]quinazolin-4-amine Chemical compound C=12C=C(OCC3CN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F JPNAFMLRYCEEAB-UHFFFAOYSA-N 0.000 claims description 2
QBSXCQDYNHLCCN-GFCCVEGCSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[(3r)-1-methylpyrrolidin-3-yl]oxyquinazolin-4-amine Chemical compound C=12C=C(O[C@H]3CN(C)CC3)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F QBSXCQDYNHLCCN-GFCCVEGCSA-N 0.000 claims description 2
VAGCDXKHNHUMSZ-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[1-(2-methoxyethyl)piperidin-4-yl]oxyquinazolin-4-amine Chemical compound C1CN(CCOC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1F VAGCDXKHNHUMSZ-UHFFFAOYSA-N 0.000 claims description 2
QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 2
125000004483 piperidin-3-yl group Chemical group N1CC(CCC1)* 0.000 claims description 2
150000003335 secondary amines Chemical class 0.000 claims description 2
CHRMMMLUWHPZAH-UHFFFAOYSA-N 7-methoxyquinazoline Chemical compound C1=NC=NC2=CC(OC)=CC=C21 CHRMMMLUWHPZAH-UHFFFAOYSA-N 0.000 claims 2
NOYQEMLFKXUGNZ-UHFFFAOYSA-N 1-[3-[[4-(3-chloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxymethyl]pyrrolidin-1-yl]ethanone Chemical compound C=12C=C(OCC3CN(CC3)C(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=CC(Cl)=C1F NOYQEMLFKXUGNZ-UHFFFAOYSA-N 0.000 claims 1
241000208202 Linaceae Species 0.000 claims 1
235000004431 Linum usitatissimum Nutrition 0.000 claims 1
ITACCIZAPGMSPO-UHFFFAOYSA-N n-(3-chloro-2-fluorophenyl)-7-methoxy-6-[[1-(2-methoxyethyl)piperidin-4-yl]methoxy]quinazolin-4-amine Chemical compound C1CN(CCOC)CCC1COC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1F ITACCIZAPGMSPO-UHFFFAOYSA-N 0.000 claims 1
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DARTVAOOTJKHQW-UHFFFAOYSA-N tert-butyl 4-[(4-methylphenyl)sulfonyloxymethyl]piperidine-1-carboxylate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCC1CCN(C(=O)OC(C)(C)C)CC1 DARTVAOOTJKHQW-UHFFFAOYSA-N 0.000 description 1
PWQLFIKTGRINFF-UHFFFAOYSA-N tert-butyl 4-hydroxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(O)CC1 PWQLFIKTGRINFF-UHFFFAOYSA-N 0.000 description 1
WOEQSXAIPTXOPY-UHFFFAOYSA-N tert-butyl 4-methylsulfonyloxypiperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1 WOEQSXAIPTXOPY-UHFFFAOYSA-N 0.000 description 1
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DLYUQMMRRRQYAE-UHFFFAOYSA-N tetraphosphorus decaoxide Chemical compound O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
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UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
229960005026 toremifene Drugs 0.000 description 1
XFCLJVABOIYOMF-QPLCGJKRSA-N toremifene Chemical compound C1=CC(OCCN(C)C)=CC=C1C(\C=1C=CC=CC=1)=C(\CCCl)C1=CC=CC=C1 XFCLJVABOIYOMF-QPLCGJKRSA-N 0.000 description 1
231100000331 toxic Toxicity 0.000 description 1
230000002588 toxic effect Effects 0.000 description 1
230000002110 toxicologic effect Effects 0.000 description 1
231100000759 toxicological effect Toxicity 0.000 description 1
VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
238000010361 transduction Methods 0.000 description 1
230000026683 transduction Effects 0.000 description 1
238000001890 transfection Methods 0.000 description 1
239000012581 transferrin Substances 0.000 description 1
238000011830 transgenic mouse model Methods 0.000 description 1
102000027257 transmembrane receptors Human genes 0.000 description 1
108091008578 transmembrane receptors Proteins 0.000 description 1
238000011269 treatment regimen Methods 0.000 description 1
TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 1
