WO1995023141A1 - 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents - Google Patents
4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents Download PDFInfo
- Publication number
- WO1995023141A1 WO1995023141A1 PCT/IB1995/000061 IB9500061W WO9523141A1 WO 1995023141 A1 WO1995023141 A1 WO 1995023141A1 IB 9500061 W IB9500061 W IB 9500061W WO 9523141 A1 WO9523141 A1 WO 9523141A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkoxy
- alkyl
- hydroxy
- mono
- alkylamino
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 128
- 125000002294 quinazolinyl group Chemical class N1=C(N=CC2=CC=CC=C12)* 0.000 title claims description 6
- 239000002246 antineoplastic agent Substances 0.000 title abstract description 7
- 238000002360 preparation method Methods 0.000 title description 41
- 230000008569 process Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 144
- -1 methylene, thio Chemical group 0.000 claims abstract description 119
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 22
- 229920006395 saturated elastomer Polymers 0.000 claims abstract description 20
- 238000011282 treatment Methods 0.000 claims abstract description 20
- 230000003463 hyperproliferative effect Effects 0.000 claims abstract description 14
- 125000000446 sulfanediyl group Chemical group *S* 0.000 claims abstract description 7
- 150000001721 carbon Chemical class 0.000 claims abstract description 5
- 201000010099 disease Diseases 0.000 claims abstract description 5
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 4
- 239000001301 oxygen Substances 0.000 claims abstract description 4
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims abstract description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims abstract description 3
- 229910052717 sulfur Inorganic materials 0.000 claims abstract description 3
- 125000004434 sulfur atom Chemical group 0.000 claims abstract description 3
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 119
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 100
- 125000003282 alkyl amino group Chemical group 0.000 claims description 85
- 125000003545 alkoxy group Chemical group 0.000 claims description 67
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 67
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 47
- 125000005236 alkanoylamino group Chemical group 0.000 claims description 33
- 125000005530 alkylenedioxy group Chemical group 0.000 claims description 33
- 125000000217 alkyl group Chemical group 0.000 claims description 32
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 29
- 206010028980 Neoplasm Diseases 0.000 claims description 25
- 125000005843 halogen group Chemical group 0.000 claims description 25
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 21
- 125000004414 alkyl thio group Chemical group 0.000 claims description 20
- 208000035475 disorder Diseases 0.000 claims description 17
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 16
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 16
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 125000004423 acyloxy group Chemical group 0.000 claims description 14
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 201000011510 cancer Diseases 0.000 claims description 12
- 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 12
- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 12
- 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 10
- 125000005518 carboxamido group Chemical group 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 125000003830 C1- C4 alkylcarbonylamino group Chemical group 0.000 claims description 7
- 241000124008 Mammalia Species 0.000 claims description 7
- 125000004457 alkyl amino carbonyl group Chemical group 0.000 claims description 7
- 125000003368 amide group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004769 (C1-C4) alkylsulfonyl group Chemical group 0.000 claims description 5
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 5
- 125000005115 alkyl carbamoyl group Chemical group 0.000 claims description 5
- 125000000043 benzamido group Chemical group [H]N([*])C(=O)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 229910052799 carbon Inorganic materials 0.000 claims description 5
- 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims description 5
- 125000001462 1-pyrrolyl group Chemical group [*]N1C([H])=C([H])C([H])=C1[H] 0.000 claims description 4
- 210000000481 breast Anatomy 0.000 claims description 4
- 125000001951 carbamoylamino group Chemical group C(N)(=O)N* 0.000 claims description 4
- 125000002861 (C1-C4) alkanoyl group Chemical group 0.000 claims description 3
- 125000004768 (C1-C4) alkylsulfinyl group Chemical group 0.000 claims description 3
- 201000004681 Psoriasis Diseases 0.000 claims description 3
- 125000000033 alkoxyamino group Chemical group 0.000 claims description 3
- 125000004466 alkoxycarbonylamino group Chemical group 0.000 claims description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 claims description 3
- 230000002496 gastric effect Effects 0.000 claims description 3
- 210000004072 lung Anatomy 0.000 claims description 3
- NVOKTPNLFPWRFT-UHFFFAOYSA-N 4-(3,4-dihydro-2h-quinolin-1-yl)quinazoline Chemical compound C1=CC=C2C(N3CCCC4=CC=CC=C43)=NC=NC2=C1 NVOKTPNLFPWRFT-UHFFFAOYSA-N 0.000 claims description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 2
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 claims description 2
- 125000005596 alkyl carboxamido group Chemical group 0.000 claims description 2
- 125000004656 alkyl sulfonylamino group Chemical group 0.000 claims description 2
- 210000004556 brain Anatomy 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 230000002440 hepatic effect Effects 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000003356 phenylsulfanyl group Chemical group [*]SC1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims description 2
- 125000001544 thienyl group Chemical group 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 125000004760 (C1-C4) alkylsulfonylamino group Chemical group 0.000 claims 1
- 201000002510 thyroid cancer Diseases 0.000 claims 1
- 150000003839 salts Chemical class 0.000 abstract description 19
- DRYRBWIFRVMRPV-UHFFFAOYSA-N quinazolin-4-amine Chemical class C1=CC=C2C(N)=NC=NC2=C1 DRYRBWIFRVMRPV-UHFFFAOYSA-N 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 118
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 103
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Substances OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 103
- 238000004128 high performance liquid chromatography Methods 0.000 description 98
- 239000000203 mixture Substances 0.000 description 77
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 64
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 52
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 50
- LLLHRNQLGUOJHP-UHFFFAOYSA-N 4-chloro-6,7-dimethoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OC)C(OC)=CC2=N1 LLLHRNQLGUOJHP-UHFFFAOYSA-N 0.000 description 48
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 48
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 47
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 44
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 42
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 41
- 238000006243 chemical reaction Methods 0.000 description 41
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 37
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 37
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 36
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 34
- 239000000243 solution Substances 0.000 description 33
- 239000012267 brine Substances 0.000 description 32
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 30
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 27
- 239000000377 silicon dioxide Substances 0.000 description 27
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 25
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 24
- HSLNYVREDLDESE-UHFFFAOYSA-N 6-chloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC=C2CCNC2=C1 HSLNYVREDLDESE-UHFFFAOYSA-N 0.000 description 23
- SIKJAQJRHWYJAI-UHFFFAOYSA-N Indole Chemical compound C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 description 23
- 239000012458 free base Substances 0.000 description 23
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 22
- 239000007832 Na2SO4 Substances 0.000 description 22
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 22
- 238000007792 addition Methods 0.000 description 22
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 22
- 235000019439 ethyl acetate Nutrition 0.000 description 22
- 229910052938 sodium sulfate Inorganic materials 0.000 description 22
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 21
- 150000001412 amines Chemical class 0.000 description 20
- 239000002585 base Substances 0.000 description 20
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 20
- 239000007787 solid Substances 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 18
- YKGMKSIHIVVYKY-UHFFFAOYSA-N dabrafenib mesylate Chemical compound CS(O)(=O)=O.S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 YKGMKSIHIVVYKY-UHFFFAOYSA-N 0.000 description 17
- 238000004519 manufacturing process Methods 0.000 description 17
- 239000012074 organic phase Substances 0.000 description 16
- 150000003246 quinazolines Chemical class 0.000 description 15
- 238000010992 reflux Methods 0.000 description 15
- 238000003818 flash chromatography Methods 0.000 description 14
- 230000009467 reduction Effects 0.000 description 14
- 238000006722 reduction reaction Methods 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- 229910000085 borane Inorganic materials 0.000 description 13
- 150000002476 indolines Chemical class 0.000 description 13
- 239000000463 material Substances 0.000 description 13
- LBUJPTNKIBCYBY-UHFFFAOYSA-N 1,2,3,4-tetrahydroquinoline Chemical class C1=CC=C2CCCNC2=C1 LBUJPTNKIBCYBY-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- 239000002253 acid Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 11
- 238000004587 chromatography analysis Methods 0.000 description 11
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 11
- 108060006698 EGF receptor Proteins 0.000 description 10
- 102000001301 EGF receptor Human genes 0.000 description 10
- 229960000583 acetic acid Drugs 0.000 description 10
- 150000002475 indoles Chemical class 0.000 description 10
- 229910000027 potassium carbonate Inorganic materials 0.000 description 10
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 9
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 9
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 229910052749 magnesium Inorganic materials 0.000 description 9
- 239000011777 magnesium Substances 0.000 description 9
- 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 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 239000012442 inert solvent Substances 0.000 description 8
- 239000000543 intermediate Substances 0.000 description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 8
- 238000000746 purification Methods 0.000 description 8
- MYXKPFMQWULLOH-UHFFFAOYSA-M tetramethylazanium;hydroxide;pentahydrate Chemical compound O.O.O.O.O.[OH-].C[N+](C)(C)C MYXKPFMQWULLOH-UHFFFAOYSA-M 0.000 description 8
- 238000010626 work up procedure Methods 0.000 description 8
- QGNCGAHOGVOFOD-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazolin-7-ol Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C2C=C(OC)C(O)=CC2=NC=N1 QGNCGAHOGVOFOD-UHFFFAOYSA-N 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000001816 cooling Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical class N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- SMPZDXOYPKEJKL-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-6-amine Chemical compound C1CC2=CC=C(N)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 SMPZDXOYPKEJKL-UHFFFAOYSA-N 0.000 description 6
- MZBVNYACSSGXID-UHFFFAOYSA-N 2,3,4,5-tetrahydro-1h-1-benzazepine Chemical class N1CCCCC2=CC=CC=C21 MZBVNYACSSGXID-UHFFFAOYSA-N 0.000 description 6
- MPCXQPXCYDDJSR-UHFFFAOYSA-N 2,3-dihydro-1h-indol-5-ol Chemical compound OC1=CC=C2NCCC2=C1 MPCXQPXCYDDJSR-UHFFFAOYSA-N 0.000 description 6
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-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
- 238000005917 acylation reaction Methods 0.000 description 6
- 150000002391 heterocyclic compounds Chemical class 0.000 description 6
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 description 6
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 description 6
- 230000002829 reductive effect Effects 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- 238000012360 testing method Methods 0.000 description 6
- KCPPEUHIFWSTDV-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-7-ol Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(O)=CC=C21 KCPPEUHIFWSTDV-UHFFFAOYSA-N 0.000 description 5
- 230000004913 activation Effects 0.000 description 5
- 230000010933 acylation Effects 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 125000002947 alkylene group Chemical group 0.000 description 5
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 238000010790 dilution Methods 0.000 description 5
- 239000012895 dilution Substances 0.000 description 5
- 230000001404 mediated effect Effects 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 5
- AOJFQRQNPXYVLM-UHFFFAOYSA-N pyridin-1-ium;chloride Chemical compound [Cl-].C1=CC=[NH+]C=C1 AOJFQRQNPXYVLM-UHFFFAOYSA-N 0.000 description 5
- 239000011541 reaction mixture Substances 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 150000003512 tertiary amines Chemical class 0.000 description 5
- 238000011200 topical administration Methods 0.000 description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- YZUPZGFPHUVJKC-UHFFFAOYSA-N 1-bromo-2-methoxyethane Chemical compound COCCBr YZUPZGFPHUVJKC-UHFFFAOYSA-N 0.000 description 4
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 4
- GUQZHZBMDPEBQG-UHFFFAOYSA-N 4-chloro-7-methoxyquinazoline Chemical compound ClC1=NC=NC2=CC(OC)=CC=C21 GUQZHZBMDPEBQG-UHFFFAOYSA-N 0.000 description 4
- LMIQERWZRIFWNZ-UHFFFAOYSA-N 5-hydroxyindole Chemical compound OC1=CC=C2NC=CC2=C1 LMIQERWZRIFWNZ-UHFFFAOYSA-N 0.000 description 4
- SVNDSMLMPVHWET-UHFFFAOYSA-N 6-bromo-5-fluoro-2,3-dihydro-1h-indole Chemical compound C1=C(Br)C(F)=CC2=C1NCC2 SVNDSMLMPVHWET-UHFFFAOYSA-N 0.000 description 4
- ANGRSSWNBDJESO-UHFFFAOYSA-N 6-chloro-5-fluoro-1h-indole Chemical compound C1=C(Cl)C(F)=CC2=C1NC=C2 ANGRSSWNBDJESO-UHFFFAOYSA-N 0.000 description 4
- GYHSHGUXLJLVAR-UHFFFAOYSA-N 6-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=C2CCNC2=C1 GYHSHGUXLJLVAR-UHFFFAOYSA-N 0.000 description 4
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 4
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 4
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 150000008064 anhydrides Chemical class 0.000 description 4
- 230000001093 anti-cancer Effects 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000012298 atmosphere Substances 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- 239000006260 foam Substances 0.000 description 4
- 235000019253 formic acid Nutrition 0.000 description 4
- 239000003701 inert diluent Substances 0.000 description 4
- 230000002401 inhibitory effect Effects 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 238000004007 reversed phase HPLC Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- 230000004614 tumor growth Effects 0.000 description 4
- VTIJFGNTDHLPLT-UHFFFAOYSA-N 1,2,3,4,5,6-hexahydro-1-benzazocine Chemical class C1CCCCNC2=CC=CC=C21 VTIJFGNTDHLPLT-UHFFFAOYSA-N 0.000 description 3
- BXUFOZCNXCIAOU-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-5-amine Chemical compound C1CC2=CC(N)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 BXUFOZCNXCIAOU-UHFFFAOYSA-N 0.000 description 3
- OISVCGZHLKNMSJ-UHFFFAOYSA-N 2,6-dimethylpyridine Chemical compound CC1=CC=CC(C)=N1 OISVCGZHLKNMSJ-UHFFFAOYSA-N 0.000 description 3
- OQZGYMRYZAKXAF-UHFFFAOYSA-N 2-(4-methylcyclohexyl)acetic acid Chemical compound CC1CCC(CC(O)=O)CC1 OQZGYMRYZAKXAF-UHFFFAOYSA-N 0.000 description 3
- RQFUZUMFPRMVDX-UHFFFAOYSA-N 3-Bromo-1-propanol Chemical compound OCCCBr RQFUZUMFPRMVDX-UHFFFAOYSA-N 0.000 description 3
- UFQUHTJSQABMJT-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-amine;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC=C(N)C=C21 UFQUHTJSQABMJT-UHFFFAOYSA-N 0.000 description 3
- NYIKWKLLJXJXDP-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-7-amine;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(N)=CC=C21 NYIKWKLLJXJXDP-UHFFFAOYSA-N 0.000 description 3
- NIKLQGXXRCUBMF-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)quinazoline-6,7-diol Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(O)=C2)O)C2=NC=N1 NIKLQGXXRCUBMF-UHFFFAOYSA-N 0.000 description 3
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- YYDYAQAVAHKFJO-UHFFFAOYSA-N 5-methoxy-2,3-dihydro-1h-indole Chemical compound COC1=CC=C2NCCC2=C1 YYDYAQAVAHKFJO-UHFFFAOYSA-N 0.000 description 3
- WHPDSANSNOUOLZ-UHFFFAOYSA-N 7-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=CC2=C1NCC2 WHPDSANSNOUOLZ-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 3
- 101710098940 Pro-epidermal growth factor Proteins 0.000 description 3
- JXDYKVIHCLTXOP-UHFFFAOYSA-N Pseudoisatin Natural products C1=CC=C2C(=O)C(=O)NC2=C1 JXDYKVIHCLTXOP-UHFFFAOYSA-N 0.000 description 3
- 230000001594 aberrant effect Effects 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 3
- 125000005422 alkyl sulfonamido group Chemical group 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000005804 alkylation reaction Methods 0.000 description 3
- 150000001540 azides Chemical class 0.000 description 3
- 230000031709 bromination Effects 0.000 description 3
- 238000005893 bromination reaction Methods 0.000 description 3
- 238000003776 cleavage reaction Methods 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004108 freeze drying Methods 0.000 description 3
- 230000014509 gene expression Effects 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000007800 oxidant agent Substances 0.000 description 3
- 150000005623 oxindoles Chemical class 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 238000006366 phosphorylation reaction Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 3
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 230000009466 transformation Effects 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 2
- OYMRVJNKFVSSSB-UHFFFAOYSA-N 1,5,6,7-tetrahydropyrrolo[2,3-f]indole Chemical compound C1=C2NCCC2=CC2=C1C=CN2 OYMRVJNKFVSSSB-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CZFOYGSZBXDBMB-UHFFFAOYSA-N 2-(2,3-dihydro-1h-indol-6-yl)ethynyl-trimethylsilane Chemical compound C[Si](C)(C)C#CC1=CC=C2CCNC2=C1 CZFOYGSZBXDBMB-UHFFFAOYSA-N 0.000 description 2
- LKMJVFRMDSNFRT-UHFFFAOYSA-N 2-(methoxymethyl)oxirane Chemical compound COCC1CO1 LKMJVFRMDSNFRT-UHFFFAOYSA-N 0.000 description 2
