CA2368041A1 - Composes d'indolinone tels que des inhibiteurs de kinase - Google Patents
Composes d'indolinone tels que des inhibiteurs de kinase Download PDFInfo
- Publication number
- CA2368041A1 CA2368041A1 CA002368041A CA2368041A CA2368041A1 CA 2368041 A1 CA2368041 A1 CA 2368041A1 CA 002368041 A CA002368041 A CA 002368041A CA 2368041 A CA2368041 A CA 2368041A CA 2368041 A1 CA2368041 A1 CA 2368041A1
- Authority
- CA
- Canada
- Prior art keywords
- group
- alkyl
- optionally substituted
- independently selected
- ester
- 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.)
- Abandoned
Links
- JYGFTBXVXVMTGB-UHFFFAOYSA-N indolin-2-one Chemical class C1=CC=C2NC(=O)CC2=C1 JYGFTBXVXVMTGB-UHFFFAOYSA-N 0.000 title claims abstract description 68
- 229940043355 kinase inhibitor Drugs 0.000 title description 4
- 239000003757 phosphotransferase inhibitor Substances 0.000 title description 4
- 238000000034 method Methods 0.000 claims abstract description 134
- 108060006633 protein kinase Proteins 0.000 claims abstract description 98
- 102000001253 Protein Kinase Human genes 0.000 claims abstract description 97
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 76
- 201000010099 disease Diseases 0.000 claims abstract description 27
- 230000019491 signal transduction Effects 0.000 claims abstract description 25
- 125000000217 alkyl group Chemical group 0.000 claims description 391
- 150000001875 compounds Chemical class 0.000 claims description 263
- 125000003118 aryl group Chemical group 0.000 claims description 224
- 229910052739 hydrogen Inorganic materials 0.000 claims description 169
- 125000001072 heteroaryl group Chemical group 0.000 claims description 164
- 125000001424 substituent group Chemical group 0.000 claims description 149
- 125000004953 trihalomethyl group Chemical group 0.000 claims description 147
- 150000002148 esters Chemical group 0.000 claims description 144
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 144
- 229910052736 halogen Inorganic materials 0.000 claims description 143
- 239000001257 hydrogen Substances 0.000 claims description 139
- 150000002367 halogens Chemical group 0.000 claims description 138
- 125000005843 halogen group Chemical group 0.000 claims description 134
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 131
- 150000007942 carboxylates Chemical group 0.000 claims description 130
- -1 N-sulfonamido Chemical group 0.000 claims description 126
- 125000001931 aliphatic group Chemical group 0.000 claims description 116
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 115
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 107
- 125000003545 alkoxy group Chemical group 0.000 claims description 104
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 93
- 150000002431 hydrogen Chemical class 0.000 claims description 80
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 58
- 229920006395 saturated elastomer Polymers 0.000 claims description 57
- 229910052799 carbon Inorganic materials 0.000 claims description 56
- 125000004417 unsaturated alkyl group Chemical group 0.000 claims description 55
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 53
- 206010028980 Neoplasm Diseases 0.000 claims description 51
- PCKPVGOLPKLUHR-UHFFFAOYSA-N OH-Indolxyl Natural products C1=CC=C2C(O)=CNC2=C1 PCKPVGOLPKLUHR-UHFFFAOYSA-N 0.000 claims description 49
