JP2000504714A - Vegfインヒビターとしてのキナゾリン誘導体 - Google Patents
Vegfインヒビターとしてのキナゾリン誘導体Info
- Publication number
- JP2000504714A JP2000504714A JP9529078A JP52907897A JP2000504714A JP 2000504714 A JP2000504714 A JP 2000504714A JP 9529078 A JP9529078 A JP 9529078A JP 52907897 A JP52907897 A JP 52907897A JP 2000504714 A JP2000504714 A JP 2000504714A
- Authority
- JP
- Japan
- Prior art keywords
- alkyl
- hydroxy
- fluoro
- quinazoline
- methoxy
- 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.)
- Granted
Links
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims abstract description 7
- 239000002525 vasculotropin inhibitor Substances 0.000 title description 2
- -1 methoxy, amino Chemical group 0.000 claims abstract description 276
- 150000001875 compounds Chemical class 0.000 claims abstract description 183
- 150000003839 salts Chemical class 0.000 claims abstract description 88
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 80
- 239000001257 hydrogen Substances 0.000 claims abstract description 80
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 58
- 125000005843 halogen group Chemical group 0.000 claims abstract description 48
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 47
- 238000000034 method Methods 0.000 claims abstract description 46
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 36
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 31
- 230000008569 process Effects 0.000 claims abstract description 31
- 230000000694 effects Effects 0.000 claims abstract description 26
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 21
- 238000011282 treatment Methods 0.000 claims abstract description 17
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 14
- 125000005842 heteroatom Chemical group 0.000 claims abstract description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims abstract description 8
- 238000002360 preparation method Methods 0.000 claims abstract description 6
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 98
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 47
- 125000001424 substituent group Chemical group 0.000 claims description 46
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 claims description 41
- 150000003246 quinazolines Chemical class 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 125000004043 oxo group Chemical group O=* 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 17
- 239000002253 acid Substances 0.000 claims description 15
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 230000008728 vascular permeability Effects 0.000 claims description 12
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 11
- 125000000719 pyrrolidinyl group Chemical group 0.000 claims description 11
- 241001465754 Metazoa Species 0.000 claims description 10
- 125000004432 carbon atom Chemical group C* 0.000 claims description 10
- 125000001153 fluoro group Chemical group F* 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- 125000003386 piperidinyl group Chemical group 0.000 claims description 9
- 229910052717 sulfur Inorganic materials 0.000 claims description 9
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 7
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 7
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- FRYNFLZWVRHSQU-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(2-methylsulfanylethoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCSC)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F FRYNFLZWVRHSQU-UHFFFAOYSA-N 0.000 claims description 6