- HFCIPEPMYJVMPM-UHFFFAOYSA-N 2-[1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-6-yl]ethynyl-trimethylsilane Chemical compound C1CC2=CC=C(C#C[Si](C)(C)C)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 HFCIPEPMYJVMPM-UHFFFAOYSA-N 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 2
- PRUNKYDDEIQDCT-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 PRUNKYDDEIQDCT-UHFFFAOYSA-N 0.000 description 2
- FRANIBSSJDMDAX-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-nitroquinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC([N+](=O)[O-])=CC=C21 FRANIBSSJDMDAX-UHFFFAOYSA-N 0.000 description 2
- HJLHWYRHMKUZAT-UHFFFAOYSA-N 4-(6-chloro-5-nitro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC([N+]([O-])=O)=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 HJLHWYRHMKUZAT-UHFFFAOYSA-N 0.000 description 2
- KVCQTKNUUQOELD-UHFFFAOYSA-N 4-amino-n-[1-(3-chloro-2-fluoroanilino)-6-methylisoquinolin-5-yl]thieno[3,2-d]pyrimidine-7-carboxamide Chemical compound N=1C=CC2=C(NC(=O)C=3C4=NC=NC(N)=C4SC=3)C(C)=CC=C2C=1NC1=CC=CC(Cl)=C1F KVCQTKNUUQOELD-UHFFFAOYSA-N 0.000 description 2
- BPSAXYWIOCKHEM-UHFFFAOYSA-N 4-bromo-7-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=C(Br)C2=C1NCC2 BPSAXYWIOCKHEM-UHFFFAOYSA-N 0.000 description 2
- MREJJMASIQVOTH-UHFFFAOYSA-N 4-chloro-6-methoxyquinazoline Chemical compound N1=CN=C(Cl)C2=CC(OC)=CC=C21 MREJJMASIQVOTH-UHFFFAOYSA-N 0.000 description 2
- JKCVBHBAFRJIKA-UHFFFAOYSA-N 6,7-dimethyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=C2CCNC2=C1C JKCVBHBAFRJIKA-UHFFFAOYSA-N 0.000 description 2
- JCTUCTVNFGEPHV-UHFFFAOYSA-N 6-bromo-7-methyl-2,3-dihydro-1h-indole Chemical compound C1=C(Br)C(C)=C2NCCC2=C1 JCTUCTVNFGEPHV-UHFFFAOYSA-N 0.000 description 2
- ZSLWUFKUPMDLQT-UHFFFAOYSA-N 6-chloro-1h-indol-5-ol Chemical compound C1=C(Cl)C(O)=CC2=C1NC=C2 ZSLWUFKUPMDLQT-UHFFFAOYSA-N 0.000 description 2
- RVYDZMQIYQISAU-UHFFFAOYSA-N 6-chloro-5-fluoro-2,3-dihydro-1h-indole Chemical compound C1=C(Cl)C(F)=CC2=C1NCC2 RVYDZMQIYQISAU-UHFFFAOYSA-N 0.000 description 2
- HTTPYSPFYDKFME-UHFFFAOYSA-N 6-chloro-5-nitro-2,3-dihydro-1h-indole Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1NCC2 HTTPYSPFYDKFME-UHFFFAOYSA-N 0.000 description 2
- KGCBZEKELZUOFI-UHFFFAOYSA-N 6-iodo-2,3-dihydro-1h-indole Chemical compound IC1=CC=C2CCNC2=C1 KGCBZEKELZUOFI-UHFFFAOYSA-N 0.000 description 2
- WQRHSWCFMVUMEH-UHFFFAOYSA-N 6-methyl-1h-indol-5-ol Chemical compound C1=C(O)C(C)=CC2=C1C=CN2 WQRHSWCFMVUMEH-UHFFFAOYSA-N 0.000 description 2
- BVWMQZXXXWEDOY-UHFFFAOYSA-N 8-bromo-2,3,4,5-tetrahydro-1h-1-benzazepine Chemical compound C1CCCNC2=CC(Br)=CC=C21 BVWMQZXXXWEDOY-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- VOPWNXZWBYDODV-UHFFFAOYSA-N Chlorodifluoromethane Chemical compound FC(F)Cl VOPWNXZWBYDODV-UHFFFAOYSA-N 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229910004373 HOAc Inorganic materials 0.000 description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N Lactic Acid Natural products CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 108700020796 Oncogene Proteins 0.000 description 2
- NFHFRUOZVGFOOS-UHFFFAOYSA-N Pd(PPh3)4 Substances [Pd].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.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 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 2
- KFSLWBXXFJQRDL-UHFFFAOYSA-N Peracetic acid Chemical compound CC(=O)OO KFSLWBXXFJQRDL-UHFFFAOYSA-N 0.000 description 2
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- 150000008065 acid anhydrides Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 125000003342 alkenyl group Chemical group 0.000 description 2
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 2
- 125000000746 allylic group Chemical group 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 239000000872 buffer Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 description 2
- 229960002327 chloral hydrate Drugs 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- XLJMAIOERFSOGZ-UHFFFAOYSA-M cyanate Chemical compound [O-]C#N XLJMAIOERFSOGZ-UHFFFAOYSA-M 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 2
- 206010020718 hyperplasia Diseases 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- PHTQWCKDNZKARW-UHFFFAOYSA-N isoamylol Chemical compound CC(C)CCO PHTQWCKDNZKARW-UHFFFAOYSA-N 0.000 description 2
- 239000012948 isocyanate Substances 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 229910052744 lithium Inorganic materials 0.000 description 2
- 229910003002 lithium salt Inorganic materials 0.000 description 2
- 159000000002 lithium salts Chemical class 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000003211 malignant effect Effects 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- VOKXPKSMYJLAIW-UHFFFAOYSA-N nickel;phosphane Chemical compound P.[Ni] VOKXPKSMYJLAIW-UHFFFAOYSA-N 0.000 description 2
- 150000002828 nitro derivatives Chemical class 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 230000002611 ovarian Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000026731 phosphorylation Effects 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 239000008057 potassium phosphate buffer Substances 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 230000002062 proliferating effect Effects 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000001959 radiotherapy Methods 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 229910052709 silver Inorganic materials 0.000 description 2
- 239000004332 silver Substances 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- 239000012279 sodium borohydride Substances 0.000 description 2
- 229910000033 sodium borohydride Inorganic materials 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 2
- JVBXVOWTABLYPX-UHFFFAOYSA-L sodium dithionite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])=O JVBXVOWTABLYPX-UHFFFAOYSA-L 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000000547 substituted alkyl group Chemical group 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000002560 therapeutic procedure Methods 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- CWMFRHBXRUITQE-UHFFFAOYSA-N trimethylsilylacetylene Chemical group C[Si](C)(C)C#C CWMFRHBXRUITQE-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 2
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- VCGRFBXVSFAGGA-UHFFFAOYSA-N (1,1-dioxo-1,4-thiazinan-4-yl)-[6-[[3-(4-fluorophenyl)-5-methyl-1,2-oxazol-4-yl]methoxy]pyridin-3-yl]methanone Chemical compound CC=1ON=C(C=2C=CC(F)=CC=2)C=1COC(N=C1)=CC=C1C(=O)N1CCS(=O)(=O)CC1 VCGRFBXVSFAGGA-UHFFFAOYSA-N 0.000 description 1
- ZJIFDEVVTPEXDL-UHFFFAOYSA-N (2,5-dioxopyrrolidin-1-yl) hydrogen carbonate Chemical compound OC(=O)ON1C(=O)CCC1=O ZJIFDEVVTPEXDL-UHFFFAOYSA-N 0.000 description 1
- PDELQDSYLBLPQO-SFYZADRCSA-N (3ar,7as)-2,3,3a,4,5,6,7,7a-octahydro-1h-indole Chemical compound C1CCC[C@@H]2NCC[C@H]21 PDELQDSYLBLPQO-SFYZADRCSA-N 0.000 description 1
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 1
- LVVKDLVKFCTWQZ-UHFFFAOYSA-N 1,2,3,5,6,7-hexahydropyrrolo[2,3-f]indole Chemical compound C1=C2NCCC2=CC2=C1CCN2 LVVKDLVKFCTWQZ-UHFFFAOYSA-N 0.000 description 1
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 1
- ULTHEAFYOOPTTB-UHFFFAOYSA-N 1,4-dibromobutane Chemical compound BrCCCCBr ULTHEAFYOOPTTB-UHFFFAOYSA-N 0.000 description 1
- WSDUFDGEYKOQRT-UHFFFAOYSA-N 1-(5-amino-2,3-dihydroindol-1-yl)ethanone Chemical compound NC1=CC=C2N(C(=O)C)CCC2=C1 WSDUFDGEYKOQRT-UHFFFAOYSA-N 0.000 description 1
- ASSANMZAXCPJPA-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-2,3,4,5-tetrahydro-1-benzazepine Chemical compound C1CCCC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 ASSANMZAXCPJPA-UHFFFAOYSA-N 0.000 description 1
- MACYQIQHBYKJNO-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-5-amine;hydrochloride Chemical compound Cl.C1CC2=CC(N)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 MACYQIQHBYKJNO-UHFFFAOYSA-N 0.000 description 1
- ZBZILFITUDUOOO-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-3,5,6,7-tetrahydro-2h-pyrrolo[2,3-f]indole Chemical compound C1CC2=CC=3NCCC=3C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 ZBZILFITUDUOOO-UHFFFAOYSA-N 0.000 description 1
- VCLCCKCSJBNJNE-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-6,7-dimethyl-2,3-dihydroindol-5-ol;hydrochloride Chemical compound Cl.C1CC2=CC(O)=C(C)C(C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 VCLCCKCSJBNJNE-UHFFFAOYSA-N 0.000 description 1
- NEWSFLBRJXXFKO-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-6-methyl-2,3-dihydroindol-5-ol Chemical compound C1CC2=CC(O)=C(C)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 NEWSFLBRJXXFKO-UHFFFAOYSA-N 0.000 description 1
- VWKDFRUOIHSPAO-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-7-methyl-2,3-dihydroindol-5-ol Chemical compound C1CC2=CC(O)=CC(C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 VWKDFRUOIHSPAO-UHFFFAOYSA-N 0.000 description 1
- YANFWVCJZZESAN-UHFFFAOYSA-N 1-(6,7-dimethoxyquinazolin-4-yl)-n-octan-2-yl-2,3-dihydroindol-5-amine Chemical compound COC1=C(OC)C=C2C(N3C4=CC=C(C=C4CC3)NC(C)CCCCCC)=NC=NC2=C1 YANFWVCJZZESAN-UHFFFAOYSA-N 0.000 description 1
- LOZKZWIQDVEDCQ-UHFFFAOYSA-N 1-(6-amino-2,3-dihydroindol-1-yl)ethanone Chemical compound C1=C(N)C=C2N(C(=O)C)CCC2=C1 LOZKZWIQDVEDCQ-UHFFFAOYSA-N 0.000 description 1
- QYOUFIOXEFUHAU-UHFFFAOYSA-N 1-(6-iodo-2,3-dihydroindol-1-yl)ethanone Chemical compound C1=C(I)C=C2N(C(=O)C)CCC2=C1 QYOUFIOXEFUHAU-UHFFFAOYSA-N 0.000 description 1
- ABDDQTDRAHXHOC-QMMMGPOBSA-N 1-[(7s)-5,7-dihydro-4h-thieno[2,3-c]pyran-7-yl]-n-methylmethanamine Chemical compound CNC[C@@H]1OCCC2=C1SC=C2 ABDDQTDRAHXHOC-QMMMGPOBSA-N 0.000 description 1
- SOGXTCTZOFKAHA-UHFFFAOYSA-N 1-bromo-2,3-dihydroindole Chemical class C1=CC=C2N(Br)CCC2=C1 SOGXTCTZOFKAHA-UHFFFAOYSA-N 0.000 description 1
- CVRVKLXIONFLIR-UHFFFAOYSA-N 1-iodo-2,3-dihydroindole Chemical compound C1=CC=C2N(I)CCC2=C1 CVRVKLXIONFLIR-UHFFFAOYSA-N 0.000 description 1
- LYUPJHVGLFETDG-UHFFFAOYSA-N 1-phenylbutan-2-ol Chemical compound CCC(O)CC1=CC=CC=C1 LYUPJHVGLFETDG-UHFFFAOYSA-N 0.000 description 1
- DRBYPARXYQPKKA-UHFFFAOYSA-N 2,3,6,7,8,9-hexahydro-1h-benzo[g]indole Chemical compound C1CCCC2=C(NCC3)C3=CC=C21 DRBYPARXYQPKKA-UHFFFAOYSA-N 0.000 description 1
- GRPOFAKYHPAXNP-UHFFFAOYSA-N 2,3-dihydro-1h-indol-2-ylmethanol Chemical compound C1=CC=C2NC(CO)CC2=C1 GRPOFAKYHPAXNP-UHFFFAOYSA-N 0.000 description 1
- VVAKEQGKZNKUSU-UHFFFAOYSA-N 2,3-dimethylaniline Chemical compound CC1=CC=CC(N)=C1C VVAKEQGKZNKUSU-UHFFFAOYSA-N 0.000 description 1
- VHJKDOLGYMULOP-UHFFFAOYSA-N 2-(2,4-dichlorophenyl)ethanamine Chemical compound NCCC1=CC=C(Cl)C=C1Cl VHJKDOLGYMULOP-UHFFFAOYSA-N 0.000 description 1
- QRWRJDVVXAXGBT-UHFFFAOYSA-N 2-Methylindoline Chemical compound C1=CC=C2NC(C)CC2=C1 QRWRJDVVXAXGBT-UHFFFAOYSA-N 0.000 description 1
- DGJGMQYSVTUKRU-UHFFFAOYSA-N 2-[4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazolin-7-yl]oxyethyl methanesulfonate Chemical class C1CC2=CC=C(Cl)C=C2N1C1=C2C=C(OC)C(OCCOS(C)(=O)=O)=CC2=NC=N1 DGJGMQYSVTUKRU-UHFFFAOYSA-N 0.000 description 1
- QPXHTHQQRGQFNM-UHFFFAOYSA-N 2-[4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazolin-7-yl]oxypropyl methanesulfonate Chemical class C1CC2=CC=C(Cl)C=C2N1C1=C2C=C(OC)C(OC(C)COS(C)(=O)=O)=CC2=NC=N1 QPXHTHQQRGQFNM-UHFFFAOYSA-N 0.000 description 1
- UHGZSFSCMFWPKU-UHFFFAOYSA-N 2-[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]oxyethanol;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OCCO)=CC=C21 UHGZSFSCMFWPKU-UHFFFAOYSA-N 0.000 description 1
- QNRCNSFCIAACAT-UHFFFAOYSA-N 2-[4-[3-[3-(dimethylamino)propyl]-3,5,6,7-tetrahydro-2h-pyrrolo[2,3-f]indol-1-yl]-7-(2-hydroxyethoxy)quinazolin-6-yl]oxyethanol Chemical compound OCCOC1=C(OCCO)C=C2C(N3CC(C4=CC=5NCCC=5C=C43)CCCN(C)C)=NC=NC2=C1 QNRCNSFCIAACAT-UHFFFAOYSA-N 0.000 description 1
- KHEXFYAHBTWVBL-UHFFFAOYSA-N 2-[6-chloro-1-(2,2-dimethyl-[1,3]dioxolo[4,5-g]quinazolin-8-yl)-2,3-dihydroindol-3-yl]-n,n-diethylethanamine Chemical compound C1=C2C(N3CC(C4=CC=C(Cl)C=C43)CCN(CC)CC)=NC=NC2=CC2=C1OC(C)(C)O2 KHEXFYAHBTWVBL-UHFFFAOYSA-N 0.000 description 1
- AMSDWLOANMAILF-UHFFFAOYSA-N 2-imidazol-1-ylethanol Chemical compound OCCN1C=CN=C1 AMSDWLOANMAILF-UHFFFAOYSA-N 0.000 description 1
- XWKFPIODWVPXLX-UHFFFAOYSA-N 2-methyl-5-methylpyridine Natural products CC1=CC=C(C)N=C1 XWKFPIODWVPXLX-UHFFFAOYSA-N 0.000 description 1
- YRLORWPBJZEGBX-UHFFFAOYSA-N 3,4-dihydro-2h-1,4-benzoxazine Chemical class C1=CC=C2NCCOC2=C1 YRLORWPBJZEGBX-UHFFFAOYSA-N 0.000 description 1
- AKRDSDDYNMVKCX-UHFFFAOYSA-N 3,5-dimethylpyrazole-1-carboxamide Chemical compound CC=1C=C(C)N(C(N)=O)N=1 AKRDSDDYNMVKCX-UHFFFAOYSA-N 0.000 description 1
- XMFBFMKDNYZGCS-UHFFFAOYSA-N 3-(2,3-dihydro-1h-indol-3-yl)-n,n-dimethylpropan-1-amine Chemical compound C1=CC=C2C(CCCN(C)C)CNC2=C1 XMFBFMKDNYZGCS-UHFFFAOYSA-N 0.000 description 1
- HCDMJFOHIXMBOV-UHFFFAOYSA-N 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-4,7-dihydropyrrolo[4,5]pyrido[1,2-d]pyrimidin-2-one Chemical compound C=1C2=C3N(CC)C(=O)N(C=4C(=C(OC)C=C(OC)C=4F)F)CC3=CN=C2NC=1CN1CCOCC1 HCDMJFOHIXMBOV-UHFFFAOYSA-N 0.000 description 1
- LJGHYPLBDBRCRZ-UHFFFAOYSA-N 3-(3-aminophenyl)sulfonylaniline Chemical compound NC1=CC=CC(S(=O)(=O)C=2C=C(N)C=CC=2)=C1 LJGHYPLBDBRCRZ-UHFFFAOYSA-N 0.000 description 1
- YLMMJMHLTALYPZ-UHFFFAOYSA-N 3-[1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-3-yl]-n,n-dimethylpropan-1-amine Chemical compound C1C(CCCN(C)C)C2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 YLMMJMHLTALYPZ-UHFFFAOYSA-N 0.000 description 1
- GVQIHSNLWAKAGK-UHFFFAOYSA-N 3-[1-[6,7-bis(2-hydroxyethoxy)quinazolin-4-yl]-6-chloro-2,3-dihydroindol-3-yl]propan-1-ol Chemical compound OCCOC1=C(OCCO)C=C2C(N3CC(C4=CC=C(Cl)C=C43)CCCO)=NC=NC2=C1 GVQIHSNLWAKAGK-UHFFFAOYSA-N 0.000 description 1
- QUONIGGACAGZAN-UHFFFAOYSA-N 3-[1-[6,7-bis(2-methoxyethoxy)quinazolin-4-yl]-6-fluoro-7-methyl-2,3-dihydroindol-3-yl]propanoic acid Chemical compound C1C(CCC(O)=O)C2=CC=C(F)C(C)=C2N1C1=C(C=C(C(OCCOC)=C2)OCCOC)C2=NC=N1 QUONIGGACAGZAN-UHFFFAOYSA-N 0.000 description 1
- QVHWEDJTHBPTBK-UHFFFAOYSA-N 3-[4-(6-bromo-7-methyl-2,3-dihydroindol-1-yl)-6-(trifluoromethoxy)quinazolin-7-yl]oxypropan-1-ol Chemical compound OCCCOC1=C(OC(F)(F)F)C=C2C(N3C4=C(C(=CC=C4CC3)Br)C)=NC=NC2=C1 QVHWEDJTHBPTBK-UHFFFAOYSA-N 0.000 description 1
- NQZJLSJSNWUNAK-UHFFFAOYSA-N 3-[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-7-yl]oxypropan-1-ol;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OCCCO)=CC=C21 NQZJLSJSNWUNAK-UHFFFAOYSA-N 0.000 description 1
- QPLSGBVCKDOOSA-UHFFFAOYSA-N 3-[4-(6-fluoro-7-methyl-2,3-dihydroindol-1-yl)-7-(3-hydroxypropoxy)quinazolin-6-yl]oxypropan-1-ol Chemical compound OCCCOC1=C(OCCCO)C=C2C(N3C4=C(C(=CC=C4CC3)F)C)=NC=NC2=C1 QPLSGBVCKDOOSA-UHFFFAOYSA-N 0.000 description 1
- SAMDMTXGUQQERF-UHFFFAOYSA-N 3-[4-[6-chloro-4-(methylamino)-2,3-dihydroindol-1-yl]-7-(3-hydroxypropoxy)quinazolin-6-yl]oxypropan-1-ol Chemical compound OCCCOC1=C(OCCCO)C=C2C(N3C=4C=C(Cl)C=C(C=4CC3)NC)=NC=NC2=C1 SAMDMTXGUQQERF-UHFFFAOYSA-N 0.000 description 1
- NYYRRBOMNHUCLB-UHFFFAOYSA-N 3-chloro-n,n-dimethylpropan-1-amine Chemical compound CN(C)CCCCl NYYRRBOMNHUCLB-UHFFFAOYSA-N 0.000 description 1
- NHQDETIJWKXCTC-UHFFFAOYSA-N 3-chloroperbenzoic acid Chemical compound OOC(=O)C1=CC=CC(Cl)=C1 NHQDETIJWKXCTC-UHFFFAOYSA-N 0.000 description 1
- SLDLVGFPFFLYBM-UHFFFAOYSA-N 3-fluoro-2-methyl-aniline Chemical compound CC1=C(N)C=CC=C1F SLDLVGFPFFLYBM-UHFFFAOYSA-N 0.000 description 1
- PHWAMXVPMNPOIU-UHFFFAOYSA-N 4,6-dichloro-7-methoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(Cl)C(OC)=CC2=N1 PHWAMXVPMNPOIU-UHFFFAOYSA-N 0.000 description 1
- FDPHWQSGEWRZOL-UHFFFAOYSA-N 4,7-dichloroquinazoline Chemical compound ClC1=NC=NC2=CC(Cl)=CC=C21 FDPHWQSGEWRZOL-UHFFFAOYSA-N 0.000 description 1
- LGRUYTZVYJCUTH-UHFFFAOYSA-N 4,8-dichloroquinazoline Chemical compound N1=CN=C2C(Cl)=CC=CC2=C1Cl LGRUYTZVYJCUTH-UHFFFAOYSA-N 0.000 description 1
- HILIXBSGQQWNDX-UHFFFAOYSA-N 4-(2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 HILIXBSGQQWNDX-UHFFFAOYSA-N 0.000 description 1
- LNQBYAMGSOBYCO-UHFFFAOYSA-N 4-(4-bromo-7-methyl-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC(C(=CC=C2C)Br)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 LNQBYAMGSOBYCO-UHFFFAOYSA-N 0.000 description 1
- PQCUFJLLYRRGOJ-UHFFFAOYSA-N 4-(4-bromo-7-methyl-2,3-dihydroindol-1-yl)-7-methoxyquinazoline Chemical compound C1CC(C(=CC=C2C)Br)=C2N1C1=NC=NC2=CC(OC)=CC=C21 PQCUFJLLYRRGOJ-UHFFFAOYSA-N 0.000 description 1
- DRMVCMNAEDTBIP-UHFFFAOYSA-N 4-(4-chloro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC(C(=CC=C2)Cl)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 DRMVCMNAEDTBIP-UHFFFAOYSA-N 0.000 description 1
- CTBIGBLHCPVDRB-UHFFFAOYSA-N 4-(5-azido-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC(N=[N+]=[N-])=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 CTBIGBLHCPVDRB-UHFFFAOYSA-N 0.000 description 1
- VULFDHZCZFWELL-UHFFFAOYSA-N 4-(5-bromo-3,4-dihydro-2h-quinolin-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CCC2=C(Br)C=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 VULFDHZCZFWELL-UHFFFAOYSA-N 0.000 description 1
- FZODPGDYKJRDLB-UHFFFAOYSA-N 4-(5-chloro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC(Cl)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 FZODPGDYKJRDLB-UHFFFAOYSA-N 0.000 description 1
- ALKANHRAMVTHCD-UHFFFAOYSA-N 4-(5-fluoro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC(F)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 ALKANHRAMVTHCD-UHFFFAOYSA-N 0.000 description 1
- VSQFTHMCFWRRIO-UHFFFAOYSA-N 4-(6,7-dimethyl-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline;methanesulfonic acid Chemical compound CS(O)(=O)=O.C1CC2=CC=C(C)C(C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 VSQFTHMCFWRRIO-UHFFFAOYSA-N 0.000 description 1
- NSACBIQKSJKRQV-UHFFFAOYSA-N 4-(6-azido-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC=C(N=[N+]=[N-])C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 NSACBIQKSJKRQV-UHFFFAOYSA-N 0.000 description 1
- LWYPISAMHNNENJ-UHFFFAOYSA-N 4-(6-bromo-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(Br)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 LWYPISAMHNNENJ-UHFFFAOYSA-N 0.000 description 1
- VWWPSWBONSXNNA-UHFFFAOYSA-N 4-(6-bromo-5-fluoro-2,3-dihydroindol-1-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline;hydrochloride Chemical compound Cl.C1CC2=CC(F)=C(Br)C=C2N1C1=C(C=C(C(OCCOC)=C2)OC)C2=NC=N1 VWWPSWBONSXNNA-UHFFFAOYSA-N 0.000 description 1
- WPTBHAKZYBNNCZ-UHFFFAOYSA-N 4-(6-bromo-5-fluoro-2,3-dihydroindol-1-yl)-7-methoxyquinazoline;hydrochloride Chemical compound Cl.C1CC2=CC(F)=C(Br)C=C2N1C1=NC=NC2=CC(OC)=CC=C21 WPTBHAKZYBNNCZ-UHFFFAOYSA-N 0.000 description 1
- KWSXTUWMZFHXHM-UHFFFAOYSA-N 4-(6-bromo-7-methyl-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC=C(Br)C(C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 KWSXTUWMZFHXHM-UHFFFAOYSA-N 0.000 description 1
- OZUDTFVZNOGTHU-UHFFFAOYSA-N 4-(6-bromo-7-methyl-2,3-dihydroindol-1-yl)-7-methoxyquinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(Br)C(C)=C2N1C1=NC=NC2=CC(OC)=CC=C21 OZUDTFVZNOGTHU-UHFFFAOYSA-N 0.000 description 1
- CEMGBTSTBYOJIU-UHFFFAOYSA-N 4-(6-butyl-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound COC1=C(OC)C=C2C(N3CCC4=CC=C(C=C43)CCCC)=NC=NC2=C1 CEMGBTSTBYOJIU-UHFFFAOYSA-N 0.000 description 1