238000001665 trituration Methods 0.000 description 1
230000005751 tumor progression Effects 0.000 description 1
231100000588 tumorigenic Toxicity 0.000 description 1
230000000381 tumorigenic effect Effects 0.000 description 1
231100000402 unacceptable toxicity Toxicity 0.000 description 1
241000701447 unidentified baculovirus Species 0.000 description 1
201000005112 urinary bladder cancer Diseases 0.000 description 1
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OGWKCGZFUXNPDA-UHFFFAOYSA-N vincristine Natural products C1C(CC)(O)CC(CC2(C(=O)OC)C=3C(=CC4=C(C56C(C(C(OC(C)=O)C7(CC)C=CCN(C67)CC5)(O)C(=O)OC)N4C=O)C=3)OC)CN1CCC1=C2NC2=CC=CC=C12 OGWKCGZFUXNPDA-UHFFFAOYSA-N 0.000 description 1
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GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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Classifications

- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Chemical & Material Sciences (AREA)
Organic Chemistry (AREA)
Health & Medical Sciences (AREA)
Veterinary Medicine (AREA)
Life Sciences & Earth Sciences (AREA)
Public Health (AREA)
General Health & Medical Sciences (AREA)
Animal Behavior & Ethology (AREA)
Chemical Kinetics & Catalysis (AREA)
General Chemical & Material Sciences (AREA)
Medicinal Chemistry (AREA)
Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
Pharmacology & Pharmacy (AREA)
Bioinformatics & Cheminformatics (AREA)
Engineering & Computer Science (AREA)
Urology & Nephrology (AREA)
Vascular Medicine (AREA)
Heart & Thoracic Surgery (AREA)
Cardiology (AREA)
Hematology (AREA)
Oncology (AREA)
Dermatology (AREA)
Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Plural Heterocyclic Compounds (AREA)
Nitrogen Condensed Heterocyclic Rings (AREA)

NO20044325A 2002-03-28 2004-10-12 4-anilinokinazolinderivater, fremgangsmate for fremstilling av slike, farmasoytiske preparater innholdende slike, slike forbindelser for anvendelse som medikament samt anvendelse av slike forbindelser for fremstilling av medikament for behandling av sykdom NO329542B1 (no)

Applications Claiming Priority (4)

Application Number	Priority Date	Filing Date	Title
GB0207323A GB0207323D0 (en)	2002-03-28	2002-03-28	Compounds
GB0230086A GB0230086D0 (en)	2002-12-24	2002-12-24	Compounds
GB0301916A GB0301916D0 (en)	2003-01-28	2003-01-28	Compounds
PCT/GB2003/001306 WO2003082831A1 (en)	2002-03-28	2003-03-26	4-anilino quinazoline derivatives as antiproliferative agents

Publications (2)

Publication Number	Publication Date
NO20044325L NO20044325L (no)	2004-12-16
NO329542B1 true NO329542B1 (no)	2010-11-08

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NO20044325A NO329542B1 (no)	2002-03-28	2004-10-12	4-anilinokinazolinderivater, fremgangsmate for fremstilling av slike, farmasoytiske preparater innholdende slike, slike forbindelser for anvendelse som medikament samt anvendelse av slike forbindelser for fremstilling av medikament for behandling av sykdom

Country Status (28)

Country	Link
US (4)	US20050215574A1 (zh)
EP (1)	EP1487806B1 (zh)
JP (2)	JP3891493B2 (zh)
KR (1)	KR101006947B1 (zh)
CN (1)	CN100439344C (zh)
AR (1)	AR039203A1 (zh)
AT (1)	ATE473215T1 (zh)
AU (1)	AU2003214443B8 (zh)
BR (1)	BR0308670A (zh)
CA (1)	CA2479642C (zh)
CY (1)	CY1111039T1 (zh)
DE (1)	DE60333262D1 (zh)
DK (1)	DK1487806T3 (zh)
ES (1)	ES2346135T3 (zh)
IL (2)	IL164135A0 (zh)
IS (1)	IS2855B (zh)
MX (1)	MXPA04009486A (zh)
MY (1)	MY158054A (zh)
NO (1)	NO329542B1 (zh)
NZ (1)	NZ535014A (zh)
PL (1)	PL214880B1 (zh)
PT (1)	PT1487806E (zh)
SA (1)	SA03240080B1 (zh)
SI (1)	SI1487806T1 (zh)
TW (2)	TW200813014A (zh)
UA (1)	UA78302C2 (zh)
UY (1)	UY27742A1 (zh)
