DE19949209A1 - In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel - Google Patents

Info

Publication number

DE19949209A1

DE19949209A1 DE19949209A DE19949209A DE19949209A1 DE 19949209 A1 DE19949209 A1 DE 19949209A1 DE 19949209 A DE19949209 A DE 19949209A DE 19949209 A DE19949209 A DE 19949209A DE 19949209 A1 DE19949209 A1 DE 19949209A1

Authority

DE

Germany

Prior art keywords

group

alkyl

phenyl

amino

methylene

Prior art date

1999-10-13

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

Withdrawn

Links

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• -1 5-substituted indolinones Chemical class 0.000 title claims abstract description 241
• 239000003814 drug Substances 0.000 title claims abstract description 5
• 238000002360 preparation method Methods 0.000 title claims description 11
• 150000001875 compounds Chemical class 0.000 claims abstract description 59
• 150000003839 salts Chemical class 0.000 claims abstract description 24
• 238000000034 method Methods 0.000 claims abstract description 8
• 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 67
• 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 66
• 125000000217 alkyl group Chemical group 0.000 claims description 53
• 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 50
• 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 37
• 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 32
• 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 32
• 229910052717 sulfur Chemical group 0.000 claims description 30
• 125000004434 sulfur atom Chemical group 0.000 claims description 30
• 125000006842 cycloalkyleneimino group Chemical group 0.000 claims description 29
• 229910052760 oxygen Inorganic materials 0.000 claims description 28
• 239000001301 oxygen Substances 0.000 claims description 28
• 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 28
• GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 27
• MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 26
• 125000006563 (C1-3) alkylaminocarbonyl group Chemical group 0.000 claims description 25
• 125000003545 alkoxy group Chemical group 0.000 claims description 23
• 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 23
• 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 23
• 229910052801 chlorine Inorganic materials 0.000 claims description 22
• 239000000460 chlorine Substances 0.000 claims description 22
• 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 21
• 125000006576 di-(C1-C3-alkyl)-aminocarbonyl group Chemical group 0.000 claims description 20
• 229910052731 fluorine Inorganic materials 0.000 claims description 19
• 239000011737 fluorine Substances 0.000 claims description 19
• 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 19
• 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 19
• 125000003282 alkyl amino group Chemical group 0.000 claims description 18
• 125000004093 cyano group Chemical group *C#N 0.000 claims description 18
• 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 18
• PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 17
• 229910052740 iodine Inorganic materials 0.000 claims description 16
• 125000006597 (C1-C3) alkylcarbonylamino group Chemical group 0.000 claims description 15
• 229910052794 bromium Inorganic materials 0.000 claims description 15
• ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 14
• KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 14
• 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 13
• 125000001841 imino group Chemical group [H]N=* 0.000 claims description 13
• 125000001624 naphthyl group Chemical group 0.000 claims description 13
• 125000006594 (C1-C3) alkylsulfony group Chemical group 0.000 claims description 11
• 125000002490 anilino group Chemical group [H]N(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 11
• 125000004104 aryloxy 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
• 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 11
• 125000000304 alkynyl group Chemical group 0.000 claims description 10
• 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 10
• 229910052757 nitrogen Inorganic materials 0.000 claims description 10
• 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims description 9
• 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 9
• 238000006243 chemical reaction Methods 0.000 claims description 9
• JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 claims description 9
• 125000004433 nitrogen atom Chemical group N* 0.000 claims description 9
