AU2003256481B2 - Substituted anthranilic amide derivatives and methods of use - Google Patents
Substituted anthranilic amide derivatives and methods of use Download PDFInfo
- Publication number
- AU2003256481B2 AU2003256481B2 AU2003256481A AU2003256481A AU2003256481B2 AU 2003256481 B2 AU2003256481 B2 AU 2003256481B2 AU 2003256481 A AU2003256481 A AU 2003256481A AU 2003256481 A AU2003256481 A AU 2003256481A AU 2003256481 B2 AU2003256481 B2 AU 2003256481B2
- Authority
- AU
- Australia
- Prior art keywords
- compound
- amino
- dimethyl
- ylmethyl
- boc
- 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.)
- Ceased
Links
- 238000000034 method Methods 0.000 title claims description 121
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 title description 24
- -1 7-isoquinolinyl Chemical group 0.000 claims description 696
- 150000001875 compounds Chemical class 0.000 claims description 320
- 238000002360 preparation method Methods 0.000 claims description 163
- 150000003839 salts Chemical class 0.000 claims description 64
- 125000000623 heterocyclic group Chemical group 0.000 claims description 56
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 54
- 206010028980 Neoplasm Diseases 0.000 claims description 53
- 238000011282 treatment Methods 0.000 claims description 47
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 45
- 125000000217 alkyl group Chemical group 0.000 claims description 43
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 41
- 125000001424 substituent group Chemical group 0.000 claims description 37
- 101100167062 Caenorhabditis elegans chch-3 gene Proteins 0.000 claims description 27
- 239000003814 drug Substances 0.000 claims description 27
- 125000005843 halogen group Chemical group 0.000 claims description 27
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 24
- 230000033115 angiogenesis Effects 0.000 claims description 23
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 22
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 22
- 201000010099 disease Diseases 0.000 claims description 22
- 208000035475 disorder Diseases 0.000 claims description 22
- 239000003795 chemical substances by application Substances 0.000 claims description 20
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 20
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 19
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 claims description 16
- 125000001188 haloalkyl group Chemical group 0.000 claims description 16
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 15
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 15
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- 201000011510 cancer Diseases 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- 125000002883 imidazolyl group Chemical group 0.000 claims description 13
- KXDAEFPNCMNJSK-UHFFFAOYSA-N benzene carboxamide Natural products NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 12
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 12
- 241000124008 Mammalia Species 0.000 claims description 11
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 11
- 125000001072 heteroaryl group Chemical group 0.000 claims description 11
- 230000035755 proliferation Effects 0.000 claims description 11
- 108091008605 VEGF receptors Proteins 0.000 claims description 10
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 claims description 10
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 claims description 10
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 10
- 125000003342 alkenyl group Chemical group 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000004043 oxo group Chemical group O=* 0.000 claims description 10
- 125000004940 pyridazin-4-yl group Chemical group N1=NC=C(C=C1)* 0.000 claims description 10
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 10
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 claims description 9
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 9
- 125000000304 alkynyl group Chemical group 0.000 claims description 9
- 229910052799 carbon Inorganic materials 0.000 claims description 9
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 9
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 claims description 8
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 8
- 125000001153 fluoro group Chemical group F* 0.000 claims description 8
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 125000002757 morpholinyl group Chemical group 0.000 claims description 8
- 125000004547 quinazolin-6-yl group Chemical group N1=CN=CC2=CC(=CC=C12)* 0.000 claims description 8
- 230000001225 therapeutic effect Effects 0.000 claims description 8