- FCHXCZHIBMQUGW-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6,7,8-trimethoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C2C=C(OC)C(OC)=C(OC)C2=NC=N1 FCHXCZHIBMQUGW-UHFFFAOYSA-N 0.000 description 1
- BEYIZGBMOGMVAG-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6,7-bis(2-methoxyethoxy)quinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OCCOC)=C2)OCCOC)C2=NC=N1 BEYIZGBMOGMVAG-UHFFFAOYSA-N 0.000 description 1
- ZQXBRMWCJCDACG-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6,7-diethoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OCC)=C2)OCC)C2=NC=N1 ZQXBRMWCJCDACG-UHFFFAOYSA-N 0.000 description 1
- AACSBEPHEOJBLP-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazolin-7-ol Chemical compound COc1cc2c(ncnc2cc1O)N1CCc2ccc(Cl)cc12.COc1cc2ncnc(N3CCc4ccc(Cl)cc34)c2cc1OC AACSBEPHEOJBLP-UHFFFAOYSA-N 0.000 description 1
- DLOGGEPZOLRYJP-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6,7-dimethylquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(C)=C2)C)C2=NC=N1 DLOGGEPZOLRYJP-UHFFFAOYSA-N 0.000 description 1
- GVRUNQMNQLWHOR-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline methanesulfonic acid Chemical compound CS(O)(=O)=O.C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OCCOC)=C2)OC)C2=NC=N1 GVRUNQMNQLWHOR-UHFFFAOYSA-N 0.000 description 1
- LKBZIEZUHKCIBF-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC=C(OC)C=C21 LKBZIEZUHKCIBF-UHFFFAOYSA-N 0.000 description 1
- KCQIGVLNLSEISI-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6-methylquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC=C(C)C=C21 KCQIGVLNLSEISI-UHFFFAOYSA-N 0.000 description 1
- NZDPINXJQFJZII-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-6-nitroquinazoline;4-chloro-6-nitroquinazoline Chemical compound N1=CN=C(Cl)C2=CC([N+](=O)[O-])=CC=C21.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC=C([N+](=O)[O-])C=C21 NZDPINXJQFJZII-UHFFFAOYSA-N 0.000 description 1
- DDTIQKHQEIONDG-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline Chemical compound O1CCOC(C=C23)=C1C=C3N=CN=C2N1CCC2=CC=C(Cl)C=C21 DDTIQKHQEIONDG-UHFFFAOYSA-N 0.000 description 1
- BNCBKIFNJAJKTR-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-(2-imidazol-1-ylethoxy)-6-methoxyquinazoline methanesulfonic acid Chemical compound CS(O)(=O)=O.CS(O)(=O)=O.COC1=CC2=C(N3C4=CC(Cl)=CC=C4CC3)N=CN=C2C=C1OCCN1C=CN=C1 BNCBKIFNJAJKTR-UHFFFAOYSA-N 0.000 description 1
- BSUWUFFTFZYRNR-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-(2-methoxyethoxy)quinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OCCOC)=CC=C21 BSUWUFFTFZYRNR-UHFFFAOYSA-N 0.000 description 1
- MJIHRLBIZBXSIN-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-methoxy-6-methylsulfanylquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)SC)C2=NC=N1 MJIHRLBIZBXSIN-UHFFFAOYSA-N 0.000 description 1
- RVVXDWPLMXOAIV-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-methoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OC)=CC=C21 RVVXDWPLMXOAIV-UHFFFAOYSA-N 0.000 description 1
- DYUJCZSCRQJQFP-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-methoxyquinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OC)=CC=C21 DYUJCZSCRQJQFP-UHFFFAOYSA-N 0.000 description 1
- RTCYCZDLLLLMNF-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-methylquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(C)=CC=C21 RTCYCZDLLLLMNF-UHFFFAOYSA-N 0.000 description 1
- CYTNVGQZDMLUOT-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-7-nitroquinazoline;n-[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]formamide Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC([N+](=O)[O-])=CC=C21.C1=C(NC=O)C=C2C(N3CCC4=CC=C(C=C43)Cl)=NC=NC2=C1 CYTNVGQZDMLUOT-UHFFFAOYSA-N 0.000 description 1
- AGUSIPWCISRVNF-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-n,n-dimethylquinazolin-7-amine;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(N(C)C)=CC=C21 AGUSIPWCISRVNF-UHFFFAOYSA-N 0.000 description 1
- RKOCXRRUKQNUQZ-UHFFFAOYSA-N 4-(6-chloro-2,3-dihydroindol-1-yl)-n-methylquinazolin-7-amine;hydrochloride Chemical compound Cl.C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(NC)=CC=C21 RKOCXRRUKQNUQZ-UHFFFAOYSA-N 0.000 description 1
- KEZZJNGCQSVTAK-UHFFFAOYSA-N 4-(6-chloro-5-fluoro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC(F)=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 KEZZJNGCQSVTAK-UHFFFAOYSA-N 0.000 description 1
- NTXKUEVTTGOFTL-UHFFFAOYSA-N 4-(6-ethyl-2,3-dihydroindol-1-yl)-7-methoxy-6-methylquinazoline Chemical compound COC1=C(C)C=C2C(N3CCC4=CC=C(C=C43)CC)=NC=NC2=C1 NTXKUEVTTGOFTL-UHFFFAOYSA-N 0.000 description 1
- CYVJSPOTVFGSOL-UHFFFAOYSA-N 4-(6-ethynyl-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC=C(C#C)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 CYVJSPOTVFGSOL-UHFFFAOYSA-N 0.000 description 1
- CZNMJSUOLWKWIS-UHFFFAOYSA-N 4-(6-fluoro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound C1CC2=CC=C(F)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 CZNMJSUOLWKWIS-UHFFFAOYSA-N 0.000 description 1
- ATAQSKUGKFALRG-UHFFFAOYSA-N 4-(6-fluoro-7-methyl-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(F)C(C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 ATAQSKUGKFALRG-UHFFFAOYSA-N 0.000 description 1
- POJMLLQNEIRBGN-OLZOCXBDSA-N 4-[(2s,3s)-2,3-dimethyl-2,3-dihydroindol-1-yl]-6,7-dimethoxyquinazoline Chemical compound C1([C@H](C)[C@@H]2C)=CC=CC=C1N2C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 POJMLLQNEIRBGN-OLZOCXBDSA-N 0.000 description 1
- PLVIBWRWOQFTJY-SWLSCSKDSA-N 4-[(3as,7ar)-2,3,3a,4,5,6,7,7a-octahydroindol-1-yl]-6,7-dimethoxyquinazoline Chemical compound C([C@H]1CC2)CCC[C@H]1N2C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 PLVIBWRWOQFTJY-SWLSCSKDSA-N 0.000 description 1
- YGWVQUZZQQHTAX-UHFFFAOYSA-N 4-[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]morpholine;4-(4-chloroquinazolin-6-yl)morpholine Chemical compound C1=C2C(Cl)=NC=NC2=CC=C1N1CCOCC1.C12=CC(Cl)=CC=C2CCN1C(C1=C2)=NC=NC1=CC=C2N1CCOCC1 YGWVQUZZQQHTAX-UHFFFAOYSA-N 0.000 description 1
- YSTLAHCXKLGBCG-UHFFFAOYSA-N 4-[6-bromo-3-(3-morpholin-4-ylpropyl)-2,3-dihydroindol-1-yl]-n-methylquinazolin-6-amine Chemical compound C12=CC(NC)=CC=C2N=CN=C1N(C1=CC(Br)=CC=C11)CC1CCCN1CCOCC1 YSTLAHCXKLGBCG-UHFFFAOYSA-N 0.000 description 1
- BBHMZHDPVNXFMI-UHFFFAOYSA-N 4-chloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC=CC2=C1CCN2 BBHMZHDPVNXFMI-UHFFFAOYSA-N 0.000 description 1
- BIICRHXSGPYQOV-UHFFFAOYSA-N 4-chloro-6,7,8-trimethoxyquinazoline Chemical compound N1=CN=C2C(OC)=C(OC)C(OC)=CC2=C1Cl BIICRHXSGPYQOV-UHFFFAOYSA-N 0.000 description 1
- ZPJLDMNVDPGZIU-UHFFFAOYSA-N 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline Chemical compound C1=NC(Cl)=C2C=C(OCCOC)C(OCCOC)=CC2=N1 ZPJLDMNVDPGZIU-UHFFFAOYSA-N 0.000 description 1
- HGMQPDNSSYTATF-UHFFFAOYSA-N 4-chloro-6,7-diethoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OCC)C(OCC)=CC2=N1 HGMQPDNSSYTATF-UHFFFAOYSA-N 0.000 description 1
- WIKQNBCDJYNKED-UHFFFAOYSA-N 4-chloro-6,7-dimethylquinazoline Chemical compound C1=NC(Cl)=C2C=C(C)C(C)=CC2=N1 WIKQNBCDJYNKED-UHFFFAOYSA-N 0.000 description 1
- SZLBNDFFNLYINW-UHFFFAOYSA-N 4-chloro-6-(4-methylpiperazin-1-yl)quinazoline;hydrochloride Chemical compound Cl.C1CN(C)CCN1C1=CC=C(N=CN=C2Cl)C2=C1 SZLBNDFFNLYINW-UHFFFAOYSA-N 0.000 description 1
- NCQOUPJMWGXARM-UHFFFAOYSA-N 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline Chemical compound C1=NC(Cl)=C2C=C(OC)C(OCCOC)=CC2=N1 NCQOUPJMWGXARM-UHFFFAOYSA-N 0.000 description 1
- XNILKVADCMYCQT-UHFFFAOYSA-N 4-chloro-6-methylquinazoline Chemical compound N1=CN=C(Cl)C2=CC(C)=CC=C21 XNILKVADCMYCQT-UHFFFAOYSA-N 0.000 description 1
- KOSFQWDAKWKNJM-UHFFFAOYSA-N 4-chloro-7,8-dihydro-[1,4]dioxino[2,3-g]quinazoline Chemical compound O1CCOC2=C1C=C1N=CN=C(Cl)C1=C2 KOSFQWDAKWKNJM-UHFFFAOYSA-N 0.000 description 1
- OCHWJELTXIZAIN-UHFFFAOYSA-N 4-chloro-7-methylquinazoline Chemical compound ClC1=NC=NC2=CC(C)=CC=C21 OCHWJELTXIZAIN-UHFFFAOYSA-N 0.000 description 1
- CCCGYXZEVXWXAU-UHFFFAOYSA-N 4-chloro-7-nitroquinazoline Chemical compound ClC1=NC=NC2=CC([N+](=O)[O-])=CC=C21 CCCGYXZEVXWXAU-UHFFFAOYSA-N 0.000 description 1
- GVRRXASZZAKBMN-UHFFFAOYSA-N 4-chloroquinazoline Chemical compound C1=CC=C2C(Cl)=NC=NC2=C1 GVRRXASZZAKBMN-UHFFFAOYSA-N 0.000 description 1
- BSRIUSPUGCAPHE-UHFFFAOYSA-N 4-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=CC2=C1CCN2 BSRIUSPUGCAPHE-UHFFFAOYSA-N 0.000 description 1
- AYGGQJHJRFZDFH-UHFFFAOYSA-N 5,7-dichloro-1h-indole-2,3-dione Chemical compound ClC1=CC(Cl)=CC2=C1NC(=O)C2=O AYGGQJHJRFZDFH-UHFFFAOYSA-N 0.000 description 1
- MCMPVUNIFSKCGJ-UHFFFAOYSA-N 5,7-dichloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC(Cl)=CC2=C1NCC2 MCMPVUNIFSKCGJ-UHFFFAOYSA-N 0.000 description 1
- WFWWOWBCWOWYAW-UHFFFAOYSA-N 5-(6,7-dimethoxyquinazolin-4-yl)-6,7-dihydro-1h-pyrrolo[2,3-f]indole Chemical compound C1CC2=CC=3NC=CC=3C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 WFWWOWBCWOWYAW-UHFFFAOYSA-N 0.000 description 1
- GLZHJQXGMFLPOI-UHFFFAOYSA-N 5-(6,7-dimethoxyquinazolin-4-yl)-6,7-dihydro-[1,3]dioxolo[4,5-f]indole Chemical compound C1CC2=CC=3OCOC=3C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 GLZHJQXGMFLPOI-UHFFFAOYSA-N 0.000 description 1
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 1
- WTZQIKXLRRDMCP-UHFFFAOYSA-N 5-bromo-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=C1C=CC=C2Br WTZQIKXLRRDMCP-UHFFFAOYSA-N 0.000 description 1
- CVICEEPAFUYBJG-UHFFFAOYSA-N 5-chloro-2,2-difluoro-1,3-benzodioxole Chemical group C1=C(Cl)C=C2OC(F)(F)OC2=C1 CVICEEPAFUYBJG-UHFFFAOYSA-N 0.000 description 1
- YMCIVAPEOZDEGH-UHFFFAOYSA-N 5-chloro-2,3-dihydro-1h-indole Chemical compound ClC1=CC=C2NCCC2=C1 YMCIVAPEOZDEGH-UHFFFAOYSA-N 0.000 description 1
- NXQRMQIYCWFDGP-UHFFFAOYSA-N 5-fluoro-2,3-dihydro-1h-indole Chemical compound FC1=CC=C2NCCC2=C1 NXQRMQIYCWFDGP-UHFFFAOYSA-N 0.000 description 1
- DWAQDRSOVMLGRQ-UHFFFAOYSA-N 5-methoxyindole Chemical compound COC1=CC=C2NC=CC2=C1 DWAQDRSOVMLGRQ-UHFFFAOYSA-N 0.000 description 1
- JFUAVVHABJWSFX-UHFFFAOYSA-N 5-methyl-2,3-dihydro-1h-indole Chemical compound CC1=CC=C2NCCC2=C1 JFUAVVHABJWSFX-UHFFFAOYSA-N 0.000 description 1
- NHULNFPNWXCXDI-UHFFFAOYSA-N 5-phenylmethoxy-2,3-dihydro-1h-indole Chemical compound C=1C=C2NCCC2=CC=1OCC1=CC=CC=C1 NHULNFPNWXCXDI-UHFFFAOYSA-N 0.000 description 1
- QXSXUCFIJKIEJX-UHFFFAOYSA-N 6,7-dihydro-5h-[1,3]dioxolo[4,5-f]indole Chemical compound C1=C2NCCC2=CC2=C1OCO2 QXSXUCFIJKIEJX-UHFFFAOYSA-N 0.000 description 1
- VKWKYKGNDBHMQZ-UHFFFAOYSA-N 6,7-dimethoxy-2-(5-nitro-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1CC2=CC([N+]([O-])=O)=CC=C2N1C1=NC=C2C=C(OC)C(OC)=CC2=N1 VKWKYKGNDBHMQZ-UHFFFAOYSA-N 0.000 description 1
- RQRKUXKKNQWDTK-UHFFFAOYSA-N 6,7-dimethoxy-4-(2-methyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound CC1CC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 RQRKUXKKNQWDTK-UHFFFAOYSA-N 0.000 description 1
- LVZMAEIFTWOUCR-UHFFFAOYSA-N 6,7-dimethoxy-4-(4-methyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1CC(C(=CC=C2)C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 LVZMAEIFTWOUCR-UHFFFAOYSA-N 0.000 description 1
- DBJZTMRUVQOJKF-UHFFFAOYSA-N 6,7-dimethoxy-4-(5-methoxy-2,3-dihydroindol-1-yl)quinazoline Chemical compound COC1=C(OC)C=C2C(N3C4=CC=C(C=C4CC3)OC)=NC=NC2=C1 DBJZTMRUVQOJKF-UHFFFAOYSA-N 0.000 description 1
- ABXQRUYLDZRXCX-UHFFFAOYSA-N 6,7-dimethoxy-4-(5-methyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1CC2=CC(C)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 ABXQRUYLDZRXCX-UHFFFAOYSA-N 0.000 description 1
- RVAVTUCIVJJSQS-UHFFFAOYSA-N 6,7-dimethoxy-4-(5-phenylmethoxy-2,3-dihydroindol-1-yl)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(C1=CC=2)CCC1=CC=2OCC1=CC=CC=C1 RVAVTUCIVJJSQS-UHFFFAOYSA-N 0.000 description 1
- WZYRCQZWGKESDJ-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-methoxy-2,3-dihydroindol-1-yl)quinazoline;hydrochloride Chemical compound Cl.COC1=C(OC)C=C2C(N3CCC4=CC=C(C=C43)OC)=NC=NC2=C1 WZYRCQZWGKESDJ-UHFFFAOYSA-N 0.000 description 1
- MXDNOGXQEDEWRL-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-methyl-2,3-dihydroindol-1-yl)quinazoline;hydrochloride Chemical compound Cl.C1CC2=CC=C(C)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 MXDNOGXQEDEWRL-UHFFFAOYSA-N 0.000 description 1
- FECDNLVAPUHYOU-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-nitro-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1CC2=CC=C([N+]([O-])=O)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 FECDNLVAPUHYOU-UHFFFAOYSA-N 0.000 description 1
- JJIRUNWAHFPXAJ-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-phenyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(C1=C2)CCC1=CC=C2C1=CC=CC=C1 JJIRUNWAHFPXAJ-UHFFFAOYSA-N 0.000 description 1
- RIYSVLRCIZYLSN-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-propyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound COC1=C(OC)C=C2C(N3CCC4=CC=C(C=C43)CCC)=NC=NC2=C1 RIYSVLRCIZYLSN-UHFFFAOYSA-N 0.000 description 1
- FHHJHIDAJGCION-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-pyrrol-1-yl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(C1=C2)CCC1=CC=C2N1C=CC=C1 FHHJHIDAJGCION-UHFFFAOYSA-N 0.000 description 1
- BITLCQTZGAMRML-UHFFFAOYSA-N 6,7-dimethoxy-4-(6-pyrrolidin-1-yl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C=12C=C(OC)C(OC)=CC2=NC=NC=1N(C1=C2)CCC1=CC=C2N1CCCC1 BITLCQTZGAMRML-UHFFFAOYSA-N 0.000 description 1
- PWWQVHSNKLJHCX-UHFFFAOYSA-N 6,7-dimethoxy-4-(7-methyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1CC2=CC=CC(C)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 PWWQVHSNKLJHCX-UHFFFAOYSA-N 0.000 description 1
- JGMGTCWONIGXMK-UHFFFAOYSA-N 6,7-dimethyl-1h-indol-5-ol Chemical compound CC1=C(O)C=C2C=CNC2=C1C JGMGTCWONIGXMK-UHFFFAOYSA-N 0.000 description 1
- NATXVTGOBMUXMM-UHFFFAOYSA-N 6,7-dimethyl-1h-indole Chemical compound CC1=CC=C2C=CNC2=C1C NATXVTGOBMUXMM-UHFFFAOYSA-N 0.000 description 1
- UCAIRQSAOUTVDH-UHFFFAOYSA-N 6,7-dimethyl-2,3-dihydro-1h-indol-5-ol Chemical compound OC1=C(C)C(C)=C2NCCC2=C1 UCAIRQSAOUTVDH-UHFFFAOYSA-N 0.000 description 1
- YTYIMDRWPTUAHP-UHFFFAOYSA-N 6-Chloroindole Chemical compound ClC1=CC=C2C=CNC2=C1 YTYIMDRWPTUAHP-UHFFFAOYSA-N 0.000 description 1
- MAWGHOPSCKCTPA-UHFFFAOYSA-N 6-bromo-1h-indole Chemical compound BrC1=CC=C2C=CNC2=C1 MAWGHOPSCKCTPA-UHFFFAOYSA-N 0.000 description 1
- MTSYZAHZABCWMS-UHFFFAOYSA-N 6-bromo-2,3-dihydro-1h-indole Chemical compound BrC1=CC=C2CCNC2=C1 MTSYZAHZABCWMS-UHFFFAOYSA-N 0.000 description 1
- RBESGQUEGGUVMD-UHFFFAOYSA-N 6-butyl-2,3-dihydro-1h-indole Chemical compound CCCCC1=CC=C2CCNC2=C1 RBESGQUEGGUVMD-UHFFFAOYSA-N 0.000 description 1
- RBIRHCZDDQZOPS-UHFFFAOYSA-N 6-chloro-1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-4-ol Chemical compound C1CC(C(=CC(Cl)=C2)O)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 RBIRHCZDDQZOPS-UHFFFAOYSA-N 0.000 description 1
- RWVFYCYOTSCQDE-UHFFFAOYSA-N 6-chloro-1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-5-ol Chemical compound C1CC2=CC(O)=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 RWVFYCYOTSCQDE-UHFFFAOYSA-N 0.000 description 1
- QKVVYFDUUKTJNT-UHFFFAOYSA-N 6-chloro-1-([1,3]dioxolo[4,5-g]quinazolin-8-yl)-n-methyl-2,3-dihydroindol-5-amine Chemical compound C1=C2C(N3CCC=4C=C(C(=CC=43)Cl)NC)=NC=NC2=CC2=C1OCO2 QKVVYFDUUKTJNT-UHFFFAOYSA-N 0.000 description 1
- AQSZBLLOXVDEAK-UHFFFAOYSA-N 6-chloro-1-[7-[2-(dimethylamino)ethoxy]quinazolin-4-yl]-2,3-dihydroindol-4-ol Chemical compound C1CC(C(=CC(Cl)=C2)O)=C2N1C1=NC=NC2=CC(OCCN(C)C)=CC=C21 AQSZBLLOXVDEAK-UHFFFAOYSA-N 0.000 description 1
- HCMSVUUSPNCLDQ-UHFFFAOYSA-N 6-chloro-2,3-dihydro-1h-indol-5-ol Chemical compound C1=C(Cl)C(O)=CC2=C1NCC2 HCMSVUUSPNCLDQ-UHFFFAOYSA-N 0.000 description 1
- JHOLXKBFVQAMCF-UHFFFAOYSA-N 6-chloro-2,3-dihydro-1h-indole;hydrochloride Chemical compound Cl.ClC1=CC=C2CCNC2=C1 JHOLXKBFVQAMCF-UHFFFAOYSA-N 0.000 description 1
- VFJDYRLAGUPNQC-UHFFFAOYSA-N 6-chloro-4-(6-chloro-2,3-dihydroindol-1-yl)-7-methoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)Cl)C2=NC=N1 VFJDYRLAGUPNQC-UHFFFAOYSA-N 0.000 description 1
- QDUXBJGXHPPFJG-UHFFFAOYSA-N 6-chloro-5-fluoro-1,3-dihydroindol-2-one Chemical compound C1=C(Cl)C(F)=CC2=C1NC(=O)C2 QDUXBJGXHPPFJG-UHFFFAOYSA-N 0.000 description 1
- KKHHDJYQGADKEQ-UHFFFAOYSA-N 6-chloro-5-nitro-1,3-dihydroindol-2-one Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1NC(=O)C2 KKHHDJYQGADKEQ-UHFFFAOYSA-N 0.000 description 1
- WZVBKWHXWRBUHL-UHFFFAOYSA-N 6-chloro-5-nitro-1h-indole Chemical compound C1=C(Cl)C([N+](=O)[O-])=CC2=C1NC=C2 WZVBKWHXWRBUHL-UHFFFAOYSA-N 0.000 description 1
- PBLNKUULIMDAIC-UHFFFAOYSA-N 6-fluoro-2,3-dihydro-1h-indole Chemical compound FC1=CC=C2CCNC2=C1 PBLNKUULIMDAIC-UHFFFAOYSA-N 0.000 description 1
- NWXBSWUAWHBOSL-UHFFFAOYSA-N 6-fluoro-7-methyl-1h-indole Chemical compound CC1=C(F)C=CC2=C1NC=C2 NWXBSWUAWHBOSL-UHFFFAOYSA-N 0.000 description 1
- SLCVFCQRQAFQHT-UHFFFAOYSA-N 6-fluoro-7-methyl-2,3-dihydro-1h-indole Chemical compound C1=C(F)C(C)=C2NCCC2=C1 SLCVFCQRQAFQHT-UHFFFAOYSA-N 0.000 description 1
- GKFGHNMPMAXWQS-UHFFFAOYSA-N 6-methoxy-2,3-dihydro-1h-indole Chemical compound COC1=CC=C2CCNC2=C1 GKFGHNMPMAXWQS-UHFFFAOYSA-N 0.000 description 1
- VYUXQFTUJSPCEU-UHFFFAOYSA-N 6-methoxyquinazolin-7-ol Chemical compound N1=CN=C2C=C(O)C(OC)=CC2=C1 VYUXQFTUJSPCEU-UHFFFAOYSA-N 0.000 description 1
- XOKMRXSMOHCNIX-UHFFFAOYSA-N 6-methyl-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(C)=CC=C21 XOKMRXSMOHCNIX-UHFFFAOYSA-N 0.000 description 1
- IOJOGNWEPXXXIU-UHFFFAOYSA-N 6-methyl-2,3-dihydro-1h-indol-5-ol Chemical compound C1=C(O)C(C)=CC2=C1CCN2 IOJOGNWEPXXXIU-UHFFFAOYSA-N 0.000 description 1
- LTNYDSMDSLOMSM-UHFFFAOYSA-N 6-nitro-2,3-dihydro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2CCNC2=C1 LTNYDSMDSLOMSM-UHFFFAOYSA-N 0.000 description 1
- VPWFWZPVWNCIEY-UHFFFAOYSA-N 6-phenyl-2,3-dihydro-1h-indole Chemical compound C1=C2NCCC2=CC=C1C1=CC=CC=C1 VPWFWZPVWNCIEY-UHFFFAOYSA-N 0.000 description 1
- FXOYDLLFRGNRMA-UHFFFAOYSA-N 6-phenylmethoxy-2,3-dihydro-1h-indole Chemical compound C=1C=C2CCNC2=CC=1OCC1=CC=CC=C1 FXOYDLLFRGNRMA-UHFFFAOYSA-N 0.000 description 1
- QZEQZIPFKWYJFS-UHFFFAOYSA-N 6-propan-2-yl-2,3-dihydro-1h-indole Chemical compound CC(C)C1=CC=C2CCNC2=C1 QZEQZIPFKWYJFS-UHFFFAOYSA-N 0.000 description 1
- SBKYRDQFRPWDMR-UHFFFAOYSA-N 6-propyl-2,3-dihydro-1h-indole Chemical compound CCCC1=CC=C2CCNC2=C1 SBKYRDQFRPWDMR-UHFFFAOYSA-N 0.000 description 1
- DRVWZEWZXCZNAR-UHFFFAOYSA-N 7-bromo-1,2,3,4-tetrahydroquinoline Chemical compound C1CCNC2=CC(Br)=CC=C21 DRVWZEWZXCZNAR-UHFFFAOYSA-N 0.000 description 1
- GAIYFVOLPSEDOJ-UHFFFAOYSA-N 7-butoxy-4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OCCCC)=C2)OC)C2=NC=N1 GAIYFVOLPSEDOJ-UHFFFAOYSA-N 0.000 description 1
- UFBHZJRMYZNOIZ-UHFFFAOYSA-N 7-butoxy-4-chloro-6-methoxyquinazoline Chemical compound C1=NC(Cl)=C2C=C(OC)C(OCCCC)=CC2=N1 UFBHZJRMYZNOIZ-UHFFFAOYSA-N 0.000 description 1
- PIOAYYGFSXRKSA-UHFFFAOYSA-N 7-chloro-4-(6-chloro-2,3-dihydroindol-1-yl)-6-(2-methoxyethylsulfanyl)quinazoline Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C2C=C(SCCOC)C(Cl)=CC2=NC=N1 PIOAYYGFSXRKSA-UHFFFAOYSA-N 0.000 description 1
