JP4363985B2 - タンパク質キナーゼ阻害剤として有用なインドリン誘導体 - Google Patents
タンパク質キナーゼ阻害剤として有用なインドリン誘導体 Download PDFInfo
- Publication number
- JP4363985B2 JP4363985B2 JP2003558005A JP2003558005A JP4363985B2 JP 4363985 B2 JP4363985 B2 JP 4363985B2 JP 2003558005 A JP2003558005 A JP 2003558005A JP 2003558005 A JP2003558005 A JP 2003558005A JP 4363985 B2 JP4363985 B2 JP 4363985B2
- Authority
- JP
- Japan
- Prior art keywords
- compound
- formula
- dimethyl
- pharmaceutically acceptable
- pyrrol
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 229940045988 antineoplastic drug protein kinase inhibitors Drugs 0.000 title 1
- 125000003387 indolinyl group Chemical class N1(CCC2=CC=CC=C12)* 0.000 title 1
- 239000003909 protein kinase inhibitor Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 135
- 238000011282 treatment Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 24
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 22
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000008194 pharmaceutical composition Substances 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 11
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 claims description 9
- 239000005483 tyrosine kinase inhibitor Substances 0.000 claims description 9
- KVIAIJLTPHXNEB-UHFFFAOYSA-N 3-[[3,5-dimethyl-4-(3-oxo-3-piperazin-1-ylpropyl)-1h-pyrrol-2-yl]methylidene]-1h-indol-2-one Chemical compound CC=1NC(C=C2C3=CC=CC=C3NC2=O)=C(C)C=1CCC(=O)N1CCNCC1 KVIAIJLTPHXNEB-UHFFFAOYSA-N 0.000 claims description 8
- 150000004917 tyrosine kinase inhibitor derivatives Chemical class 0.000 claims description 7
- 239000003814 drug Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000006239 protecting group Chemical group 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 claims description 3
- 101150065749 Churc1 gene Proteins 0.000 claims description 3
- 102100038239 Protein Churchill Human genes 0.000 claims description 3
- 239000003085 diluting agent Substances 0.000 claims description 3
- 125000001140 1,4-phenylene group Chemical group [H]C1=C([H])C([*:2])=C([H])C([H])=C1[*:1] 0.000 claims description 2
- UCIAJIBDPDKOAD-UHFFFAOYSA-N 3-[[4-[3-(1,4-diazepan-1-yl)-3-oxopropyl]-3,5-dimethyl-1h-pyrrol-2-yl]methylidene]-1h-indol-2-one Chemical compound CC=1NC(C=C2C3=CC=CC=C3NC2=O)=C(C)C=1CCC(=O)N1CCCNCC1 UCIAJIBDPDKOAD-UHFFFAOYSA-N 0.000 claims description 2
- 238000002560 therapeutic procedure Methods 0.000 claims description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 12
- 229940127361 Receptor Tyrosine Kinase Inhibitors Drugs 0.000 abstract description 8
- 230000002062 proliferating effect Effects 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 description 30
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 28
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 25
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 25
- 125000000217 alkyl group Chemical group 0.000 description 21
- -1 pyrrole-substituted 2-indolinone Chemical class 0.000 description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 16
- 239000007787 solid Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 238000003556 assay Methods 0.000 description 14
- 101100335081 Mus musculus Flt3 gene Proteins 0.000 description 13
- 238000005481 NMR spectroscopy Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 11
- 108010038512 Platelet-Derived Growth Factor Proteins 0.000 description 11
- 102000010780 Platelet-Derived Growth Factor Human genes 0.000 description 11
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 11
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- 108010073929 Vascular Endothelial Growth Factor A Proteins 0.000 description 10
- 239000004615 ingredient Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 239000000706 filtrate Substances 0.000 description 9
- 239000007903 gelatin capsule Substances 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 8
- 239000002775 capsule Substances 0.000 description 8
- 201000010099 disease Diseases 0.000 description 8
- 125000003386 piperidinyl group Chemical group 0.000 description 8
- 102000005962 receptors Human genes 0.000 description 8
- 108020003175 receptors Proteins 0.000 description 8