WO (1)	WO2003082831A1 (zh)

Families Citing this family (69)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
MEP45508A (en) *	1999-06-21	2011-02-10	Boehringer Ingelheim Pharma	Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof
US7019012B2 (en) *	2000-12-20	2006-03-28	Boehringer Ingelheim International Pharma Gmbh & Co. Kg	Quinazoline derivatives and pharmaceutical compositions containing them
WO2003040108A1 (en) *	2001-11-03	2003-05-15	Astrazeneca Ab	Quinazoline derivatives as antitumor agents
GB0126433D0 (en) *	2001-11-03	2002-01-02	Astrazeneca Ab	Compounds
KR101019131B1 (ko) *	2001-11-19	2011-03-07	인터레우킨 제네틱스, 인코포레이티드	염증성 질환 및 감염성 질환에 대한 감수성 및 전사에영향을 미치는 인터루킨-1 좌의 기능적 다형성
TW200813014A (en) *	2002-03-28	2008-03-16	Astrazeneca Ab	Quinazoline derivatives
DE10214412A1 (de) *	2002-03-30	2003-10-09	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6924285B2 (en)	2002-03-30	2005-08-02	Boehringer Ingelheim Pharma Gmbh & Co.	Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
RS85404A (en) *	2002-03-30	2007-02-05	Boehringer Ingelheim Pharma Gmbh. & Co.Kg.,	4-(n-phenylamino)- quinazolines/quinolines as tyrosine kinase inhibitors
DE10221018A1 (de) *	2002-05-11	2003-11-27	Boehringer Ingelheim Pharma	Verwendung von Hemmern der EGFR-vermittelten Signaltransduktion zur Behandlung von gutartiger Prostatahyperplasie (BPH)/Prostatahypertrophie
EP2277867B1 (en)	2002-07-15	2012-12-05	Symphony Evolution, Inc.	Compounds, pharmaceutical compositions thereof and their use in treating cancer
GB0309009D0 (en) *	2003-04-22	2003-05-28	Astrazeneca Ab	Quinazoline derivatives
GB0309850D0 (en) *	2003-04-30	2003-06-04	Astrazeneca Ab	Quinazoline derivatives
GB0317665D0 (en) *	2003-07-29	2003-09-03	Astrazeneca Ab	Qinazoline derivatives
BRPI0413066A (pt) *	2003-07-29	2006-10-17	Astrazeneca Ab	derivado de quinazolina, ou um sal farmaceuticamente aceitável, ou um éster farmaceuticamente aceitável do mesmo, da fórmula i, uso e processo para a preparação do mesmo, composto, composição farmacêutica, e, métodos para a produção de um efeito antiproliferativo em um animal de sangue quente, para a prevenção ou tratamento de um tumor, para prover um efeito inibitório de tirosina quinase de egfr seletivo, e para tratar um cáncer em um animal de sangue quente
GB0321648D0 (en) *	2003-09-16	2003-10-15	Astrazeneca Ab	Quinazoline derivatives
CA2539022A1 (en) *	2003-09-16	2005-03-24	Astrazeneca Ab	Quinazoline derivatives as tyrosine kinase inhibitors
MXPA06002962A (es) *	2003-09-16	2006-06-14	Astrazeneca Ab	Derivados de quinazolina.
AU2004272345A1 (en) *	2003-09-16	2005-03-24	Astrazeneca Ab	Quinazoline derivatives
DE602004013806D1 (en) *	2003-09-16	2008-06-26	Astrazeneca Ab	Chinazolinderivate als tyrosinkinaseinhibitoren
BRPI0414532B1 (pt) *	2003-09-19	2018-06-05	Astrazeneca Ab	Composto derivado de quinazolina, processo para preparar 0 mesmo, composição farmaceutica, e, uso de um composto derivado de quinazolina
CN1882570B (zh) *	2003-09-19	2010-12-08	阿斯利康(瑞典)有限公司	喹唑啉衍生物
GB0322409D0 (en) *	2003-09-25	2003-10-29	Astrazeneca Ab	Quinazoline derivatives
EP1670786A1 (en) *	2003-09-25	2006-06-21	Astrazeneca AB	Quinazoline derivatives
JP2007510708A (ja) *	2003-11-06	2007-04-26	ファイザー・プロダクツ・インク	癌の治療における選択的ｅｒｂＢ２阻害剤／抗ｅｒｂＢ抗体の組合せ
GB0326459D0 (en) *	2003-11-13	2003-12-17	Astrazeneca Ab	Quinazoline derivatives
ATE413389T1 (de)	2004-02-03	2008-11-15	Astrazeneca Ab	Chinazolinderivate
WO2005107758A1 (en)	2004-05-06	2005-11-17	Warner-Lambert Company Llc	4-phenylamino-quinazolin-6-yl-amides