- SNFVWPZFGHAGPP-UHFFFAOYSA-N 7-chloro-4-(6-chloro-2,3-dihydroindol-1-yl)quinazoline Chemical compound ClC1=CC=C2C(N3CCC4=CC=C(C=C43)Cl)=NC=NC2=C1 SNFVWPZFGHAGPP-UHFFFAOYSA-N 0.000 description 1
- JUNITDZNGHCTTL-UHFFFAOYSA-N 7-methoxy-4-(7-methyl-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1CC2=CC=CC(C)=C2N1C1=NC=NC2=CC(OC)=CC=C21 JUNITDZNGHCTTL-UHFFFAOYSA-N 0.000 description 1
- IGYHZJNICRWVJU-UHFFFAOYSA-N 7-methyl-1h-indol-5-ol Chemical compound CC1=CC(O)=CC2=C1NC=C2 IGYHZJNICRWVJU-UHFFFAOYSA-N 0.000 description 1
- MNEQKDCNNVVAAC-UHFFFAOYSA-N 7-methyl-2,3-dihydro-1h-indol-5-ol Chemical compound CC1=CC(O)=CC2=C1NCC2 MNEQKDCNNVVAAC-UHFFFAOYSA-N 0.000 description 1
- CYJRNFFLTBEQSQ-UHFFFAOYSA-N 8-(3-methyl-1-benzothiophen-5-yl)-N-(4-methylsulfonylpyridin-3-yl)quinoxalin-6-amine Chemical compound CS(=O)(=O)C1=C(C=NC=C1)NC=1C=C2N=CC=NC2=C(C=1)C=1C=CC2=C(C(=CS2)C)C=1 CYJRNFFLTBEQSQ-UHFFFAOYSA-N 0.000 description 1
- 239000005725 8-Hydroxyquinoline Substances 0.000 description 1
- YPPIWUZADCJFOR-UHFFFAOYSA-N 8-bromo-1-(6,7-dimethoxyquinazolin-4-yl)-2,3,4,5-tetrahydro-1-benzazepine Chemical compound C1CCCC2=CC=C(Br)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 YPPIWUZADCJFOR-UHFFFAOYSA-N 0.000 description 1
- KPDFHWZIGSUFFO-UHFFFAOYSA-N 8-chloro-4-(6-chloro-2,3-dihydroindol-1-yl)quinazoline Chemical compound C1=CC=C2C(N3CCC4=CC=C(C=C43)Cl)=NC=NC2=C1Cl KPDFHWZIGSUFFO-UHFFFAOYSA-N 0.000 description 1
- 241000220479 Acacia Species 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 238000005679 Batcho-Leimgruber synthesis reaction Methods 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- SGKWYDUCBQEPGJ-UHFFFAOYSA-N C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OC(F)F)=CC=C21 Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=NC=NC2=CC(OC(F)F)=CC=C21 SGKWYDUCBQEPGJ-UHFFFAOYSA-N 0.000 description 1
- PLVIBWRWOQFTJY-WFASDCNBSA-N COC=1C=C2C(=NC=NC2=CC1OC)N1CC[C@@H]2CCCC[C@H]12 Chemical compound COC=1C=C2C(=NC=NC2=CC1OC)N1CC[C@@H]2CCCC[C@H]12 PLVIBWRWOQFTJY-WFASDCNBSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- RENMDAKOXSCIGH-UHFFFAOYSA-N Chloroacetonitrile Chemical compound ClCC#N RENMDAKOXSCIGH-UHFFFAOYSA-N 0.000 description 1
- OGOHHZXQKPDDNZ-UHFFFAOYSA-N Cl.C1CC2=CC(F)=C(Br)C=C2N1C1=C(C=C(C(OCCOC)=C2)OCCOC)C2=NC=N1 Chemical compound Cl.C1CC2=CC(F)=C(Br)C=C2N1C1=C(C=C(C(OCCOC)=C2)OCCOC)C2=NC=N1 OGOHHZXQKPDDNZ-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 101800003838 Epidermal growth factor Proteins 0.000 description 1
- 208000009849 Female Genital Neoplasms Diseases 0.000 description 1
- 238000006783 Fischer indole synthesis reaction Methods 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 102400000921 Gastrin Human genes 0.000 description 1
- 108010052343 Gastrins Proteins 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 101000851176 Homo sapiens Pro-epidermal growth factor Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- AVXURJPOCDRRFD-UHFFFAOYSA-N Hydroxylamine Chemical compound ON AVXURJPOCDRRFD-UHFFFAOYSA-N 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- 239000002841 Lewis acid Substances 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- JLTDJTHDQAWBAV-UHFFFAOYSA-N N,N-dimethylaniline Chemical compound CN(C)C1=CC=CC=C1 JLTDJTHDQAWBAV-UHFFFAOYSA-N 0.000 description 1
- AYCPARAPKDAOEN-LJQANCHMSA-N N-[(1S)-2-(dimethylamino)-1-phenylethyl]-6,6-dimethyl-3-[(2-methyl-4-thieno[3,2-d]pyrimidinyl)amino]-1,4-dihydropyrrolo[3,4-c]pyrazole-5-carboxamide Chemical compound C1([C@H](NC(=O)N2C(C=3NN=C(NC=4C=5SC=CC=5N=C(C)N=4)C=3C2)(C)C)CN(C)C)=CC=CC=C1 AYCPARAPKDAOEN-LJQANCHMSA-N 0.000 description 1
- LPGDEHBASRKTDG-UHFFFAOYSA-N N-acetylisatin Chemical class C1=CC=C2N(C(=O)C)C(=O)C(=O)C2=C1 LPGDEHBASRKTDG-UHFFFAOYSA-N 0.000 description 1
- 229910021205 NaH2PO2 Inorganic materials 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- LTQMSYLATOSRDQ-UHFFFAOYSA-N [1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-2-yl]methanol Chemical compound OCC1CC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 LTQMSYLATOSRDQ-UHFFFAOYSA-N 0.000 description 1
- JJXTZNBWZUEMFX-UHFFFAOYSA-N [1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-5-yl] methanesulfonate Chemical class C1CC2=CC(OS(C)(=O)=O)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 JJXTZNBWZUEMFX-UHFFFAOYSA-N 0.000 description 1
- QDQVKENZKDYHOL-UHFFFAOYSA-N [4-[6-chloro-3-[3-(dimethylamino)propyl]-2,3-dihydroindol-1-yl]-7-methoxyquinazolin-6-yl]methanol Chemical compound C1C(CCCN(C)C)C2=CC=C(Cl)C=C2N1C1=C(C=C(C(OC)=C2)CO)C2=NC=N1 QDQVKENZKDYHOL-UHFFFAOYSA-N 0.000 description 1
- FWVPTXMSCSONPZ-UHFFFAOYSA-N [6-amino-4-(6-ethenyl-2,3-dihydroindol-1-yl)quinazolin-7-yl]methanol Chemical compound C1CC2=CC=C(C=C)C=C2N1C1=C2C=C(N)C(CO)=CC2=NC=N1 FWVPTXMSCSONPZ-UHFFFAOYSA-N 0.000 description 1
- WLLIXJBWWFGEHT-UHFFFAOYSA-N [tert-butyl(dimethyl)silyl] trifluoromethanesulfonate Chemical compound CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F WLLIXJBWWFGEHT-UHFFFAOYSA-N 0.000 description 1
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 1
- 159000000021 acetate salts Chemical class 0.000 description 1
- UBOJLPCDEFNDQO-UHFFFAOYSA-N acetic acid;4-(5,7-dichloro-2,3-dihydroindol-1-yl)-6,7-dimethoxyquinazoline Chemical compound CC(O)=O.C1CC2=CC(Cl)=CC(Cl)=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 UBOJLPCDEFNDQO-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 239000003377 acid catalyst Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000001266 acyl halides Chemical class 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000004644 alkyl sulfinyl group Chemical group 0.000 description 1
- 125000005278 alkyl sulfonyloxy group Chemical group 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 238000005905 alkynylation reaction Methods 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 238000007098 aminolysis reaction Methods 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000002491 angiogenic effect Effects 0.000 description 1
- HOPRXXXSABQWAV-UHFFFAOYSA-N anhydrous collidine Natural products CC1=CC=NC(C)=C1C HOPRXXXSABQWAV-UHFFFAOYSA-N 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 238000011717 athymic nude mouse Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- DXZDEAJXVCLRLE-UHFFFAOYSA-N azepin-2-one Chemical compound O=C1C=CC=CC=N1 DXZDEAJXVCLRLE-UHFFFAOYSA-N 0.000 description 1
- 150000004916 azocines Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 125000005605 benzo group Chemical group 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- PFYXSUNOLOJMDX-UHFFFAOYSA-N bis(2,5-dioxopyrrolidin-1-yl) carbonate Chemical compound O=C1CCC(=O)N1OC(=O)ON1C(=O)CCC1=O PFYXSUNOLOJMDX-UHFFFAOYSA-N 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 229910052796 boron Inorganic materials 0.000 description 1
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 230000000711 cancerogenic effect Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000002252 carbamoylating effect Effects 0.000 description 1
- 230000021235 carbamoylation Effects 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 231100000357 carcinogen Toxicity 0.000 description 1
- 239000003183 carcinogenic agent Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 239000013043 chemical agent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 description 1
- FZFAMSAMCHXGEF-UHFFFAOYSA-N chloro formate Chemical compound ClOC=O FZFAMSAMCHXGEF-UHFFFAOYSA-N 0.000 description 1
- BULLHNJGPPOUOX-UHFFFAOYSA-N chloroacetone Chemical class CC(=O)CCl BULLHNJGPPOUOX-UHFFFAOYSA-N 0.000 description 1
- 229940117975 chromium trioxide Drugs 0.000 description 1
- WGLPBDUCMAPZCE-UHFFFAOYSA-N chromium trioxide Inorganic materials O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 1
- GAMDZJFZMJECOS-UHFFFAOYSA-N chromium(6+);oxygen(2-) Chemical compound [O-2].[O-2].[O-2].[Cr+6] GAMDZJFZMJECOS-UHFFFAOYSA-N 0.000 description 1
- UTBIMNXEDGNJFE-UHFFFAOYSA-N collidine Natural products CC1=CC=C(C)C(C)=N1 UTBIMNXEDGNJFE-UHFFFAOYSA-N 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000012059 conventional drug carrier Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 210000000448 cultured tumor cell Anatomy 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000006900 dealkylation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- RAFNCPHFRHZCPS-UHFFFAOYSA-N di(imidazol-1-yl)methanethione Chemical compound C1=CN=CN1C(=S)N1C=CN=C1 RAFNCPHFRHZCPS-UHFFFAOYSA-N 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- JZBWUTVDIDNCMW-UHFFFAOYSA-L dipotassium;oxido sulfate Chemical compound [K+].[K+].[O-]OS([O-])(=O)=O JZBWUTVDIDNCMW-UHFFFAOYSA-L 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- GKIPXFAANLTWBM-UHFFFAOYSA-N epibromohydrin Chemical compound BrCC1CO1 GKIPXFAANLTWBM-UHFFFAOYSA-N 0.000 description 1
- 229940116977 epidermal growth factor Drugs 0.000 description 1
- SIHZWGODIRRSRA-ONEGZZNKSA-N erbstatin Chemical compound OC1=CC=C(O)C(\C=C\NC=O)=C1 SIHZWGODIRRSRA-ONEGZZNKSA-N 0.000 description 1
- ZPDLNKYQLFHNRM-UHFFFAOYSA-N ethyl 2-(4-chloro-6-methoxyquinazolin-7-yl)oxyacetate Chemical compound C1=NC(Cl)=C2C=C(OC)C(OCC(=O)OCC)=CC2=N1 ZPDLNKYQLFHNRM-UHFFFAOYSA-N 0.000 description 1
- TWVPGBBZBSKHLW-UHFFFAOYSA-N ethyl 2-[4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazolin-7-yl]oxyacetate Chemical compound C1CC2=CC=C(Cl)C=C2N1C1=C(C=C(C(OCC(=O)OCC)=C2)OC)C2=NC=N1 TWVPGBBZBSKHLW-UHFFFAOYSA-N 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- ZHNUHDYFZUAESO-UHFFFAOYSA-N formamide Substances NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 206010017758 gastric cancer Diseases 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000000762 glandular Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000002518 glial effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 201000003911 head and neck carcinoma Diseases 0.000 description 1
- 208000014829 head and neck neoplasm Diseases 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002349 hydroxyamino group Chemical group [H]ON([H])[*] 0.000 description 1
- 125000005027 hydroxyaryl group Chemical group 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 230000002390 hyperplastic effect Effects 0.000 description 1
- 230000002267 hypothalamic effect Effects 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000002505 iron Chemical class 0.000 description 1
- 150000002513 isocyanates Chemical class 0.000 description 1
- 150000002540 isothiocyanates Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 150000007517 lewis acids Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000005567 liquid scintillation counting Methods 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- UIZGOKYLCJWFOL-UHFFFAOYSA-M lithium;1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindole-2-carboxylate Chemical compound [Li+].[O-]C(=O)C1CC2=CC=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 UIZGOKYLCJWFOL-UHFFFAOYSA-M 0.000 description 1
- BTZYWHBSQCISMK-UHFFFAOYSA-M lithium;2-[4-(6-chloro-2,3-dihydroindol-1-yl)-6-methoxyquinazolin-7-yl]oxyacetate Chemical compound [Li+].C1CC2=CC=C(Cl)C=C2N1C1=C2C=C(OC)C(OCC([O-])=O)=CC2=NC=N1 BTZYWHBSQCISMK-UHFFFAOYSA-M 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 159000000003 magnesium salts Chemical class 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- WFTOWZKVXAEFDW-UHFFFAOYSA-N methyl 1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindole-2-carboxylate Chemical compound COC1=C(OC)C=C2C(N3C4=CC=CC=C4CC3C(=O)OC)=NC=NC2=C1 WFTOWZKVXAEFDW-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- KCKYNQNYSRGSDS-UHFFFAOYSA-N n-[1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-5-yl]acetamide Chemical compound C1CC2=CC(NC(C)=O)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 KCKYNQNYSRGSDS-UHFFFAOYSA-N 0.000 description 1
- GNNBPQCFKBCYNP-UHFFFAOYSA-N n-[1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-5-yl]formamide Chemical compound C1CC2=CC(NC=O)=CC=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 GNNBPQCFKBCYNP-UHFFFAOYSA-N 0.000 description 1
- WSGSKAJFOPYLNT-UHFFFAOYSA-N n-[1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-6-yl]-2,2,2-trifluoroacetamide Chemical compound C1CC2=CC=C(NC(=O)C(F)(F)F)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 WSGSKAJFOPYLNT-UHFFFAOYSA-N 0.000 description 1
- CUUNQRMZUVQHLM-UHFFFAOYSA-N n-[1-(6,7-dimethoxyquinazolin-4-yl)-2,3-dihydroindol-6-yl]acetamide Chemical compound C1CC2=CC=C(NC(C)=O)C=C2N1C1=C(C=C(C(OC)=C2)OC)C2=NC=N1 CUUNQRMZUVQHLM-UHFFFAOYSA-N 0.000 description 1
- FBVIQIBYZJROFH-UHFFFAOYSA-N n-[4-(6-chloro-2,3-dihydroindol-1-yl)quinazolin-6-yl]formamide Chemical compound C1=C(NC=O)C=C2C(N3CCC4=CC=C(C=C43)Cl)=NC=NC2=C1 FBVIQIBYZJROFH-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- GVUGOAYIVIDWIO-UFWWTJHBSA-N nepidermin Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H](CS)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CS)NC(=O)[C@H](C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C(C)C)C(C)C)C1=CC=C(O)C=C1 GVUGOAYIVIDWIO-UFWWTJHBSA-N 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 231100000590 oncogenic Toxicity 0.000 description 1
- 230000002246 oncogenic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229960003540 oxyquinoline Drugs 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 238000010647 peptide synthesis reaction Methods 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- IMACFCSSMIZSPP-UHFFFAOYSA-N phenacyl chloride Chemical compound ClCC(=O)C1=CC=CC=C1 IMACFCSSMIZSPP-UHFFFAOYSA-N 0.000 description 1
- DGTNSSLYPYDJGL-UHFFFAOYSA-N phenyl isocyanate Chemical compound O=C=NC1=CC=CC=C1 DGTNSSLYPYDJGL-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000003880 polar aprotic solvent Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol 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
- FJVZDOGVDJCCCR-UHFFFAOYSA-M potassium periodate Chemical compound [K+].[O-]I(=O)(=O)=O FJVZDOGVDJCCCR-UHFFFAOYSA-M 0.000 description 1
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000009696 proliferative response Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- MCJGNVYPOGVAJF-UHFFFAOYSA-N quinolin-8-ol Chemical compound C1=CN=C2C(O)=CC=CC2=C1 MCJGNVYPOGVAJF-UHFFFAOYSA-N 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 229920005604 random copolymer Polymers 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000006476 reductive cyclization reaction Methods 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 230000007781 signaling event Effects 0.000 description 1
- 150000004760 silicates Chemical class 0.000 description 1
- 229910000367 silver sulfate Inorganic materials 0.000 description 1
- XGVXKJKTISMIOW-ZDUSSCGKSA-N simurosertib Chemical compound N1N=CC(C=2SC=3C(=O)NC(=NC=3C=2)[C@H]2N3CCC(CC3)C2)=C1C XGVXKJKTISMIOW-ZDUSSCGKSA-N 0.000 description 1
- ZVCDLGYNFYZZOK-UHFFFAOYSA-M sodium cyanate Chemical compound [Na]OC#N ZVCDLGYNFYZZOK-UHFFFAOYSA-M 0.000 description 1
- QJDUDPQVDAASMV-UHFFFAOYSA-M sodium;ethanethiolate Chemical compound [Na+].CC[S-] QJDUDPQVDAASMV-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008174 sterile solution Substances 0.000 description 1
- 239000012258 stirred mixture Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 239000012089 stop solution Substances 0.000 description 1
- 125000003011 styrenyl group Chemical class [H]\C(*)=C(/[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 125000005415 substituted alkoxy group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000005420 sulfonamido group Chemical group S(=O)(=O)(N*)* 0.000 description 1
- 150000003461 sulfonyl halides Chemical class 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000003765 sweetening agent 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
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 208000013076 thyroid tumor Diseases 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
- 238000000844 transformation Methods 0.000 description 1
- 125000005389 trialkylsiloxy group Chemical group 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
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 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
- 210000003932 urinary bladder Anatomy 0.000 description 1
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 1
- 238000007738 vacuum evaporation Methods 0.000 description 1
- LSGOVYNHVSXFFJ-UHFFFAOYSA-N vanadate(3-) Chemical compound [O-][V]([O-])([O-])=O LSGOVYNHVSXFFJ-UHFFFAOYSA-N 0.000 description 1
- 238000006886 vinylation reaction Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61P35/04—Antineoplastic agents specific for metastasis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- 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
-
- 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
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/0803—Compounds with Si-C or Si-Si linkages
- C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
- C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
Definitions
- This invention relates to quinazoline derivatives and methods of using the same, particularly as anti-cancer agents, in mammals.
- a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene (i.e. a gene which, on activation, leads to the formation of malignant tumor cells).
- oncogenes encode proteins which are aberrant tyrosine kinases capable of causing cell transformation.
- the overexpression of a normal proto-oncogenic tyrosine kinase may also result in proliferative disorders, sometimes resulting in a malignant phenotype.
- Receptor tyrosine kinases are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor, a transmembrane domain, and an intraceliular portion which functions as a kinase to phosphorylate specific tyrosine residues in proteins and hence to influence cell proliferation. It is known that such kinases are frequently aberrantly expressed in common human cancers such as breast cancer, gastrointestinal cancer such as colon, rectal or stomach cancer, leukemia, and ovarian, bronchial or pancreatic cancer.
- epidermal growth factor receptor which possesses tyrosine kinase activity is mutated and/or overexpressed in many human cancers such as brain, lung, squamous cell, bladder, gastric, breast, head and neck, oesophageal, gynecological and thyroid tumors.
- inhibitors of receptor tyrosine kinases are useful as a selective inhibitors of the growth of mammalian cancer cells.
- erbstatin a tyrosine kinase inhibitor selectively attenuates the growth in athymic nude mice of a transplanted human mammary carcinoma which expresses epidermal growth factor receptor tyrosine kinase (EGFR) but is without effect on the growth of another carcinoma which does not express the EGF receptor.
- EGFR epidermal growth factor receptor tyrosine kinase
- U.S. Patent No.4,012,513 discloses certain 1-(heterocyclic)-indol-3-yl-acetic acid derivatives that have anti-inflammatory, analgesic and antipyretic activity.
- This invention is directed to quinazoline derivatives, particularly 4-amino-quinazolines, that are useful as anti-cancer agents.