- XHXOJKOXEKXDSQ-UHFFFAOYSA-N 5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluoro-2-methylphenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(C)C=C1F XHXOJKOXEKXDSQ-UHFFFAOYSA-N 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
- 229920006395 saturated elastomer Polymers 0.000 claims description 6
- KJHZBMRRZLEZEY-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-pyrrolidin-1-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F KJHZBMRRZLEZEY-UHFFFAOYSA-N 0.000 claims description 5
- MLPJQRZMIKCLAE-UHFFFAOYSA-N 2-chloro-5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(Cl)C=C1F MLPJQRZMIKCLAE-UHFFFAOYSA-N 0.000 claims description 5
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims description 5
- POLXJKGYTJUZNO-UHFFFAOYSA-N 4-fluoro-5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F POLXJKGYTJUZNO-UHFFFAOYSA-N 0.000 claims description 5
- 125000004103 aminoalkyl group Chemical group 0.000 claims description 5
- 125000004122 cyclic group Chemical group 0.000 claims description 5
- WDTZDAYILMUQLA-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-amine Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=C(F)C=C(Br)C=C1F WDTZDAYILMUQLA-UHFFFAOYSA-N 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 4
- QOXOZONBQWIKDA-UHFFFAOYSA-N 3-hydroxypropyl Chemical group [CH2]CCO QOXOZONBQWIKDA-UHFFFAOYSA-N 0.000 claims description 4
- KXAGMEUPTWULJN-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-methoxyethylamino)quinazolin-4-yl]amino]-2-methylphenol Chemical compound N=1C=NC2=CC(NCCOC)=CC=C2C=1NC1=CC(O)=C(C)C=C1F KXAGMEUPTWULJN-UHFFFAOYSA-N 0.000 claims description 4
- BGPMVNFAGBHYEC-UHFFFAOYSA-N 5-(6,7-dimethoxyquinazolin-4-yl)oxy-2-methylphenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1OC1=CC=C(C)C(O)=C1 BGPMVNFAGBHYEC-UHFFFAOYSA-N 0.000 claims description 4
- FHZCSNTVCRCIKT-UHFFFAOYSA-N 5-[(6,7-dimethoxyquinazolin-4-yl)amino]-2,4-difluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(F)C=C1F FHZCSNTVCRCIKT-UHFFFAOYSA-N 0.000 claims description 4
- 229940100198 alkylating agent Drugs 0.000 claims description 4
- 239000002168 alkylating agent Substances 0.000 claims description 4
- 230000003527 anti-angiogenesis Effects 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 4
- 125000004193 piperazinyl group Chemical group 0.000 claims description 4
- QSLPNSWXUQHVLP-UHFFFAOYSA-N $l^{1}-sulfanylmethane Chemical compound [S]C QSLPNSWXUQHVLP-UHFFFAOYSA-N 0.000 claims description 3
- CLSDZDFPIGPTBE-UHFFFAOYSA-N 2,4-difluoro-5-[[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yl]amino]phenol Chemical compound C=12C=C(OC)C(OCCOC)=CC2=NC=NC=1NC1=CC(O)=C(F)C=C1F CLSDZDFPIGPTBE-UHFFFAOYSA-N 0.000 claims description 3
- SPBPKQJZKCGMNA-UHFFFAOYSA-N 2-bromo-5-[(6,7-dimethoxyquinazolin-4-yl)amino]-4-fluorophenol Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=CC(O)=C(Br)C=C1F SPBPKQJZKCGMNA-UHFFFAOYSA-N 0.000 claims description 3
- UEUPJXFRYBVXCU-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-morpholin-4-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F UEUPJXFRYBVXCU-UHFFFAOYSA-N 0.000 claims description 3
- SOIKJFMWXGNLOF-UHFFFAOYSA-N 4-fluoro-5-[[7-(2-hydroxyethoxy)-6-methoxyquinazolin-4-yl]amino]-2-methylphenol Chemical compound N1=CN=C2C=C(OCCO)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F SOIKJFMWXGNLOF-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- YMMYOYOZKAMGGJ-UHFFFAOYSA-N 2-[4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazolin-7-yl]oxyethyl acetate Chemical compound N1=CN=C2C=C(OCCOC(C)=O)C(OC)=CC2=C1NC1=CC(O)=C(C)C=C1F YMMYOYOZKAMGGJ-UHFFFAOYSA-N 0.000 claims description 2