- 125000001424 substituent group Chemical group 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 7
- 230000035578 autophosphorylation Effects 0.000 description 7
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000005457 ice water Substances 0.000 description 7
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 7
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 description 6
- 208000031261 Acute myeloid leukaemia Diseases 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 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
- 238000001990 intravenous administration Methods 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 description 6
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 6
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 5
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 5
- 125000006242 amine protecting group Chemical group 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 125000005843 halogen group Chemical group 0.000 description 5
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 description 5
- 238000004007 reversed phase HPLC Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 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 4
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 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 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 208000033776 Myeloid Acute Leukemia Diseases 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 4
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 4
- 125000003545 alkoxy group Chemical group 0.000 description 4
- 125000002947 alkylene group Chemical group 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000001114 immunoprecipitation Methods 0.000 description 4
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 125000000168 pyrrolyl group Chemical group 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OZLGRUXZXMRXGP-UHFFFAOYSA-N Fluo-3 Chemical compound CC1=CC=C(N(CC(O)=O)CC(O)=O)C(OCCOC=2C(=CC=C(C=2)C2=C3C=C(Cl)C(=O)C=C3OC3=CC(O)=C(Cl)C=C32)N(CC(O)=O)CC(O)=O)=C1 OZLGRUXZXMRXGP-UHFFFAOYSA-N 0.000 description 3
- 239000007821 HATU Substances 0.000 description 3
- 229910004373 HOAc Inorganic materials 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 102000016971 Proto-Oncogene Proteins c-kit Human genes 0.000 description 3
- 108010014608 Proto-Oncogene Proteins c-kit Proteins 0.000 description 3
- 239000012891 Ringer solution Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 3
- 229910052794 bromium Inorganic materials 0.000 description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 150000002431 hydrogen Chemical group 0.000 description 3
- 229940090044 injection Drugs 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 3
- WUWDLXZGHZSWQZ-WQLSENKSSA-N semaxanib Chemical compound N1C(C)=CC(C)=C1\C=C/1C2=CC=CC=C2NC\1=O WUWDLXZGHZSWQZ-WQLSENKSSA-N 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- NHFDRBXTEDBWCZ-ZROIWOOFSA-N 3-[2,4-dimethyl-5-[(z)-(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]propanoic acid Chemical compound OC(=O)CCC1=C(C)NC(\C=C/2C3=CC=CC=C3NC\2=O)=C1C NHFDRBXTEDBWCZ-ZROIWOOFSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 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 2
- 241001465754 Metazoa Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 108091000080 Phosphotransferase Proteins 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- 241000219289 Silene Species 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical group 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 125000002529 biphenylenyl group Chemical group C1(=CC=CC=2C3=CC=CC=C3C12)* 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 229910052918 calcium silicate Inorganic materials 0.000 description 2
- 238000001516 cell proliferation assay Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 238000002372 labelling Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000011068 loading method Methods 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
- 229940001087 magnesium sulfate 10 mg Drugs 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000011159 matrix material Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 2