- 208000035475 disorder Diseases 0.000 claims description 49
- 229910052757 nitrogen Inorganic materials 0.000 claims description 49
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 48
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 43
- 230000000694 effects Effects 0.000 claims description 39
- 238000006243 chemical reaction Methods 0.000 claims description 33
- 230000027455 binding Effects 0.000 claims description 32
- 229910052760 oxygen Inorganic materials 0.000 claims description 31
- 201000011510 cancer Diseases 0.000 claims description 29
- QRTHVOUKWCEPKJ-UHFFFAOYSA-N 4-(2-hydroxyethyl)-1,3-dihydroindol-2-one Chemical compound OCCC1=CC=CC2=C1CC(=O)N2 QRTHVOUKWCEPKJ-UHFFFAOYSA-N 0.000 claims description 28
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 28
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 28
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 27
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 27
- 239000001301 oxygen Substances 0.000 claims description 27
- 229910052717 sulfur Inorganic materials 0.000 claims description 27
- 239000011593 sulfur Substances 0.000 claims description 27
- 230000003993 interaction Effects 0.000 claims description 24
- 230000003197 catalytic effect Effects 0.000 claims description 23
- 239000000126 substance Substances 0.000 claims description 23
- 230000002159 abnormal effect Effects 0.000 claims description 22
- 230000008859 change Effects 0.000 claims description 22
- 230000006870 function Effects 0.000 claims description 20
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 19
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 18
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 17
- 150000002576 ketones Chemical class 0.000 claims description 17
- 125000005631 S-sulfonamido group Chemical group 0.000 claims description 16
- 230000004663 cell proliferation Effects 0.000 claims description 16
- 230000001413 cellular effect Effects 0.000 claims description 15
- 230000033115 angiogenesis Effects 0.000 claims description 14
- 125000004104 aryloxy group Chemical group 0.000 claims description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 14
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 13
- 102000009516 Protein Serine-Threonine Kinases Human genes 0.000 claims description 12
- 108010009341 Protein Serine-Threonine Kinases Proteins 0.000 claims description 12
- 229910052700 potassium Inorganic materials 0.000 claims description 12
- 150000001408 amides Chemical class 0.000 claims description 11
- 150000001412 amines Chemical class 0.000 claims description 11
- 150000003457 sulfones Chemical class 0.000 claims description 11
- 125000004183 alkoxy alkyl group Chemical group 0.000 claims description 10
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 10
- 125000003396 thiol group Chemical class [H]S* 0.000 claims description 10
- 238000011282 treatment Methods 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 125000003342 alkenyl group Chemical group 0.000 claims description 8
- 125000000304 alkynyl group Chemical group 0.000 claims description 8
- 229940124530 sulfonamide Drugs 0.000 claims description 8
- 150000003456 sulfonamides Chemical class 0.000 claims description 8
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 claims description 8