- VJINORGYVPPLAU-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(2-piperidin-1-ylethoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCCCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F VJINORGYVPPLAU-UHFFFAOYSA-N 0.000 claims description 2
- ICSJRTHEPBTIHO-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F ICSJRTHEPBTIHO-UHFFFAOYSA-N 0.000 claims description 2
- PKPDNFNJEGKHGS-UHFFFAOYSA-N 2-chloro-4-fluoro-5-[[6-methoxy-7-[2-(4-methylpiperazin-1-yl)ethoxy]quinazolin-4-yl]amino]phenol Chemical compound N1=CN=C2C=C(OCCN3CCN(C)CC3)C(OC)=CC2=C1NC1=CC(O)=C(Cl)C=C1F PKPDNFNJEGKHGS-UHFFFAOYSA-N 0.000 claims description 2
- XOVJAYNMQDTIJD-UHFFFAOYSA-N cyclopentobarbital Chemical compound C1CC=CC1C1(CC=C)C(=O)NC(=O)NC1=O XOVJAYNMQDTIJD-UHFFFAOYSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 2
- OHUQJWOIRKREPF-UHFFFAOYSA-N n-(4-bromo-2,6-difluorophenyl)-6,7-dimethoxyquinazolin-4-amine Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1NC1=C(F)C=C(Br)C=C1F OHUQJWOIRKREPF-UHFFFAOYSA-N 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000005505 thiomorpholino group Chemical group 0.000 claims description 2
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 claims 2
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims 1
- 125000003282 alkyl amino group Chemical group 0.000 claims 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims 1
- 150000003017 phosphorus Chemical class 0.000 claims 1
- 125000005023 xylyl group Chemical group 0.000 claims 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 abstract description 17
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 abstract description 17
- 206010028980 Neoplasm Diseases 0.000 abstract description 10
- 125000003342 alkenyl group Chemical group 0.000 abstract description 7
- 201000011510 cancer Diseases 0.000 abstract description 6
- 201000010099 disease Diseases 0.000 abstract description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 6
- 125000000304 alkynyl group Chemical group 0.000 abstract description 5
- 206010039073 rheumatoid arthritis Diseases 0.000 abstract description 4
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract 3
- 125000004423 acyloxy group Chemical group 0.000 abstract 1
- 125000004414 alkyl thio group Chemical group 0.000 abstract 1
- 125000002837 carbocyclic group Chemical group 0.000 abstract 1
- 125000005647 linker group Chemical group 0.000 abstract 1
- 125000004426 substituted alkynyl group Chemical group 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 210
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 177
- 239000000203 mixture Substances 0.000 description 176
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 144
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 97
- 238000001704 evaporation Methods 0.000 description 97
- 230000008020 evaporation Effects 0.000 description 97
- 239000007787 solid Substances 0.000 description 82
- 238000001914 filtration Methods 0.000 description 79
- 239000000243 solution Substances 0.000 description 76
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 74
- 239000002904 solvent Substances 0.000 description 74
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 72
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 70
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 67
- 239000007858 starting material Substances 0.000 description 61
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 55
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 52
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 48
- 238000010992 reflux Methods 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 43