• 125000006239 protecting group Chemical group 0.000 claims description 9
• ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
• 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 8
• 125000003277 amino group Chemical group 0.000 claims description 7
• 125000001072 heteroaryl group Chemical group 0.000 claims description 7
• 125000006595 (C1-C3) alkylsulfinyl group Chemical group 0.000 claims description 6
• 125000003342 alkenyl group Chemical group 0.000 claims description 6
• 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
• 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
• 239000007790 solid phase Substances 0.000 claims description 6
• WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
• 230000010933 acylation Effects 0.000 claims description 5
• 238000005917 acylation reaction Methods 0.000 claims description 5
• 125000004448 alkyl carbonyl group Chemical group 0.000 claims description 5
• 150000002148 esters Chemical class 0.000 claims description 5
• 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 claims description 5
• 150000003951 lactams Chemical group 0.000 claims description 5
• 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
• 239000000651 prodrug Chemical group 0.000 claims description 5
• 229940002612 prodrug Drugs 0.000 claims description 5
• 125000006603 (C1-C3) alkylaminosulfonyl group Chemical group 0.000 claims description 4
• 125000006602 (C1-C3) alkylsulfonylamino group Chemical group 0.000 claims description 4
• 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 4
• 125000002252 acyl group Chemical group 0.000 claims description 4
• 125000004414 alkyl thio group Chemical group 0.000 claims description 4
• 150000001412 amines Chemical class 0.000 claims description 4
• 125000004391 aryl sulfonyl group Chemical group 0.000 claims description 4
• 125000001246 bromo group Chemical group Br* 0.000 claims description 4
• 125000000753 cycloalkyl group Chemical group 0.000 claims description 4
• 125000002993 cycloalkylene group Chemical group 0.000 claims description 4
• 125000001153 fluoro group Chemical group F* 0.000 claims description 4
• 238000001727 in vivo Methods 0.000 claims description 4
• 125000004076 pyridyl group Chemical group 0.000 claims description 4
• 125000001424 substituent group Chemical group 0.000 claims description 4
• 125000003831 tetrazolyl group Chemical group 0.000 claims description 4
• HHVBCDVRJXTJAE-KARKAFJISA-N (3z)-3-[[4-[[benzyl(methyl)amino]methyl]anilino]-phenylmethylidene]-5-diethoxyphosphoryl-1h-indol-2-one Chemical compound C12=CC(P(=O)(OCC)OCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN(C)CC1=CC=CC=C1 HHVBCDVRJXTJAE-KARKAFJISA-N 0.000 claims description 3
• RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims description 3
• 125000003806 alkyl carbonyl amino group Chemical group 0.000 claims description 3
• 125000003118 aryl group Chemical group 0.000 claims description 3
• 239000003085 diluting agent Substances 0.000 claims description 3
• 230000032050 esterification Effects 0.000 claims description 3
• 238000005886 esterification reaction Methods 0.000 claims description 3
• 125000005843 halogen group Chemical group 0.000 claims description 3
• 230000007062 hydrolysis Effects 0.000 claims description 3
• 238000006460 hydrolysis reaction Methods 0.000 claims description 3
• 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 3
• 125000002883 imidazolyl group Chemical group 0.000 claims description 3
• 238000006722 reduction reaction Methods 0.000 claims description 3
• 238000005932 reductive alkylation reaction Methods 0.000 claims description 3
• 239000000126 substance Substances 0.000 claims description 3
• GPIWFBZLTMDTGZ-RQZHXJHFSA-N (3z)-5-methylsulfinyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indol-2-one Chemical compound C12=CC(S(=O)C)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 GPIWFBZLTMDTGZ-RQZHXJHFSA-N 0.000 claims description 2
• 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
• CAAMSDWKXXPUJR-UHFFFAOYSA-N 3,5-dihydro-4H-imidazol-4-one Chemical compound O=C1CNC=N1 CAAMSDWKXXPUJR-UHFFFAOYSA-N 0.000 claims description 2
• 230000002159 abnormal effect Effects 0.000 claims description 2
• 150000003855 acyl compounds Chemical class 0.000 claims description 2
• 125000005037 alkyl phenyl group Chemical group 0.000 claims description 2
• 230000029936 alkylation Effects 0.000 claims description 2
• 238000005804 alkylation reaction Methods 0.000 claims description 2