- OZYOXARIWZIBEI-UHFFFAOYSA-N 2-(2-oxo-1,3-dihydroindol-4-yl)ethyl n-ethylcarbamate Chemical compound CCNC(=O)OCCC1=CC=CC2=C1CC(=O)N2 OZYOXARIWZIBEI-UHFFFAOYSA-N 0.000 claims description 7
- USRZZPHRQZGXFH-UHFFFAOYSA-N 4-methyl-1,3-dihydroindol-2-one Chemical compound CC1=CC=CC2=C1CC(=O)N2 USRZZPHRQZGXFH-UHFFFAOYSA-N 0.000 claims description 7
- WWJLCYHYLZZXBE-UHFFFAOYSA-N 5-chloro-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C2NC(=O)CC2=C1 WWJLCYHYLZZXBE-UHFFFAOYSA-N 0.000 claims description 7
- 125000004414 alkyl thio group Chemical group 0.000 claims description 7
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 206010012601 diabetes mellitus Diseases 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Chemical group C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- FLYJHFWRIXFQBP-UHFFFAOYSA-N 2-(2-oxo-1,3-dihydroindol-4-yl)ethyl n-(2-phenylphenyl)carbamate Chemical compound C=1C=CC=2NC(=O)CC=2C=1CCOC(=O)NC1=CC=CC=C1C1=CC=CC=C1 FLYJHFWRIXFQBP-UHFFFAOYSA-N 0.000 claims description 6
- ZIPMEQYRWUBIOX-UHFFFAOYSA-N 2-(2-oxo-1,3-dihydroindol-4-yl)ethyl n-cyclohexylcarbamate Chemical compound C=1C=CC=2NC(=O)CC=2C=1CCOC(=O)NC1CCCCC1 ZIPMEQYRWUBIOX-UHFFFAOYSA-N 0.000 claims description 6
- ZNTIIGGRSHMQKI-UHFFFAOYSA-N 2-(2-oxo-1,3-dihydroindol-4-yl)ethyl n-phenylcarbamate Chemical compound C=1C=CC=2NC(=O)CC=2C=1CCOC(=O)NC1=CC=CC=C1 ZNTIIGGRSHMQKI-UHFFFAOYSA-N 0.000 claims description 6
- LLZBBKYDEOXYIN-UHFFFAOYSA-N 3-[(4-bromophenyl)methylidene]-4-(2-hydroxyethyl)-1h-indol-2-one Chemical compound C1=2C(CCO)=CC=CC=2NC(=O)C1=CC1=CC=C(Br)C=C1 LLZBBKYDEOXYIN-UHFFFAOYSA-N 0.000 claims description 6
- LWZSRLZSGUZWOY-UHFFFAOYSA-N 4-(2-hydroxyethyl)-3-[(6-methylpyridin-2-yl)methylidene]-1h-indol-2-one Chemical compound CC1=CC=CC(C=C2C3=C(CCO)C=CC=C3NC2=O)=N1 LWZSRLZSGUZWOY-UHFFFAOYSA-N 0.000 claims description 6
- ZYSKQDWGVBAZAE-UHFFFAOYSA-N 4-[2-(2-propan-2-ylphenoxy)ethyl]-1,3-dihydroindol-2-one Chemical compound CC(C)C1=CC=CC=C1OCCC1=CC=CC2=C1CC(=O)N2 ZYSKQDWGVBAZAE-UHFFFAOYSA-N 0.000 claims description 6
- QEFKIPHPUBHDGD-UHFFFAOYSA-N 4-[2-(3-phenylphenoxy)ethyl]-1,3-dihydroindol-2-one Chemical compound N1C(=O)CC2=C1C=CC=C2CCOC(C=1)=CC=CC=1C1=CC=CC=C1 QEFKIPHPUBHDGD-UHFFFAOYSA-N 0.000 claims description 6
- GDZVODBMOJRKRS-UHFFFAOYSA-N 4-[2-(3-propan-2-ylphenoxy)ethyl]-1,3-dihydroindol-2-one Chemical compound CC(C)C1=CC=CC(OCCC=2C=3CC(=O)NC=3C=CC=2)=C1 GDZVODBMOJRKRS-UHFFFAOYSA-N 0.000 claims description 6
- VIMNAEVMZXIKFL-UHFFFAOYSA-N 5-bromo-1,3-dihydroindol-2-one Chemical compound BrC1=CC=C2NC(=O)CC2=C1 VIMNAEVMZXIKFL-UHFFFAOYSA-N 0.000 claims description 6
- CENVPIZOTHULGJ-UHFFFAOYSA-N 6-chloro-1,3-dihydroindol-2-one Chemical compound ClC1=CC=C2CC(=O)NC2=C1 CENVPIZOTHULGJ-UHFFFAOYSA-N 0.000 claims description 6
- OXOQGUGIJKUSRP-UHFFFAOYSA-N 6-methoxy-1,3-dihydroindol-2-one Chemical compound COC1=CC=C2CC(=O)NC2=C1 OXOQGUGIJKUSRP-UHFFFAOYSA-N 0.000 claims description 6
- 201000004681 Psoriasis Diseases 0.000 claims description 6
- AIPAMLNUDUNFPS-UHFFFAOYSA-N benzene;2-(2-oxo-1,3-dihydroindol-4-yl)ethyl n-sulfonylcarbamate Chemical compound C1=CC=CC=C1.O=S(=O)=NC(=O)OCCC1=CC=CC2=C1CC(=O)N2 AIPAMLNUDUNFPS-UHFFFAOYSA-N 0.000 claims description 6
- 125000002619 bicyclic group Chemical group 0.000 claims description 6