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- NHFDRBXTEDBWCZ-UHFFFAOYSA-N orantinib Chemical compound OC(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C NHFDRBXTEDBWCZ-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 125000000843 phenylene group Chemical group C1(=C(C=CC=C1)*)* 0.000 description 2
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 description 2
- 102000020233 phosphotransferase Human genes 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 231100000747 viability assay Toxicity 0.000 description 2
- 238000003026 viability measurement method Methods 0.000 description 2
- QBYIENPQHBMVBV-HFEGYEGKSA-N (2R)-2-hydroxy-2-phenylacetic acid Chemical compound O[C@@H](C(O)=O)c1ccccc1.O[C@@H](C(O)=O)c1ccccc1 QBYIENPQHBMVBV-HFEGYEGKSA-N 0.000 description 1
- MIOPJNTWMNEORI-GMSGAONNSA-N (S)-camphorsulfonic acid Chemical compound C1C[C@@]2(CS(O)(=O)=O)C(=O)C[C@@H]1C2(C)C MIOPJNTWMNEORI-GMSGAONNSA-N 0.000 description 1
- AZUYLZMQTIKGSC-UHFFFAOYSA-N 1-[6-[4-(5-chloro-6-methyl-1H-indazol-4-yl)-5-methyl-3-(1-methylindazol-5-yl)pyrazol-1-yl]-2-azaspiro[3.3]heptan-2-yl]prop-2-en-1-one Chemical compound ClC=1C(=C2C=NNC2=CC=1C)C=1C(=NN(C=1C)C1CC2(CN(C2)C(C=C)=O)C1)C=1C=C2C=NN(C2=CC=1)C AZUYLZMQTIKGSC-UHFFFAOYSA-N 0.000 description 1
- BHKKSKOHRFHHIN-MRVPVSSYSA-N 1-[[2-[(1R)-1-aminoethyl]-4-chlorophenyl]methyl]-2-sulfanylidene-5H-pyrrolo[3,2-d]pyrimidin-4-one Chemical compound N[C@H](C)C1=C(CN2C(NC(C3=C2C=CN3)=O)=S)C=CC(=C1)Cl BHKKSKOHRFHHIN-MRVPVSSYSA-N 0.000 description 1
- 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 1
- UHTQHHLSGVOGQR-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-4-ium-1-yl]ethanesulfonate Chemical compound OCCN1CCN(CCS(O)(=O)=O)CC1.OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 UHTQHHLSGVOGQR-UHFFFAOYSA-N 0.000 description 1
- SAGABBLUUSFKNW-UHFFFAOYSA-N 3-(2,4-dimethyl-1h-pyrrol-3-yl)propanoic acid Chemical compound CC1=CNC(C)=C1CCC(O)=O SAGABBLUUSFKNW-UHFFFAOYSA-N 0.000 description 1
- NLLSXQZFJKZXKL-UHFFFAOYSA-N 3-(2,4-dimethylpyrrol-1-yl)propanoic acid Chemical compound CC=1C=C(C)N(CCC(O)=O)C=1 NLLSXQZFJKZXKL-UHFFFAOYSA-N 0.000 description 1
- DUSIQYJZIANKDG-UHFFFAOYSA-N 3-(3-formyl-2,4-dimethylpyrrol-1-yl)propanoic acid Chemical compound CC1=CN(CCC(O)=O)C(C)=C1C=O DUSIQYJZIANKDG-UHFFFAOYSA-N 0.000 description 1
- AZKSAVLVSZKNRD-UHFFFAOYSA-M 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide Chemical compound [Br-].S1C(C)=C(C)N=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 AZKSAVLVSZKNRD-UHFFFAOYSA-M 0.000 description 1
- RUILENPFHDHTRC-UHFFFAOYSA-N 3-(5-formyl-2,4-dimethyl-1h-pyrrol-3-yl)propanoic acid Chemical compound CC=1NC(C=O)=C(C)C=1CCC(O)=O RUILENPFHDHTRC-UHFFFAOYSA-N 0.000 description 1
- HFFCKKXPNMELRI-UHFFFAOYSA-N 3-[1-(2-carboxyethyl)-2,4-dimethylpyrrol-3-yl]propanoic acid Chemical compound CC1=CN(CCC(O)=O)C(C)=C1CCC(O)=O HFFCKKXPNMELRI-UHFFFAOYSA-N 0.000 description 1
- HXEBVUPMCFPUHF-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[10-(methylamino)decyl]propanamide Chemical compound CNCCCCCCCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C HXEBVUPMCFPUHF-UHFFFAOYSA-N 0.000 description 1
- RPXRBNQLBRVCEO-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[12-(methylamino)dodecyl]propanamide Chemical compound CNCCCCCCCCCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C RPXRBNQLBRVCEO-UHFFFAOYSA-N 0.000 description 1
- LPKSEJBRAAVTMM-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[2-(methylamino)ethyl]propanamide Chemical compound CNCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C LPKSEJBRAAVTMM-UHFFFAOYSA-N 0.000 description 1
- QNUCGDBWALQCEF-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[2-[2-[2-(methylamino)ethoxy]ethoxy]ethyl]propanamide Chemical compound CNCCOCCOCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C QNUCGDBWALQCEF-UHFFFAOYSA-N 0.000 description 1
- DKNSOFNGKYCMIR-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[3-(methylamino)propyl]propanamide Chemical compound CNCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C DKNSOFNGKYCMIR-UHFFFAOYSA-N 0.000 description 1