BRPI0511741A (pt) *	2004-06-04	2008-01-02	Astrazeneca Ab	derivado de quinazolina ou um sal farmaceuticamente aceitável do mesmo, composição farmacêutica, processo para a preparação de um derivado de quinazolina ou de um sal farmaceuticamente aceitável do mesmo
DE602005026865D1 (de) *	2004-12-14	2011-04-21	Astrazeneca Ab	Pyrazolopyrimidinverbindungen als antitumormittel
KR20070107151A (ko) *	2005-02-26	2007-11-06	아스트라제네카 아베	티로신 키나제 억제제로서의 퀴나졸린 유도체
GB0504474D0 (en) *	2005-03-04	2005-04-13	Astrazeneca Ab	Chemical compounds
GB0508715D0 (en) *	2005-04-29	2005-06-08	Astrazeneca Ab	Chemical compounds
GB0508717D0 (en) *	2005-04-29	2005-06-08	Astrazeneca Ab	Chemical compounds
GB0509227D0 (en) *	2005-05-05	2005-06-15	Chroma Therapeutics Ltd	Intracellular enzyme inhibitors
JP2009506990A (ja) *	2005-08-22	2009-02-19	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	二環式複素環、これら化合物を含む医薬、それらの使用及びそれらの製造方法
EP1940825A1 (en) *	2005-09-20	2008-07-09	Astra Zeneca AB	Quinazoline derivatives as anticancer agents
DE602006018331D1 (de) *	2005-09-20	2010-12-30	Astrazeneca Ab	4-(1h-indazol-5-ylamino)chinazolinverbindungen als inhibitoren der erbb-rezeptortyrosinkinase zur behandlung von krebs
EP1948179A1 (en)	2005-11-11	2008-07-30	Boehringer Ingelheim International GmbH	Quinazoline derivatives for the treatment of cancer diseases
ATE443053T1 (de) *	2005-12-02	2009-10-15	Astrazeneca Ab	Als inhibitoren von erbb-tyrosinkinase verwendete chinazoleinderivate
WO2007063291A1 (en) *	2005-12-02	2007-06-07	Astrazeneca Ab	4-anilino-substituted quinazoline derivatives as tyrosine kinase inhibitors
EP1968579A1 (en) *	2005-12-30	2008-09-17	Astex Therapeutics Limited	Pharmaceutical compounds
CA2663599A1 (en) *	2006-09-18	2008-03-27	Boehringer Ingelheim International Gmbh	Method for treating cancer harboring egfr mutations
EP1921070A1 (de) *	2006-11-10	2008-05-14	Boehringer Ingelheim Pharma GmbH & Co. KG	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstelllung
BRPI0807234A2 (pt)	2007-02-06	2014-06-03	Boehringer Ingelheim Int	Heterociclos bicíclicos, composições farmacêuticas que contêm estes compostos, o uso dos mesmos e processos para a preparação dos mesmos
TWI377944B (en) *	2007-06-05	2012-12-01	Hanmi Holdings Co Ltd	Novel amide derivative for inhibiting the growth of cancer cells
JP5336516B2 (ja)	2008-02-07	2013-11-06	ベーリンガーインゲルハイムインターナショナルゲゼルシャフトミットベシュレンクテルハフツング	スピロ環式複素環化合物、該化合物を含む医薬品、その使用及びその製造方法
WO2009138779A1 (en) *	2008-05-13	2009-11-19	Astrazeneca Ab	Combination comprising 4- (3-chloro-2-fluoroanilino) -7-meth0xy-6- { [1- (n-methylcarbamoylmethyl) piperidin- 4-yl] oxyjquinazoline
MX2010012442A (es) *	2008-05-13	2011-10-11	Astrazeneca Ab	Sal de fumarato de 4-(3-cloro-2-fluoroanilino)-7-metoxi-6-{[1-(n-m etilcarbamoilmetil) piperidin-4-il]oxi}quinazolina.
CN101584696A (zh)	2008-05-21	2009-11-25	上海艾力斯医药科技有限公司	包含喹唑啉衍生物的组合物及制备方法、用途
WO2010015522A1 (de) *	2008-08-08	2010-02-11	Boehringer Ingelheim International Gmbh	Cyclohexyloxy-substituierte heterocyclen, diese verbindungen enthaltende arzneimittel, deren verwendung und verfahren zu ihrer herstellung
EP2313377B1 (de) *	2008-08-08	2016-01-06	Boehringer Ingelheim International Gmbh	Verfahren zur stereoselektiven synthese bicyclischer heterocyclen
TWI511956B (zh)	2009-01-16	2015-12-11	Exelixis Inc	製備ｎ-（４-｛〔６，７-雙（甲氧基）喹啉-４-基〕氧基｝苯基）-ｎ’-（４-氟苯基）環丙烷-１，１-二甲醯胺之方法
JP2012524769A (ja)	2009-04-23	2012-10-18	アストラゼネカアクチボラグ	４−（３−クロロ−２−フルオロアニリノ）−７−メトキシ−６−｛［１−（ｎ−メチルカルバモイルメチル）ピペリジン−４−イル］オキシ｝キナゾリンの製造方法
EP2451445B1 (en)	2009-07-06	2019-04-03	Boehringer Ingelheim International GmbH	Process for drying of bibw2992, of its salts and of solid pharmaceutical formulations comprising this active ingredient