- 229910052731 fluorine Inorganic materials 0.000 claims description 6
- 125000002950 monocyclic group Chemical group 0.000 claims description 6
- OFPDLGTXUNOWNA-UHFFFAOYSA-N o-[2-(2-oxo-1,3-dihydroindol-4-yl)ethyl] n-phenylcarbamothioate Chemical compound N1C(=O)CC2=C1C=CC=C2CCOC(=S)NC1=CC=CC=C1 OFPDLGTXUNOWNA-UHFFFAOYSA-N 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 150000003568 thioethers Chemical class 0.000 claims description 6
- LXCMRBBAPWRIGZ-UHFFFAOYSA-N 4-(2-ethoxyethyl)-1,3-dihydroindol-2-one Chemical compound CCOCCC1=CC=CC2=C1CC(=O)N2 LXCMRBBAPWRIGZ-UHFFFAOYSA-N 0.000 claims description 5
- STNFQVCOVBMYCR-UHFFFAOYSA-N 4-(2-methoxyethyl)-1,3-dihydroindol-2-one Chemical compound COCCC1=CC=CC2=C1CC(=O)N2 STNFQVCOVBMYCR-UHFFFAOYSA-N 0.000 claims description 5
- AIVFWURNBSXFCD-UHFFFAOYSA-N 4-[2-(4-methoxyphenoxy)ethyl]-1,3-dihydroindol-2-one Chemical compound C1=CC(OC)=CC=C1OCCC1=CC=CC2=C1CC(=O)N2 AIVFWURNBSXFCD-UHFFFAOYSA-N 0.000 claims description 5
- QKRKKIDDVWTRIQ-UHFFFAOYSA-N 4-[2-(5-chloropyridin-3-yl)oxyethyl]-1,3-dihydroindol-2-one Chemical compound ClC1=CN=CC(OCCC=2C=3CC(=O)NC=3C=CC=2)=C1 QKRKKIDDVWTRIQ-UHFFFAOYSA-N 0.000 claims description 5
- DFGZEOUBIHLXFD-UHFFFAOYSA-N 5-methoxy-1,3-dihydroindol-2-one Chemical compound COC1=CC=C2NC(=O)CC2=C1 DFGZEOUBIHLXFD-UHFFFAOYSA-N 0.000 claims description 5
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 claims description 5
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 claims description 5
- 125000005842 heteroatom Chemical group 0.000 claims description 5
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 5
- QCTTURYDKWVDHW-UHFFFAOYSA-N 2-(2-oxo-1,3-dihydroindol-4-yl)ethyl n-tert-butylcarbamate Chemical compound CC(C)(C)NC(=O)OCCC1=CC=CC2=C1CC(=O)N2 QCTTURYDKWVDHW-UHFFFAOYSA-N 0.000 claims description 4
- HYDKXIJOAJNVFW-UHFFFAOYSA-N 4-(2-hydroxyethyl)-3-(1h-indol-5-ylmethylidene)-1h-indol-2-one Chemical compound C1=C2NC=CC2=CC(C=C2C(=O)NC=3C=CC=C(C2=3)CCO)=C1 HYDKXIJOAJNVFW-UHFFFAOYSA-N 0.000 claims description 4
- QPXVHHKQAQCRKV-UHFFFAOYSA-N 4-(2-hydroxyethyl)-3-(pyridin-2-ylmethylidene)-1h-indol-2-one Chemical compound C1=2C(CCO)=CC=CC=2NC(=O)C1=CC1=CC=CC=N1 QPXVHHKQAQCRKV-UHFFFAOYSA-N 0.000 claims description 4
- XTEAGYUOVWCQGA-UHFFFAOYSA-N 4-[2-(4-propan-2-ylphenoxy)ethyl]-1,3-dihydroindol-2-one Chemical compound C1=CC(C(C)C)=CC=C1OCCC1=CC=CC2=C1CC(=O)N2 XTEAGYUOVWCQGA-UHFFFAOYSA-N 0.000 claims description 4
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- 125000005129 aryl carbonyl group Chemical group 0.000 claims description 4
- 229910052796 boron Inorganic materials 0.000 claims description 4
- 208000027866 inflammatory disease Diseases 0.000 claims description 4
- 230000002401 inhibitory effect Effects 0.000 claims description 4
- 238000012544 monitoring process Methods 0.000 claims description 4
- 125000004385 trihaloalkyl group Chemical group 0.000 claims description 4
- 125000004951 trihalomethoxy group Chemical group 0.000 claims description 4
- LLLKBUWXODIMEW-UHFFFAOYSA-N 2-oxo-1,3-dihydroindole-5-carboxylic acid Chemical compound OC(=O)C1=CC=C2NC(=O)CC2=C1 LLLKBUWXODIMEW-UHFFFAOYSA-N 0.000 claims description 3
- 230000004075 alteration Effects 0.000 claims description 3
- 125000005110 aryl thio group Chemical group 0.000 claims description 3