- 239000000047 product Substances 0.000 description 38
- 239000000284 extract Substances 0.000 description 31
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 28
- 238000004440 column chromatography Methods 0.000 description 27
- 239000011541 reaction mixture Substances 0.000 description 27
- 235000017557 sodium bicarbonate Nutrition 0.000 description 26
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 26
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 24
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 23
- 239000000706 filtrate Substances 0.000 description 22
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 22
- 239000002244 precipitate Substances 0.000 description 22
- 239000003039 volatile agent Substances 0.000 description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 20
- 239000003054 catalyst Substances 0.000 description 20
- 239000012267 brine Substances 0.000 description 19
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 19
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 18
- 238000003756 stirring Methods 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 16
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000012265 solid product Substances 0.000 description 15
- 239000000725 suspension Substances 0.000 description 14
- 239000002585 base Substances 0.000 description 13
- 210000004027 cell Anatomy 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 238000003556 assay Methods 0.000 description 11
- 239000012442 inert solvent Substances 0.000 description 11
- 229910000027 potassium carbonate Inorganic materials 0.000 description 11
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 10
- 239000003102 growth factor Substances 0.000 description 10
- 239000003701 inert diluent Substances 0.000 description 10
- 102000005962 receptors Human genes 0.000 description 10
- 108020003175 receptors Proteins 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- 102000004190 Enzymes Human genes 0.000 description 9
- 108090000790 Enzymes Proteins 0.000 description 9
- 239000005909 Kieselgur Substances 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 229910021529 ammonia Inorganic materials 0.000 description 9
- 229940088598 enzyme Drugs 0.000 description 9
- 239000002198 insoluble material Substances 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 8
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 238000004587 chromatography analysis Methods 0.000 description 8
- 239000010410 layer Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229940050176 methyl chloride Drugs 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000005191 phase separation Methods 0.000 description 8
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 8
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 8
- AFZLCOLNTRPSIF-UHFFFAOYSA-N 5-amino-2-chloro-4-fluorophenol Chemical compound NC1=CC(O)=C(Cl)C=C1F AFZLCOLNTRPSIF-UHFFFAOYSA-N 0.000 description 7
- 241000700159 Rattus Species 0.000 description 7
- 229960000583 acetic acid Drugs 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- YBYRMVIVWMBXKQ-UHFFFAOYSA-N phenylmethanesulfonyl fluoride Chemical compound FS(=O)(=O)CC1=CC=CC=C1 YBYRMVIVWMBXKQ-UHFFFAOYSA-N 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 230000009466 transformation Effects 0.000 description 7
- HEAQOCBITATQEW-UHFFFAOYSA-N 5-amino-4-fluoro-2-methylphenol Chemical compound CC1=CC(F)=C(N)C=C1O HEAQOCBITATQEW-UHFFFAOYSA-N 0.000 description 6
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 241000282414 Homo sapiens Species 0.000 description 6