- GOEDFHDXSSUIAO-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[4-(methylamino)but-2-enyl]propanamide Chemical compound CNCC=CCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C GOEDFHDXSSUIAO-UHFFFAOYSA-N 0.000 description 1
- CFRJUUGQCMQIAO-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[4-(methylamino)butyl]propanamide Chemical compound CNCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C CFRJUUGQCMQIAO-UHFFFAOYSA-N 0.000 description 1
- RJHSRTLXZQWIIN-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[5-(methylamino)pentyl]propanamide Chemical compound CNCCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C RJHSRTLXZQWIIN-UHFFFAOYSA-N 0.000 description 1
- COUXITPMPONYFG-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[7-(methylamino)heptyl]propanamide Chemical compound CNCCCCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C COUXITPMPONYFG-UHFFFAOYSA-N 0.000 description 1
- VUBHAXHUEAPXKY-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[8-(methylamino)octyl]propanamide Chemical compound CNCCCCCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C VUBHAXHUEAPXKY-UHFFFAOYSA-N 0.000 description 1
- XEGNZBRSXUGZKP-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]-n-methyl-n-[9-(methylamino)nonyl]propanamide Chemical compound CNCCCCCCCCCN(C)C(=O)CCC1=C(C)NC(C=C2C3=CC=CC=C3NC2=O)=C1C XEGNZBRSXUGZKP-UHFFFAOYSA-N 0.000 description 1
- WYLMTLWFCFZPRI-UHFFFAOYSA-N 3-[4-(2-carboxyethenyl)-3,5-dimethyl-1h-pyrrol-2-yl]propanoic acid Chemical compound CC=1NC(CCC(O)=O)=C(C)C=1C=CC(O)=O WYLMTLWFCFZPRI-UHFFFAOYSA-N 0.000 description 1
- UARYVLMOHISHNY-UHFFFAOYSA-N 3-[[3,5-dimethyl-4-(3-oxo-3-piperidin-1-ylpropyl)-1h-pyrrol-2-yl]methylidene]-1h-indol-2-one Chemical compound CC=1NC(C=C2C3=CC=CC=C3NC2=O)=C(C)C=1CCC(=O)N1CCCCC1 UARYVLMOHISHNY-UHFFFAOYSA-N 0.000 description 1
- MCSXGCZMEPXKIW-UHFFFAOYSA-N 3-hydroxy-4-[(4-methyl-2-nitrophenyl)diazenyl]-N-(3-nitrophenyl)naphthalene-2-carboxamide Chemical compound Cc1ccc(N=Nc2c(O)c(cc3ccccc23)C(=O)Nc2cccc(c2)[N+]([O-])=O)c(c1)[N+]([O-])=O MCSXGCZMEPXKIW-UHFFFAOYSA-N 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
- 239000005711 Benzoic acid Substances 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 0 Cc1c(C=C(c2ccccc2N2)C2=O)[n]c(C)c1CCC(N1CCN(*)CC1)=O Chemical compound Cc1c(C=C(c2ccccc2N2)C2=O)[n]c(C)c1CCC(N1CCN(*)CC1)=O 0.000 description 1
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- 206010017993 Gastrointestinal neoplasms Diseases 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 101100519721 Homo sapiens PDGFRB gene Proteins 0.000 description 1
- 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 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 description 1
- 108091008606 PDGF receptors Proteins 0.000 description 1
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 102000001253 Protein Kinase Human genes 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-N R-2-phenyl-2-hydroxyacetic acid Natural products OC(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-N 0.000 description 1
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 1
- 101710151245 Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 1
- 229940124639 Selective inhibitor Drugs 0.000 description 1
- 206010041067 Small cell lung cancer Diseases 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 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
- 101710120037 Toxin CcdB Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 108091008605 VEGF receptors Proteins 0.000 description 1
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 1
- WXIONIWNXBAHRU-UHFFFAOYSA-N [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylidene]-dimethylazanium Chemical compound C1=CN=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 WXIONIWNXBAHRU-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000005101 aryl methoxy carbonyl group Chemical group 0.000 description 1
- 125000005002 aryl methyl group Chemical group 0.000 description 1
- 239000011324 bead Substances 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
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- 150000001559 benzoic acids Chemical class 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
