JP4386967B2 - プロテインチロシンキナーゼ阻害剤としての縮合複素環式化合物 - Google Patents
プロテインチロシンキナーゼ阻害剤としての縮合複素環式化合物 Download PDFInfo
- Publication number
- JP4386967B2 JP4386967B2 JP50559698A JP50559698A JP4386967B2 JP 4386967 B2 JP4386967 B2 JP 4386967B2 JP 50559698 A JP50559698 A JP 50559698A JP 50559698 A JP50559698 A JP 50559698A JP 4386967 B2 JP4386967 B2 JP 4386967B2
- Authority
- JP
- Japan
- Prior art keywords
- quinazolin
- methyl
- benzyloxy
- amine
- phenyl
- Prior art date
- Legal status (The legal status 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 status listed.)
- Expired - Lifetime
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- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 title 1
- -1 methylsulfonylethylamino, methylsulfinylethylamino, methylsulfonylethyl Chemical group 0.000 claims description 245
- 150000001875 compounds Chemical class 0.000 claims description 206
- 229910052739 hydrogen Inorganic materials 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 60
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical compound C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 52
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 48
- 150000003839 salts Chemical class 0.000 claims description 44
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 40
- 125000000217 alkyl group Chemical group 0.000 claims description 40
- 239000012453 solvate Substances 0.000 claims description 36
- 238000011282 treatment Methods 0.000 claims description 26
- 125000005843 halogen group Chemical group 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 22
- 150000002431 hydrogen Chemical class 0.000 claims description 20
- WCPAKWJPBJAGKN-UHFFFAOYSA-N oxadiazole Chemical compound C1=CON=N1 WCPAKWJPBJAGKN-UHFFFAOYSA-N 0.000 claims description 17
- 239000008194 pharmaceutical composition Substances 0.000 claims description 17
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 16
- 150000003852 triazoles Chemical class 0.000 claims description 16
- 206010028980 Neoplasm Diseases 0.000 claims description 15
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 15
- 125000005842 heteroatom Chemical group 0.000 claims description 15
- 125000003453 indazolyl group Chemical group N1N=C(C2=C1C=CC=C2)* 0.000 claims description 14
- 125000004175 fluorobenzyl group Chemical group 0.000 claims description 12
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 claims description 12
- 229910052736 halogen Inorganic materials 0.000 claims description 11
- 150000002367 halogens Chemical class 0.000 claims description 11
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 11
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 claims description 10
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 10
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000006287 difluorobenzyl group Chemical group 0.000 claims description 9
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 9
- 201000011510 cancer Diseases 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 5
- WUJYYMGQHNKEGQ-UHFFFAOYSA-N 6-[5-[[methyl(2-methylsulfonylethyl)amino]methyl]furan-2-yl]-n-(4-phenylmethoxyphenyl)quinazolin-4-amine Chemical compound O1C(CN(CCS(C)(=O)=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=CC=CC=4)=CC=3)C2=C1 WUJYYMGQHNKEGQ-UHFFFAOYSA-N 0.000 claims description 4
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 4
- 125000005955 1H-indazolyl group Chemical group 0.000 claims description 3
- CAIJGAFHVSALOJ-UHFFFAOYSA-N 2-[[5-[4-(4-phenylmethoxyanilino)quinazolin-6-yl]furan-2-yl]methylamino]ethanesulfonamide Chemical compound O1C(CNCCS(=O)(=O)N)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=CC=CC=4)=CC=3)C2=C1 CAIJGAFHVSALOJ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004414 alkyl thio group Chemical group 0.000 claims description 3
- MGRNWJPWIAFGQE-UHFFFAOYSA-N n-(1-benzylindazol-5-yl)-6-[5-[(2-methylsulfonylethylamino)methyl]-1,2,4-oxadiazol-3-yl]quinazolin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=NC(C=2C=C3C(NC=4C=C5C=NN(CC=6C=CC=CC=6)C5=CC=4)=NC=NC3=CC=2)=N1 MGRNWJPWIAFGQE-UHFFFAOYSA-N 0.000 claims description 3