- the compounds of this invention have the Formula I
- X is methylene, thio, -N(H)- or oxy
- Y completes a 5 or 6 membered aromatic, or partially saturated ring which may incorporate an oxygen or sulfur atom;
- T is methylene, -N(H)-, thio or oxy
- D may be saturated carbon, oxy or thio
- A completes a 7 to 9 membered mono-unsaturated mono-aza ring
- R 1 for each occurrence is independently
- any phenyl in a R 1 substituent is optionally mono- or di- substituted with halo, nitro, trifluoromethyl, hydroxy, (C 1 -C 4 )alkoxy or (C 1 -C 4 )alkyl and said (C 1 -C 4 )alkylenedioxy is linked at both ends to the quinazoline moiety;
- R 2 for each occurrence is independently mono-, di- or tri-fluoromethyl, halo, nitro, hydroxy, amino, azido, isothiocyano, (C 1 -C 4 )alkyl, phenyl, thienyl, (C 1 -C 4 )alkoxy, benzyloxy, phenoxy, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 4 )alkylenedioxy, cyano, benzoylamino.trifluoromethylcarbonylamino, (C 1 -C 4 )alkanoylamino, (C 1 -C 4 )alkanoyl, N-mono- or N , N-di-(C 1 -C 4 )alkylamino , (C 1 -C 4 )alkylsuifonylamino , trifluoromethylsulfonylamin
- R 3 for each occurrence is independently hydroxy, amino, N-mono- or N,N-di-(C 1 -C 4 )alkylamino, sulfo, or (C 1 -C 4 )alkoxy (provided that such groups are not attached to a ring carbon which is adjacent to an oxy, thio or -N-), or R 3 for each occurrence is independently carboxy, hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl, mono-N- or di-N,N-(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl, morpholino (C 1 -C 4 )alkyl, 4- (C 1 -C 4 )alkyl-piperazin-1 -yl(C 1 -C 4 )alkyl , carboxy(C 1
- n 0-4;
- p 0, 1 or 2;
- q 0, 1 or 2;
- a first group of preferred compounds of Formula I consists of those compounds wherein
- R 1 for each occurrence is independently hydroxy, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, amino(C 2 -C 4 )alkyl, amino(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkylenedioxy, hydroxy(C 1 -C 4 )alkyl(C 1 -C 4 )alkylenedioxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl(C 1 -C 4 )alkylenedioxy, mono-N- or di-N,N-(C 1 -C 4 )alkylamino(C 2 -C 4 )alkoxy, 3- or 4-(C 1 -C 4 )alkoxy-(2-hydroxy)-(C 3 -C 4 )alkoxy, carboxy(C
- R 2 for each occurrence is independently nitro, halo, (C 1 -C 4 )alkyl, pyrrol-1-yl, hydroxyl, amino, mono-N- or di-N,N-(C 1 -C 4 )alkylamino, amino(C 1 -C 4 )alkyl, azido, ethenyl, ethynyl, (C 1 -C 4 )alkylenedioxy, phenyl or (C 1 -C 4 )alkylthio;
- R 3 for each occurrence is independently hydroxy(C 1 -C 4 )alkyl, (C 1 -C 4 )alkyl, amino(C 1 -C 4 )alkyl, carboxy(C 1 -C 4 )alkyl or mono-N- or di-N,N-(C 1 -C 4 )alkylamino(C 1 -C 4 )alkyl;
- n 0, 1 or 2;
- p is 0 or 1
- n 0, 1 , 2, or 3.
- X is -N(H)-
- R 1 for each occurrence is substituted independently in the 6 and/or 7 position.
- a second group of especially preferred compounds within the above first group of preferred compounds of Formula I are compounds wherein
- R 1 for each occurrence is substituted in the 6 and/or 7 position.
- a third group of especially preferred compounds within the above first group of preferred compounds of Formula I are compounds wherein
- n 1 , 2 or 3;
- R 1 for each occurrence is substituted independently in the 6 and/or 7 positions and is (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkoxy, carboxy(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 4 )alkoxy, imidazol-1 -yl-(C 2 -C 4 )alkoxy, morpholino(C 2 -C 4 )alkoxy, 4-(C 1 -C 4 )alkylpiperazin-1 -yl-(C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-2-hydroxy(C 3 -C 4 )alkoxy, amino, (C 1 -C 4 ) alkylamino
- R 2 for each occurrence is independently 4-hydroxy, 4-amino, 5-fluoro, 5-hydroxy, 5-amino, 6-halo, 6-methyl, 6-ethenyl, 6-ethynyI, 6-nitro or 7-methyl.
- Particularly preferred compounds within the above group of especially preferred compounds are compounds wherein
- R 2 for each occurrence is independently halo, nitro, hydroxy or methyl
- R 1 is (C 1 -C 4 )alkoxy or (C 1 -C 4 )alkyl
- n 2;
- n 1 or 2.
- a. m is 2;
- R 1 is 6-methoxy
- R 1 is 7-methoxy
- n 2 ;
- R 2 is 5-fluoro
- R 2 is 6-bromo
- R 1 is 6-(2-methoxyethoxy);
- R 1 is 7-(2-methoxyethoxy) ;
- n 1 ;
- R 2 is 6-chloro
- R 1 is 6-methoxy
- R 1 is 7-(2-hydroxyethoxy);
- n 1 ;
- R 2 is 6-chloro; d. m is 1 ;
- R 1 is 6-amino
- n 1 ;
- R 2 is 6-chloro
- R 1 is 6-methoxy
- R 1 is 7-(3-hydroxypropoxy); n is 1;
- R 2 is 6-chloro
- R 1 is 7-(2-imidazol-1-yl-ethoxy); R 1 is 6-methoxy;
- n 1;
- R 2 is 6-chloro
- R 1 is 6-methoxy
- R 1 is 7-methoxy
- n 1 ;
- R 2 is 5-amino
- R 1 is 6-methoxy
- R 1 is 7-(2-methoxy-ethoxy); n is 2 ;
- R 2 is 5-fluoro
- R 2 is 6-bromo
- R 1 is 6-methoxy
- R 1 is 7-methoxy
- n 2;
- R 2 is 5-amino
- R 2 is 6-chloro
- R 1 is 6-methoxy
- R 1 is 7-(2-hydroxy-3-methoxy)propoxy
- n 1 ;
- R 2 is 6-chloro.
- a second group of preferred compounds of Formula I are those compounds wherein
- the B six membered ring has 0, 1 or 2 double bonds in the dotted line region; n is 0-2;
- R 2 for each occurrence is independently halo, hydroxy or (C 1 -C 4 )alkyl
- n 0, 1 or 2;
- R 1 for each occurrence is substituted independently in the 6 and/or 7 positions and is hydroxy, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, amino(C 2 -C 4 )alkyl, amino(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkylenedioxy, hydroxy(C 1 -C 4 )alkyl(C 1 -C 4 )alkylenedioxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl(C 1 -C 4 )alkylenedioxy, mono-N- or di-N,N-(C 1 -C 4 )alkylamino(C 2 -C 4 )alkoxy, 3- or 4-(C 1 -C 4 )alkoxy-(2-hydroxy)-(C 3 -
- a third group of preferred compounds of Formula I are those compounds wherein
- n 0, 1 or 2;
- R 2 for each occurrence is independently halo, hydroxy, amino, nitro, trifluoromethyl, ethenyl, ethynyi or (C 1 -C 4 )alkyl;
- n 0, 1 or 2;
- R 1 for each occurrence is substituted independently in the 6 and/or 7 positions and is hydroxy, (C 1 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, amino(C 2 -C 4 )alkyl, amino(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkoxy, (C 1 -C 4 )alkylenedioxy, hydroxy(C 1 -C 4 )alkyl(C 1 -C 4 )alkylenedioxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkyl(C 1 -C 4 )alkylenedioxy, mono-N- or di-N,N-(C 1 -C 4 )alkylamino(C 2 -C 4 )alkoxy, 3- or 4- (C 1 -C 4 )alkoxy-(2-hydroxy)-(C 3 -
- R 2 for each occurrence is independently halo, nitro, hydroxy, (C 1 -C 4 )alkyl or trifluoromethyl;
- R 1 is (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylenedioxy or (C 1 -C 4 )alkyl;
- n 2;
- n 1 or 2.
- Yet another aspect of this invention is a group of preferred compounds within the Formula I compounds, such compounds having the Formula IZ
- each R 1 taken independently is hydrogen, trifluoromethyl, halo, nitro, hydroxy, amino, (C 1 -C 4 )alkyl, carboxy, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy(C 1 -C 4 )alkylene, (C 1 -C 4 )alkoxy(C 2 -C 4 )alkoxy, hydroxy(C 2 -C 4 )alkoxy, trifluoromethyloxy, (C 1 -C 4 )alkoxycarbonyl,(C 1 -C 4 )alkylenedioxy, (C 1 -C 4 )alkylsulfinyl, (C 1 -C 4 )alkylsulfonyl, pyrrolidin-1-yl, piperidin-1-yl, morpholino 4-(C 1 -C 4 )alkylpiperazin-1-yl, carbamoyl, N,N-di-(
- each R 3 taken independently is hydroxy, N,N-di-(C 1 -C 4 )alkylamino, sulfo, (C 1 - C 4 )alkoxy, provided that such groups are not attached to a ring carbon which is adjacent to an -O- or -S- and that such groups are not at the 2 position, carboxy, hydroxy(C 1 -C 3 )alkylene, (C 1 -C 4 )aIkoxy(C 1 -C 3 )alkylene, N,N-di-(C 1 -C 4 )alkylamino(C 1 - C 3 )alkylene, carboxy(C 1 -C 3 )aIkylene, (C 1 -C 4 )alkoxycarbonyl or sulfo(C 1 -C 3 )alkylene; n is 1 or 2;
- p 0, 1 or 2;
- m 1 , 2 or 3.
- Yet another aspect of this invention is directed to a method for treating a hyperproliferative disorder in a mammal by administering to a mammal suffering from a hyperproliferative disorder, a hyperproliferative disorder treating amount of a Formula I compound.
- This invention is also directed to pharmaceutical compositions for the treatment of a hyperproliferative disorder in mammals which comprise a hyperproliferative disorder treating amount of a compound of the Formula I and a pharmaceutically acceptable carrier.
- halo is meant chloro, bromo, iodo, or fluoro.
- alkyl straight chain or branched saturated hydrocarbon.
- mono-unsaturated is meant that the A ring's only unsaturated bond is the bond shared with the benzene ring.
- reaction-inert solvent refers to a solvent which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product.
- the Formula I compounds, or a pharmaceutically acceptable salt thereof may be prepared by any process known to be applicable to the preparation of chemicallyrelated compounds.
- the Formula I quinazolines may be made by preparing the 4-amino adjunct of the appropriately substituted quinazoline using the appropriately substituted amine.
- the appropriately substituted 4-haloquinazoline (or a quinazoline bearing a suitable dispiaceable leaving group in the 4-position such as aryloxy, alkyl sulfonyloxy such as trifluoromethanesuffonyloxy, arylsurfbnyloxy, trialkyl-siloxy, cyano, pyrazolo, triazolo or tetrazolo), preferably a 4-chloroquinazoline, is combined with the appropriate amine in a solvent such as a (C 1 -C 6 )alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloroform, acetonitrile, tetrahydrofuran (THF), 1 ,4-dioxane, dimethylsulfoxide or other aprotic solvent.
- a solvent such as a (C 1 -C 6 )alcohol, dimethylformamide, N-methylpyrrolidin-2-one, chloro
- This combination may occur in the presence of a base, and it is preferred that this combination occurs in the presence of an alkali or alkaline earth metal carbonate or hydroxide, or a tertiary amine base, such as pyridine, 2,6-lutidine, collidine, N-methyl-morphoiine, triethyiamine, diisopropylethylamine, 4-dimethylamino-pyridine or N.N-dimethylaniline.
- bases are hereinafter refered to as suitable bases.
- the mixture is maintained at a temperature of about ambient to about reflux, preferably about 35 °C to about reflux, until substantially no remaining 4-haloquinazoline can be detected, typically about 2 hours to about 24 hours.
- the reaction is performed under an inert atmosphere such as dry nitrogen gas.
- the reactants are combined stoichiometrically when an amine base is used (alternatively, if an amine base is not used an excess of the amine may be used) however, for those compounds where a salt (typically HCI) of an amine is used, it is preferable to use excess amine base, generally an extra equivalent of amine base.
- a salt typically HCI
- a sterically hindered amine such as a 2-alkylindoline
- very reactive 4-haIoquinazoline it is preferable to use t-butyl alcohol or a polar aprotic solvent such as dimethylformamide, dimethylacetamide, or N-methylpyrolidin-2-one as the solvent.
- the reduction may conveniently be carried out by any of the many procedures known for such transformations.
- the reduction may be carried out, for example, by the hydrogenation of a solution of the nitro compound in a reaction-inert solvent in the presence of a suitable metal catalyst such as palladium or platinum.
- suitable metal catalyst such as palladium or platinum.
- suitable reducing agents are, for example, sodium dithionite in formic acid or an activated metal such as activated iron (produced by washing iron powder with a dilute solution of an acid such as hydrochloric acid).
- the reduction may be carried out by heating a mixture of the nitro compound and the activated metal in a solvent such as a mixture of water and an alcohol, for example, methanol or ethanol, to a temperature in the range, for example, 50 to 150°C, conveniently at or near 70°C.
- a solvent such as a mixture of water and an alcohol, for example, methanol or ethanol
- nitrogen protecting groups can be used.
- groups include (C 1 -C 6 )alkoxycarbonyl, optionally substituted benzyloxycarbonyl, aryloxycarbonyl, trityl, vinyloxycarbonyl, o-nrtrophenyisulfonyl, diphenylphosphinyl, p-toluenesuffonyl, and benzyl.
- the addition of the nitrogen protecting group may be carried out in a chlorinated hydrocarbon solvent such as methylene chloride or 1 ,2-dichloroethane, or an ethereal solvent such as glyme, diglyme or THF, in the presence or absence of a tertiary amine base such as triethylamine, diisopropylethylamine or pyridine, preferably triethylamine, at a temperature from about 0°C to about 50°C, preferably about ambient temperature.
- a chlorinated hydrocarbon solvent such as methylene chloride or 1 ,2-dichloroethane
- an ethereal solvent such as glyme, diglyme or THF
- a tertiary amine base such as triethylamine, diisopropylethylamine or pyridine, preferably triethylamine, at a temperature from about 0°C to about 50°C, preferably about ambient temperature.
- the protecting groups
- the protecting group may be removed by deprotecting methods known to those skilled in the art such as trifluoroacetic acid in methylene chloride for the tert-butoxycarbonyl protected products.
- deprotecting methods known to those skilled in the art such as trifluoroacetic acid in methylene chloride for the tert-butoxycarbonyl protected products.
- the cleavage reaction may conveniently be carried out by any of the many procedures known for such a transformation.
- Treatment of the quinazoline derivative of Formula I with molten pyridine hydrochloride (20-30 eq.) at 150 to 175°C may be employed for such O-dealkylations.
- the reaction may be carried out, for example, by treatment of the quinazoline derivative with an alkali metal (C 1 - C 4 )alkylsulphide such as sodium ethanethiolate or, for example, by treatment with an alkali metal diarylphosphide such as lithium diphenylphosphide.
- the cleavage reaction may conveniently be carried out, for example, by treatment of the quinazoline derivative with a boron or aluminum trihalide such as boron tribromide.
- a reaction-inert solvent such as boron tribromide.
- a suitable oxidizing agent is, for example, an agent known in the art for the oxidation of thio to sulphinyl and/or sulphonyl, for example, hydrogen peroxide, a peracid (such as 3-chloroperbenzoic, performic or peracetic acid), an alkali metal peroxysulphate (such as potassium peroxymonosulphate), chromium trioxide or gaseous oxygen in the presence of platinum.
- the oxidation is generally carried out under as mild conditions as possible and with the required stoichiometric amount of oxidizing agent in order to reduce the risk of over oxidation and damage to other functional groups.
- reaction is carried out in a suitable solvent such as methylene chloride, chloroform, acetone, tetrahydrofuran or tert-butyl methyl ether and at a temperature, for example, -25 to 50°C, conveniently at or near ambient temperature, that is in the range of 15 to 35°C.
- a milder oxidizing agent may also be used, for example sodium or potassium metaperiodate, conveniently in a polar solvent such as acetic acid or ethanol.
- a suitable acylating agent is, for example, any agent known in the art for the acylation of amino to acylamino, for example an acyl halide (e.g., a (C 2 -C 4 )alkanoyl chloride or bromide or a benzoyl chloride or bromide), an alkanoic acid anhydride or mixed anhydride (e.g., (C 2 -C 4 )alkanoic acid anhydride such as acetic anhydride or the mixed anhydride formed by the reaction of an alkanoic acid and a (C 1 -C 4 )alkoxycarbonyl halide, for example (C 1 -C 4 )alkoxycarbonyl chloride, in the presence of a suitable base).
- an acyl halide e.g., a (C 2 -C 4 )alkanoyl chloride or bromide or a benzoyl chloride or bromide
- a suitable acylating agent is, for example, a cyanate, for example an alkali metal cyanate such as sodium cyanate or, for example, an isocyanate such as phenyl isocyanate.
- N-Surfonylations may be carried out with suitable sulfonyl halides or suifonylanhydrides in the presence of a tertiary amine base.
- the acylation or surfonylation is carried out in a reaction-inert solvent and at a temperature, in the range, for example, -30 to 120°C, conveniently at or near ambient temperature.
- R 1 is (C 1 -C 4 )alkoxy or substituted (C 1 -C 4 )alkoxy or R 1 is (C 1 -C 4 )alkylamino or substituted mono-N- or di-N,N-(C 1 -C 4 )alkylamino
- the alkylation, preferably in the presence of a suitable base, of a Formula I compound wherein R 1 is hydroxy or amino as appropriate may be preferred.
- a suitable alkylating agent is, for example, any agent known in the art for the alkylation of hydroxy to alkoxy or substituted alkoxy, or for the alkylation of amino to alkylamino or substituted alkylamino, for example an alkyl or substituted alkyl halide, for example a (C 1 -C 4 )alkyl chloride, bromide or iodide or a substituted (C 1 -C 4 )alkyl chloride, bromide or iodide, in the presence of a suitable base in a reaction-inert solvent and at a temperature in the range, for example, 10 to 140° C, conveniently at or near ambient temperature.
- a suitable base in a reaction-inert solvent and at a temperature in the range, for example, 10 to 140° C, conveniently at or near ambient temperature.
- reaction for the production of those compounds of Formula I wherein R 1 is an amino-, oxy- or cyano-substituted (C 1 -C 4 )alkyl substitue ⁇ t, the reaction, preferably in the presence of a suitable base, of a Formula I compound wherein R 1 is a (C 1 -C 4 )alkyl substituent bearing a displaceable group with an appropriate amine, alcohol or cyanide is appropriate.
- the reaction is preferably carried out in a reaction-inert solvent or diluent and at a temperature in the range, for example, 10 to 100°C, conveniently at or near ambient temperature.
- the hydrolysis may conveniently be performed, for example, under basic conditions such as an alkali metal hydroxide mediated hydrolysis as illustrated in the accompanying Examples.
- the reaction is preferably carried out, usually in the presence of a suitable base, in a reaction-inert solvent or diluent and at a temperature in the range, for example, 10 to 180°C, conveniently in the range 100 to 150°C.
- the reaction is preferably carried out, usually in the presence of a suitable base, in a reaction-inert solvent or diluent and at a temperature in the range, for example, 10 to 100°C, conveniently at or near ambient temperature.
- Suitable acylating agents are for example any agent known in the art for acylation of hydroxyaryl moieties to alkanoyloxy aryl.
- (C 2 -C 4 )alkanoyl halides, (C 2 -C 4 )alkanoyl anhydrides or mixed anhydrides, and suitable substituted derivatives thereof may be employed, typically in the presence of a suitable base.
- (C 2 -C 4 )alkanoic acids or suitably substituted derivatives thereof may be coupled with a Formula I compound wherein R 1 is hydroxy with the aid of a condensing agent such as a carbodiimide.
- suitable carbamoylating agents are for example a cyanate or an alkyl or aryl isocyanate, typically in the presence of a suitable base.
- a suitable intermediate such as the chloroformate, succinimido carbonate, or imidazolocarbonyl derivative of a quinazoline of Formula I in which R 1 is hydroxy may be generated, for example by treatment of said derivative with phosgene (or a phosgene equivalent), disuccinimidocarbonate, or carbonyldiimidazole.
- phosgene or a phosgene equivalent
- disuccinimidocarbonate or carbonyldiimidazole.
- the resulting intermediate may then be reacted with an appropriate amine or substituted amine to produce the desired carbamoyl derivatives.
- the activation and coupling of a Formula I compound wherein R 1 is carboxy may be performed by a variety of methods known to those skilled in the art. Suitable methods include activation of the carboxyl as an acid halide, azide, symmetric or mixed anhydride, or active ester of appropriate reactivity for coupling with the desired amine. Examples of such types of intermediates and their production and use in couplings with amines may be found extensively in the literature; for example M. Bodansky and A. Bodansky, The Practice of Peptide Synthesis", Springer,-Verlag, New York, 1984.
- the resulting Formula I compounds may be isolated and purified by standard methods, such as solvent removal and recrystallization or chromatography, if desired.
- the desired Formula II, III, IV or V indoline based compounds may be conveniently prepared by reduction of the corresponding Formula IX indole based compounds (the dotted line circles refer to the fused monocyclic and bicyclic moieties of Formulas III, IV and V).
- the Formula IX compounds bearing aprotic R 2 or R 3 substituents are treated with ZnBH 4 (prepared from ZnCI 2 and NaBH 4 according to W.J. Gensier et al., J. Am. Soc. 82, 6074-6081 (1960)) in an etheral solvent such as diethyl ether at a temperature of about 10°C to about 40° C, preferably at ambient.
- ZnBH 4 prepared from ZnCI 2 and NaBH 4 according to W.J. Gensier et al., J. Am. Soc. 82, 6074-6081 (1960)
- an etheral solvent such as diethyl ether
- the Formula IX compounds may be treated with a borane/pyridine complex (or other borane/tertiary amine complex) in the absence of solvent, or presence of solvent, such as tetrahydrofuran at a temperature of about 10°C to about 30° C, preferably at ambient, followed by treatment of the mixture with an acid such as hydrochloric acid, trifluoroacetic acid or acetic acid to provide compounds of Formula II, III, IV or V.
- a borane/pyridine complex or other borane/tertiary amine complex
- solvent such as tetrahydrofuran
- the desired Formula IX compounds wherein p is one or two may be prepared from the appropriate Formula XIV compound via a Fisher Indole synthesis or modification thereof (The Fischer Indole Synthesis", B. Robinson, Wiley Interscience, N.Y., 1982; or alternatively U. Pindur, R. Adam, J. Het. Chem. 25, 1-8 (1988) and references therein).
- the Formula IX indoles wherein p is zero may typically be prepared from the Formula XII aniline-type compounds from either of two routes: via the Formula X compounds or the Formula XI compounds. However, the route via Formula XI compound is not preferred for preparation of nitro or carboalkoxy substituted indoles.
- Formula X compound (e.g., isatins, oxindoles) by reduction, or from the appropriate Formula XI compound via a reductive cyclization.
- the Formula X compound is treated with borane in an etheral solvent such as tetrahydrofuran at a temperature of about 0°C to about 30°C, preferably ambient.
- the Formula XI compound is treated with sodium borohydnde in an etheral solvent such as dioxane at a temperature of about 20°C to about 100°C, preferably reflux.
- the desired Formula X isatin compound may be prepared from the appropriate Formula XII compound by combination with chloral hydrate and hydroxylamine followed by an acid catalyzed cyclization, such process being adapted from Org. Syn., Coll. Vol. I, 327-330.
- the desired Formula XI compound may be prepared from the appropriate Formula XII compound by a Lewis acid catalyzed ortho-acylation.
- the typical preparation is adapted from T. Sugasawa et al., J. Org. Chem. 44 (4), 578-586 (1979).
