HRP20050069A2 - Indoline derivatives substituted in position 6, production and use thereof as medicaments - Google Patents

Info

Publication number

HRP20050069A2

HRP20050069A2 HR20050069A HRP20050069A HRP20050069A2 HR P20050069 A2 HRP20050069 A2 HR P20050069A2 HR 20050069 A HR20050069 A HR 20050069A HR P20050069 A HRP20050069 A HR P20050069A HR P20050069 A2 HRP20050069 A2 HR P20050069A2

Authority

HR

Croatia

Prior art keywords

alkyl

group

phenyl

carbonyl

amino

Prior art date

2002-07-23

Links

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• 239000003814 drug Substances 0.000 title claims description 9
• 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 title 1
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 126
• -1 thiophen-2-yl-carbonyl Chemical group 0.000 claims description 114
• 150000001875 compounds Chemical class 0.000 claims description 113
• 239000000203 mixture Substances 0.000 claims description 56
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 43
• 238000002360 preparation method Methods 0.000 claims description 38
• 150000003839 salts Chemical class 0.000 claims description 23
• 238000006243 chemical reaction Methods 0.000 claims description 22
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 21
• 239000002253 acid Substances 0.000 claims description 19
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 18
• 229910052801 chlorine Inorganic materials 0.000 claims description 17
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 16
• 125000006239 protecting group Chemical group 0.000 claims description 16
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 15
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 15
• 239000000460 chlorine Chemical group 0.000 claims description 14
• 238000000034 method Methods 0.000 claims description 14
• 229910052794 bromium Inorganic materials 0.000 claims description 13
• 229910052731 fluorine Inorganic materials 0.000 claims description 13
• 239000011737 fluorine Substances 0.000 claims description 13
• 239000007790 solid phase Substances 0.000 claims description 13
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 12
• 238000001727 in vivo Methods 0.000 claims description 12
• 150000003951 lactams Chemical group 0.000 claims description 12
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
• 125000003282 alkyl amino group Chemical group 0.000 claims description 11
• 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 11
• 229910052757 nitrogen Inorganic materials 0.000 claims description 11
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 9
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
• 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 8
• 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 claims description 8
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
• 230000004663 cell proliferation Effects 0.000 claims description 8
• 125000001153 fluoro group Chemical group F* 0.000 claims description 8
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
• 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 7
• 125000000217 alkyl group Chemical group 0.000 claims description 7
• 125000003277 amino group Chemical group 0.000 claims description 7
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 6
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical group ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 6
• 238000006722 reduction reaction Methods 0.000 claims description 6
• 125000004429 atom Chemical group 0.000 claims description 5
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 5
• 125000005843 halogen group Chemical group 0.000 claims description 5
• 230000007062 hydrolysis Effects 0.000 claims description 5
• 238000006460 hydrolysis reaction Methods 0.000 claims description 5
• 229910052740 iodine Chemical group 0.000 claims description 5
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 5
• 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 5
• 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 claims description 4
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 4
• 230000029936 alkylation Effects 0.000 claims description 4
• 238000005804 alkylation reaction Methods 0.000 claims description 4
• 230000009435 amidation Effects 0.000 claims description 4
• 238000007112 amidation reaction Methods 0.000 claims description 4
• 150000001412 amines Chemical class 0.000 claims description 4
• 239000012876 carrier material Substances 0.000 claims description 4
• 239000003085 diluting agent Substances 0.000 claims description 4
• 229940079593 drug Drugs 0.000 claims description 4
• 230000032050 esterification Effects 0.000 claims description 4
• 238000005886 esterification reaction Methods 0.000 claims description 4
• 150000002148 esters Chemical class 0.000 claims description 4
• XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 4
• 125000001624 naphthyl group Chemical group 0.000 claims description 4
• 229940002612 prodrug Drugs 0.000 claims description 4
• 239000000651 prodrug Substances 0.000 claims description 4
• 125000001424 substituent group Chemical group 0.000 claims description 4