- NIWCLOVPIUBQEZ-UHFFFAOYSA-N n-(1-benzylindazol-5-yl)-6-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C4C=NN(CC=5C=CC=CC=5)C4=CC=3)C2=C1 NIWCLOVPIUBQEZ-UHFFFAOYSA-N 0.000 claims description 3
- PGUXMZHODKGDJQ-UHFFFAOYSA-N n-(1-benzylindazol-5-yl)-7-[5-[(2-methylsulfonylethylamino)methyl]furan-2-yl]quinazolin-4-amine Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(C(NC=2C=C3C=NN(CC=4C=CC=CC=4)C3=CC=2)=NC=N2)C2=C1 PGUXMZHODKGDJQ-UHFFFAOYSA-N 0.000 claims description 3
- JFYXRFGHVISHRB-UHFFFAOYSA-N n-[2-[[5-[4-(4-phenylmethoxyanilino)quinazolin-6-yl]furan-2-yl]methylamino]ethyl]methanesulfonamide Chemical compound O1C(CNCCNS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=CC=CC=4)=CC=3)C2=C1 JFYXRFGHVISHRB-UHFFFAOYSA-N 0.000 claims description 3
- GPURBJOXKSEHNK-UHFFFAOYSA-N n-methyl-2-[[5-[4-(4-phenylmethoxyanilino)quinazolin-6-yl]furan-2-yl]methylamino]ethanesulfonamide Chemical compound O1C(CNCCS(=O)(=O)NC)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=CC=CC=4)=CC=3)C2=C1 GPURBJOXKSEHNK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 2
- 239000004471 Glycine Substances 0.000 claims description 2
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 2
- 125000003282 alkyl amino group Chemical group 0.000 claims description 2
- 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- BEBCJVAWIBVWNZ-UHFFFAOYSA-N glycinamide Chemical compound NCC(N)=O BEBCJVAWIBVWNZ-UHFFFAOYSA-N 0.000 claims description 2
- KQSSATDQUYCRGS-UHFFFAOYSA-N methyl glycinate Chemical compound COC(=O)CN KQSSATDQUYCRGS-UHFFFAOYSA-N 0.000 claims description 2
- PEGMJAWCBJOPAD-UHFFFAOYSA-N n-(2-methylsulfonylethyl)-5-[4-(4-phenylmethoxyanilino)quinazolin-6-yl]furan-2-carboxamide Chemical compound O1C(C(=O)NCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=CC(OCC=4C=CC=CC=4)=CC=3)C2=C1 PEGMJAWCBJOPAD-UHFFFAOYSA-N 0.000 claims description 2
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 202
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 159
- 239000000203 mixture Substances 0.000 description 123
- 239000007787 solid Substances 0.000 description 99
- 238000000034 method Methods 0.000 description 88
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 83
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 71
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 70
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 63
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 60
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 60
- 229910052757 nitrogen Inorganic materials 0.000 description 60
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 59
- 235000019439 ethyl acetate Nutrition 0.000 description 57
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 52
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 51
- 238000006243 chemical reaction Methods 0.000 description 51
- 239000000243 solution Substances 0.000 description 47
- 239000000047 product Substances 0.000 description 43
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 42
- 238000010992 reflux Methods 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 34
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M sodium hydroxide Inorganic materials [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 29
- 125000000623 heterocyclic group Chemical group 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 27
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 25
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- 230000000694 effects Effects 0.000 description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 23
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 22
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 21
- 239000002904 solvent Substances 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 20
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 description 20
- 229910052760 oxygen Inorganic materials 0.000 description 19
- 125000001424 substituent group Chemical group 0.000 description 19