- 239000011230 binding agent Substances 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000003833 cell viability Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- BJDCWCLMFKKGEE-CMDXXVQNSA-N chembl252518 Chemical compound C([C@@](OO1)(C)O2)C[C@H]3[C@H](C)CC[C@@H]4[C@@]31[C@@H]2O[C@H](O)[C@@H]4C BJDCWCLMFKKGEE-CMDXXVQNSA-N 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 125000004956 cyclohexylene group Chemical group 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000006114 decarboxylation reaction Methods 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000008157 edible vegetable oil Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 108700014844 flt3 ligand Proteins 0.000 description 1
- 239000007850 fluorescent dye Substances 0.000 description 1
- PTCGDEVVHUXTMP-UHFFFAOYSA-N flutolanil Chemical compound CC(C)OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)C(F)(F)F)=C1 PTCGDEVVHUXTMP-UHFFFAOYSA-N 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 229960001031 glucose Drugs 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960000443 hydrochloric acid Drugs 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 125000005647 linker group Chemical group 0.000 description 1
- 239000006166 lysate Substances 0.000 description 1
- 239000012139 lysis buffer Substances 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000003760 magnetic stirring Methods 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000013160 medical therapy Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- KVKFRMCSXWQSNT-UHFFFAOYSA-N n,n'-dimethylethane-1,2-diamine Chemical compound CNCCNC KVKFRMCSXWQSNT-UHFFFAOYSA-N 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229940080553 normosol-m Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940055726 pantothenic acid Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 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
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical group OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 1
- 229960004838 phosphoric acid Drugs 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical group OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 229940080818 propionamide Drugs 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 108060006633 protein kinase Proteins 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 229940124617 receptor tyrosine kinase inhibitor Drugs 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 208000000587 small cell lung carcinoma Diseases 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000007974 sodium acetate buffer Substances 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940032330 sulfuric acid Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- QHQATUUBFDYJOC-UHFFFAOYSA-N tert-butyl 4-[3-[2,4-dimethyl-5-[(2-oxo-1h-indol-3-ylidene)methyl]-1h-pyrrol-3-yl]propanoyl]piperazine-1-carboxylate Chemical compound CC=1NC(C=C2C3=CC=CC=C3NC2=O)=C(C)C=1CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1 QHQATUUBFDYJOC-UHFFFAOYSA-N 0.000 description 1
- CWXPZXBSDSIRCS-UHFFFAOYSA-N tert-butyl piperazine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCNCC1 CWXPZXBSDSIRCS-UHFFFAOYSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
- 210000003606 umbilical vein Anatomy 0.000 description 1
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- 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
- C07D403/06—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 linked by a carbon chain containing only aliphatic 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61P35/02—Antineoplastic agents specific for leukemia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Oncology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
- Peptides Or Proteins (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US34381301P | 2001-12-27 | 2001-12-27 | |
| US34374601P | 2001-12-27 | 2001-12-27 | |
| PCT/US2002/041252 WO2003057690A1 (en) | 2001-12-27 | 2002-12-20 | Indolinone derivatives useful as protein kinase inhibitors |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| JP2005514420A JP2005514420A (ja) | 2005-05-19 |