• 125000004214 1-pyrrolidinyl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 3
• CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 3
• VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 3
• AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 3
• DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 3
• 125000002252 acyl group Chemical group 0.000 claims description 3
• 230000010933 acylation Effects 0.000 claims description 3
• 238000005917 acylation reaction Methods 0.000 claims description 3
• 125000003545 alkoxy group Chemical group 0.000 claims description 3
• 125000004103 aminoalkyl group Chemical group 0.000 claims description 3
• 125000003710 aryl alkyl group Chemical group 0.000 claims description 3
• 125000004566 azetidin-1-yl group Chemical group N1(CCC1)* 0.000 claims description 3
• 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
• 125000002962 imidazol-1-yl group Chemical group [*]N1C([H])=NC([H])=C1[H] 0.000 claims description 3
• 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 claims description 3
• 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
• 238000006277 sulfonation reaction Methods 0.000 claims description 3
• 125000004571 thiomorpholin-4-yl group Chemical group N1(CCSCC1)* 0.000 claims description 3
• JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 claims description 3
• 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 2
• 125000006592 (C2-C3) alkenyl group Chemical group 0.000 claims description 2
• 230000002159 abnormal effect Effects 0.000 claims description 2
• 150000001336 alkenes Chemical class 0.000 claims description 2
• 125000005278 alkyl sulfonyloxy group Chemical group 0.000 claims description 2
• 125000005279 aryl sulfonyloxy group Chemical group 0.000 claims description 2
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
• 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 2
• 150000002825 nitriles Chemical class 0.000 claims description 2
• 238000005932 reductive alkylation reaction Methods 0.000 claims description 2
• 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 claims 16
• 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims 1
• 125000002102 aryl alkyloxo group Chemical group 0.000 claims 1
• 229940126601 medicinal product Drugs 0.000 claims 1
• 239000000126 substance Substances 0.000 claims 1
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 270
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 252
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 252
• 239000007858 starting material Substances 0.000 description 82
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 71
• 239000000741 silica gel Substances 0.000 description 70
• 229910002027 silica gel Inorganic materials 0.000 description 70
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 69
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 60
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 54
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 53
• 239000002904 solvent Substances 0.000 description 35
• 229910021529 ammonia Inorganic materials 0.000 description 30
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 27
• 238000001819 mass spectrum Methods 0.000 description 27
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 24
• 239000002244 precipitate Substances 0.000 description 23
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 22
• FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
• 239000000243 solution Substances 0.000 description 22
• 230000002829 reductive effect Effects 0.000 description 20
• DVFHFXFORJYWPC-UHFFFAOYSA-N 1-acetyl-6-fluoro-3h-indol-2-one Chemical compound C1=C(F)C=C2N(C(=O)C)C(=O)CC2=C1 DVFHFXFORJYWPC-UHFFFAOYSA-N 0.000 description 19
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 19
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 18
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 18
• 239000012071 phase Substances 0.000 description 18
• 239000000047 product Substances 0.000 description 17
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
• 239000003054 catalyst Substances 0.000 description 14
• 210000004027 cell Anatomy 0.000 description 14
• 239000001257 hydrogen Substances 0.000 description 14
• 229910052739 hydrogen Inorganic materials 0.000 description 14
• 238000002844 melting Methods 0.000 description 14
• 230000008018 melting Effects 0.000 description 14
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 13
• 239000003208 petroleum Substances 0.000 description 13
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 12
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 12
• KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 12
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
• 239000002585 base Substances 0.000 description 12
• 239000003480 eluent Substances 0.000 description 12
• 150000003254 radicals Chemical class 0.000 description 12
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 11
• 239000011780 sodium chloride Substances 0.000 description 11
• 230000002441 reversible effect Effects 0.000 description 10
• WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 9
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 9
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 9
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
• 229960000583 acetic acid Drugs 0.000 description 8
• 239000004927 clay Substances 0.000 description 8
• 238000001816 cooling Methods 0.000 description 8
• 210000002889 endothelial cell Anatomy 0.000 description 8
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 8
• 229910052938 sodium sulfate Inorganic materials 0.000 description 8
• 235000011152 sodium sulphate Nutrition 0.000 description 8
• SEJDHBXBPUHCFY-UHFFFAOYSA-N 1-acetyl-6-chloro-3h-indol-2-one Chemical compound C1=C(Cl)C=C2N(C(=O)C)C(=O)CC2=C1 SEJDHBXBPUHCFY-UHFFFAOYSA-N 0.000 description 7
• 150000007530 organic bases Chemical class 0.000 description 7
• 230000035755 proliferation Effects 0.000 description 7
• PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
• JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
• 239000007868 Raney catalyst Substances 0.000 description 6
• 229910000564 Raney nickel Inorganic materials 0.000 description 6
• NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 6
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
• 150000007513 acids Chemical class 0.000 description 6
• 239000012074 organic phase Substances 0.000 description 6
• 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 6
• ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
• NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 5
• 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 5
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 5
• 239000012362 glacial acetic acid Substances 0.000 description 5
• 238000005984 hydrogenation reaction Methods 0.000 description 5
• 239000003112 inhibitor Substances 0.000 description 5
• 230000002401 inhibitory effect Effects 0.000 description 5
• 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 description 4
• VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
• NNCCQALFJIMRKB-UHFFFAOYSA-N 4-[(dimethylamino)methyl]aniline Chemical compound CN(C)CC1=CC=C(N)C=C1 NNCCQALFJIMRKB-UHFFFAOYSA-N 0.000 description 4
• JARRYVQFBQVOBE-UHFFFAOYSA-N 6-bromo-1,3-dihydroindol-2-one Chemical compound BrC1=CC=C2CC(=O)NC2=C1 JARRYVQFBQVOBE-UHFFFAOYSA-N 0.000 description 4
• 229920002261 Corn starch Polymers 0.000 description 4
• FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
• 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 4
• 229930195725 Mannitol Natural products 0.000 description 4
• AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
• 102000001253 Protein Kinase Human genes 0.000 description 4
• CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 4
• 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 4
• 239000002775 capsule Substances 0.000 description 4
• PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 4
• IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 4
• 239000008120 corn starch Substances 0.000 description 4
• 238000011049 filling Methods 0.000 description 4
• 239000008101 lactose Substances 0.000 description 4
• 235000019359 magnesium stearate Nutrition 0.000 description 4
• 239000000594 mannitol Substances 0.000 description 4
• 235000010355 mannitol Nutrition 0.000 description 4
• 239000000463 material Substances 0.000 description 4
• 230000000144 pharmacologic effect Effects 0.000 description 4
• BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
• 108060006633 protein kinase Proteins 0.000 description 4
• UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
• 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
• VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 4
• FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
• 239000008215 water for injection Substances 0.000 description 4
• WDYXTBQUPCLKQQ-UHFFFAOYSA-N 4-(3-methoxy-3-oxopropyl)benzoic acid Chemical compound COC(=O)CCC1=CC=C(C(O)=O)C=C1 WDYXTBQUPCLKQQ-UHFFFAOYSA-N 0.000 description 3
• PKQNTFAOZIVXCE-UHFFFAOYSA-N 6-fluoro-1,3-dihydroindol-2-one Chemical compound FC1=CC=C2CC(=O)NC2=C1 PKQNTFAOZIVXCE-UHFFFAOYSA-N 0.000 description 3
• OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
• HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
• NQTADLQHYWFPDB-UHFFFAOYSA-N N-Hydroxysuccinimide Chemical compound ON1C(=O)CCC1=O NQTADLQHYWFPDB-UHFFFAOYSA-N 0.000 description 3
• SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 3
• 206010028980 Neoplasm Diseases 0.000 description 3
• 239000002202 Polyethylene glycol Substances 0.000 description 3
• 239000012317 TBTU Substances 0.000 description 3
• 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 3
• 229910052783 alkali metal Inorganic materials 0.000 description 3
• 150000001340 alkali metals Chemical class 0.000 description 3
• 230000033115 angiogenesis Effects 0.000 description 3
• 150000008064 anhydrides Chemical class 0.000 description 3
• HQABUPZFAYXKJW-UHFFFAOYSA-N butan-1-amine Chemical compound CCCCN HQABUPZFAYXKJW-UHFFFAOYSA-N 0.000 description 3
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