EP2289881A1 (de)	2009-08-06	2011-03-02	Boehringer Ingelheim International GmbH	Verfahren zur stereoselektiven Synthese bicyclischer Heterocyclen
UA108618C2 (uk)	2009-08-07	2015-05-25		Застосування c-met-модуляторів в комбінації з темозоломідом та/або променевою терапією для лікування раку
CN103608336A (zh)	2011-02-01	2014-02-26	勃林格殷格翰国际有限公司	9-[4-(3-氯-2-氟-苯基氨基)-7-甲氧基-喹唑啉-6-基氧基]-1,4-二氮杂-螺[5.5]十一烷-5-酮二马来酸盐、其作为药物的用途及其制备方法
KR102061743B1 (ko)	2011-03-04	2020-01-03	뉴젠 세러퓨틱스 인코포레이티드	알킨 치환된 퀴나졸린 화합물 및 그것의 사용 방법
WO2012155339A1 (zh)	2011-05-17	2012-11-22	江苏康缘药业股份有限公司	4-苯胺-6-丁烯酰胺-7-烷醚喹唑啉衍生物及其制备方法和用途
KR101272613B1 (ko) *	2011-10-05	2013-06-10	한미사이언스 주식회사	1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온 염산염의 제조 방법 및 이에 사용되는 중간체
EP2752413B1 (en)	2012-03-26	2016-03-23	Fujian Institute Of Research On The Structure Of Matter, Chinese Academy Of Sciences	Quinazoline derivative and application thereof
CN102659692B (zh)	2012-05-04	2014-04-09	郑州泰基鸿诺药物科技有限公司	双联厄洛替尼及其制备方法
EP2875020B1 (en)	2012-07-19	2017-09-06	Boehringer Ingelheim International GmbH	Process for the preparation of a fumaric acid salt of 9-[4-(3-chloro-2-fluoro-phenylamino)-7-methoxy- chinazolin-6-yloxy]-1,4-diaza-spiro[5.5]undecan-5-one
KR20140096571A (ko) *	2013-01-28	2014-08-06	한미약품 주식회사	1-(4-(4-(3,4-디클로로-2-플루오로페닐아미노)-7-메톡시퀴나졸린-6-일옥시)피페리딘-1-일)프로프-2-엔-1-온의 제조방법
AU2014224382B2 (en)	2013-03-06	2016-11-10	Astrazeneca Ab	Quinazoline inhibitors of activating mutant forms of epidermal growth factor receptor
US9242965B2 (en)	2013-12-31	2016-01-26	Boehringer Ingelheim International Gmbh	Process for the manufacture of (E)-4-N,N-dialkylamino crotonic acid in HX salt form and use thereof for synthesis of EGFR tyrosine kinase inhibitors
CN104530063B (zh) *	2015-01-13	2017-01-18	北京赛特明强医药科技有限公司	喹唑啉并杂环类化合物及其制备方法和作为用于治疗癌症的表皮生长因子受体抑制剂的应用
UY37935A (es) *	2017-10-18	2020-03-31	Spectrum Pharmaceuticals Inc	Inhibidores de tirosina quinasas de la familia de los egfr mutantes

Family Cites Families (88)

* Cited by examiner, † Cited by third party
Publication number	Priority date	Publication date	Assignee	Title
US2616582A (en) *	1950-11-28	1952-11-04	Whitney Kappes Co	Bung
IT1019480B (it) *	1973-10-27	1977-11-10	Deutsche Automobilgesellsch	Perfezionamento negli elettrodi di zinco picaricabili
US3985749A (en) *	1975-12-22	1976-10-12	Eastman Kodak Company	Process for preparation of 4-aminoquinazoline
JPS5538325A (en) *	1978-09-11	1980-03-17	Sankyo Co Ltd	4-anilinoquinazoline derivative and its preparation
US4335127A (en) *	1979-01-08	1982-06-15	Janssen Pharmaceutica, N.V.	Piperidinylalkyl quinazoline compounds, composition and method of use
US4456359A (en)	1981-11-04	1984-06-26	Ciba-Geigy Ag	Flat photographic sheet processing cassette
GB2160201B (en) *	1984-06-14	1988-05-11	Wyeth John & Brother Ltd	Quinazoline and cinnoline derivatives
KR910006138B1 (ko)	1986-09-30	1991-08-16	에자이 가부시끼가이샤	환상아민 유도체
IL89029A (en)	1988-01-29	1993-01-31	Lilly Co Eli	Fungicidal quinoline and cinnoline derivatives, compositions containing them, and fungicidal methods of using them
US4921863A (en) *	1988-02-17	1990-05-01	Eisai Co., Ltd.	Cyclic amine derivatives
CA1340821C (en) *	1988-10-06	1999-11-16	Nobuyuki Fukazawa	Heterocyclic compounds and anticancer-drug reinforcing agents containing them as effective components
US5252586A (en) *	1990-09-28	1993-10-12	The Du Pont Merck Pharmaceutical Company	Ether derivatives of alkyl piperidines and pyrrolidines as antipsychotic agents
US5721237A (en) *	1991-05-10	1998-02-24	Rhone-Poulenc Rorer Pharmaceuticals Inc.	Protein tyrosine kinase aryl and heteroaryl quinazoline compounds having selective inhibition of HER-2 autophosphorylation properties