- 230000004761 fibrosis Effects 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 208000026278 immune system disease Diseases 0.000 claims description 3
- 125000004531 indol-5-yl group Chemical group [H]N1C([H])=C([H])C2=C([H])C(*)=C([H])C([H])=C12 0.000 claims description 3
- SBULNBMWGLBIMA-UHFFFAOYSA-N n,n-dimethyl-2-oxo-1,3-dihydroindole-5-sulfonamide Chemical compound CN(C)S(=O)(=O)C1=CC=C2NC(=O)CC2=C1 SBULNBMWGLBIMA-UHFFFAOYSA-N 0.000 claims description 3
- GAPFXVWCGZCQPI-UHFFFAOYSA-N n-(2-oxo-1,3-dihydroindol-5-yl)acetamide Chemical compound CC(=O)NC1=CC=C2NC(=O)CC2=C1 GAPFXVWCGZCQPI-UHFFFAOYSA-N 0.000 claims description 3
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 claims description 3
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- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 3
- 229910052720 vanadium Inorganic materials 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 2
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- VIRGIOQJECYOKB-UHFFFAOYSA-N 3-[[4-[3-(dimethylamino)propyl]-3,5-dimethyl-1h-pyrrol-2-yl]methylidene]-4-(2-hydroxyethyl)-1h-indol-2-one Chemical compound CN(C)CCCC1=C(C)NC(C=C2C3=C(CCO)C=CC=C3NC2=O)=C1C VIRGIOQJECYOKB-UHFFFAOYSA-N 0.000 claims description 2
- UGXPJVUDLCNSRY-UHFFFAOYSA-N 4-(2-hydroxyethyl)-3-[(4-methoxy-3-thiophen-2-ylphenyl)methylidene]-1h-indol-2-one Chemical compound COC1=CC=C(C=C2C3=C(CCO)C=CC=C3NC2=O)C=C1C1=CC=CS1 UGXPJVUDLCNSRY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004861 4-isopropyl phenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 2
- TZZJYIFVSMXGFO-UHFFFAOYSA-N n-(5-methyl-2-oxo-1,3-dihydroindol-6-yl)acetamide Chemical compound C1=C(C)C(NC(=O)C)=CC2=C1CC(=O)N2 TZZJYIFVSMXGFO-UHFFFAOYSA-N 0.000 claims description 2
- 201000008482 osteoarthritis Diseases 0.000 claims description 2
- CCUBWMSDLZLBBV-UHFFFAOYSA-N 3-[2,4-dimethyl-5-[[2-oxo-4-[2-(4-propan-2-ylphenoxy)ethyl]-1h-indol-3-ylidene]methyl]-1h-pyrrol-3-yl]propanoic acid Chemical compound C1=CC(C(C)C)=CC=C1OCCC1=CC=CC(NC2=O)=C1C2=CC1=C(C)C(CCC(O)=O)=C(C)N1 CCUBWMSDLZLBBV-UHFFFAOYSA-N 0.000 claims 2
- UVDQNMJHQLAWBM-UHFFFAOYSA-N 3-[[4-[3-(dimethylamino)propyl]-3,5-dimethyl-1h-pyrrol-2-yl]methylidene]-4-[2-(3-propan-2-ylphenoxy)ethyl]-1h-indol-2-one Chemical compound CC(C)C1=CC=CC(OCCC=2C=3C(=CC4=C(C(CCCN(C)C)=C(C)N4)C)C(=O)NC=3C=CC=2)=C1 UVDQNMJHQLAWBM-UHFFFAOYSA-N 0.000 claims 2
- XEPLFVMODFMRLB-UHFFFAOYSA-N 4-(2-hydroxyethyl)-3-[(3-hydroxy-6-methylpyridin-2-yl)methylidene]-1h-indol-2-one Chemical compound CC1=CC=C(O)C(C=C2C3=C(CCO)C=CC=C3NC2=O)=N1 XEPLFVMODFMRLB-UHFFFAOYSA-N 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 142
- 239000000203 mixture Substances 0.000 description 90
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- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
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- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 34
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 30
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
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- 230000002829 reductive effect Effects 0.000 description 28
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- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000012267 brine Substances 0.000 description 24
- 239000011541 reaction mixture Substances 0.000 description 24