- the Formula XII compound is reacted with 2-chloroac ⁇ tonrtrile in the presence of boron trichloride and an auxiliary acid catalyst such as aluminum chloride, typically in an aromatic solvent such as xylene, toluene or chlorobenzene at a temperature of about 50°C to about reflux.
- the desired Formula XII aminoaromatic compounds may be prepared from the appropriate corresponding nitroaromatic compounds by various reductive methods (such as those given above).
- indoline-based compounds may be prepared from other of the above described indoline-based compounds by further modification prior to combination with the quinazoline moieties of Formula I.
- the appropriately substituted desired 5-hydroxyindole may be prepared from the corresponding indolines by hydroxylation according to an adaptation of the procedure of H.J. Teuber and G. Staiger, Chem. Ber. 89, 489-508 (1956) followed by reduction to achieve the corresponding 5-hydroxyindoline.
- potassium nitrosodisulfonate in aqueous phosphate buffer is added to the appropriately substituted indoline in acetone at neutral pH at a temperature of about 0°C to about 25° C to produce the 5-hydroxyindole derivative, which may be subsequently reduced with borane/pyridine/aqueous HCI to afford the 5-hydr oxyindoline.
- the appropriately substituted desired bromoindolines may be prepared from the corresponding indolines by bromination analogous to the procedure described by: Y. Miyake and Y. Kikugawa, J. Het. Chem. 20, 349-352 (1983).
- This procedure may also be utilized for brominations of other larger rings (e.g., 1,2,3,4-tetrahydroquinolines, 2,3,4,5-tetrahydro-1H-benzo[b]azepines and 1 ,2,3,4,5,6-hexahydro-benzo[b]azocines, particularly in the 5/7, 6/8, and 7/9-positions).
- the appropriately substituted indoline is reacted with bromine in the presence of a halophile such as silver surfate under strongly acidic conditions at 0°C to 25°C.
- hydroxyalkylindolines can be prepared by reduction of the appropriate carboxylic acids or their esters, for example according to E. J. Corey et al. J. Am. Chem. Soc. 92 (8), 2476-2488 (1970).
- the appropriately substituted desired alkyl, alkenyl or allylic substituted indolines may be prepared from the corresponding trialkylsilyl-protected 4-, 5- or 6-haloindolines via a Nickel-phosphine catalyzed Grignard addition analogous to the general procedure described by K. Tamao et al., Bull. Chem. Soc. Japan 49, 1958-1969 (1976).
- the indoline is N-protected by reaction with tert-butyldimethylsilyltriflate in a halogenated solvent in the presence of a tertiary amine.
- N-siiylated halo-indoline is subsequently reacted with the appropriate alkyl, alkenyl or allylic Grignard in an etheral solvent in the presence of a suitable nickel-phosphine complex, typically [Ni(dppe)CI 2 ].
- a suitable nickel-phosphine complex typically [Ni(dppe)CI 2 ].
- Subsequent treatment with methanol containing a trace of acid such as trifuoroacetic acid, or with fluoride anion in a suitable solvent such as THF liberates the desired indoline product.
- the desired substituted alkenyl- or alkynyl- indolines may be prepared by the palladium-catalyzed vinylation or alkynylation of the appropriate 4-, 5-, 6- or 7- haloindoline, for example, according to references reviewed by V. N. Kalinin, Synthesis 1991 , 413-432.
- alkynylindolines generally the corresponding bromo- or iodoindoline in diethylamine is treated with an alkyl-, appropriately substituted alkyl, or trimethylsilylacetylene in the presence of catalytic amounts of Cul and Pd(PPh 3 ) 4 at reflux.
- Certain Formula I quinazolines can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated as well as unsolvated forms which possess activity against hyperproliferative diseases.
- a suitable pharmaceutically-acceptable salt of a quinazoline derivative of the invention is, for example, an acid-addition salt of a quinazoline derivative of the invention which is sufficiently basic, for example an acid-addition salt with, for example, an inorganic or organic acid, for example, hydrochloric, hydrobromic, sulphuric, phosphoric, methanesuifonic, benzenesulfonic, trifluoroacetic, citric, lactic or maleic acid.
- a suitable pharmaceutically-acceptable base-addition salt of a quinazoline derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a lithium, sodium or potassium salt; an alkaline earth metal salt, for example a calcium or magnesium salt; an ammonium salt; or a salt with an organic base which affords a physiologically-acceptable cation for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. All such salts are within the scope of this invention and they can be prepared by conventional methods.
- they can be prepared simply by contacting the acidic and basic entities, usually in a stoichiometric ratio, in either an aqueous, non-aqueous or partially aqueous medium, as appropriate.
- the salts are recovered either by filtration, by precipitation with a non-solvent, preferably an etheral or hydrocarbon solvent, followed by filtration, by evaporation of the solvent, or, in the case of aqueous solutions, by lyophilization, as appropriate.
- Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known per se., for example, by chromatography and/or fractional crystallization.
- Enantiomers can be separated by converting the enantiomeric mixtures into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., alcohol or acid), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomer.
- an appropriate optically active compound e.g., alcohol or acid
- enantiomers may be resolved by differential crystallizations as diastereomeric salts. All such isomers, including diastereomers and enantiomers are considered as part of the invention.
- the compounds of this invention are potent inhibitors of the erbB family of oncogenic and protooncogenic protein tyrosine kinases such as epidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thus are all adapted to therapeutic use as antiproliferative agents (e.g., anticancer) in mammals, particularly humans.
- EGFR epidermal growth factor receptor
- erbB2 HER3, or HER4
- HER4 epidermal growth factor receptor
- the compounds of this invention are therapeutants or prophylactics for the treatment of a variety of benign or malignant human tumors (renal, liver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate, pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas, gliobiastomas, various head and neck tumors), and other noncancerous hyperplastic disorders such as benign hyperplasia of the skin (e.g., psoriasis) or prostate (e.g., BPH).
- benign hyperplasia of the skin e.g., psoriasis
- prostate e.g., BPH
- Such activity against benign disorders can be determined by standard assays such as described in J. Invest. Dermatol. 98, 296-301 (1992). It is in addition expected that a quinazoline of the present invention may possess activity against a range of leukemias and lymphoid malignancies.
- the compounds of Formula I also potentiate responses to conventional cancer chemotherapies and radiotherapy in a dose and schedule-dependent manner based upon the substantial synergy observed between neutralizing anti-EGFR antibodies and conventional chemotherapeutants (J. Baselga et al., J. Nat. Cancer
- the compounds of Formula I may also be expected to be useful in the treatment of additional disorders in which aberrant expression, ligand/receptor interactions, activation, or signalling events related to various protein tyrosine kinases, whose activity is inhibited by the agents of Formula I, are involved.
- Such disorders may include those of neuronal, glial, astrocytal, hypothalamic, and other glandular, macrophagal, epithelial, stromal, and blastocoelic nature in which aberrant function, expression, activation or signalling of the erbB tyrosine kinases may be involved.
- compounds of Formula I may have
- Activity of compunds of Formula I in vftro can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., Lys 3 - Gastrin or polyGluTyr (4:1) random copolymer (I. Posner et. al., J. Biol. Chem. 267 (29), 20638-47 (1992)) on tyrosine by epidermal growth factor receptor kinase by a test compound relative to a control.
- an exogenous substrate e.g., Lys 3 - Gastrin or polyGluTyr (4:1) random copolymer (I. Posner et. al., J. Biol. Chem. 267 (29), 20638-47 (1992)
- Affinity purified, soluble human EGF receptor (96 ng) is obtained according to the procedure in G. N. Gill, W.
- the phosphorylation reaction is initiated by addition of 20 ⁇ l 33 P-ATP/ substrate mix (120 ⁇ M Lys 3 -Gastrin (sequence in single letter code for amino acids, KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4, 40 ⁇ M ATP, 2 ⁇ Ci ⁇ -[ 33 P]-ATP) to the EGFr/EGF mix and incubated for 20 minutes at room temperature.
- the reaction is stopped by addition of 10 ⁇ I stop solution (0.5 M EDTA, pH 8; 2mM ATP) and 6 ⁇ l 2N HCI.
- the tubes are centrifuged at 14,000 RPM, 4°C, for 10 minutes.
- Incorporation in the absence of substrate is subtracted from all values as a background and percent inhibition is calculated relative to controls without test compound present.
- Activfty of compounds of Formula I in vivo can be determined by the amount of inhibition of tumor growth by a test compound relative to a control.
- the tumor growth inhibitory effects of various compounds are measured according to the methods of Corbett, T. H., et al. Tumor induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, with a Note on Carcinogen Structure", Cancer Res., 35, 2434-2439 (1975) and Corbett, T.
- Tumors are induced in the left flank by s.c. injection of 1 X 10 ⁇ log phase cultured tumor cells (human MDA-MB-468 breast or human HN5 head and neck carcinoma cells) suspended in 0.10 ml RPMI 1640.
- test animals (athymic mice) are treated with compound (formulated by dissolution in DMSO typically at a concentration of 50 to 100 mg/mL followed by 1:9 dilution into 0.1% Pluronic ⁇ P105 in 0.9% saline) by the test animals (athymic mice) are treated with compound (formulated by dissolution in DMSO typically at a concentration of 50 to 100 mg/mL followed by 1:9 dilution into 0.1% Pluronic ⁇ P105 in 0.9% saline) by the test animals (formulated by dissolution in DMSO typically at a concentration of 50 to 100 mg/mL followed by 1:9 dilution into 0.1% Pluronic ⁇ P105 in 0.9% saline) by the test animals (formulated by dissolution in DMSO typically at a concentration of 50 to 100 mg/mL followed by 1:9 dilution into 0.1% Pluronic ⁇ P105 in 0.9% saline) by the test animals (formulated by dissolution in DMSO typically at a concentration of 50 to 100
- TuW control - TuW test TuW control - TuW test
- the flank site of tumor implantation provides reproducible dose/response effects for a variety of chemotherapeutic agents, and the method of measurement (tumor diameter) is a reliable method for assessing tumor growth rates.
- Administration of the compounds of this invention can be via any method which enables delivery of the compounds to the site of action (e.g., cancer cells). These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical administration, etc.
- the amount of compound of this invention administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician.
- an effective dosage is in the range of approximately 0.1-100 mg/kg, preferably 1 to 35 mg/kg in single or divided doses. For an average 70kg human, this would amount to 0.05 to 7 g/day, preferably 0.2 to 2.5 g/day.
- a suitable formulation would include 0.01% to 5% of a compound of this invention, preferably 0.05% to 0.5%. Preferably the topical administration is applied directly to the site of affliction.
- the pharmaceutical composition of the invention may, for example, be in a form suitable for oral administration as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection as a sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository.
- the pharmaceutical composition may be in unit dosage forms suitable for single administration of precise dosages.
- the pharmaceutical compositions will include a conventional pharmaceutical carrier or excipient and a compound according to the invention as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.
- compositions for non-topical administration according to the invention may contain 0.1%-95% of the compound, preferably 1%-70%.
- the composition or formulation to be administered will contain a quantity of a compound according to the invention in an amount effective to alleviate or reduce the signs in the subject being treated, i.e., proliferative disorders, over the course of the treatment.
- Exemplary parenteral administration forms include solutions or suspensions of a compound according to the invention Formula I in sterile aqueous solutions, for example aqueous propylene glycol or dextrose solutions are employed. Such dosage forms can be suitably buffered, if desired.
- Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like.
- excipients such as citric acid
- disintegrants such as starch, alginic acid and certain complex silicates
- binding agents such as sucrose, gelatin and acacia.
- lubricating agents such as magnesium stearate, sodium lauryl suffate and talc are often useful for tableting purposes.
- Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules.
- Preferred materials therefore include lactose or milk sugar and high molecular weight polyethylene glycols.
- the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof.
- the anticancer treatment described above may be applied as a sole therapy or may involve, in addition to the quinazoline derivative of the invention, one or more other antitumor substances or radiotherapy. Such conjoint treatment may be achieved by way of the simultaneous, sequential, cyclic or separate dosing of the individual components of the treatment.
- Analytical reversed-phase HPLC (anal. RP18-HPLC) was performed by injecting samples dissolved in a water-miscible solvent onto a Perkin-Eimer
- Pecosphere ® 3X3C cartridge column (3mm X 3cm, C18; available from Perkin Elmer Corp., Norwalk, CT 06859) preceded by a Brownlee RP-8 Newguard precolumn (7 micron, 3.2mm X 15mm, available from Applied Biosystems Inc. San Jose, CA 95134) both of which were previously equilibrated in pH4.50, 200 mM NH 4 OAc buffer.
- Samples were eluted using a linear gradient of 0-100% MeCN/pH4.50, 200 mM NH 4 OAc over 10 minutes with a flow rate of 3.0 mL/min. Chromatograms were generated over the range 240-400nm using a Diode array detector.
- this product was prepared in 94% yield from indoline (2 eq.) and 4-chloro-6,7-dimethoxyquinazoline (1.0 eq) in i-PrOH. (M.P. 162-163°C; LC-MS: 308 (MH + ); anal. RP18-HPLC RT: 4.11 min.).
- this product was prepared in 92% yield from 4-chloro-indoline (2 eq.) and 4-chloro-6,7-dimethoxyquinazoline (1.0 eq) in i-PrOH. (M.P. 172-179°C (dec); LC-MS: 342 (MH + ); anal. RP18-HPLC RT: 4.60 min.).
- this product was prepared in 94% yield from 6-methyl-1 ,2,3,4-tetrahydroquinoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 147-148° C ; LC-MS: 336 (MH + ); anal. RP18-HPLC RT: 4.51 min.).
- this product was prepared in 66% recrystallized yield (from CHCI 3 /hexane) from 6-trifluoromethyl-1,2,3,4-tetrahydr oquinoline (2 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 184-185°C ; LC-MS: 390 (MH + ); anal. RP18-HPLC RT: 5.10 min.).
- this product was prepared in 78% yield from 6-iodo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxyquinazoiine (1.0 eq) in i-PrOH.
- the HCI salt was generated from the purified free base according to the procedure given in Example 2 (M.P. >230°C; GC/MS: 433 (M + ); anal. RP18-HPLC RT: 5.20 min.).
- this product was prepared in 91% yield from 6-methoxy-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH.
- the HCI salt was generated from the purified free base according to a procedure analogous to that given in Example 2. (M.P. 246-247° C(dec); LC-MS: 338 (MH + ); anal. RP18-HPLC RT: 4.27 min.).
- this product was prepared in 88% yield from 6-bromo-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH.
- the HCI salt was generated from the purified free base according to a procedure analogous to that given in Example 2. (M.P. 245-248° C(dec); LC-MS: 386, 388 (MH + ); anal. RP18-HPLC RT: 4.95 min.).
- this product was prepared in 57% yield from 2-hydroxymethyl-indoline (1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 145.5-147° C; LC-MS: 338 (MH + ); anal. RP18-HPLC RT: 4.03 min.).
- this product was prepared in 93% yield from 6-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in DMF. (M.P. 240-242° C; LC-MS: 400, 402 (MH + ); anal. RP18-HPLC RT: 5.13 min.).
- the hydrochloride salt was produced using procedures analogous to that as described for Example 2: M.P. 243-244°C.
- this product was prepared in 43% yield from 6-isopropyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 128-129° C ; LC-MS: 350 (MH + ); anal. RP18-HPLC RT: 5.51 min.).
- this product was prepared in 95% yield from 5-methoxy-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in hPrOH.
- the free-base obtained following column chromatography on silica (45% acetone/hexanes) was dissolved in minimal CH 2 CI 2 and treated with 1eq. of methanesulfonic acid in CH 2 CI 2 followed by dilution with several volumes of ether to precipitate the mesylate salt which was filtered and dried in vacuo. (M.P. 285-292° C (dec); LC-MS: 338 (MH + ); anal. RP18-HPLC RT: 3.82 min.).
- 6-Chloro-5-fluoro-indoline 157 mg, 0.915 mmol
- pyridine 48 ⁇ L
- 4-chloro-6,7-djmethoxy-quinazoline 210 mg, 0.895 mmol
- the mixture was partitioned between EtOAc and saturated aqueous NaHCO 3 and the organic phase was washed several times with water and brine, dried over MgSO 4(s) , filtered and concentrated in vacuo.
- this product was prepared in 49% yield from 6-chloro-5-hydroxy-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 268-275° C; LC-MS: 358 (MH + ); anal. RP18-HPLC RT: 3.45 min.).
- this product was prepared in 73% yield from 5-hydroxy-7-methyl-indoline (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 145-146° C (dec); LC-MS: 338 (MH + ); anal. RP18-HPLC RT: 3.20 min.).
- this product was prepared in 49% yield from 6-bromo-7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxyquinazoline (1.0 eq) in i-PrOH. (M.P. 200-205° C (dec); LC-MS: 370, 372 (MH + ); anal. RP18-HPLC RT: 5.76 min.).
- the precipitated orange solid was recovered by filtration, dried by azeotropic removal of H 2 O with CH 3 CN at 40°C in vacuo. dissolved in 15% i-PrOH/CHCI 3 (75 mL) and washed with saturated aqueous NaHCO 3 (2X). The organic phase was dried over Na 2 SO 4(a) , filtered and concentrated in vacuo. The residue ( ⁇ 800 mg) was triturated with CHCI 3 (60 mL) and filtered to recover the 6,7-diol (typically 200 mg, 94% purity; used without further purification)(M.P. 200° C (dec); LC-MS: 314 (MH + ); anal. RP18-HPLC RT: 4.07 min.).
- Example 72 4-(6-Chloro-2,3-dihydro-indol-1-yl)-6-methoxy-quinazolin-7-ol (100 mg, 0.305 mmol; from Example 70) was reacted with 2-bromoethyl methyl ether as described in Example 66 and worked-up as described for Example 1 to yield 53 mg of product which was converted to the methanesulfonate salt as outlined in Example 44. (M.P. 248° C (dec); LC-MS: 386 (MH + ); anal. RP18-HPLC RT: 4.56 min.).
- Example 72 4-(6-Chloro-2,3-dihydro-indol-1-yl)-6-methoxy-quinazolin-7-ol (100 mg, 0.305 mmol; from Example 70) was reacted with 2-bromoethyl methyl ether as described in Example 66 and worked-up as described for Example 1 to yield 53 mg of product which
- Example 44 The mixture was stirred at 50° C under N 2(g) for 5 hours and then worked-up as described for Example 1 to yield 131 mg of product which was converted to the methanesulfonate salt as outlined in Example 44. (M.P. 185° C (dec); LC-MS: 430 (MH + ); anal. RP18-HPLC RT: 4.68 min.).
- This product was produced in 50% yield from 4-(6-chloro-2,3-dihydro-indol-1-yl)-6-methoxy-quinazolin-7-ol and N-(2-hydroxyethyl)imidazole (1.1 eq.) in a manner analogous to that described for Example 76. (M.P. 162-168° C (dec); LC-MS: 422 (MH + ); anal. RP18-HPLC RT: 3.94 min.).
- Example 80 of free-base: 152-153°C), and salt formation analogous to that described for Example 78 the product was obtained in 84% yield. (M.P. 195-205° C (dec); LC-MS: 386 (MH + ); anal. RP18-HPLC RT: 3.95 min.).
- Example 80
- this product was prepared in 78% yield from 6-bromo-5-fluoro-indoline (1.1 eq.), and 4-chloro-6,7-bis-(2-methoxy-ethoxy)-quinazoline (1.0 eq) in i-PrOH. (M.P. of free-base: 146-148°C)(For.HCI salt: M.P. 215-223° C (dec); LC-MS: 492, 494 (MH + ); anal. RP18-HPLC RT: 4.64 min.).
- this product was prepared in 58% yield from 6-bromo-5-fluoro-indoline (1.1 eq.), and 4-chloro-6-methoxy-7-(2-methoxy-ethoxy)-quinazoline (1.0 eq) in i;PrOH. (M.P. of free-base: 150-150.5°C)(For HCI salt: M.P. 243-251 °C (dec); LC-MS: 448, 450 (MH + ); anal. RP18-HPLC RT: 4.79 min.).
- this product was prepared in 18% yield from 6-chloro-indoline and 4-chloro-7-methoxy-6-methylsurfanylquinazoline. (M.P. 210 °C; LC-MS: 358 (MH + )).
- Example 103 Utilizing a procedure analogous to that described in Example 1 , this product was prepared in 4% yield from 5-bromo-1 ,2,3,4-tetrahydroquinoline and 4-chloro-6,7dimethoxy-quinazoline. (film; LC-MS: 399 (MH + )).
- Example 103
- this product was prepared in 19% yield from 1 ,2,3,4-tetrahydroquinoline and (4-chloro-7-ethoxycarbonyimethoxy-quinazolin-6-yloxy)-acetic acid ethyl ester, (film; LC-MS: 465 (MH + )).
- reaction mixture was poured into 50 mL of water and extracted with 3 ⁇ 50 mL of ethyl acetate.
- the pooled organic layers were washed with 50 mL of brine, dried with magnesium suifate, filtered and vacuum evaporated to a yellow residue, 0.121 g.
- This was purified by chromatography using a Chromatotron mounted with a 2 mm silica gel plate and eluted with 5% methanol in chloroform. Pure product was isolated by vacuum evaporation of the appropriate fractions; 0.015 g (8.7%) M.P. 240-245 °C (dec) .
- Example 113 Chromatotron chromatography in Example 111 was treated in an identical manner with ethanolic HCI to give bright yellow solid, 0.0145g (13%): M.P. 281-282°C (dec); LC-MS: 325 (MH + ), 327 ((M+2)H + ).
- Example 113 Chromatotron chromatography in Example 111 was treated in an identical manner with ethanolic HCI to give bright yellow solid, 0.0145g (13%): M.P. 281-282°C (dec); LC-MS: 325 (MH + ), 327 ((M+2)H + ).
- Example 113 Chromatotron chromatography in Example 111 was treated in an identical manner with ethanolic HCI to give bright yellow solid, 0.0145g (13%): M.P. 281-282°C (dec); LC-MS: 325 (MH + ), 327 ((M+2)H + ).
- Example 113 Chromatotron chromatography in Example 111 was treated in an identical manner with ethanolic
- N-[4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-6-yl]-formamide (1.0055 g, 3.10 mmol) was slurried into 20 mL methanol, treated with 20 mL 1N HCI in methanol, and stirred at room temperature for one hour. Dilution to 125 mL with diethyl ether afforded yellow solid, 0.8430 g (82%; another .089 g obtained from subsequent cooling of mother liquor): M.P. 289-290° C (dec); LC-MS: 297 (MH + ), 299 ((M+2)H + ).
- Example 116 The compound of the preceding Example 116 (0.22 g 0.634 mmol) was reacted in 1 mL of a 50% solution of acetic formic anhydride in acetic acid for one hour and precipitated with 10 mL of ethyl ether. The solid thus obtained was filtered and dried in vacuo to give a yellow solid; 0.14 g (67%) M.P. 178-179°C.
- 6-Methyiindole (2.785g, 21.2 mmol) in dry Et 2 O (30 mL) was chilled to 0°C and a solution of ZnBH 4 in Et 2 O ( ⁇ 1.5 eq.; 215 mL of 0.15 M) was added. The mixture was stirred 3 days at 22 °C in darkness and then quenched by addition of 1 M aqueous HCI (until no further H 2(g) evolved on mixing) followed by basification to pH >10 with 2N NaOH.