NZ243082A (en)	1991-06-28	1995-02-24	Ici Plc	4-anilino-quinazoline derivatives; pharmaceutical compositions, preparatory processes, and use thereof
PT100905A (pt)	1991-09-30	1994-02-28	Eisai Co Ltd	Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem
AU661533B2 (en) *	1992-01-20	1995-07-27	Astrazeneca Ab	Quinazoline derivatives
US5770609A (en) *	1993-01-28	1998-06-23	Neorx Corporation	Prevention and treatment of cardiovascular pathologies
GB9323290D0 (en)	1992-12-10	1994-01-05	Zeneca Ltd	Quinazoline derivatives
GB9314884D0 (en)	1993-07-19	1993-09-01	Zeneca Ltd	Tricyclic derivatives
TW321649B (zh) *	1994-11-12	1997-12-01	Zeneca Ltd
GB2295387A (en)	1994-11-23	1996-05-29	Glaxo Inc	Quinazoline antagonists of alpha 1c adrenergic receptors
GB9508538D0 (en) *	1995-04-27	1995-06-14	Zeneca Ltd	Quinazoline derivatives
US5932574A (en) *	1995-04-27	1999-08-03	Zeneca Limited	Quinazoline derivatives
US5747498A (en) *	1996-05-28	1998-05-05	Pfizer Inc.	Alkynyl and azido-substituted 4-anilinoquinazolines
US6046206A (en) *	1995-06-07	2000-04-04	Cell Pathways, Inc.	Method of treating a patient having a precancerous lesions with amide quinazoline derivatives
GB9624482D0 (en) *	1995-12-18	1997-01-15	Zeneca Phaema S A	Chemical compounds
AU1721697A (en) *	1996-01-31	1997-08-22	Gist-Brocades B.V.	Use of compositions comprising stabilized biologically effective compounds
US6262054B1 (en) *	1996-02-01	2001-07-17	Sloan-Kettering Institute Of Cancer Research	Combination therapy method for treating breast cancer using edatrexate
GB9603095D0 (en) *	1996-02-14	1996-04-10	Zeneca Ltd	Quinazoline derivatives
GB9607729D0 (en) *	1996-04-13	1996-06-19	Zeneca Ltd	Quinazoline derivatives
US6004967A (en) *	1996-09-13	1999-12-21	Sugen, Inc.	Psoriasis treatment with quinazoline compounds
GB9718972D0 (en) *	1996-09-25	1997-11-12	Zeneca Ltd	Chemical compounds
EP0837063A1 (en)	1996-10-17	1998-04-22	Pfizer Inc.	4-Aminoquinazoline derivatives
US6225318B1 (en) *	1996-10-17	2001-05-01	Pfizer Inc	4-aminoquinazolone derivatives
GB9626589D0 (en) *	1996-12-20	1997-02-05	Prolifix Ltd	Peptides
US5929080A (en) *	1997-05-06	1999-07-27	American Cyanamid Company	Method of treating polycystic kidney disease
JP4245682B2 (ja)	1997-12-25	2009-03-25	協和発酵キリン株式会社	キノリン誘導体、イソキノリン誘導体、およびシンノリン誘導体、並びに抗炎症剤および抗アレルギー剤
US6384223B1 (en) *	1998-07-30	2002-05-07	American Home Products Corporation	Substituted quinazoline derivatives
US6297258B1 (en) *	1998-09-29	2001-10-02	American Cyanamid Company	Substituted 3-cyanoquinolines
AU3281600A (en) *	1999-02-27	2000-09-21	Boehringer Ingelheim Pharma Gmbh & Co. Kg	4-amino-quinazoline and quinoline derivatives having an inhibitory effect on signal transsduction mediated by tyrosine kinases
US6080747A (en) *	1999-03-05	2000-06-27	Hughes Institute	JAK-3 inhibitors for treating allergic disorders
DE19911509A1 (de) *	1999-03-15	2000-09-21	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US6258820B1 (en) *	1999-03-19	2001-07-10	Parker Hughes Institute	Synthesis and anti-tumor activity of 6,7-dialkoxy-4-phenylamino-quinazolines
US6627651B1 (en) *	1999-05-07	2003-09-30	Takeda Chemical Industries, Ltd.	Cyclic compounds and uses thereof
US6126917A (en) *	1999-06-01	2000-10-03	Hadasit Medical Research Services And Development Ltd.	Epidermal growth factor receptor binding compounds for positron emission tomography
MEP45508A (en) *	1999-06-21	2011-02-10	Boehringer Ingelheim Pharma	Bicyclic heterocycles, medicaments containing these compounds, their use and methods for the production thereof
NL1014401C2 (nl) *	2000-02-17	2001-09-04	Stichting Tech Wetenschapp	Ceriumhoudend anorganisch scintillatormateriaal.