| JP2005514420A5 JP2005514420A5 (https=) | 2005-12-22 |
| JP4363985B2 true JP4363985B2 (ja) | 2009-11-11 |
Family
ID=26993599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2003558005A Expired - Fee Related JP4363985B2 (ja) | 2001-12-27 | 2002-12-20 | タンパク質キナーゼ阻害剤として有用なインドリン誘導体 |
Country Status (21)
| Country | Link |
|---|---|
| US (3) | US6686362B2 (https=) |
| EP (1) | EP1458713B1 (https=) |
| JP (1) | JP4363985B2 (https=) |
| KR (1) | KR100965519B1 (https=) |
| CN (1) | CN1290844C (https=) |
| AT (1) | ATE302771T1 (https=) |
| AU (1) | AU2002360753B2 (https=) |
| BR (1) | BR0215360A (https=) |
| CA (1) | CA2470480C (https=) |
| CO (1) | CO5611126A2 (https=) |
| DE (1) | DE60205776T2 (https=) |
| DK (1) | DK1458713T3 (https=) |
| ES (1) | ES2247411T3 (https=) |
| HU (1) | HUP0500111A3 (https=) |
| IL (1) | IL162203A0 (https=) |
| MX (1) | MXPA04006271A (https=) |
| NO (1) | NO327550B1 (https=) |
| NZ (1) | NZ533219A (https=) |
| PL (1) | PL208283B1 (https=) |
| RU (1) | RU2316554C2 (https=) |
| WO (1) | WO2003057690A1 (https=) |
Families Citing this family (31)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7195876B2 (en) * | 2002-08-09 | 2007-03-27 | Theravance, Inc. | Oncokinase fusion polypeptides associated with hyperproliferative and related disorders, nucleic acids encoding the same and methods for detecting and identifying the same |
| RU2006117635A (ru) * | 2003-10-24 | 2007-12-10 | Шеринг Акциенгезельшафт (De) | Производные индолинона и их применение для лечения патологических состояний, таких как злокачественное новообразование |
| US20050171182A1 (en) * | 2003-12-11 | 2005-08-04 | Roger Briesewitz | Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases |
| SE0401790D0 (sv) * | 2004-07-07 | 2004-07-07 | Forskarpatent I Syd Ab | Tamoxifen response in pre- and postmenopausal breast cancer patients |
| US7825244B2 (en) | 2005-06-10 | 2010-11-02 | Janssen Pharmaceutica Nv | Intermediates useful in the synthesis of alkylquinoline and alkylquinazoline kinase modulators, and related methods of synthesis |
| US8071768B2 (en) | 2005-06-10 | 2011-12-06 | Janssen Pharmaceutica, N.V. | Alkylquinoline and alkylquinazoline kinase modulators |
| US20060281788A1 (en) | 2005-06-10 | 2006-12-14 | Baumann Christian A | Synergistic modulation of flt3 kinase using a flt3 inhibitor and a farnesyl transferase inhibitor |
| AU2006304897B2 (en) | 2005-10-18 | 2012-07-12 | Janssen Pharmaceutica N.V. | Method of inhibiting FLT3 kinase |
| US8697716B2 (en) | 2006-04-20 | 2014-04-15 | Janssen Pharmaceutica Nv | Method of inhibiting C-KIT kinase |
| WO2007124319A1 (en) | 2006-04-20 | 2007-11-01 | Janssen Pharmaceutica N.V. | Inhibitors of c-fms kinase |
| PL2021335T3 (pl) | 2006-04-20 | 2011-10-31 | Janssen Pharmaceutica Nv | Związki heterocykliczne jako inhibitory kinazy C-FMS |
| JP2010502741A (ja) * | 2006-09-11 | 2010-01-28 | キュリス，インコーポレイテッド | Ｐｔｋインヒビターとしての亜鉛結合部分を含む置換２−インドリノン |
| JO3240B1 (ar) | 2007-10-17 | 2018-03-08 | Janssen Pharmaceutica Nv | c-fms مثبطات كيناز |
| FR2948940B1 (fr) * | 2009-08-04 | 2011-07-22 | Servier Lab | Nouveaux derives dihydroindolones, leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
| HUE045270T2 (hu) | 2010-01-05 | 2019-12-30 | Inst Nat Sante Rech Med | FLT3 receptor anatgonisták fájdalom rendellenességek kezelésére |
| ES2539170T3 (es) | 2010-01-12 | 2015-06-26 | Ab Science | Inhibidores de quinasas de oxazol |
| CN104870454B (zh) | 2012-08-07 | 2020-03-03 | 詹森药业有限公司 | 用于制备杂环酯衍生物的方法 |
| ES2658773T3 (es) | 2012-08-07 | 2018-03-12 | Janssen Pharmaceutica N.V. | Procedimiento de sulfonilación usando fluoruro de nonafluorobutanosulfonilo |
| KR101738063B1 (ko) | 2012-09-21 | 2017-05-19 | 아로그 파마슈티칼스, 인코퍼레이티드 | 구조적으로 활성인 인산화된 ｆｌｔ３ 키나제의 억제 방법 |
| BR112015016282A2 (en) | 2013-01-07 | 2017-07-11 | Arog Pharmaceuticals, Inc. | crenolanib for treatment of mutated flt3 proliferative disorders |
| FR3008411B1 (fr) * | 2013-07-12 | 2015-07-03 | Servier Lab | Nouveau sel de la 3-[(3-{[4-(4-morpholinylmethyl)-1h-pyrrol-2-yl]methylene}-2-oxo-2,3-dihydro-1h-indol-5-yl)methyl]-1,3-thiazolidine-2,4-dione, sa preparation, et les formulations qui le contiennent |