- 108091000080 Phosphotransferase Proteins 0.000 description 6
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 6
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 230000033115 angiogenesis Effects 0.000 description 6
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 6
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 6
- 229960001701 chloroform Drugs 0.000 description 6
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- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000000583 progesterone congener Substances 0.000 description 1
- 229940095055 progestogen systemic hormonal contraceptives Drugs 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 239000003586 protic polar solvent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 229960004622 raloxifene Drugs 0.000 description 1
- GZUITABIAKMVPG-UHFFFAOYSA-N raloxifene Chemical compound C1=CC(O)=CC=C1C1=C(C(=O)C=2C=CC(OCCN3CCCCC3)=CC=2)C2=CC=C(O)C=C2S1 GZUITABIAKMVPG-UHFFFAOYSA-N 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- BMKDZUISNHGIBY-UHFFFAOYSA-N razoxane Chemical compound C1C(=O)NC(=O)CN1C(C)CN1CC(=O)NC(=O)C1 BMKDZUISNHGIBY-UHFFFAOYSA-N 0.000 description 1
- 229960000460 razoxane Drugs 0.000 description 1
- 230000001850 reproductive effect Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
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- 230000002441 reversible effect Effects 0.000 description 1
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- 238000002390 rotary evaporation Methods 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 1
- 239000004317 sodium nitrate Substances 0.000 description 1
- 235000010344 sodium nitrate Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000000021 stimulant Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- GFYHSKONPJXCDE-UHFFFAOYSA-N sym-collidine Natural products CC1=CN=C(C)C(C)=C1 GFYHSKONPJXCDE-UHFFFAOYSA-N 0.000 description 1
- 229960001603 tamoxifen Drugs 0.000 description 1
- 238000003419 tautomerization reaction Methods 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 150000004579 taxol derivatives Chemical class 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- MWYCVYHWIXZDSN-UHFFFAOYSA-N tert-butyl n-(4-chloro-2,6-difluorophenyl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=C(F)C=C(Cl)C=C1F MWYCVYHWIXZDSN-UHFFFAOYSA-N 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- 229960003604 testosterone Drugs 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 229960003433 thalidomide Drugs 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 229940044693 topoisomerase inhibitor Drugs 0.000 description 1
- 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
- 229960000303 topotecan Drugs 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
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- IHIXIJGXTJIKRB-UHFFFAOYSA-N trisodium vanadate Chemical compound [Na+].[Na+].[Na+].[O-][V]([O-])([O-])=O IHIXIJGXTJIKRB-UHFFFAOYSA-N 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 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
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000004862 vasculogenesis Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- RXPRRQLKFXBCSJ-GIVPXCGWSA-N vincamine Chemical compound C1=CC=C2C(CCN3CCC4)=C5[C@@H]3[C@]4(CC)C[C@](O)(C(=O)OC)N5C2=C1 RXPRRQLKFXBCSJ-GIVPXCGWSA-N 0.000 description 1
- 239000000052 vinegar Substances 0.000 description 1
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- 210000003905 vulva Anatomy 0.000 description 1
- 239000010938 white gold Chemical class 0.000 description 1