• 125000005141 aryl amino sulfonyl group Chemical group 0.000 claims description 2
• 125000005129 aryl carbonyl group Chemical group 0.000 claims description 2
• 125000005142 aryl oxy sulfonyl group Chemical group 0.000 claims description 2
• 125000005135 aryl sulfinyl group Chemical group 0.000 claims description 2
• 239000000969 carrier Substances 0.000 claims description 2
• 230000004663 cell proliferation Effects 0.000 claims description 2
• 125000006844 cycloalkyleneimino-C1-3-alkyl group Chemical group 0.000 claims description 2
• 125000006312 cyclopentyl amino group Chemical group [H]N(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000004663 dialkyl amino group Chemical group 0.000 claims description 2
• 125000002541 furyl group Chemical group 0.000 claims description 2
• 150000007522 mineralic acids Chemical class 0.000 claims description 2
• 150000007524 organic acids Chemical class 0.000 claims description 2
• 125000002971 oxazolyl group Chemical group 0.000 claims description 2
• 230000001681 protective effect Effects 0.000 claims description 2
• 125000000714 pyrimidinyl group Chemical group 0.000 claims description 2
• 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 2
• 125000000168 pyrrolyl group Chemical group 0.000 claims description 2
• PXQLVRUNWNTZOS-UHFFFAOYSA-N sulfanyl Chemical class [SH] PXQLVRUNWNTZOS-UHFFFAOYSA-N 0.000 claims description 2
• 125000000335 thiazolyl group Chemical group 0.000 claims description 2
• 125000001544 thienyl group Chemical group 0.000 claims description 2
• 125000003396 thiol group Chemical class [H]S* 0.000 claims description 2
• UQLKRWKVLYXDMW-MVJHLKBCSA-N (3z)-2-oxo-n-phenyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indole-5-sulfonamide Chemical compound O=C1NC2=CC=C(S(=O)(=O)NC=3C=CC=CC=3)C=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1CN1CCCCC1 UQLKRWKVLYXDMW-MVJHLKBCSA-N 0.000 claims 1
• YUJQSBOMKGIIID-RQZHXJHFSA-N (3z)-5-methylsulfonyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indol-2-one Chemical compound C12=CC(S(=O)(=O)C)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 YUJQSBOMKGIIID-RQZHXJHFSA-N 0.000 claims 1
• LXUKTKWJGSMCAI-KTMFPKCZSA-N (3z)-n-butyl-n-methyl-2-oxo-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indole-5-sulfonamide Chemical compound C12=CC(S(=O)(=O)N(C)CCCC)=CC=C2NC(=O)\C1=C(C=1C=CC=CC=1)/NC(C=C1)=CC=C1CN1CCCCC1 LXUKTKWJGSMCAI-KTMFPKCZSA-N 0.000 claims 1
• CXNZOTVYJUQCIA-KARKAFJISA-N (3z)-n-methyl-2-oxo-n-phenyl-3-[phenyl-[4-(piperidin-1-ylmethyl)anilino]methylidene]-1h-indole-5-sulfonamide Chemical compound C=1C=C2NC(=O)\C(=C(/NC=3C=CC(CN4CCCCC4)=CC=3)C=3C=CC=CC=3)C2=CC=1S(=O)(=O)N(C)C1=CC=CC=C1 CXNZOTVYJUQCIA-KARKAFJISA-N 0.000 claims 1
• 125000005036 alkoxyphenyl group Chemical group 0.000 claims 1
• 125000004644 alkyl sulfinyl group Chemical group 0.000 claims 1
• 125000004390 alkyl sulfonyl group Chemical group 0.000 claims 1
• 238000005576 amination reaction Methods 0.000 claims 1
• 229940079593 drug Drugs 0.000 claims 1
• 239000008194 pharmaceutical composition Substances 0.000 claims 1
• 125000000020 sulfo group Chemical group O=S(=O)([*])O[H] 0.000 claims 1
• 238000004519 manufacturing process Methods 0.000 abstract description 9
• 210000004881 tumor cell Anatomy 0.000 abstract description 7
• 108050006400 Cyclin Proteins 0.000 abstract description 6
• 102000016736 Cyclin Human genes 0.000 abstract description 6
• 108091000080 Phosphotransferase Proteins 0.000 abstract description 5
• 102000020233 phosphotransferase Human genes 0.000 abstract description 5
• 230000000144 pharmacologic effect Effects 0.000 abstract description 4
• 230000035755 proliferation Effects 0.000 abstract description 4
• 230000002401 inhibitory effect Effects 0.000 abstract description 3
• YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 144
• OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 102
• LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 83
• XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 44
• XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
• QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 40
• ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 40
• VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
• 239000000741 silica gel Substances 0.000 description 39
• 229910002027 silica gel Inorganic materials 0.000 description 39
• CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 33
• WFDIJRYMOXRFFG-UHFFFAOYSA-N acetic acid anhydride Natural products CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 32