| US10463658B2 (en) | 2013-10-25 | 2019-11-05 | Videra Pharmaceuticals, Llc | Method of inhibiting FLT3 kinase |
| BR112017002001B1 (pt) | 2014-07-31 | 2022-10-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Compostos e composição farmacêutica |
| EP3254698A1 (en) | 2016-06-08 | 2017-12-13 | Universite De Montpellier | Flt3 receptor inhibitor at low dosage for the treatment of neuropathic pain |
| US12534764B2 (en) | 2016-11-02 | 2026-01-27 | Arog Pharmaceuticals, Inc. | Crenolanib for treating FLT3 mutated proliferative disorders associated mutations |
| EA201991078A1 (ru) | 2016-11-02 | 2019-11-29 | Креноланиб для лечения пролиферативных расстройств, связанных с мутацией flt3 | |
| JP2020519665A (ja) | 2017-05-17 | 2020-07-02 | アンセルム（アンスティテュト ナショナル ド ラ サンテ エ ド ラ ルシェルシュ メディカル） | オピオイドによる痛みの処置を改善する為のｆｌｔ３阻害剤 |
| WO2019057649A1 (en) | 2017-09-19 | 2019-03-28 | INSERM (Institut National de la Santé et de la Recherche Médicale) | METHODS AND PHARMACEUTICAL COMPOSITIONS FOR THE TREATMENT OF ACUTE MYELOID LEUKEMIA |
| WO2022019998A1 (en) | 2020-07-20 | 2022-01-27 | Arog Pharmaceuticals, Inc. | Crystal forms of crenolanib and methods of use thereof |
| US11969420B2 (en) | 2020-10-30 | 2024-04-30 | Arog Pharmaceuticals, Inc. | Combination therapy of crenolanib and apoptosis pathway agents for the treatment of proliferative disorders |
| WO2022090547A1 (en) | 2020-10-30 | 2022-05-05 | Dsm Ip Assets B.V. | Production of carotenoids by fermentation |
Family Cites Families (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| MC2096A1 (fr) * | 1989-02-23 | 1991-02-15 | Hoffmann La Roche | Pyrroles substitues |
| US5880141A (en) | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| CO4950519A1 (es) | 1997-02-13 | 2000-09-01 | Novartis Ag | Ftalazinas, preparaciones farmaceuticas que las comprenden y proceso para su preparacion |
| SK287132B6 (sk) * | 1998-05-29 | 2009-12-07 | Sugen, Inc. | Farmaceutická kompozícia obsahujúca pyrolom substituovaný 2-indolinón, súprava obsahujúca uvedenú kompozíciu a použitie pyrolom substituovaného 2-indolinónu |
| BR9916327A (pt) * | 1998-12-17 | 2001-09-18 | Hoffmann La Roche | Oxindóis de 4-alquenila (e alquinila) como inibidores de cinases dependentes de ciclina, em particular, cdk2 |
| MXPA01006742A (es) | 1998-12-31 | 2004-04-21 | Sugen Inc | Compuestos 3-heteroarilidenil-2-indolinona para modular la actividad de la quinasa de proteina y para utilizarse en la quimioterapia de cancer. |
| DE19924401A1 (de) | 1999-05-27 | 2000-11-30 | Boehringer Ingelheim Pharma | Neue substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
| CA2381821A1 (en) | 1999-08-27 | 2001-03-08 | Boehringer Ingelheim Pharma Kg | Substituted indolinones, their manufacture and their use as medicaments |
| CA2384378C (en) | 1999-10-06 | 2011-05-24 | Boehringer Ingelheim Pharmaceuticals, Inc. | Heterocyclic compounds useful as inhibitors of tyrosine kinases |
| UA75054C2 (uk) | 1999-10-13 | 2006-03-15 | Бьорінгер Інгельхайм Фарма Гмбх & Ко. Кг | Заміщені в положенні 6 індолінони, їх одержання та їх застосування як лікарського засобу |
| DE19949209A1 (de) | 1999-10-13 | 2001-04-19 | Boehringer Ingelheim Pharma | In 5-Stellung substituierte Indolinone, ihre Herstellung und ihre Verwendung als Arzneimittel |
| WO2001042243A2 (en) | 1999-12-08 | 2001-06-14 | Advanced Medicine, Inc. | Protein kinase inhibitors |
| JP3663382B2 (ja) * | 2000-02-15 | 2005-06-22 | スージェン・インコーポレーテッド | ピロール置換２−インドリノン蛋白質キナーゼ阻害剤 |
| WO2002002551A1 (en) | 2000-06-30 | 2002-01-10 | Sugen, Inc. | 4-heteroaryl-3-heteroarylidenyl-2-indolinones and their use as protein kinase inhibitors |
| PT1315715E (pt) | 2000-08-18 | 2008-10-30 | Millennium Pharm Inc | Derivados de quianazolina utilizados como inibidores de quinase |
| WO2002055517A2 (en) | 2000-12-20 | 2002-07-18 | Jingrong Cui | 4-(hetero)aryl substituted indolinones |
| US7195876B2 (en) | 2002-08-09 | 2007-03-27 | Theravance, Inc. | Oncokinase fusion polypeptides associated with hyperproliferative and related disorders, nucleic acids encoding the same and methods for detecting and identifying the same |