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- 238000010626 work up procedure Methods 0.000 description 1
- 230000029663 wound healing Effects 0.000 description 1
- 239000012991 xanthate Substances 0.000 description 1
Classifications
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Abstract
Description
Claims (1)
- 【特許請求の範囲】 1.以下の式Iのキナゾリン誘導体およびその塩: [ここで: Zは、-O-、-NH-または-S-を表す(mは1〜5の整数、ただしZが-NH-の場合、mは3 〜5の整数である); R1は、水素、ヒドロキシ、ハロゲノ、ニトロ、トリフルオロメチル、シアノC1 〜 3 アルキル、C1 〜3アルコキシ、C1 〜3アルキルチオ、または-NR5R6を表す(ここ で、R5およびR6は、同じであっても異なってもよく、それぞれ、水素またはC1 〜 3 アルキルを表す); R2は、水素、ヒドロキシ、ハロゲノ、メトキシ、アミノ、またはニトロを表す; R3は、ヒドロキシ、ハロゲノ、C1 〜3アルキル、C1 〜3アルコキシ、C1 〜3アルカ ノイルオキシ、トリフルオロメチル、シアノ、アミノまたはニトロを表す; X1は、-O-、-CH2-、-S-、-SO−、-SO2-、-NR7、-NR8CO-、-CONR9-、-SO2NR10-、 または-NR11SO2−を表す(ここで、R7、R8、R9、R10およびR11は、それぞれ、水 素、C1 〜3アルキルまたはC1 〜3アルコキシC2 〜3アルキルを表す); R4は、以下の7つの群の1つから選択される: 1)水素、C1 〜5アルキル、C1 〜5ヒドロキシルアルキル(好ましくはC2 〜5ヒド ロキシルアルキル)、C1 〜5フルオロアルキル、C1 〜5アミノアルキル; 2)Cl 〜5アルキルX2COR12(ここでX2は、-O-または-NR13-(ここでR13は、水素 、C1 〜3アルキルまたはC1 〜3アルコキシC2 〜3アルキルを表す)を表し、R12は、 C1 〜3アルキル、-NR14R15または-OR16を表す(ここで、R14、R15およびR16は、 同じであっても異なってもよく、それぞれ水素、C1 〜3アルキルまたはC1 〜3アル コキシC2 〜3アルキルを表す); 3)C1 〜5アルキルX3R17(ここで、X3は、-O-、-S-、-SO-、-SO2-、-OCO-、-NR1 8 CO-、-CONR19-、-SO2NR20-、-NR21SO2-または-NR22-を表し(ここで、R18、R19 、R20、R21およびR22は、それぞれ独立して、水素、C1 〜3アルキルまたはC1 〜3 アルコキシC2 〜3アルキルを表す)、R17は、水素、C1 〜3アルキル、シクロペン チル、シクロヘキシル、または0、SおよびNから独立して選択される1個または2 個のヘテロ原子を有する5員または6員飽和ヘテロ環式基を表し、該C1 〜3アルキ ル基は、オキソ、ヒドロキシ、ハロゲノおよびC1 〜4アルコキシから選択される1 個または2個の置換基を有し得、そして、該環式基は、オキソ、ヒドロキシ、ハ ロゲノ、C1 〜4アルキル、C1 〜4ヒドロキシアルキルおよびC1 〜4アルコキシから 選択される1個または2個の置換基を有し得る); 4)C1 〜5アルキルR23(ここで、R23は、0、SおよびNから独立して選択される1 個または2個のヘテロ原子を有する5員または6員飽和ヘテロ環式基であり、該ヘ テロ環式基は、オキソ、ヒドロキシ、ハロゲノ、C1 〜4アルキル、C1 〜4ヒドロキ シルアルキルおよびC1 〜4アルコキシから選択される1個または2個の置換基を有 し得る); 5)C2 〜5アルケニルR23(ここで、R23は、上記で定義された通りである); 6)C2 〜5アルキニルR23(ここで、R23は、上記で定義された通りである);お よび 7)C1 〜5アルキルX4C1 〜5アルキルX5R24(ここで、X4およびX5は、同じであっ ても異なってもよく、各々、-O-、-S-、-SO-、-SO2-、-NR25CO-、-CONR26-、-SO2 NR27-、-NR28SO2-または-NR29-を表し(ここで、R25、R26、R27、R28およびR29 は、それぞれ独立して、水素、C1 〜3アルキルまたはC1 〜3アルコキシC2 〜3アル キルを表す)、およびR24は、水素またはC1 〜3アルキルを表す)]。 2.請求項1に記載のキナゾリン誘導体であって、R1が、水素、ヒドロキシ、シ アノ、ニトロ、トリフルオロメチル、メチル、エチル、メトキシまたはエトキシ である、キナゾリン誘導体。 3.請求項1または請求項2に記載のキナゾリン誘導体であって、R2が水素であ る、キナゾリン誘導体。 4.請求項1〜3のいずれか1項に記載のキナゾリン誘導体であって、(R3)mを 有するフェニル基が、以下の式IIである、キナゾリン誘導体: (ここで、 Raは、水素、メチル、フルオロまたはクロロを表す; Rbは、水素、メチル、メトキシ、ブロモ、フルオロまたはクロロを表す; Rcは、水素またはヒドロキシを表す;および Rdは、水素、フルオロまたはクロロを表す。 5.請求項1〜4のいずれか1項に記載のキナゾリン誘導体であって、ZがNHで ある、キナゾリン誘導体。 6.請求項1〜5のいずれか1項に記載のキナゾリン誘導体であって、X1が-O- 、-S-、-NR8CO-、-NR11SO2-(ここで、R8およびR11は、それぞれ独立して、水素 、またはC1 〜2アルキルを表す)またはNHを表す、キナゾリン誘導体。 7.請求項1〜6のいずれか1項に記載のキナゾリン誘導体であって、R4が、以 下の9つの群の1つから選択される、キナゾリン誘導体: 1)C1 〜5アルキル、C2 〜5ヒドロキシルアルキル、C1 〜5フルオロアルキル、C2 〜4 アミノアルキル; 2)C2 〜3アルキルX2COR12(ここでX2は、請求項1で定義されたものであり、R1 2 は、C1 〜3アルキル、-NR14R15または-OR16を表す(ここで、R14、R15およびR16 は、同じであっても異なってもよく、それぞれC1 〜2アルキルまたはC1 〜2アルコ キシエチルである); 3)C2 〜4アルキルX3R17(ここで、X3は、請求項1で定義されたものであり、R1 7 は、C1 〜3アルキル、シクロペンチル、シクロヘキシル、ピロリジニルおよびピ ペリジニルから選択される基であり、この基は、炭素原子を介してX3に連結され 、そして該C1 〜3アルキル基は、オキソ、ヒドロキシ、ハロゲノおよびC1 〜2アル コキシから選択される1個または2個の置換基を有し得、該シクロペンチル、シク ロヘキシル、ピロリジニルおよびピペリジニル基は、オキソ、ヒドロキシ、ハロ ゲノ、C1 〜2アルキル、C1 〜2ヒドロキシルアルキルおよびC1 〜2アルコキシから 選択される1個または2個の置換基を有し得る); 4)C1 〜4アルキルR30(ここで、R30は、ピロリジニル、ピペラジニル、ピペリ ジニル、1,3-ジオキソラン-2-イル、1,3-ジオキサン-2-イル、1,3-ジチオラン-2 -イルおよび1,3-ジチアン-2-イルであり、該基は、炭素原子を介して、C1 〜4ア ルキルに連結し、および該基は、オキソ、ヒドロキシ、ハロゲノ、C1 〜2アルキ ル、C1 〜2ヒドロキシルアルキルおよびC1 〜2アルコキシから選択される1個また は2個の置換基を有し得る)またはC2 〜4アルキルR31(ここで、R31は、モルホリ ノ、チオモルホリノ、ピロリジン-1-イル、ピペラジン-1-イルおよびビペリジノ であり、該基は、オキソ、ヒドロキシ、ハロゲノ、C1 〜2アルキル、C1 〜2ヒドロ キシルアルキルおよびC1 〜2アルコキシから選択される1個または2個の置換基を 有し得る); 5)C3 〜4アルケニルR30(ここで、R30は、上記で定義された通りである); 6)C3 〜4アルキニルR30(ここで、R30は、上記で定義された通りである); 7)C3 〜4アルケニルR31(ここで、R31は、上記で定義された通りである); 8)C3 〜4アルキニルR31(ここで、R31は、上記で定義された通りである);お よび 9)C2 〜3アルキルX4C2 〜3アルキルX5R24(ここで、X4およびX5は、請求項1で 定義されたものであり、R24は、水素またはC1 〜3アルキルを表す)]。 