- 101710100968 Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 18
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 18
- 239000003153 chemical reaction reagent Substances 0.000 description 17
- 239000002253 acid Substances 0.000 description 15
- 239000003054 catalyst Substances 0.000 description 14
- 201000010099 disease Diseases 0.000 description 14
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 14
- 239000012299 nitrogen atmosphere Substances 0.000 description 14
- 238000010898 silica gel chromatography Methods 0.000 description 14
- 238000006467 substitution reaction Methods 0.000 description 14
- 229910052717 sulfur Inorganic materials 0.000 description 14
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 13
- 150000001412 amines Chemical class 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 13
- 125000004433 nitrogen atom Chemical group N* 0.000 description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 12
- 125000003118 aryl group Chemical group 0.000 description 12
- 239000002585 base Substances 0.000 description 12
- YNHIGQDRGKUECZ-UHFFFAOYSA-L bis(triphenylphosphine)palladium(ii) dichloride Chemical compound [Cl-].[Cl-].[Pd+2].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 YNHIGQDRGKUECZ-UHFFFAOYSA-L 0.000 description 12
- 238000004587 chromatography analysis Methods 0.000 description 12
- 239000003921 oil Substances 0.000 description 11
- 239000002244 precipitate Substances 0.000 description 11
- 238000000746 purification Methods 0.000 description 11
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 10
- 108060006698 EGF receptor Proteins 0.000 description 10
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 10
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 10
- 210000004027 cell Anatomy 0.000 description 10
- 239000006071 cream Substances 0.000 description 10
- 238000009472 formulation Methods 0.000 description 10
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 10
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 10
- 238000001665 trituration Methods 0.000 description 10
- AYBKEGIZSWJSIZ-UHFFFAOYSA-N 2-(4-chloroquinazolin-6-yl)-5-(trifluoromethyl)-1,3,4-oxadiazole Chemical compound O1C(C(F)(F)F)=NN=C1C1=CC=C(N=CN=C2Cl)C2=C1 AYBKEGIZSWJSIZ-UHFFFAOYSA-N 0.000 description 9
- YNQNAOZPEQKXJY-UHFFFAOYSA-N 2-(4-chloroquinazolin-6-yl)-5-methyl-1,3,4-oxadiazole Chemical compound O1C(C)=NN=C1C1=CC=C(N=CN=C2Cl)C2=C1 YNQNAOZPEQKXJY-UHFFFAOYSA-N 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 239000003112 inhibitor Substances 0.000 description 9
- CTAPFRYPJLPFDF-UHFFFAOYSA-N isoxazole Chemical compound C=1C=NOC=1 CTAPFRYPJLPFDF-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- 239000011541 reaction mixture Substances 0.000 description 9
- 150000003536 tetrazoles Chemical class 0.000 description 9
- 238000004809 thin layer chromatography Methods 0.000 description 9
- 229930192474 thiophene Natural products 0.000 description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- 239000004480 active ingredient Substances 0.000 description 8
- 125000002837 carbocyclic group Chemical group 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- 239000000725 suspension Substances 0.000 description 8
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 7
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 7
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 239000006196 drop Substances 0.000 description 7
- 125000001041 indolyl group Chemical group 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- JQXJBXVWVPVTOO-UHFFFAOYSA-L 4-diphenylphosphanylbutyl(diphenyl)phosphane;palladium(2+);dichloride Chemical compound Cl[Pd]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 JQXJBXVWVPVTOO-UHFFFAOYSA-L 0.000 description 6
- XFTUDEYATQLWOU-UHFFFAOYSA-N 6-bromo-n-(4-phenylmethoxyphenyl)quinazolin-4-amine Chemical compound C12=CC(Br)=CC=C2N=CN=C1NC(C=C1)=CC=C1OCC1=CC=CC=C1 XFTUDEYATQLWOU-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
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- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 6