EP1275398A4 (en) *	2000-04-06	2004-09-01	Kyowa Hakko Kogyo Kk	DIAGNOSTIC AND MEDICINAL PRODUCTS FOR TREATING RHEUMATOID ARTHRITES
AU2001258771A1 (en)	2000-05-19	2001-11-26	Takeda Chemical Industries Ltd.	-secretase inhibitors
AU2001278609B2 (en) *	2000-08-21	2005-04-14	Astrazeneca Ab	Quinazoline derivatives
US6617329B2 (en) *	2000-08-26	2003-09-09	Boehringer Ingelheim Pharma Kg	Aminoquinazolines and their use as medicaments
US6656946B2 (en) *	2000-08-26	2003-12-02	Boehringer Ingelheim Pharma Kg	Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
DE10042061A1 (de)	2000-08-26	2002-03-07	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen,diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042062A1 (de)	2000-08-26	2002-03-07	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Hertellung
DE10042059A1 (de) *	2000-08-26	2002-03-07	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042058A1 (de)	2000-08-26	2002-03-07	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
DE10042060A1 (de)	2000-08-26	2002-03-07	Boehringer Ingelheim Pharma	Bicyclische Heterocyclen, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung
US20020082270A1 (en) *	2000-08-26	2002-06-27	Frank Himmelsbach	Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US6653305B2 (en) *	2000-08-26	2003-11-25	Boehringer Ingelheim Pharma Kg	Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
US6740651B2 (en) *	2000-08-26	2004-05-25	Boehringer Ingelheim Pharma Kg	Aminoquinazolines which inhibit signal transduction mediated by tyrosine kinases
US20030158196A1 (en) *	2002-02-16	2003-08-21	Boehringer Ingelheim Pharma Gmbh Co. Kg	Pharmaceutical compositions based on anticholinergics and EGFR kinase inhibitors
US20040053972A1 (en) *	2000-12-11	2004-03-18	Eiji Nara	Medicinal compositions having improved absorbability
US7019012B2 (en) *	2000-12-20	2006-03-28	Boehringer Ingelheim International Pharma Gmbh & Co. Kg	Quinazoline derivatives and pharmaceutical compositions containing them
NZ516873A (en)	2001-02-12	2003-11-28	Warner Lambert Co	Compositions containing retinoids and erb inhibitors and their use in inhibiting retinoid skin damage
EP1369418B1 (en)	2001-02-21	2010-07-28	Mitsubishi Tanabe Pharma Corporation	Quinazoline derivatives
US6562319B2 (en) *	2001-03-12	2003-05-13	Yissum Research Development Company Of The Hebrew University Of Jerusalem	Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy
EP1396488A1 (en) *	2001-05-23	2004-03-10	Mitsubishi Pharma Corporation	Fused heterocyclic compound and medicinal use thereof
GB0126879D0 (en) *	2001-11-08	2002-01-02	Astrazeneca Ab	Combination therapy
JP2003246780A (ja)	2001-12-17	2003-09-02	Eisai Co Ltd	含窒素芳香環化合物の製造方法
DE10204462A1 (de) *	2002-02-05	2003-08-07	Boehringer Ingelheim Pharma	Verwendung von Tyrosinkinase-Inhibitoren zur Behandlung inflammatorischer Prozesse
WO2003066602A1 (fr) *	2002-02-06	2003-08-14	Ube Industries, Ltd.	Procede relatif a l'elaboration d'un compose 4-aminoquinazoline
TW200813014A (en) *	2002-03-28	2008-03-16	Astrazeneca Ab	Quinazoline derivatives
US6924285B2 (en) *	2002-03-30	2005-08-02	Boehringer Ingelheim Pharma Gmbh & Co.	Bicyclic heterocyclic compounds, pharmaceutical compositions containing these compounds, their use and process for preparing them
US20040044014A1 (en) *	2002-04-19	2004-03-04	Boehringer Ingelheim Pharma Gmbh & Co. Kg	Bicyclic heterocycles, pharmaceutical compositions containing these compounds, their use and processes for the preparation thereof