• 239000000203 mixture Substances 0.000 description 31
• 235000019441 ethanol Nutrition 0.000 description 30
• 229960004756 ethanol Drugs 0.000 description 27
• RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
• VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
• 239000002904 solvent Substances 0.000 description 21
• DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 20
• 229960000583 acetic acid Drugs 0.000 description 19
• HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
• YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
• ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
• 239000002253 acid Substances 0.000 description 16
• 238000001819 mass spectrum Methods 0.000 description 16
• 238000000119 electrospray ionisation mass spectrum Methods 0.000 description 15
• 239000012362 glacial acetic acid Substances 0.000 description 15
• WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
• 239000000243 solution Substances 0.000 description 12
• QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 11
• 239000013543 active substance Substances 0.000 description 11
• 230000000875 corresponding effect Effects 0.000 description 11
• IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
• KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 10
• WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
• 210000004027 cell Anatomy 0.000 description 10
• HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
• WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
• KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
• 239000002585 base Substances 0.000 description 9
• FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 9
• MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 8
• JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
• QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 8
• 238000003776 cleavage reaction Methods 0.000 description 8
• BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
• 230000007017 scission Effects 0.000 description 8
• RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 7
• WNHZGLYJICWPFH-UHFFFAOYSA-N 1-acetyl-5-diethoxyphosphoryl-3-[ethoxy(phenyl)methylidene]indol-2-one Chemical compound O=C1N(C(C)=O)C2=CC=C(P(=O)(OCC)OCC)C=C2C1=C(OCC)C1=CC=CC=C1 WNHZGLYJICWPFH-UHFFFAOYSA-N 0.000 description 7
• DRYFDUUAYSVNSN-UHFFFAOYSA-N 4-(piperidin-1-ylmethyl)aniline Chemical compound C1=CC(N)=CC=C1CN1CCCCC1 DRYFDUUAYSVNSN-UHFFFAOYSA-N 0.000 description 7
• 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 7
• 239000004480 active ingredient Substances 0.000 description 7
• 239000002775 capsule Substances 0.000 description 7
• XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 6
• SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 6
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• PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
• KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
• 229910052739 hydrogen Inorganic materials 0.000 description 6
• 239000001257 hydrogen Substances 0.000 description 6
• BQFPCTXLBRVFJL-UHFFFAOYSA-N triethoxymethylbenzene Chemical compound CCOC(OCC)(OCC)C1=CC=CC=C1 BQFPCTXLBRVFJL-UHFFFAOYSA-N 0.000 description 6
• FYBNVKMJOOYPGI-UHFFFAOYSA-N 2-oxo-1,3-dihydroindole-5-sulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=C2NC(=O)CC2=C1 FYBNVKMJOOYPGI-UHFFFAOYSA-N 0.000 description 5
• 108091007914 CDKs Proteins 0.000 description 5
• 229920002261 Corn starch Polymers 0.000 description 5
• 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 5
• 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 5
• QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 5
• UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
• 229910021529 ammonia Inorganic materials 0.000 description 5
• 239000008120 corn starch Substances 0.000 description 5
• 239000000706 filtrate Substances 0.000 description 5
• 230000005764 inhibitory process Effects 0.000 description 5
• 235000019359 magnesium stearate Nutrition 0.000 description 5
• 239000012074 organic phase Substances 0.000 description 5
• 239000007800 oxidant agent Substances 0.000 description 5
• 239000002244 precipitate Substances 0.000 description 5
• 229910052938 sodium sulfate Inorganic materials 0.000 description 5
• 235000011152 sodium sulphate Nutrition 0.000 description 5
• 239000000758 substrate Substances 0.000 description 5
• YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
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