- indolines were prepared in an analogous manner by treatment of the appropriately substituted indoles with 4-6 eq. of borane/pyridine complex (with 5-hydroxy-indole starting materials generated according to the procedure described below when necessary).
- This material was prepared from 3-fluoro-2-methylaniline via its ⁇ -chloromethyl ketone derivative in 46% overall yield utilizing a procedure analogous to that described above for Preparation 25 ((GC-MS: 149 (M + )).
- 6-lodo-indoline (499 mg, 2.04 mmol) was added to a mixture of Cul (77.5 mg, 0.407 mmol), Pd(PPh 3 ) 4 (113 mg, 0.097 mmol), and trimethylsilylacetylene (0.432 mL, 3.06 mmol) in degassed Et 2 NH (10 mL). The mixture was stirred at reflux under N 2(g) for 30 minutes. Solvent was removed in vacuo and the residue was flash chromatographed on silica (25% EtOAc/hexanes) to afford 364 mg of pure 6-trimethylsilanylethynyl-indoline (GC-MS: 215 (M + )).
- This material was conveniently prepared on muttigram scale from the cyclization of 2,4-dichlorophenethylamine in the presence of Na 2 CO 3 (s) (1.2 moi eq), Cu 2 CI 2 (0.01 mol eq) and 8-hydroxyquinoline (0.012 mol eq) in isoamyl alcohol (1 vol) at 130°C for 5 hours. After addition of hydrazine (0.0055 vol) and 1 hour reflux, the mixture was filtered, solvent was removed in vacuo (45° C @ ⁇ 10mm Hg) and 6-chloro-indoline was obtained pure by vacuum distillation (95-100°C @ 2mm Hg)(65-95%).
- 1,2,3,4,5,6-Hexahydro-benzo[b]azocine was prepared by the BH 3 /T ⁇ F mediated reduction of the 1,2,3,4,5,6-hexahydro-1-benzo[b]azocin-2-one in a manner analogous to that described above for preparation 41.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oncology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
Description
Claims
Priority Applications (14)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PL95315941A PL315941A1 (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclic substituted derivatives of quinazoline, methods of obtaining them and their application as anticarcinogenic agents |
US08/682,565 US5736534A (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
KR1019960704612A KR100225721B1 (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substitute quinazoline derivatives, processes for their preparation and their use as anti-cancer agents. |
RU96119255A RU2137762C1 (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substituted derivative of quinazoline, pharmaceutical composition |
CA002183655A CA2183655C (en) | 1994-02-23 | 1995-01-27 | 4-polycyclic amino-substituted quinazoline derivatives |
BR9506936A BR9506936A (en) | 1994-02-23 | 1995-01-27 | Quinazoline derivatives replaced with 4-heterocyclyl processes for their preparation and use as anti-cancer agents |
EP95905737A EP0746554A1 (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
AU29727/95A AU686843B2 (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
CZ19962413A CZ288955B6 (en) | 1994-02-23 | 1995-01-27 | Substituted quinazoline derivatives, their use and pharmaceutical preparations based thereon |
JP7522227A JP2890267B2 (en) | 1994-02-23 | 1995-01-27 | 4-Heterocyclyl-substituted quinazoline derivatives, their preparation and their use as anticancer agents |
MX9603593A MX9603593A (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents. |
NZ278135A NZ278135A (en) | 1994-02-23 | 1996-08-19 | Nitrogen containing heterocyclically substituted quinazoline derivatives and pharmaceutical compositions |
NO963506A NO963506L (en) | 1994-02-23 | 1996-08-22 | 4-Heterocyclyl-substituted quinazoline derivatives, process for their preparation and their use as anti-cancer agents |
FI963283A FI963283A0 (en) | 1994-02-23 | 1996-08-22 | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as cancer drugs |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US20025994A | 1994-02-23 | 1994-02-23 | |
US08/200,259 | 1994-02-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995023141A1 true WO1995023141A1 (en) | 1995-08-31 |
Family
ID=22740969
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB1995/000061 WO1995023141A1 (en) | 1994-02-23 | 1995-01-27 | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents |
Country Status (22)
Country | Link |
---|---|
US (1) | US5736534A (en) |
EP (1) | EP0746554A1 (en) |
JP (1) | JP2890267B2 (en) |
KR (1) | KR100225721B1 (en) |
CN (1) | CN1141633A (en) |
AU (1) | AU686843B2 (en) |
BR (1) | BR9506936A (en) |
CA (1) | CA2183655C (en) |
CO (1) | CO4340688A1 (en) |
CZ (1) | CZ288955B6 (en) |
FI (1) | FI963283A0 (en) |
HU (1) | HUT76291A (en) |
IL (1) | IL112673A0 (en) |
MX (1) | MX9603593A (en) |
NO (1) | NO963506L (en) |
NZ (1) | NZ278135A (en) |
PE (1) | PE4896A1 (en) |
PL (1) | PL315941A1 (en) |
RU (1) | RU2137762C1 (en) |
TW (1) | TW404946B (en) |
WO (1) | WO1995023141A1 (en) |
ZA (1) | ZA951458B (en) |
Cited By (91)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996016960A1 (en) * | 1994-11-30 | 1996-06-06 | Zeneca Limited | Quinazoline derivatives |
WO1997031611A2 (en) * | 1996-03-01 | 1997-09-04 | Chiron Corporation | Treatment of begnin prostatic hyperplasia |
WO1997042187A1 (en) * | 1996-05-06 | 1997-11-13 | Zeneca Limited | Oxindole derivatives |
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 |
US5714493A (en) * | 1991-05-10 | 1998-02-03 | Rhone-Poulenc Rorer Pharmaceuticals, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
EP0837063A1 (en) * | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
US5760041A (en) * | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
WO1998023613A1 (en) * | 1996-11-27 | 1998-06-04 | Pfizer Inc. | Fused bicyclic pyrimidine derivatives |
US5770603A (en) * | 1996-04-13 | 1998-06-23 | Zeneca Limited | Quinazoline derivatives |
US5770599A (en) * | 1995-04-27 | 1998-06-23 | Zeneca Limited | Quinazoline derivatives |
US5814630A (en) * | 1996-02-14 | 1998-09-29 | Zeneca Limited | Quinazoline compounds |
US5821246A (en) * | 1994-11-12 | 1998-10-13 | Zeneca Limited | Aniline derivatives |
US5866572A (en) * | 1996-02-14 | 1999-02-02 | Zeneca Limited | Quinazoline derivatives |
WO1999006378A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
WO1999006396A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
WO1999010349A1 (en) * | 1997-08-22 | 1999-03-04 | Zeneca Limited | Oxindolylquinazoline derivatives as angiogenesis inhibitors |
US5929080A (en) * | 1997-05-06 | 1999-07-27 | American Cyanamid Company | Method of treating polycystic kidney disease |
US5932574A (en) * | 1995-04-27 | 1999-08-03 | Zeneca Limited | Quinazoline derivatives |
US5942514A (en) * | 1995-04-27 | 1999-08-24 | Zeneca Limited | Quinazoline derivatives |
US5952333A (en) * | 1995-04-27 | 1999-09-14 | Zeneca Limited | Quinazoline derivative |
US5962458A (en) * | 1995-12-18 | 1999-10-05 | Zeneca Limited | Substituted quinazolines |
US6002008A (en) * | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
US6015814A (en) * | 1995-04-27 | 2000-01-18 | Zeneca Limited | Quinazoline derivative |
US6080769A (en) * | 1997-12-30 | 2000-06-27 | Pfizer Inc. | Imidazolidin-4-one derivatives useful as anticancer agents |
US6140317A (en) * | 1996-01-23 | 2000-10-31 | Novartis Ag | Pyrrolopyrimidines and processes for their preparation |
US6174903B1 (en) | 1998-12-28 | 2001-01-16 | Pfizer Inc. | Imidazolidin-4-one derivatives useful as anticancer agents |
US6184225B1 (en) | 1996-02-13 | 2001-02-06 | Zeneca Limited | Quinazoline derivatives as VEGF inhibitors |
US6225318B1 (en) | 1996-10-17 | 2001-05-01 | Pfizer Inc | 4-aminoquinazolone derivatives |
US6251912B1 (en) | 1997-08-01 | 2001-06-26 | American Cyanamid Company | Substituted quinazoline derivatives |
US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
US6291455B1 (en) | 1996-03-05 | 2001-09-18 | Zeneca Limited | 4-anilinoquinazoline derivatives |
US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
US6323209B1 (en) | 1997-11-06 | 2001-11-27 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
US6344459B1 (en) | 1996-04-12 | 2002-02-05 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
USRE37650E1 (en) | 1991-05-10 | 2002-04-09 | Aventis Pharmacetical Products, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US6432979B1 (en) | 1999-08-12 | 2002-08-13 | American Cyanamid Company | Method of treating or inhibiting colonic polyps and colorectal cancer |
US6465449B1 (en) | 1999-01-27 | 2002-10-15 | Pfizer Inc. | Heteroaromatic bicyclic derivatives useful as anticancer agents |
US6541481B2 (en) | 1999-01-27 | 2003-04-01 | Pfizer Inc | Substituted bicyclic derivatives useful as anticancer agents |
US6645969B1 (en) | 1991-05-10 | 2003-11-11 | Aventis Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US6673803B2 (en) | 1996-09-25 | 2004-01-06 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
US6833456B2 (en) | 2002-03-01 | 2004-12-21 | Agouron Pharmaceuticals, Inc. | Indolyl-urea derivatives of thienopyridines useful as antiangiogenic agents, and methods for their use |
US6849625B2 (en) | 2000-10-13 | 2005-02-01 | Astrazeneca Ab | Quinazoline derivatives with anti-tumour activity |
US6869962B2 (en) | 2002-06-14 | 2005-03-22 | Agouron Pharmaceuticals, Inc. | Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use |
US6939866B2 (en) | 2000-10-13 | 2005-09-06 | Astrazeneca Ab | Quinazoline derivatives |
US6995171B2 (en) | 2001-06-21 | 2006-02-07 | Agouron Pharmaceuticals, Inc. | Bicyclic pyrimidine and pyrimidine derivatives useful as anticancer agents |
US7074800B1 (en) | 1999-02-10 | 2006-07-11 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
US7115615B2 (en) | 2000-08-21 | 2006-10-03 | Astrazeneca | Quinazoline derivatives |
US7141577B2 (en) | 2001-04-19 | 2006-11-28 | Astrazeneca Ab | Quinazoline derivatives |
US7160889B2 (en) | 2000-04-07 | 2007-01-09 | Astrazeneca Ab | Quinazoline compounds |
US7173038B1 (en) | 1999-11-05 | 2007-02-06 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
US7208500B2 (en) | 2003-08-29 | 2007-04-24 | Agouron Pharmaceuticals, Inc. | Thienopyridine-phenylacetamides and their derivatives useful as new anti-angiogenic agents |
US7226923B2 (en) | 2004-09-24 | 2007-06-05 | Hoffman-La Roche Inc. | Phthalazinone derivatives |
US7268230B2 (en) | 2002-02-01 | 2007-09-11 | Astrazeneca Ab | Quinazoline compounds |
US7285569B2 (en) | 2004-09-24 | 2007-10-23 | Hoff Hoffmann-La Roche Inc. | Tricycles, their manufacture and use as pharmaceutical agents |
WO2007129745A1 (en) | 2006-05-09 | 2007-11-15 | Daiichi Sankyo Company, Limited | Heteroarylamide lower carboxylic acid derivative |
US7381824B2 (en) | 2003-12-23 | 2008-06-03 | Agouron Pharmaceuticals, Inc. | Quinoline derivatives |
US7399780B2 (en) | 2002-03-28 | 2008-07-15 | Astrazeneca Ab | 3-Heterocyclyl-indole inhibitors of glycogen synthase kinase-3 |
EP1950201A1 (en) | 1998-09-29 | 2008-07-30 | Wyeth Holdings Corporation | Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors |
US7462639B2 (en) | 2005-04-14 | 2008-12-09 | Hoffmann-La Roche Inc. | Aminopyrazole derivatives |
US7595325B2 (en) | 2004-05-27 | 2009-09-29 | Pfizer Inc. | Substituted pyrrolo[2,3-d]pyrimidine derivatives useful in cancer treatment |
DE102008022221A1 (en) | 2008-05-06 | 2009-11-12 | Universität des Saarlandes | Inhibitors of human aldosterone synthase CYP11B2 |
US7696214B2 (en) | 2000-06-06 | 2010-04-13 | Astrazeneca Ab | Quinazoline derivatives for the treatment of tumours |
US8541404B2 (en) | 2009-11-09 | 2013-09-24 | Elexopharm Gmbh | Inhibitors of the human aldosterone synthase CYP11B2 |
US8859570B2 (en) | 2003-12-24 | 2014-10-14 | Astrazeneca Ab | Maleate salts of a quinazoline derivative useful as an antiangiogenic agent |
EP2857393A4 (en) * | 2012-05-31 | 2015-12-23 | Inst Pharm & Toxicology Amms | N-aryl unsaturated fused ring tertiary amine compound, preparation method thereof and antitumor application thereof |
CN108014112A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Adjacent toluidino acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108014114A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Chloro acetylamino quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108014116A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Amino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108014113A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
CN108014115A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Pivaloyl amino anisyl benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108042546A (en) * | 2018-01-24 | 2018-05-18 | 浙江工业大学 | Morpholinyl acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108078992A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | Pivaloyl amino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108078994A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | 6- (2- morpholinyls acetylamino) quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108078995A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | Benzamido quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108078993A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | 6- nitro-quinazoline class compounds are preparing the application in treating lung-cancer medicament |
CN108125962A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108125959A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Dimethoxy benzene aminoacetylamino quinazoline compounds are preparing the application in treating leukemia medicament |
CN108125961A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Morpholinyl acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108125958A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Adjacent toluidino acetylamino chloro benzo azepine * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108125960A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Isobutyryl amino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108143736A (en) * | 2018-01-24 | 2018-06-12 | 浙江工业大学 | Application of butyrylaminobenzo [ d ] aza-based quinazoline in preparation of drugs for treating lung cancer |
CN108186649A (en) * | 2018-01-24 | 2018-06-22 | 浙江工业大学 | Propionamido chloro benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating leukemia medicament |
CN108245521A (en) * | 2018-01-24 | 2018-07-06 | 浙江工业大学 | Dipropyl aminoacetylamino benzo-aza * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108245520A (en) * | 2018-01-24 | 2018-07-06 | 浙江工业大学 | Acetylamino quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108245519A (en) * | 2018-01-24 | 2018-07-06 | 浙江工业大学 | Application of butyrylaminoquinazoline compound in preparation of drugs for treating leukemia |
CN108295076A (en) * | 2018-01-24 | 2018-07-20 | 浙江工业大学 | Propionamido dimethoxy benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament |
CN108309984A (en) * | 2018-01-24 | 2018-07-24 | 浙江工业大学 | Propionamido quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108324719A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Adjacent toluidino acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108324718A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Application of the cyclohexyl methoxy formamido group chloro benzo azepine * bases quinazoline compounds in treating leukemia medicament |
CN108324717A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Pivaloyl amino chloro benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug |
WO2024086296A1 (en) * | 2022-10-20 | 2024-04-25 | Mekanistic Therapeutics Llc | Compounds useful in modulating egfr and pi3k |
Families Citing this family (38)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5747498A (en) | 1996-05-28 | 1998-05-05 | Pfizer Inc. | Alkynyl and azido-substituted 4-anilinoquinazolines |
US7060808B1 (en) * | 1995-06-07 | 2006-06-13 | Imclone Systems Incorporated | Humanized anti-EGF receptor monoclonal antibody |
US20030224001A1 (en) * | 1998-03-19 | 2003-12-04 | Goldstein Neil I. | Antibody and antibody fragments for inhibiting the growth of tumors |
ZA200007412B (en) * | 1998-05-15 | 2002-03-12 | Imclone Systems Inc | Treatment of human tumors with radiation and inhibitors of growth factor receptor tyrosine kinases. |
CA2373815A1 (en) * | 1999-05-14 | 2000-11-23 | Imclone Systems Incorporated | Treatment of refractory human tumors with epidermal growth factor receptor antagonists |
AU9500201A (en) * | 2000-08-09 | 2002-02-18 | Imclone Systems Inc | Treatment of hyperproliferative diseases with epidermal growth factor receptor antagonists |
US20080008704A1 (en) * | 2001-03-16 | 2008-01-10 | Mark Rubin | Methods of treating colorectal cancer with anti-epidermal growth factor antibodies |
US20030144308A1 (en) * | 2001-09-24 | 2003-07-31 | Bauer Paul H. | Fructose 1,6-bisphosphatase inhibitors |
US20030202973A1 (en) * | 2002-04-29 | 2003-10-30 | Dr. George Pieczenik | Treatment of refractory human tumors with epidermal growth factor receptor and HER1 mitogenic ligand (EGFRML) antagonists |
CA2494061C (en) * | 2002-07-31 | 2011-06-14 | Wayne R. Danter | Protein tyrosine kinase inhibitors |
US7629347B2 (en) * | 2002-10-09 | 2009-12-08 | Critical Outcome Technologies, Inc. | Protein tyrosine kinase inhibitors |
EP1622941A2 (en) * | 2003-03-20 | 2006-02-08 | ImClone Systems Incorporated | Method of producing an antibody to epidermal growth factor receptor |
US7598350B2 (en) * | 2004-03-19 | 2009-10-06 | Imclone Llc | Human anti-epidermal growth factor receptor antibody |
DK1746999T3 (en) * | 2004-05-06 | 2012-01-23 | Warner Lambert Co | 4-phenylamino-quinazolin-6-yl-amides |
US20070093515A1 (en) * | 2005-08-16 | 2007-04-26 | Arrington Mark P | Phosphodiesterase 10 inhibitors |
AU2007217750A1 (en) * | 2006-02-21 | 2007-08-30 | Amgen Inc. | Cinnoline derivatives as phosphodiesterase 10 inhibitors |
MX2008010953A (en) * | 2006-02-28 | 2008-09-08 | Amgen Inc | Cinnoline and quinazoline derivates as phosphodiesterase 10 inhibitors. |
US20090099175A1 (en) * | 2006-03-01 | 2009-04-16 | Arrington Mark P | Phosphodiesterase 10 inhibitors |
WO2008083491A1 (en) | 2007-01-11 | 2008-07-17 | Critical Outcome Technologies Inc. | Compounds and method for treatment of cancer |
US20080190689A1 (en) * | 2007-02-12 | 2008-08-14 | Ballard Ebbin C | Inserts for engine exhaust systems |
EP2225226B1 (en) * | 2007-12-26 | 2016-08-17 | Critical Outcome Technologies, Inc. | Compounds and their use in a method for treatment of cancer |
US20110086834A1 (en) * | 2008-06-26 | 2011-04-14 | Amgen Inc. | Alkynyl alcohols as kinase inhibitors |
WO2010006438A1 (en) | 2008-07-17 | 2010-01-21 | Critical Outcome Technologies Inc. | Thiosemicarbazone inhibitor compounds and cancer treatment methods |
WO2011120153A1 (en) | 2010-04-01 | 2011-10-06 | Critical Outcome Technologies Inc. | Compounds and method for treatment of hiv |
CN108017621B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof |
CN108250185B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | 6- (2- (o-toluidine amino) acetamido) quinazoline compound, preparation and application thereof |
CN109251196B (en) * | 2018-01-24 | 2020-11-13 | 浙江工业大学 | Aminobenzo [ d ] aza-quinazoline compound and preparation method and application thereof |
CN108276386B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Cyclohexyl methoxy formyl amino quinazoline compound and preparation and application thereof |
CN108276385B (en) * | 2018-01-24 | 2019-12-06 | 浙江工业大学 | Isobutyrylaminoquinazoline compounds, and preparation and application thereof |
CN108164510B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Chloroacetamidobenzo [ d ] aza-based quinazoline compound and preparation method and application thereof |
CN108129460B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Methoxyphenylbenzo [ d ] aza-quinazoline compound and preparation and application thereof |
CN108276384B (en) * | 2018-01-24 | 2019-12-06 | 浙江工业大学 | acetaminobenzo [ d ] azepinyl quinazoline compound and preparation and application thereof |
CN108117542B (en) * | 2018-01-24 | 2019-12-24 | 浙江工业大学 | Propionyl amino methoxyphenyl benzo [ d ] nitrogen hetero-pinyl quinazoline compound, preparation and application |
CN108329300B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof |
CN108047206B (en) * | 2018-01-24 | 2019-11-29 | 浙江工业大学 | Pivaloyl amino benzo [d] azepine * base quinazoline compounds and preparation and application |
CN108033949B (en) * | 2018-01-24 | 2019-11-29 | 浙江工业大学 | 6- (2- dipropyl aminoacetylamino) quinazoline compounds and preparation and application |
CN108084162B (en) * | 2018-01-24 | 2019-11-29 | 浙江工业大学 | Dimethoxy benzene aminoacetylamino benzo [d] azepine * base quinazoline compounds and preparation and application |
CN108129461B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Benzoylaminobenzo [ d ] aza-quinazoline compound, preparation and application thereof |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4012513A (en) * | 1971-11-03 | 1977-03-15 | Imperial Chemical Industries Limited | Indole derivatives for providing analgesic and anti-inflammatory effects |
WO1992020642A1 (en) * | 1991-05-10 | 1992-11-26 | Rhone-Poulenc Rorer International (Holdings) Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
EP0520722A1 (en) * | 1991-06-28 | 1992-12-30 | Zeneca Limited | Therapeutic preparations containing quinazoline derivatives |
EP0566226A1 (en) * | 1992-01-20 | 1993-10-20 | Zeneca Limited | Quinazoline derivatives |
EP0602851A1 (en) * | 1992-12-10 | 1994-06-22 | Zeneca Limited | Quinazoline derivatives |
EP0635498A1 (en) * | 1993-07-19 | 1995-01-25 | Zeneca Limited | Quinazoline derivatives and their use as anti-cancer agents |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BE790679A (en) * | 1971-11-03 | 1973-04-27 | Ici Ltd | INDOLE DERIVATIVES |
PT100905A (en) * | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | BICYCLE HYGIENEOUS HETEROCYCLIC COMPOUNDS CONTAINING BENZENE, CYCLOHEXAN OR PYRIDINE AND PYRIMIDINE, PYRIDINE OR IMIDAZOLE SUBSTITUTES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
-
1995
- 1995-01-27 EP EP95905737A patent/EP0746554A1/en not_active Withdrawn