| US20050171182A1 (en) | 2003-12-11 | 2005-08-04 | Roger Briesewitz | Methods and compositions for use in the treatment of mutant receptor tyrosine kinase driven cellular proliferative diseases |
-
2002
- 2002-12-20 EP EP02796035A patent/EP1458713B1/en not_active Expired - Lifetime
- 2002-12-20 AT AT02796035T patent/ATE302771T1/de active
- 2002-12-20 IL IL16220302A patent/IL162203A0/xx unknown
- 2002-12-20 BR BR0215360-2A patent/BR0215360A/pt not_active IP Right Cessation
- 2002-12-20 NZ NZ533219A patent/NZ533219A/en not_active IP Right Cessation
- 2002-12-20 DE DE60205776T patent/DE60205776T2/de not_active Expired - Lifetime
- 2002-12-20 CA CA2470480A patent/CA2470480C/en not_active Expired - Fee Related
- 2002-12-20 KR KR1020047010148A patent/KR100965519B1/ko not_active Expired - Fee Related
- 2002-12-20 HU HU0500111A patent/HUP0500111A3/hu unknown
- 2002-12-20 DK DK02796035T patent/DK1458713T3/da active
- 2002-12-20 ES ES02796035T patent/ES2247411T3/es not_active Expired - Lifetime
- 2002-12-20 MX MXPA04006271A patent/MXPA04006271A/es active IP Right Grant
- 2002-12-20 RU RU2004122918/04A patent/RU2316554C2/ru not_active IP Right Cessation
- 2002-12-20 US US10/327,385 patent/US6686362B2/en not_active Expired - Lifetime
- 2002-12-20 AU AU2002360753A patent/AU2002360753B2/en not_active Ceased
- 2002-12-20 JP JP2003558005A patent/JP4363985B2/ja not_active Expired - Fee Related
- 2002-12-20 CN CNB028261399A patent/CN1290844C/zh not_active Expired - Fee Related
- 2002-12-20 WO PCT/US2002/041252 patent/WO2003057690A1/en not_active Ceased
- 2002-12-20 PL PL369602A patent/PL208283B1/pl not_active IP Right Cessation
-
2003
- 2003-10-22 US US10/691,094 patent/US7060703B2/en not_active Expired - Lifetime
-
2004
- 2004-07-08 NO NO20042926A patent/NO327550B1/no not_active IP Right Cessation
- 2004-07-22 CO CO04070253A patent/CO5611126A2/es not_active Application Discontinuation
-
2006
- 2006-02-21 US US11/358,305 patent/US7223783B2/en not_active Expired - Lifetime
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP4363985B2 (ja) | タンパク質キナーゼ阻害剤として有用なインドリン誘導体 | |
| CN102408411B (zh) | 一种含喹啉基的羟肟酸类化合物及其制备方法、以及含有该化合物的药物组合物及其应用 | |
| JP6321821B2 (ja) | ２，３，４，６−４置換ベンゼン−１，５−ジアミン誘導体、その製造方法および医薬品における使用 | |
| JP7793217B2 (ja) | アルキニルフェニルベンズアミド化合物およびその使用 | |
| KR102274755B1 (ko) | Ｐｅｒｋ 저해제로서의 신규한 ｎ―（２，３―디히드로―１ｈ―피롤로［２，３―ｂ］피리딘―５―일）―４―퀴나졸린아민 및 ｎ―（２，３―디히드로―１ｈ―인돌―５―일）―４―퀴나졸린아민 유도체 | |
| TW201629060A (zh) | 一種週期素依賴性蛋白激酶抑制劑的羥乙基磺酸鹽、其結晶形式及製備方法 | |
| CN111617083B (zh) | 甲氧基取代苯基酰胺类氨基嘧啶衍生物的应用 | |
| CA2841897A1 (en) | Novel compound having parp inhibitory activity | |
| TWI786303B (zh) | 抑制ｃｄｋ4/6活性化合物的晶型及其應用 | |
| CN107089968A (zh) | 1‑(2‑氨基吡啶‑4‑基)‑3‑哌啶甲酰胺衍生物及其合成方法和应用 | |
| CN1267288A (zh) | 用作法呢基蛋白转移酶抑制剂的三环酮酰胺衍生物 | |
| CN1816543B (zh) | 具有细胞凋亡诱导效应的吲哚衍生物 | |
| CN104119321B (zh) | 二氢吲哚酮衍生物的二马来酸盐及其多晶型物 | |
| CN102666528B (zh) | 晶体cdc7 抑制剂盐 | |
| CN113135918B (zh) | 一种吡唑并[1,2]二氮杂类化合物 | |
| HK1068886B (en) | Indolinone derivatives useful as protein kinase inhibitors | |
| CN109952296A (zh) | 4-氰基-n-(2-(4,4-二甲基环己-1-烯-1-基)-6-(2,2,6,6-四甲基四氢-2h-吡喃-4-基)吡啶-3-基)-1h-咪唑-2-甲酰胺的结晶形式 | |
| ZA200404088B (en) | Indolinone derivatives useful as protein kinase inhibitors. | |
| KR20020063215A (ko) | 세포 증식 저해용 치환된 비신돌일말레이미드 | |
| WO2023046114A1 (zh) | 蝶啶酮衍生物及其应用 | |
| EP4735113A1 (en) | Pyrazole derivatives as pd-1/pd-l1 interaction inhibitors | |
| CN117946165A (zh) | 一种新型结构化合物axl抑制剂及其应用 | |
| HK40095801A (zh) | 稠合嘧啶类衍生物及其应用 | |
| HK1260821B (zh) | 作为egfr抑制剂的苯胺嘧啶化合物的结晶 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20050829 |
|
| A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20090422 |
|
| A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20090717 |
|
| TRDD | Decision of grant or rejection written | ||
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20090811 |
|
| A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 |
|
| A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20090818 |
|
| FPAY | Renewal fee payment (event date is renewal date of database) |
Free format text: PAYMENT UNTIL: 20120828 Year of fee payment: 3 |
|
| R150 | Certificate of patent or registration of utility model |
Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
| LAPS | Cancellation because of no payment of annual fees |