- 201000004681 Psoriasis Diseases 0.000 description 6
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000002159 abnormal effect Effects 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 125000005879 dioxolanyl group Chemical group 0.000 description 6
- 239000000284 extract Substances 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- MZRVEZGGRBJDDB-UHFFFAOYSA-N n-Butyllithium Substances [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 125000004076 pyridyl group Chemical group 0.000 description 6
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 6
- 238000003786 synthesis reaction Methods 0.000 description 6
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 5
- BQUSMTPKYUILPD-UHFFFAOYSA-N 1-benzylindazol-5-amine Chemical compound N1=CC2=CC(N)=CC=C2N1CC1=CC=CC=C1 BQUSMTPKYUILPD-UHFFFAOYSA-N 0.000 description 5
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 5
- FIIDVVUUWRJXLF-UHFFFAOYSA-N 4-phenylmethoxyaniline Chemical compound C1=CC(N)=CC=C1OCC1=CC=CC=C1 FIIDVVUUWRJXLF-UHFFFAOYSA-N 0.000 description 5
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 5
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- VLJNHYLEOZPXFW-BYPYZUCNSA-N L-prolinamide Chemical compound NC(=O)[C@@H]1CCCN1 VLJNHYLEOZPXFW-BYPYZUCNSA-N 0.000 description 5
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- PRQYVPZTRJFDHX-UHFFFAOYSA-N n-[4-[(4-fluorophenyl)methoxy]phenyl]-6-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]quinazolin-4-amine Chemical compound C1=CC(F)=CC=C1COC(C=C1)=CC=C1NC1=NC=NC2=CC=C(C=3OC(=NN=3)C(F)(F)F)C=C12 PRQYVPZTRJFDHX-UHFFFAOYSA-N 0.000 description 1
- UGXCGCLUZOLGKT-UHFFFAOYSA-N n-[4-[(4-fluorophenyl)methoxy]phenyl]-6-[5-(trifluoromethyl)-1,3,4-oxadiazol-2-yl]quinazolin-4-amine;hydrochloride Chemical compound Cl.C1=CC(F)=CC=C1COC(C=C1)=CC=C1NC1=NC=NC2=CC=C(C=3OC(=NN=3)C(F)(F)F)C=C12 UGXCGCLUZOLGKT-UHFFFAOYSA-N 0.000 description 1
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- XIMLAVRHZBUYBE-UHFFFAOYSA-N piperidin-2-one;hydrate;hydrochloride Chemical compound O.Cl.O=C1CCCCN1 XIMLAVRHZBUYBE-UHFFFAOYSA-N 0.000 description 1
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- 229910052697 platinum Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
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- 230000000069 prophylactic effect Effects 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000004353 pyrazol-1-yl group Chemical group [H]C1=NN(*)C([H])=C1[H] 0.000 description 1
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- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- UDJFFSGCRRMVFH-UHFFFAOYSA-N pyrido[2,3-d]pyrimidine Chemical compound N1=CN=CC2=CC=CN=C21 UDJFFSGCRRMVFH-UHFFFAOYSA-N 0.000 description 1
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- JOZPEVMCAKXSEY-UHFFFAOYSA-N pyrimido[5,4-d]pyrimidine Chemical class N1=CN=CC2=NC=NC=C21 JOZPEVMCAKXSEY-UHFFFAOYSA-N 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
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- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
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- KXCAEQNNTZANTK-UHFFFAOYSA-N stannane Chemical class [SnH4] KXCAEQNNTZANTK-UHFFFAOYSA-N 0.000 description 1
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- BUUPQKDIAURBJP-UHFFFAOYSA-N sulfinic acid Chemical compound OS=O BUUPQKDIAURBJP-UHFFFAOYSA-N 0.000 description 1
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- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical compound ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
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- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 125000000147 tetrahydroquinolinyl group Chemical group N1(CCCC2=CC=CC=C12)* 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 125000005306 thianaphthenyl group Chemical group 0.000 description 1
- 125000003777 thiepinyl group Chemical group 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 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
- 238000012546 transfer Methods 0.000 description 1