8.請求項1〜7のいずれか1項に記載のキナゾリン誘導体であって、R4が、以 下の5つの群の1つから選択される、キナゾリン誘導体: 1)C1 〜3アルキル、C2 〜3ヒドロキシルアルキル、C1 〜3フルオロアルキル、C2 〜3 アミノアルキル; 2)2-(3,3-ジメチルウレイド)エチル、3-(3,3-ジメチルウレイド)プロピル、2- (3-メチルウレイド)エチル、3-(3-メチルウレイド)プロピル、2-ウレイドエチル 、3-ウレイドプロピル、2-(N,N-ジメチルカルバモイルオキシ)エチル、3-(N,N- ジメチルカルバモイルオキシ)プロピル、2-(N-メチルカルバモイルオキシ)エチ ル、3-(N-メチルカルバモイルオキシ)プロピル、2-(カルバモイルオキシ)エチル 、3-(カルバモイルオキシ)プロピル; 3)C2 〜3アルキルX3R17(ここで、X3は、請求項1で定義されたものであり、R1 7 は、C1 〜2アルキル、シクロペンチル、シクロヘキシル、ピロリジニルおよびピ ペリジニルから選択される基であり、この基は、炭素原子を介してX3に連結され 、そして、該C1 〜2アルキル基は、ヒドロキシ、ハロゲノおよびC1 〜2アルコキシ から選択される1個または2個の置換基を有し得、該シクロペンチル、シクロヘ キシル、ピロリジニルおよびピペリジニル基は、オキソ、ヒドロキシ、ハロゲノ 、C1 〜2アルキル、C1 〜2ヒドロキシルアルキルおよびC1 〜2アルコキシから選択 される1個の置換基を有し得る); 4)C1 〜2アルキルR30(ここで、R30は、ピロリジニル、ピペラジニル、ピペリ ジニル、1,3-ジオキソラン-2-イル、1,3-ジオキサン-2-イル、1,3-ジチオラン-2 -イルおよび1,3-ジチアン-2-イルであり、該基は、炭素原子を介して、C1 〜2ア ルキルに連結し、かつ該基は、オキソ、ヒドロキシ、ハロゲノ、C1 〜2アルキル 、C1 〜2ヒドロキシルアルキルおよびC1 〜2アルコキシから選択される1個の置換 基を有し得る)またはC2 〜3アルキルR31(ここで、R31は、モルホリノ、チオモ ルホリノ、ピペリジノ、ピロリジン-1-イル、およびピペラジン-1-イルであり、 該基は、オキソ、ヒドロキシ、ハロゲノ、C1 〜2アルキル、C1 〜2ヒドロキシルア ルキルおよびC1 〜 2 アルコキシから選択される1個の置換基を有し得る);および 5)C2 〜3アルキルX4C2 〜3アルキルX5R24(ここで、X4およびX5は、請求項1で 定義されたものであり、R24は、水素またはC1 〜2アルキルを表す)。 9.請求項1〜8のいずれか1項に記載のキナゾリン誘導体であって、R4が以下 を表す、キナゾリン誘導体:メチル、エチル、トリフルオロメチル、2,2,2-トリ フルオロエチル、2-ヒドロキシエチル、3-ヒドロキシプロピル、2-メトキシエチ ル、3-メトキシプロピル、2-(メチルスルフィニル)エチル、2-(メチルスルホニ ル)エチル、2-(N,N-ジメチルスルファモイル)エチル、2-(N-メチルスルファモイ ル)エチル、2-スルファモイルエチル、2-(N,N-ジメチルアミノ)エチル、3-(N,N- ジメチルアミノ)プロピル、2-モルホリノエチル、3-モルホリノプロピル、2-ピ ペリジノエチル、3-ピペリジノプロピル、2-(ピペラジン-1-イル)エチル、3-(ピ ペラジン-1-イル)プロピル、2-(ピロリジン-1-イル)エチル、3-(ピロリジン-1- イル)プロピル、(1,3-ジオキソラン-2-イル)メチル、2-(1,3−ジオキソラン-2- イル)エチル、2-(2-メトキシエチルアミノ)エチル、2-(2-ヒドロキシエチルアミ ノ)エチル、3-(2-メトキシエチルアミノ)プロピル、3-(2-ヒドロキシエチルアミ ノ)プロピル、2-チオモルホリノエチル、3-チオモルホリノプロピル、2-(4-メチ ルピペラジン-1-イル)エチル、3-(4-メチルピペラジン-1-イル)プロピルまたは2 -(2-メトキシエトキシ)エチル。 10.請求項1〜9のいずれか1項に記載のキナゾリン誘導体であって、R4が、以 下を表す、キナゾリン誘導体:2-ヒドロキシエチル、3-ヒドロキシプロピル、2- メトキシエチル、3-メトキシプロピル、2-(メチルスルフィニル)エチル、2-(メ チルスルホニル)エチル、2-(N,N-ジメチルアミノ)エチル、3-(N,N-ジメチルアミ ノ)プロピル、2-モルホリノエチル、3-モルホリノプロピル、2-ピペリジノエチ ル、3-ピペリジノプロピル、2-(ピペラジン-1-イル)エチル、3-(ピペラジン-1- イル)プロピル、2-(ピロリジン-1-イル)エチル、3-(ピロリジン-1-イル)プロピ ル、(1,3-ジオキソラン-2-イル)メチル、2-(1,3-ジオキソラン-2-イル)エチル、 2-(2-メトキシエチルアミノ)エチル、2-(2-ヒドロキシエチルアミノ)エチル、3- (2-メトキシエチルアミノ)プロピル、3-(2-ヒドロキシエチルアミノ)プロピル、 2-チオモルホリノエチル、3-チオモルホリノプロピル、2-(4-メチルピペラジン- 1-イル)エチル、3-(4-メチルピペラジン-1-イル)プロピルまたは2-(2-メトキシ エトキシ)エチル。 11.以下から選ばれる請求項1に記載のキナゾリン誘導体およびそれらの塩: 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-6,7-ジメトキシキナゾリン、4 -(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-6-メトキシ-7-(2-メトキシエト キシ)キナゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-7-メトキシアセトアミドキナ ゾリン、 4-(4-ブロモ-2,6-ジフルオロアニリノ)-6-メトキシ-7-(3-モルホリノプロポキシ )キナゾリン。 12.以下から選ばれる請求項1に記載のキナゾリン誘導体およびそれらの塩: 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-(ピロリジン -1-イル)エトキシ)キナゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-6-メトキシ-7-(2-メチルチオ エトキシ)キナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6,7-ジメトキシキナゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-6-メトキシ-7-(3-モルホリノ プロポキシ)キナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7(2-メトキシエ トキシ)キナゾリン、 7-(2-アセトキシエトキシ)-4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-6- メトキシキナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-モルホリノ エトキシ)キナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-ピペリジノ エトキシ)キナゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-7-(2-メトキシエチルアミノ) キナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-シクロペン チルオキシエトキシ)キナゾリン、 4-(2,4-ジフルオロ-5-ヒドロキシアニリノ)-6,7-ジメトキシキナゾリン、 4-(2,4-ジフルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-メトキシエトキシ )キナゾリン。 