WO2003101491A1 (fr) *	2002-06-03	2003-12-11	Mitsubishi Pharma Corporation	Moyens preventifs et/ou therapeutiques destines a des sujets presentant l'expression ou l'activation de her2 et/ou egfr
CN1192564C (zh) *	2002-06-06	2005-03-09	华为技术有限公司	开放最短路径优先协议第五类链路状态通告分组刷新的方法
AT6168U1 (de) *	2002-07-15	2003-05-26	Blum Gmbh Julius	Scharnier
US7560558B2 (en) *	2002-08-23	2009-07-14	Kirin Beer Kabushiki Kaisha	Compound having TGFβ inhibitory activity and medicinal composition containing the same
WO2004060400A1 (ja)	2003-01-06	2004-07-22	Mitsubishi Pharma Corp	上皮成長因子受容体を分子標的とする抗精神病薬
DE10300098A1 (de) *	2003-01-07	2004-07-15	Bayer Ag	Kupfer-Carben-Komplexe und ihre Verwendung
DE10300097A1 (de) *	2003-01-07	2004-07-22	Bayer Ag	Kupfer-Komplexe und ihre Verwendung
BRPI0413066A (pt) *	2003-07-29	2006-10-17	Astrazeneca Ab	derivado de quinazolina, ou um sal farmaceuticamente aceitável, ou um éster farmaceuticamente aceitável do mesmo, da fórmula i, uso e processo para a preparação do mesmo, composto, composição farmacêutica, e, métodos para a produção de um efeito antiproliferativo em um animal de sangue quente, para a prevenção ou tratamento de um tumor, para prover um efeito inibitório de tirosina quinase de egfr seletivo, e para tratar um cáncer em um animal de sangue quente
GB0317665D0 (en) *	2003-07-29	2003-09-03	Astrazeneca Ab	Qinazoline derivatives
CN1882570B (zh) *	2003-09-19	2010-12-08	阿斯利康(瑞典)有限公司	喹唑啉衍生物
BRPI0414532B1 (pt) *	2003-09-19	2018-06-05	Astrazeneca Ab	Composto derivado de quinazolina, processo para preparar 0 mesmo, composição farmaceutica, e, uso de um composto derivado de quinazolina
EP1670786A1 (en) *	2003-09-25	2006-06-21	Astrazeneca AB	Quinazoline derivatives
SE526965C2 (sv) *	2005-01-24	2005-11-29	Jan Hansen	Anordning vid minigolfspel
KR20080028813A (ko) *	2006-09-27	2008-04-01	삼성전자주식회사	통신 시스템에서 파일럿 채널 탐색 제어 장치 및 방법

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Publication number	Publication date
US20100152442A1 (en)	2010-06-17
PL214880B1 (pl)	2013-09-30
JP3891493B2 (ja)	2007-03-14
SA03240080B1 (ar)	2009-04-20
TWI324597B (en)	2010-05-11
TW200813014A (en)	2008-03-16
HK1070888A1 (zh)	2005-06-30
IS7469A (is)	2004-09-24
HK1079521A1 (zh)	2006-04-07
DK1487806T3 (da)	2010-09-20
MXPA04009486A (es)	2005-01-25
US8399667B2 (en)	2013-03-19
IL164135A (en)	2011-07-31
EP1487806B1 (en)	2010-07-07
UA78302C2 (uk)	2007-03-15
BR0308670A (pt)	2005-02-01
AR039203A1 (es)	2005-02-09
AU2003214443B8 (en)	2009-08-20
IS2855B (is)	2013-11-15
CA2479642A1 (en)	2003-10-09
US20130005727A1 (en)	2013-01-03
TW200403227A (en)	2004-03-01
KR101006947B1 (ko)	2011-01-12
NO20044325L (no)	2004-12-16
JP2005529092A (ja)	2005-09-29
WO2003082831A1 (en)	2003-10-09
CY1111039T1 (el)	2015-06-11
JP2006249093A (ja)	2006-09-21
US20080269487A1 (en)	2008-10-30
ATE473215T1 (de)	2010-07-15
US20050215574A1 (en)	2005-09-29
UY27742A1 (es)	2003-10-31
PT1487806E (pt)	2010-08-27
PL372889A1 (en)	2005-08-08
CA2479642C (en)	2010-06-08
KR20040094891A (ko)	2004-11-10
IL164135A0 (en)	2005-12-18
CN1656081A (zh)	2005-08-17
EP1487806A1 (en)	2004-12-22
CN100439344C (zh)	2008-12-03
ES2346135T3 (es)	2010-10-11
AU2003214443A1 (en)	2003-10-13
NZ535014A (en)	2007-07-27
SI1487806T1 (sl)	2010-09-30
DE60333262D1 (en)	2010-08-19
MY158054A (en)	2016-08-30
AU2003214443B2 (en)	2009-07-16

Publication	Publication Date	Title
AU2003214443B2 (en)	2009-07-16	4-anilino quinazoline derivatives as antiproliferative agents
US20070043010A1 (en)	2007-02-22	Quinazoline derivatives
AU2004276067A1 (en)	2005-04-07	Quinazoline derivatives as antiproliferative agents
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