- 102000005962 receptors Human genes 0.000 description 24
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 24
- 229910001868 water Inorganic materials 0.000 description 24
- 108020003175 receptors Proteins 0.000 description 23
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 22
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 22
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 21
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- 239000012044 organic layer Substances 0.000 description 21
- 108090000623 proteins and genes Proteins 0.000 description 20
- 239000002904 solvent Substances 0.000 description 20
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 18
- 108091005682 Receptor kinases Proteins 0.000 description 17
- 239000002585 base Substances 0.000 description 17
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- 229940029284 trichlorofluoromethane Drugs 0.000 description 1
- 125000005423 trihalomethanesulfonamido group Chemical group 0.000 description 1
- 125000005152 trihalomethanesulfonyl group Chemical group 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000005740 tumor formation Effects 0.000 description 1
- 230000000982 vasogenic effect Effects 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229940100445 wheat starch Drugs 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- 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
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Diabetes (AREA)
- Immunology (AREA)
- Heart & Thoracic Surgery (AREA)
- Rheumatology (AREA)
- Cardiology (AREA)
- Emergency Medicine (AREA)
- Vascular Medicine (AREA)
- Endocrinology (AREA)
- Urology & Nephrology (AREA)
- Obesity (AREA)
- Pain & Pain Management (AREA)
- Hematology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Dermatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Abstract
L'invention concerne certains composés d'indolinone, leur méthode de synthèse, et une bibliothèque combinatoire contenant les composés d'indolinone de cette invention. Cette dernière concerne également des méthodes de modulation de la fonction des protéines kinases au moyen des composés d'indolinone de cette invention, et des méthodes de traitement de maladies par modulation de la fonction des protéines kinases et des voies relatives de transduction de signaux.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US12594599P | 1999-03-24 | 1999-03-24 | |
| US60/125,945 | 1999-03-24 | ||
| US12786399P | 1999-04-05 | 1999-04-05 | |
| US60/127,863 | 1999-04-05 | ||
| US13119299P | 1999-04-26 | 1999-04-26 | |
| US60/131,192 | 1999-04-26 | ||
| US13224399P | 1999-05-03 | 1999-05-03 | |
| US60/132,243 | 1999-05-03 | ||
| PCT/US2000/007704 WO2000056709A1 (fr) | 1999-03-24 | 2000-03-22 | Composes d'indolinone tels que des inhibiteurs de kinase |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2368041A1 true CA2368041A1 (fr) | 2000-09-28 |
Family
ID=27494607
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002368041A Abandoned CA2368041A1 (fr) | 1999-03-24 | 2000-03-22 | Composes d'indolinone tels que des inhibiteurs de kinase |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP1165513A1 (fr) |
| JP (1) | JP2002540096A (fr) |
| AU (1) | AU3770000A (fr) |
| CA (1) | CA2368041A1 (fr) |
| WO (1) | WO2000056709A1 (fr) |