13.以下から選ばれる請求項1に記載のキナゾリン誘導体およびそれらの塩: 4-(4-ブロモ-2,6-ジフルオロアニリノ)-6,7-ジメトキシキナゾリン、 4-(4-ブロモ-2-フルオロ-5-ヒドロキシアニリノ)-6,7-ジメトキシキナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-チオモルホ リノエトキシ)キナゾリン、 6,7-ジメトキシ-4-(3-ヒドロキシ-4-メチルフェノキシ)キナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(3-モルホリノ プロポキシ)キナゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-7-(2-ヒドロキシエトキシ)-6- メトキシキナゾリン、 4-(4-クロロ-2-フルオロ-5-ヒドロキシアニリノ)-6-メトキシ-7-(2-(4-メチルピ ペラジン-1-イル)エトキシ)キナゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-7-(2-メトキシエトキシ)キナ ゾリン、 4-(2-フルオロ-5-ヒドロキシ-4-メチルアニリノ)-6-メトキシ-7-(2-(メチルスル フィニル)エトキシ)キナゾリン。 14.請求項1から13のいずれか1項に記載のキナゾリン誘導体であって、薬学的 受容可能な塩の形態であるキナゾリン誘導体。 15.請求項1で定義された式Iのキナゾリン誘導体またはその塩の調製プロセス であって、以下の工程を包含する、プロセス: (a)以下の式IIIの化合物: (ここで、R1、R2、X1およびR4は、請求項1に定義された通りであり、そしてL1 は、置換可能な部分である)と、式IVの化合物: (ここで、Z、R3およびmは、請求項1に定義された通りである)とを反応させ、 該反応により式Iの化合物およびその塩を得る工程; (b)以下の式IIaの基: (ここで、R3およびmは、請求項1に定義された通りである)が、1つ以上のヒ ドロキシ基を有するフェニル基を表す、式Iの化合物およびその塩を調製するた めに、以下の式Vの化合物: (ここで、X1、m,R1、R2、R3、R4およびZは、請求項1に定義された通りであり 、Pは、フェノール性ヒドロキシ保護基を表し、そしてp1は、保護されたヒドロ キシ基の数と等しい1〜5の整数であり、その結果、m-p1は、保護されたヒドロ キシではないR3置換基の数と等しくなる)を脱保護する工程; (c)該置換基X1が-O-、-S-または-NR7-(ここで、R7は、請求項1で定義された ものである)である式Iの化合物およびその塩を調製するために、以下の式VIの 化合物: (ここで、m,X1、R1、R2、R3およびZは、請求項1に定義された通りである)と 、以下の式VIIの化合物: R4-L1 (VII) (ここで、R4は、請求項1に定義された通りであり、そしてL1は、上記に定義さ れた通りである)とを反応させる工程; (d)以下の式VIIIの化合物: (ここで、R1、R2、R3、Zおよびmは、請求項1に定義された通りであり、そして L1は、上記に定義された通りである)と、以下の式IXの化合物: R4-X1-H (IX) (ここで、R4およびX1は、請求項1に定義された通りである)とを反応させる工 程; (e)R4が、C1 〜5アルキルR32[ここで、R32は、以下の4つの群の1つから選択 される: 1)X6C1 〜3アルキル(ここで、X6は、-O-、-S-、-SO2-、-NR33CO-または-NR34S O2-(ここで、R33およびR34は、それぞれ独立して、水素、C1 〜3アルキルまたは C1 〜3アルコキシC2 〜3アルキルである); 2)NR35R36(ここで、R35およびR36は、同じであってもまたは異なってもよく 、各々、水素、C1 〜3アルキルまたはC1 〜3アルコキシC2 〜3アルキルである); 3)X7C1 〜5アルキルX5R24(ここで、X7は、-O-、-S-、-SO2-、-NR37CO-、-NR38 SO2-または-NR39-(ここで、R37、R38およびR39は、それぞれ独立して、水素、C1 〜3 アルキルまたはC1 〜3アルコキシC2 〜3アルキルを表し、X5およびR24は、請 求項1で定義された通りである);および 4)R31(ここで、R31は、1個または2個のヘテロ原子を有する5員または6員飽和 ヘテロ環式基であって、該ヘテロ原子の一方がNであり、そして他方がO、Sおよ びNから独立に選択され、該ヘテロ環式基は、窒素原子を介してC2 〜5アルキルに 連結しており、そして該ヘテロ環式基はオキソ、ヒドロキシ、ハロゲノ、C1 〜4 アルキル、C1 〜4ヒドロキシアルキルおよびC1 〜4アルコキシから選択される1個 または2個の置換基を有し得る)]である式Iの化合物およびその塩を調製する ために、以下の式Xの化合物: (ここで、X1、R1,R2、R3、Zおよびmは、請求項1に定義された通りであり、L1 は本明細書中に定義された通りであり、そしてR40は、C1 〜5アルキルである)と 、以下の式XIの化合物: R32-H (XI) (ここで、R32は、上記に定義された通りである)とを反応させる工程; (f)置換基R1がNR5R6(ここで、R5およびR6の1つまたは両方がC1 〜3アルキル であり、および/または、置換基R4-X1が、アルキルアミノまたはジアルキルア ミノ基である)で表される式Iの化合物およびその塩を調製するために、置換基R1 および/または置換基R4-X1がアミノ基である式Iの化合物と、アルキル化剤と を反応させる工程; (g)置換基R1、R2またはR3の1つ以上がアミノ基であるか、またはR4-X1がアミ ノ 基である式Iの化合物およびその塩を調製するために、キナゾリン環および/また はフェニル環の対応する位置(単数または複数)の置換基(単数または複数)が 、ニトロ基(単数または複数)である、式Iの対応する化合物を還元する工程; そして式Iのキナゾリン誘導体の塩が必要とされる場合、得られた化合物と、酸 または塩基とを反応させ、該反応により所望の塩を得る。 16.薬学的に受容可能な賦形剤またはキャリアと共に、請求項1に定義された通 りである式Iのキナゾリン誘導体またはその薬学的に受容可能な塩を活性成分と して含む、薬学的組成物。 17.抗脈管形成および/または血管透過性を低減する効果を、そのような処置が 必要とされる温血動物において引き起こすための方法であって、該動物に請求項 1に定義された通りである式Iの化合物またはその薬学的に受容可能な塩の有効 量を投与する工程を含む、方法。 18.医薬品として使用するための請求項1から14のいずれか1項に記載のキナゾ リン誘導体。
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Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
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JP2002522535A (ja) * | 1998-08-11 | 2002-07-23 | ノバルティス アクチエンゲゼルシャフト | 血管形成阻害活性を有するイソキノリン誘導体 |
JP2002293773A (ja) * | 2001-03-30 | 2002-10-09 | Sumika Fine Chemicals Co Ltd | キナゾリン誘導体の製造方法 |
JP2005514384A (ja) * | 2001-11-27 | 2005-05-19 | ワイス・ホールディングズ・コーポレイション | Egf−rおよびher2キナーゼの阻害剤としての3−シアノキノリン |
JP2006515871A (ja) * | 2003-01-23 | 2006-06-08 | ティー.ケイ. シグナル リミテッド | 上皮増殖因子受容体チロシンキナーゼの不可逆阻害剤ならびにその使用 |
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