- QTYBKWIPVOTUQI-UHFFFAOYSA-N tributyl(2,3-dihydrofuran-5-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CCCO1 QTYBKWIPVOTUQI-UHFFFAOYSA-N 0.000 description 1
- GYUURHMITDQTRU-UHFFFAOYSA-N tributyl(pyridin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CC=N1 GYUURHMITDQTRU-UHFFFAOYSA-N 0.000 description 1
- WTFFOOAJSDVASL-UHFFFAOYSA-N tributyl(pyrimidin-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CC=N1 WTFFOOAJSDVASL-UHFFFAOYSA-N 0.000 description 1
- UKTDFYOZPFNQOQ-UHFFFAOYSA-N tributyl(thiophen-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CC=CS1 UKTDFYOZPFNQOQ-UHFFFAOYSA-N 0.000 description 1
- KFWFYOPKNSYTMV-UHFFFAOYSA-N tributyl-(1-methylimidazol-2-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=NC=CN1C KFWFYOPKNSYTMV-UHFFFAOYSA-N 0.000 description 1
- CWAPIHCLJCNFTN-UHFFFAOYSA-N tributyl-(2,3-dimethylimidazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=C(C)N1C CWAPIHCLJCNFTN-UHFFFAOYSA-N 0.000 description 1
- FFSUQKBGKWNUQW-UHFFFAOYSA-N tributyl-(3-methyl-1,2-oxazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CON=C1C FFSUQKBGKWNUQW-UHFFFAOYSA-N 0.000 description 1
- OGYWKJKAIAEDQX-UHFFFAOYSA-N tributyl-(3-methylimidazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=CN1C OGYWKJKAIAEDQX-UHFFFAOYSA-N 0.000 description 1
- DPCBHPVSSFQHLW-UHFFFAOYSA-N tributyl-(3-methyltriazol-4-yl)stannane Chemical compound CCCC[Sn](CCCC)(CCCC)C1=CN=NN1C DPCBHPVSSFQHLW-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 1
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 description 1
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- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 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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- PXXNTAGJWPJAGM-UHFFFAOYSA-N vertaline Natural products C1C2C=3C=C(OC)C(OC)=CC=3OC(C=C3)=CC=C3CCC(=O)OC1CC1N2CCCC1 PXXNTAGJWPJAGM-UHFFFAOYSA-N 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
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
- C07D401/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
-
- 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
- C07D403/04—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 directly linked by a ring-member-to-ring-member bond
-
- 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
- C07D403/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- 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
- C07D405/04—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 directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—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
- C07D405/14—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 three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9614755.8 | 1996-07-13 | ||
| GBGB9614755.8A GB9614755D0 (en) | 1996-07-13 | 1996-07-13 | Heterocyclic compounds |
| GB9625458.6 | 1996-12-07 | ||
| GBGB9625458.6A GB9625458D0 (en) | 1996-12-07 | 1996-12-07 | Heterocyclic compounds |
| PCT/EP1997/003672 WO1998002434A1 (en) | 1996-07-13 | 1997-07-11 | Fused heterocyclic compounds as protein tyrosine kinase inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2000514806A JP2000514806A (ja) | 2000-11-07 |
| JP2000514806A5 JP2000514806A5 (OSRAM) | 2005-03-10 |
| JP4386967B2 true JP4386967B2 (ja) | 2009-12-16 |
Family
ID=26309690
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP50559698A Expired - Lifetime JP4386967B2 (ja) | 1996-07-13 | 1997-07-11 | プロテインチロシンキナーゼ阻害剤としての縮合複素環式化合物 |
Country Status (13)
| Country | Link |
|---|---|
| US (2) | US6391874B1 (OSRAM) |
| EP (1) | EP0912559B1 (OSRAM) |
| JP (1) | JP4386967B2 (OSRAM) |
| AR (1) | AR007857A1 (OSRAM) |
| AT (1) | ATE227283T1 (OSRAM) |
| AU (1) | AU3766897A (OSRAM) |
| CY (1) | CY2451B1 (OSRAM) |
| DE (1) | DE69716916T2 (OSRAM) |
| DK (1) | DK0912559T3 (OSRAM) |
| ES (1) | ES2186908T3 (OSRAM) |
| ID (1) | ID19609A (OSRAM) |
| PT (1) | PT912559E (OSRAM) |
| WO (1) | WO1998002434A1 (OSRAM) |
Families Citing this family (515)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU719434B2 (en) | 1996-02-13 | 2000-05-11 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
| GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
| ES2169355T3 (es) | 1996-03-05 | 2002-07-01 | Astrazeneca Ab | Derivados de 4-anilinoquinazolina. |
| GB9707800D0 (en) | 1996-05-06 | 1997-06-04 | Zeneca Ltd | Chemical compounds |
| HRP970371A2 (en) | 1996-07-13 | 1998-08-31 | Kathryn Jane Smith | Heterocyclic compounds |
| CN1252054C (zh) | 1996-09-25 | 2006-04-19 | 曾尼卡有限公司 | 抑制生长因子的作用的喹啉衍生物 |
| GB9718972D0 (en) | 1996-09-25 | 1997-11-12 | Zeneca Ltd | Chemical compounds |
| US6294532B1 (en) | 1997-08-22 | 2001-09-25 | Zeneca Limited | Oxindolylquinazoline derivatives as angiogenesis inhibitors |
| RS49779B (sr) * | 1998-01-12 | 2008-06-05 | Glaxo Group Limited, | Biciklična heteroaromatična jedinjenja kao inhibitori protein tirozin kinaze |
| US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
| US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
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| US5710158A (en) | 1991-05-10 | 1998-01-20 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit EGF and/or PDGF receptor tyrosine kinase |
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| IL112249A (en) | 1994-01-25 | 2001-11-25 | Warner Lambert Co | Pharmaceutical compositions containing di and tricyclic pyrimidine derivatives for inhibiting tyrosine kinases of the epidermal growth factor receptor family and some new such compounds |
| TW414798B (en) | 1994-09-07 | 2000-12-11 | Thomae Gmbh Dr K | Pyrimido (5,4-d) pyrimidines, medicaments comprising these compounds, their use and processes for their preparation |
| GB9510757D0 (en) * | 1994-09-19 | 1995-07-19 | Wellcome Found | Therapeuticaly active compounds |
| TW321649B (OSRAM) * | 1994-11-12 | 1997-12-01 | Zeneca Ltd | |
| SK281724B6 (sk) | 1994-11-14 | 2001-07-10 | Warner-Lambert Company | 6-arylpyrido[2,3-d]pyrimidíny, ich použitie a farmaceutické prostriedky na ich báze |
| GB9424233D0 (en) | 1994-11-30 | 1995-01-18 | Zeneca Ltd | Quinazoline derivatives |
| GB9514265D0 (en) * | 1995-07-13 | 1995-09-13 | Wellcome Found | Hetrocyclic compounds |
| GB9603095D0 (en) | 1996-02-14 | 1996-04-10 | Zeneca Ltd | Quinazoline derivatives |
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1997
- 1997-07-11 EP EP97934458A patent/EP0912559B1/en not_active Expired - Lifetime
- 1997-07-11 WO PCT/EP1997/003672 patent/WO1998002434A1/en not_active Ceased
- 1997-07-11 AR ARP970103103A patent/AR007857A1/es unknown
- 1997-07-11 US US09/214,267 patent/US6391874B1/en not_active Expired - Lifetime
- 1997-07-11 PT PT97934458T patent/PT912559E/pt unknown
- 1997-07-11 AT AT97934458T patent/ATE227283T1/de active
- 1997-07-11 JP JP50559698A patent/JP4386967B2/ja not_active Expired - Lifetime
- 1997-07-11 DK DK97934458T patent/DK0912559T3/da active
- 1997-07-11 ID IDP972414A patent/ID19609A/id unknown
- 1997-07-11 AU AU37668/97A patent/AU3766897A/en not_active Abandoned
- 1997-07-11 DE DE69716916T patent/DE69716916T2/de not_active Expired - Lifetime
- 1997-07-11 ES ES97934458T patent/ES2186908T3/es not_active Expired - Lifetime
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2002
- 2002-01-31 US US10/062,647 patent/US6828320B2/en not_active Expired - Lifetime
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2004
- 2004-04-29 CY CY0400034A patent/CY2451B1/xx unknown
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|---|---|
| US6828320B2 (en) | 2004-12-07 |
| JP2000514806A (ja) | 2000-11-07 |
| DE69716916D1 (de) | 2002-12-12 |
| PT912559E (pt) | 2003-03-31 |
| EP0912559A1 (en) | 1999-05-06 |
| US6391874B1 (en) | 2002-05-21 |
| DE69716916T2 (de) | 2003-07-03 |
| DK0912559T3 (da) | 2003-03-10 |
| ID19609A (id) | 1998-07-23 |
| ATE227283T1 (de) | 2002-11-15 |
| CY2451B1 (en) | 2005-06-03 |
| US20020147214A1 (en) | 2002-10-10 |
| WO1998002434A1 (en) | 1998-01-22 |
| AR007857A1 (es) | 1999-11-24 |
| ES2186908T3 (es) | 2003-05-16 |
| EP0912559B1 (en) | 2002-11-06 |
| AU3766897A (en) | 1998-02-09 |
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