Families Citing this family (29)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6569868B2 (en) | 1998-04-16 | 2003-05-27 | Sugen, Inc. | 2-indolinone derivatives as modulators of protein kinase activity |
| US6525072B1 (en) | 1998-08-31 | 2003-02-25 | Sugen, Inc. | Geometrically restricted 2-indolinone derivatives as modulators of protein kinase activity |
| US6878733B1 (en) | 1999-11-24 | 2005-04-12 | Sugen, Inc. | Formulations for pharmaceutical agents ionizable as free acids or free bases |
| JP5336686B2 (ja) * | 1999-11-24 | 2013-11-06 | スージェン, インク. | 遊離酸または遊離塩基としてイオン化可能な医薬品のための処方 |
| CA2395461C (fr) * | 1999-12-22 | 2010-05-25 | Sugen, Inc. | Procedes de modulation de la fonction kinase de proteine tyrosine de type c-kit avec des composes indolinone |
| HRP20020751B1 (hr) | 2000-02-15 | 2011-01-31 | Sugen | Pirolom supstituirani 2-indolinoni kao inhibitori protein kinaze |
| MY128449A (en) | 2000-05-24 | 2007-02-28 | Sugen Inc | Prodrugs of 3-(pyrrol-2-ylmethylidene)-2-indolinone derivatives |
| JP2003535847A (ja) | 2000-06-02 | 2003-12-02 | スージェン・インコーポレーテッド | 蛋白質キナーゼ/ホスファターゼ阻害剤としてのインドリノン誘導体 |
| WO2002002551A1 (fr) * | 2000-06-30 | 2002-01-10 | Sugen, Inc. | 4-heteroaryl-3-heteroarylidenyl-2-indolinones et leur utilisation comme inhibiteurs des proteine kinases |
| AR042586A1 (es) | 2001-02-15 | 2005-06-29 | Sugen Inc | 3-(4-amidopirrol-2-ilmetiliden)-2-indolinona como inhibidores de la protein quinasa; sus composiciones farmaceuticas; un metodo para la modulacion de la actividad catalitica de la proteinquinasa; un metodo para tratar o prevenir una afeccion relacionada con la proteinquinasa |
| WO2002070478A1 (fr) | 2001-03-06 | 2002-09-12 | Astrazeneca Ab | Dérivés indolone capable de dégrader des vaisseaux |
| WO2002096361A2 (fr) | 2001-05-30 | 2002-12-05 | Sugen, Inc. | Derives de 5-aralkylsulfonyl-3-(pyrrol-2-ylmethylidene)-2-indolinone utilises comme inhibiteurs de kinase |
| WO2003002105A2 (fr) * | 2001-06-29 | 2003-01-09 | Ab Science | Utilisation d'inhibiteurs de la tyrosine kinase dans le traitement de la perte osseuse |
| ES2274993T3 (es) | 2001-06-29 | 2007-06-01 | Ab Science | Utilizacion de inhibidores de tirosina cinasa para el tratamiento de enfermedades alergicas. |
| WO2003003006A2 (fr) | 2001-06-29 | 2003-01-09 | Ab Science | Nouveaux inhibiteurs selectifs puissants et non toxiques de c-kit |
| PT1401416E (pt) | 2001-06-29 | 2007-02-28 | Ab Science | Utilização de inibidores de c-kit para tratar doenças inflamatórias intestinais (dii) |
| ATE330608T1 (de) | 2001-06-29 | 2006-07-15 | Ab Science | Die verwendung von n-phenyl-2-pyrimidine-amine derivaten zur behandlung von entzündlichen erkrankungen |
| US6797825B2 (en) | 2001-12-13 | 2004-09-28 | Abbott Laboratories | Protein kinase inhibitors |
| US20030119839A1 (en) * | 2001-12-13 | 2003-06-26 | Nan-Horng Lin | Protein kinase inhibitors |
| US20030187026A1 (en) | 2001-12-13 | 2003-10-02 | Qun Li | Kinase inhibitors |
| AU2003302665B2 (en) | 2002-11-15 | 2009-12-24 | Symphony Evolution, Inc. | Kinase modulators |
| MXPA06004438A (es) | 2003-10-24 | 2006-06-20 | Schering Ag | Derivados de indolinona y su uso en el tratamiento de enfermedades como el cancer. |
| EP1828123A1 (fr) * | 2004-12-17 | 2007-09-05 | Boehringer Ingelheim International GmbH | Indolinones comme agents antiprolifératifs |