- 1995-01-27 PL PL95315941A patent/PL315941A1/en unknown
- 1995-01-27 AU AU29727/95A patent/AU686843B2/en not_active Ceased
- 1995-01-27 CA CA002183655A patent/CA2183655C/en not_active Expired - Fee Related
- 1995-01-27 RU RU96119255A patent/RU2137762C1/en active
- 1995-01-27 KR KR1019960704612A patent/KR100225721B1/en not_active IP Right Cessation
- 1995-01-27 US US08/682,565 patent/US5736534A/en not_active Expired - Fee Related
- 1995-01-27 WO PCT/IB1995/000061 patent/WO1995023141A1/en active IP Right Grant
- 1995-01-27 HU HU9602305A patent/HUT76291A/en unknown
- 1995-01-27 MX MX9603593A patent/MX9603593A/en not_active IP Right Cessation
- 1995-01-27 BR BR9506936A patent/BR9506936A/en not_active Application Discontinuation
- 1995-01-27 CN CN95191723A patent/CN1141633A/en active Pending
- 1995-01-27 JP JP7522227A patent/JP2890267B2/en not_active Expired - Lifetime
- 1995-01-27 CZ CZ19962413A patent/CZ288955B6/en not_active IP Right Cessation
- 1995-02-06 TW TW084100928A patent/TW404946B/en not_active IP Right Cessation
- 1995-02-16 IL IL11267395A patent/IL112673A0/en unknown
- 1995-02-17 PE PE1995262160A patent/PE4896A1/en not_active Application Discontinuation
- 1995-02-22 CO CO95006643A patent/CO4340688A1/en unknown
- 1995-02-22 ZA ZA951458A patent/ZA951458B/en unknown
-
1996
- 1996-08-19 NZ NZ278135A patent/NZ278135A/en unknown
- 1996-08-22 FI FI963283A patent/FI963283A0/en unknown
- 1996-08-22 NO NO963506A patent/NO963506L/en not_active Application Discontinuation
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4012513A (en) * | 1971-11-03 | 1977-03-15 | Imperial Chemical Industries Limited | Indole derivatives for providing analgesic and anti-inflammatory effects |
WO1992020642A1 (en) * | 1991-05-10 | 1992-11-26 | Rhone-Poulenc Rorer International (Holdings) Inc. | Bis mono-and bicyclic aryl and heteroaryl compounds which inhibit egf and/or pdgf receptor tyrosine kinase |
EP0520722A1 (en) * | 1991-06-28 | 1992-12-30 | Zeneca Limited | Therapeutic preparations containing quinazoline derivatives |
EP0566226A1 (en) * | 1992-01-20 | 1993-10-20 | Zeneca Limited | Quinazoline derivatives |
EP0602851A1 (en) * | 1992-12-10 | 1994-06-22 | Zeneca Limited | Quinazoline derivatives |
EP0635498A1 (en) * | 1993-07-19 | 1995-01-25 | Zeneca Limited | Quinazoline derivatives and their use as anti-cancer agents |
Non-Patent Citations (1)
Title |
---|
GOODALE G.M. & MC KEE R.L.: "Quinazoline derivatives", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, vol. 71, pages 1893 * |
Cited By (133)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
USRE37650E1 (en) | 1991-05-10 | 2002-04-09 | Aventis Pharmacetical Products, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US5714493A (en) * | 1991-05-10 | 1998-02-03 | Rhone-Poulenc Rorer Pharmaceuticals, Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US6645969B1 (en) | 1991-05-10 | 2003-11-11 | Aventis Pharmaceuticals Inc. | Aryl and heteroaryl quinazoline compounds which inhibit CSF-1R receptor tyrosine kinase |
US5821246A (en) * | 1994-11-12 | 1998-10-13 | Zeneca Limited | Aniline derivatives |
WO1996016960A1 (en) * | 1994-11-30 | 1996-06-06 | Zeneca Limited | Quinazoline derivatives |
US6015814A (en) * | 1995-04-27 | 2000-01-18 | Zeneca Limited | Quinazoline derivative |
US5770599A (en) * | 1995-04-27 | 1998-06-23 | Zeneca Limited | Quinazoline derivatives |
US5932574A (en) * | 1995-04-27 | 1999-08-03 | Zeneca Limited | Quinazoline derivatives |
US5952333A (en) * | 1995-04-27 | 1999-09-14 | Zeneca Limited | Quinazoline derivative |
US5942514A (en) * | 1995-04-27 | 1999-08-24 | Zeneca Limited | Quinazoline derivatives |
US6258951B1 (en) | 1995-12-18 | 2001-07-10 | Zeneca Limited | Chemical compounds |
US6362336B1 (en) | 1995-12-18 | 2002-03-26 | Zeneca Limited | Chemical compounds |
US6071921A (en) * | 1995-12-18 | 2000-06-06 | Zeneca Limited | Chemical compounds |
US5962458A (en) * | 1995-12-18 | 1999-10-05 | Zeneca Limited | Substituted quinazolines |
US6140317A (en) * | 1996-01-23 | 2000-10-31 | Novartis Ag | Pyrrolopyrimidines and processes for their preparation |
US5760041A (en) * | 1996-02-05 | 1998-06-02 | American Cyanamid Company | 4-aminoquinazoline EGFR Inhibitors |
US6184225B1 (en) | 1996-02-13 | 2001-02-06 | Zeneca Limited | Quinazoline derivatives as VEGF inhibitors |
US6897214B2 (en) | 1996-02-14 | 2005-05-24 | Zeneca Limited | Quinazoline derivatives |
US5866572A (en) * | 1996-02-14 | 1999-02-02 | Zeneca Limited | Quinazoline derivatives |
US5814630A (en) * | 1996-02-14 | 1998-09-29 | Zeneca Limited | Quinazoline compounds |
WO1997031611A3 (en) * | 1996-03-01 | 1997-11-13 | Chiron Corp | Treatment of begnin prostatic hyperplasia |
WO1997031611A2 (en) * | 1996-03-01 | 1997-09-04 | Chiron Corporation | Treatment of begnin prostatic hyperplasia |
US6291455B1 (en) | 1996-03-05 | 2001-09-18 | Zeneca Limited | 4-anilinoquinazoline derivatives |
US6344459B1 (en) | 1996-04-12 | 2002-02-05 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
US7786131B2 (en) | 1996-04-12 | 2010-08-31 | Warner-Lambert Company | Pyrimido[5,4-d]pyrimidines derivatives as irreversible inhibitors of tyrosine kinases |
US6602863B1 (en) | 1996-04-12 | 2003-08-05 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
US5770603A (en) * | 1996-04-13 | 1998-06-23 | Zeneca Limited | Quinazoline derivatives |
WO1997042187A1 (en) * | 1996-05-06 | 1997-11-13 | Zeneca Limited | Oxindole derivatives |
USRE42353E1 (en) | 1996-09-25 | 2011-05-10 | Astrazeneca Uk Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
US6673803B2 (en) | 1996-09-25 | 2004-01-06 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
US6897210B2 (en) | 1996-09-25 | 2005-05-24 | Zeneca Limited | Quinazoline derivatives and pharmaceutical compositions containing them |
US6225318B1 (en) | 1996-10-17 | 2001-05-01 | Pfizer Inc | 4-aminoquinazolone derivatives |
EP0837063A1 (en) * | 1996-10-17 | 1998-04-22 | Pfizer Inc. | 4-Aminoquinazoline derivatives |
US6413971B1 (en) | 1996-11-27 | 2002-07-02 | Pfizer Inc | Fused bicyclic pyrimidine derivatives |
WO1998023613A1 (en) * | 1996-11-27 | 1998-06-04 | Pfizer Inc. | Fused bicyclic pyrimidine derivatives |
US6002008A (en) * | 1997-04-03 | 1999-12-14 | American Cyanamid Company | Substituted 3-cyano quinolines |
US5929080A (en) * | 1997-05-06 | 1999-07-27 | American Cyanamid Company | Method of treating polycystic kidney disease |
US6153617A (en) * | 1997-07-29 | 2000-11-28 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
WO1999006378A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
WO1999006396A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
US6562818B1 (en) | 1997-07-29 | 2003-05-13 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
US6127374A (en) * | 1997-07-29 | 2000-10-03 | Warner-Lambert Company | Irreversible inhibitors of tyrosine kinases |
US6251912B1 (en) | 1997-08-01 | 2001-06-26 | American Cyanamid Company | Substituted quinazoline derivatives |
WO1999010349A1 (en) * | 1997-08-22 | 1999-03-04 | Zeneca Limited | Oxindolylquinazoline derivatives as angiogenesis inhibitors |
US6294532B1 (en) | 1997-08-22 | 2001-09-25 | Zeneca Limited | Oxindolylquinazoline derivatives as angiogenesis inhibitors |
US6323209B1 (en) | 1997-11-06 | 2001-11-27 | American Cyanamid Company | Method of treating or inhibiting colonic polyps |
US6080769A (en) * | 1997-12-30 | 2000-06-27 | Pfizer Inc. | Imidazolidin-4-one derivatives useful as anticancer agents |
EP1950201A1 (en) | 1998-09-29 | 2008-07-30 | Wyeth Holdings Corporation | Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors |
EP2896612A1 (en) | 1998-09-29 | 2015-07-22 | Wyeth Holdings LLC | Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors |
US6297258B1 (en) | 1998-09-29 | 2001-10-02 | American Cyanamid Company | Substituted 3-cyanoquinolines |
EP2253620A1 (en) | 1998-09-29 | 2010-11-24 | Wyeth Holdings Corporation | Substituted 3-cyanoquinolines as protein tyrosine kinases inhibitors |
USRE42376E1 (en) | 1998-09-29 | 2011-05-17 | Wyeth Holdings Corporation | Substituted 3-cyanoquinolines |
US6288082B1 (en) | 1998-09-29 | 2001-09-11 | American Cyanamid Company | Substituted 3-cyanoquinolines |
US6174903B1 (en) | 1998-12-28 | 2001-01-16 | Pfizer Inc. | Imidazolidin-4-one derivatives useful as anticancer agents |
US6867201B2 (en) | 1999-01-27 | 2005-03-15 | Pfizer Inc | Heteroaromatic bicyclic derivatives useful as anticancer agents |
US6465449B1 (en) | 1999-01-27 | 2002-10-15 | Pfizer Inc. | Heteroaromatic bicyclic derivatives useful as anticancer agents |
US6541481B2 (en) | 1999-01-27 | 2003-04-01 | Pfizer Inc | Substituted bicyclic derivatives useful as anticancer agents |
US8492560B2 (en) | 1999-02-10 | 2013-07-23 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
US7074800B1 (en) | 1999-02-10 | 2006-07-11 | Astrazeneca Ab | Quinazoline derivatives as angiogenesis inhibitors |
US6432979B1 (en) | 1999-08-12 | 2002-08-13 | American Cyanamid Company | Method of treating or inhibiting colonic polyps and colorectal cancer |
US10457664B2 (en) | 1999-11-05 | 2019-10-29 | Genzyme Corporation | Quinazoline derivatives as VEGF inhibitors |
US7173038B1 (en) | 1999-11-05 | 2007-02-06 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
US9040548B2 (en) | 1999-11-05 | 2015-05-26 | Astrazeneca Ab | Quinazoline derivatives as VEGF inhibitors |
US7160889B2 (en) | 2000-04-07 | 2007-01-09 | Astrazeneca Ab | Quinazoline compounds |
US7696214B2 (en) | 2000-06-06 | 2010-04-13 | Astrazeneca Ab | Quinazoline derivatives for the treatment of tumours |
US7115615B2 (en) | 2000-08-21 | 2006-10-03 | Astrazeneca | Quinazoline derivatives |
US6939866B2 (en) | 2000-10-13 | 2005-09-06 | Astrazeneca Ab | Quinazoline derivatives |
US6849625B2 (en) | 2000-10-13 | 2005-02-01 | Astrazeneca Ab | Quinazoline derivatives with anti-tumour activity |
US7141577B2 (en) | 2001-04-19 | 2006-11-28 | Astrazeneca Ab | Quinazoline derivatives |
US6995171B2 (en) | 2001-06-21 | 2006-02-07 | Agouron Pharmaceuticals, Inc. | Bicyclic pyrimidine and pyrimidine derivatives useful as anticancer agents |
US7268230B2 (en) | 2002-02-01 | 2007-09-11 | Astrazeneca Ab | Quinazoline compounds |
US8293902B2 (en) | 2002-02-01 | 2012-10-23 | Astrazeneca Ab | Quinazoline compounds |
US6833456B2 (en) | 2002-03-01 | 2004-12-21 | Agouron Pharmaceuticals, Inc. | Indolyl-urea derivatives of thienopyridines useful as antiangiogenic agents, and methods for their use |
US7399780B2 (en) | 2002-03-28 | 2008-07-15 | Astrazeneca Ab | 3-Heterocyclyl-indole inhibitors of glycogen synthase kinase-3 |
US7045528B2 (en) | 2002-06-14 | 2006-05-16 | Agouron Pharmaceuticals, Inc. | Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use |
US6869962B2 (en) | 2002-06-14 | 2005-03-22 | Agouron Pharmaceuticals, Inc. | Benzofused heterozryl amide derivatives of thienopyridines useful as therapeutic agents, pharmaceutical compositions including the same, and methods for their use |
US7208500B2 (en) | 2003-08-29 | 2007-04-24 | Agouron Pharmaceuticals, Inc. | Thienopyridine-phenylacetamides and their derivatives useful as new anti-angiogenic agents |
US7381824B2 (en) | 2003-12-23 | 2008-06-03 | Agouron Pharmaceuticals, Inc. | Quinoline derivatives |
US7923457B2 (en) | 2003-12-23 | 2011-04-12 | Agouron Pharmaceuticals Inc. | Quinoline derivatives |
US8859570B2 (en) | 2003-12-24 | 2014-10-14 | Astrazeneca Ab | Maleate salts of a quinazoline derivative useful as an antiangiogenic agent |
US9556151B2 (en) | 2003-12-24 | 2017-01-31 | Astrazeneca Ab | Maleate salts of a quinazoline derivative useful as an antiangiogenic agent |
US9890140B2 (en) | 2003-12-24 | 2018-02-13 | Astrazeneca Ab | Maleate salts of a quinazoline derivative useful as an antiangiogenic agent |
US7595325B2 (en) | 2004-05-27 | 2009-09-29 | Pfizer Inc. | Substituted pyrrolo[2,3-d]pyrimidine derivatives useful in cancer treatment |
US7226923B2 (en) | 2004-09-24 | 2007-06-05 | Hoffman-La Roche Inc. | Phthalazinone derivatives |
US7285569B2 (en) | 2004-09-24 | 2007-10-23 | Hoff Hoffmann-La Roche Inc. | Tricycles, their manufacture and use as pharmaceutical agents |
US7462639B2 (en) | 2005-04-14 | 2008-12-09 | Hoffmann-La Roche Inc. | Aminopyrazole derivatives |
WO2007129745A1 (en) | 2006-05-09 | 2007-11-15 | Daiichi Sankyo Company, Limited | Heteroarylamide lower carboxylic acid derivative |
US8685960B2 (en) | 2008-05-06 | 2014-04-01 | Elexopharm Gmbh | 6-pyridin-3-yl-3,4-dihydro-1h-quinolin-2-one derivatives and related compounds as inhibitors of the human aldosterone synthase CYP11B2 |
DE102008022221A1 (en) | 2008-05-06 | 2009-11-12 | Universität des Saarlandes | Inhibitors of human aldosterone synthase CYP11B2 |
US8541404B2 (en) | 2009-11-09 | 2013-09-24 | Elexopharm Gmbh | Inhibitors of the human aldosterone synthase CYP11B2 |
EP2857393A4 (en) * | 2012-05-31 | 2015-12-23 | Inst Pharm & Toxicology Amms | N-aryl unsaturated fused ring tertiary amine compound, preparation method thereof and antitumor application thereof |
US9751884B2 (en) | 2012-05-31 | 2017-09-05 | Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China | N-aryl unsaturated fused ring tertiary amine compounds, preparation method and anti-tumor applications thereof |
CN108245521A (en) * | 2018-01-24 | 2018-07-06 | 浙江工业大学 | Dipropyl aminoacetylamino benzo-aza * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108295076A (en) * | 2018-01-24 | 2018-07-20 | 浙江工业大学 | Propionamido dimethoxy benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating lung-cancer medicament |
CN108014113A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
CN108014115A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Pivaloyl amino anisyl benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108042546A (en) * | 2018-01-24 | 2018-05-18 | 浙江工业大学 | Morpholinyl acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108078992A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | Pivaloyl amino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108078994A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | 6- (2- morpholinyls acetylamino) quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108078995A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | Benzamido quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108078993A (en) * | 2018-01-24 | 2018-05-29 | 浙江工业大学 | 6- nitro-quinazoline class compounds are preparing the application in treating lung-cancer medicament |
CN108125962A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108125959A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Dimethoxy benzene aminoacetylamino quinazoline compounds are preparing the application in treating leukemia medicament |
CN108125961A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Morpholinyl acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108125958A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Adjacent toluidino acetylamino chloro benzo azepine * bases quinazoline compounds are preparing the application in treating leukemia medicament |
CN108125960A (en) * | 2018-01-24 | 2018-06-08 | 浙江工业大学 | Isobutyryl amino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108143736A (en) * | 2018-01-24 | 2018-06-12 | 浙江工业大学 | Application of butyrylaminobenzo [ d ] aza-based quinazoline in preparation of drugs for treating lung cancer |
CN108186649A (en) * | 2018-01-24 | 2018-06-22 | 浙江工业大学 | Propionamido chloro benzo [d] azepine * bases quinazoline ditosylate salt is preparing the application in treating leukemia medicament |
CN108014114A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Chloro acetylamino quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108245520A (en) * | 2018-01-24 | 2018-07-06 | 浙江工业大学 | Acetylamino quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108245519A (en) * | 2018-01-24 | 2018-07-06 | 浙江工业大学 | Application of butyrylaminoquinazoline compound in preparation of drugs for treating leukemia |
CN108014116A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Amino dimethoxy benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108309984A (en) * | 2018-01-24 | 2018-07-24 | 浙江工业大学 | Propionamido quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108324719A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Adjacent toluidino acetylamino anisyl benzo-aza * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108324718A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Application of the cyclohexyl methoxy formamido group chloro benzo azepine * bases quinazoline compounds in treating leukemia medicament |
CN108324717A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Pivaloyl amino chloro benzo [d] azepine * bases quinazoline compounds are preparing the application in treating uterine neck cancer drug |
CN108014112A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Adjacent toluidino acetylamino benzo [d] azepine * bases quinazoline compounds are preparing the application in treating lung-cancer medicament |
CN108245520B (en) * | 2018-01-24 | 2019-12-24 | 浙江工业大学 | Application of acetamido quinazoline compound in preparation of drugs for treating lung cancer |
CN108078994B (en) * | 2018-01-24 | 2020-01-03 | 浙江工业大学 | Application of 6- (2-morpholinyl acetamido) quinazoline compound in preparation of medicine for treating lung cancer |
CN108078995B (en) * | 2018-01-24 | 2020-01-03 | 浙江工业大学 | Application of benzoylaminoquinazoline compound in preparation of drugs for treating lung cancer |
CN108309984B (en) * | 2018-01-24 | 2020-02-21 | 浙江工业大学 | Application of propionyl aminoquinazoline compound in preparation of medicine for treating cervical cancer |
CN108295076B (en) * | 2018-01-24 | 2020-05-22 | 浙江工业大学 | Application of propionyl-amino-dimethoxy-benzo [ d ] aza-quinazoline in preparation of drugs for treating lung cancer |
CN108186649B (en) * | 2018-01-24 | 2020-05-26 | 浙江工业大学 | Application of propionyl amino chloro benzo [ d ] aza-quinazoline in preparing medicament for treating leukemia |
CN108125961B (en) * | 2018-01-24 | 2020-05-26 | 浙江工业大学 | Application of morpholinyl acetamido methoxyphenyl benzazepinyl quinazoline compound in preparation of drugs for treating leukemia |
CN108014114B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Application of chloroacetylamidoquinazoline compounds in preparation of drugs for treating lung cancer |
CN108078992B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Application of pivaloyl-amino-dimethoxy-benzo [ d ] aza-quinazoline compound in preparation of drugs for treating leukemia |
CN108014116B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Application of aminodimethoxybenzo [ d ] aza-quinazoline compound in preparation of drugs for treating lung cancer |
CN108014115B (en) * | 2018-01-24 | 2020-10-02 | 浙江工业大学 | Application of pivaloylaminomethoxyphenyl benzo [ d ] aza-quinazoline compound in preparation of lung cancer treatment drug |
CN108014113B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Application of butyrylamidodimethoxybenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
CN108014112B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Application of o-toluidine amino acetamido benzo [ d ] aza-based quinazoline compound in preparation of drugs for treating lung cancer |
CN108042546B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Application of morpholinyl acetamidobenzo [ d ] aza-based quinazoline compound in preparation of drugs for treating cervical cancer |
WO2024086296A1 (en) * | 2022-10-20 | 2024-04-25 | Mekanistic Therapeutics Llc | Compounds useful in modulating egfr and pi3k |
Also Published As
Publication number | Publication date |
---|---|
FI963283A (en) | 1996-08-22 |
MX9603593A (en) | 1997-03-29 |
CN1141633A (en) | 1997-01-29 |
CA2183655A1 (en) | 1995-08-31 |
PE4896A1 (en) | 1996-03-09 |
HU9602305D0 (en) | 1996-10-28 |
NO963506L (en) | 1996-10-22 |
NZ278135A (en) | 1998-03-25 |
KR100225721B1 (en) | 1999-10-15 |
CA2183655C (en) | 2001-03-06 |
TW404946B (en) | 2000-09-11 |
RU2137762C1 (en) | 1999-09-20 |
NO963506D0 (en) | 1996-08-22 |
AU686843B2 (en) | 1998-02-12 |
JP2890267B2 (en) | 1999-05-10 |
AU2972795A (en) | 1995-09-11 |
FI963283A0 (en) | 1996-08-22 |
IL112673A0 (en) | 1995-05-26 |
US5736534A (en) | 1998-04-07 |
ZA951458B (en) | 1996-08-22 |
BR9506936A (en) | 1997-09-09 |
KR970701183A (en) | 1997-03-17 |
CO4340688A1 (en) | 1996-07-30 |
HUT76291A (en) | 1997-07-28 |
JPH09501953A (en) | 1997-02-25 |
PL315941A1 (en) | 1996-12-09 |
CZ288955B6 (en) | 2001-10-17 |
EP0746554A1 (en) | 1996-12-11 |
CZ241396A3 (en) | 1997-07-16 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5736534A (en) | 4-heterocyclyl-substituted quinazoline derivatives, processes for their preparation and their use as anti-cancer agents | |
CA2216796C (en) | Quinazoline derivatives | |
EP0831829B1 (en) | Heterocyclic ring-fused pyrimidine derivatives | |
US6413971B1 (en) | Fused bicyclic pyrimidine derivatives | |
US5747498A (en) | Alkynyl and azido-substituted 4-anilinoquinazolines |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
WWE | Wipo information: entry into national phase |
Ref document number: 95191723.4 Country of ref document: CN |
|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA CN CZ FI HU JP KR MX NO NZ PL RU US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 278135 Country of ref document: NZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1995905737 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08682565 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: PV1996-2413 Country of ref document: CZ |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2183655 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 963283 Country of ref document: FI |
|
WWP | Wipo information: published in national office |
Ref document number: 1995905737 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: PV1996-2413 Country of ref document: CZ |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995905737 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: PV1996-2413 Country of ref document: CZ |