| EP2235004A4 (fr) | 2007-12-21 | 2011-05-04 | Univ Health Network | Dérivés d'indolmone à substitution indazolyle, benzimidazolyle, benzotriazolyle en tant qu'inhibiteurs de kinases utilisés dans le traitement du cancer |
| WO2010115279A1 (fr) | 2009-04-06 | 2010-10-14 | University Health Network | Inhibiteurs de kinases et procédé de traitement du cancer avec ceux-ci |
| TWI516262B (zh) | 2010-04-06 | 2016-01-11 | 健康網路大學 | 激酶抑制劑及以其治療癌症的方法 |
| ES2590531T3 (es) | 2012-09-13 | 2016-11-22 | F. Hoffmann-La Roche Ag | 2-oxo-2,3-dihidro-indoles para el tratamiento de trastornos del SNC |
| EA030089B1 (ru) | 2013-10-18 | 2018-06-29 | Юниверсити Хелс Нетуорк | Лечение рака поджелудочной железы |
| CN105037243B (zh) * | 2015-06-28 | 2017-09-05 | 贵州大学 | 一种紫杉醇侧链苯基异丝氨酸衍生物及其制备方法及应用 |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3308134A (en) * | 1965-10-22 | 1967-03-07 | Mcneilab Inc | Spiro(indan-2, 3'-indoline)-1, 2'-diones |
| FR1599772A (fr) * | 1968-09-17 | 1970-07-20 | ||
| DE3874257T2 (de) * | 1987-03-11 | 1993-02-11 | Kanegafuchi Chemical Ind | Hydroxystyren-derivate. |
| GB9004483D0 (en) * | 1990-02-28 | 1990-04-25 | Erba Carlo Spa | New aryl-and heteroarylethenylene derivatives and process for their preparation |
| GB9115160D0 (en) * | 1991-07-12 | 1991-08-28 | Erba Carlo Spa | Methylen-oxindole derivatives and process for their preparation |
| GB9226855D0 (en) * | 1992-12-23 | 1993-02-17 | Erba Carlo Spa | Vinylene-azaindole derivatives and process for their preparation |
| GB9313638D0 (en) * | 1993-07-01 | 1993-08-18 | Erba Carlo Spa | Arylidene and heteroarylidene oxindole derivatives and process for their preparation |
| GB9501567D0 (en) * | 1995-01-26 | 1995-03-15 | Pharmacia Spa | Hydrosoluble 3-arylidene-2-oxindole derivatives as tyrosine kinase inhibitors |
| GB9507298D0 (en) * | 1995-04-07 | 1995-05-31 | Pharmacia Spa | Substituted indolylmethylene-oxindale analogues as tyrosine kinase inhibitors |
| US5880141A (en) * | 1995-06-07 | 1999-03-09 | Sugen, Inc. | Benzylidene-Z-indoline compounds for the treatment of disease |
| EP0929520B1 (fr) * | 1996-08-23 | 2005-11-02 | Sugen, Inc. | Banques combinatoires d'indolinone, produits et procedes associes pour traiter des maladies |
| AU7622698A (en) * | 1996-12-05 | 1998-06-29 | Sugen, Inc. | Use of indolinone compounds as modulators of protein kinases |
| CA2289102A1 (fr) * | 1997-05-07 | 1998-11-12 | Sugen, Inc. | Derives de 2-indolinone utilises en tant que modulateurs de l'activite de la proteine kinase |
| GB9716557D0 (en) * | 1997-08-06 | 1997-10-08 | Glaxo Group Ltd | Benzylidene-1,3-dihydro-indol-2-one derivatives having anti-cancer activity |
-
2000
- 2000-03-22 AU AU37700/00A patent/AU3770000A/en not_active Abandoned
- 2000-03-22 JP JP2000606571A patent/JP2002540096A/ja not_active Withdrawn
- 2000-03-22 WO PCT/US2000/007704 patent/WO2000056709A1/fr not_active Ceased
- 2000-03-22 CA CA002368041A patent/CA2368041A1/fr not_active Abandoned
- 2000-03-22 EP EP00916622A patent/EP1165513A1/fr not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| AU3770000A (en) | 2000-10-09 |
| EP1165513A1 (fr) | 2002-01-02 |
| JP2002540096A (ja) | 2002-11-26 |
| WO2000056709A1 (fr) | 2000-09-28 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| FZDE | Discontinued | ||
| FZDE | Discontinued |
Effective date: 20090323 |