- 230000017531 blood circulation Effects 0.000 claims description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 claims description 7
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 6
- 206010061218 Inflammation Diseases 0.000 claims description 6
- 241001465754 Metazoa Species 0.000 claims description 6
- 125000001246 bromo group Chemical group Br* 0.000 claims description 6
- 230000004054 inflammatory process Effects 0.000 claims description 6
- 125000004674 methylcarbonyl group Chemical group CC(=O)* 0.000 claims description 6
- 125000005246 nonafluorobutyl group Chemical group FC(F)(F)C(F)(F)C(F)(F)C(F)(F)* 0.000 claims description 6
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 6
- 125000004076 pyridyl group Chemical group 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 125000001544 thienyl group Chemical group 0.000 claims description 6
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- SZPWXAOBLNYOHY-UHFFFAOYSA-N [C]1=CC=NC2=CC=CC=C12 Chemical group [C]1=CC=NC2=CC=CC=C12 SZPWXAOBLNYOHY-UHFFFAOYSA-N 0.000 claims description 5
- 239000003937 drug carrier Substances 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 230000001404 mediated effect Effects 0.000 claims description 5
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 claims description 5
- 125000004527 pyrimidin-4-yl group Chemical group N1=CN=C(C=C1)* 0.000 claims description 5
- 125000004066 1-hydroxyethyl group Chemical group [H]OC([H])([*])C([H])([H])[H] 0.000 claims description 4
- HBLHQDSWCAZXOG-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-quinolin-7-yl)-2-(quinazolin-6-ylamino)benzamide Chemical compound N1=CN=CC2=CC(NC3=CC=CC=C3C(=O)NC=3C=C4NCCC(C4=CC=3)(C)C)=CC=C21 HBLHQDSWCAZXOG-UHFFFAOYSA-N 0.000 claims description 4
- YTITUUIWIKQKDQ-UHFFFAOYSA-N n-(4-tert-butylphenyl)-2-(isoquinolin-7-ylamino)benzamide Chemical compound C1=CC(C(C)(C)C)=CC=C1NC(=O)C1=CC=CC=C1NC1=CC=C(C=CN=C2)C2=C1 YTITUUIWIKQKDQ-UHFFFAOYSA-N 0.000 claims description 4
- 125000004482 piperidin-4-yl group Chemical group N1CCC(CC1)* 0.000 claims description 4
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 4
- 125000000171 (C1-C6) haloalkyl group Chemical group 0.000 claims description 3
- 239000002256 antimetabolite Substances 0.000 claims description 3
- 230000036952 cancer formation Effects 0.000 claims description 3
- 229940125697 hormonal agent Drugs 0.000 claims description 3
- 125000004942 pyridazin-6-yl group Chemical group N1=NC=CC=C1* 0.000 claims description 3
- 125000004737 (C1-C6) haloalkoxy group Chemical group 0.000 claims description 2
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 claims description 2
- 229940100198 alkylating agent Drugs 0.000 claims description 2
- 239000002168 alkylating agent Substances 0.000 claims description 2
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 claims description 2
- 239000000677 immunologic agent Substances 0.000 claims description 2
- 229940124541 immunological agent Drugs 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- FTNKCGULGWHQPV-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-isoquinolin-7-yl)-2-[(4-fluorophenyl)methylamino]benzamide Chemical compound C=1C=C2C(C)(C)CNCC2=CC=1NC(=O)C1=CC=CC=C1NCC1=CC=C(F)C=C1 FTNKCGULGWHQPV-UHFFFAOYSA-N 0.000 claims description 2
- FNFSNNWULZMNNC-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-isoquinolin-7-yl)-2-[[2-(methylamino)pyrimidin-4-yl]methylamino]benzamide Chemical compound CNC1=NC=CC(CNC=2C(=CC=CC=2)C(=O)NC=2C=C3C(C(CNC3)(C)C)=CC=2)=N1 FNFSNNWULZMNNC-UHFFFAOYSA-N 0.000 claims description 2
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims description 2
- 230000000052 comparative effect Effects 0.000 claims 4
- QLFQMDKFOJZHBK-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-isoquinolin-7-yl)-2-(pyridazin-4-ylmethylamino)benzamide Chemical compound C=1C=C2C(C)(C)CNCC2=CC=1NC(=O)C1=CC=CC=C1NCC1=CC=NN=C1 QLFQMDKFOJZHBK-UHFFFAOYSA-N 0.000 claims 1
- GUIOOGNPPDHMRU-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-isoquinolin-7-yl)-2-[1-[2-(methylamino)pyrimidin-4-yl]ethylamino]benzamide Chemical compound CNC1=NC=CC(C(C)NC=2C(=CC=CC=2)C(=O)NC=2C=C3C(C(CNC3)(C)C)=CC=2)=N1 GUIOOGNPPDHMRU-UHFFFAOYSA-N 0.000 claims 1
- YAWXEPJVBFFVAI-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-isoquinolin-7-yl)-3-fluoro-2-[(4-fluorophenyl)methylamino]benzamide Chemical compound C=1C=C2C(C)(C)CNCC2=CC=1NC(=O)C1=CC=CC(F)=C1NCC1=CC=C(F)C=C1 YAWXEPJVBFFVAI-UHFFFAOYSA-N 0.000 claims 1
- JQUISUUSKKADNO-UHFFFAOYSA-N n-(4,4-dimethyl-2,3-dihydro-1h-isoquinolin-7-yl)-6-fluoro-6-[(4-fluorophenyl)methylamino]cyclohexa-2,4-diene-1-carboxamide Chemical compound C=1C=C2C(C)(C)CNCC2=CC=1NC(=O)C1C=CC=CC1(F)NCC1=CC=C(F)C=C1 JQUISUUSKKADNO-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 212
- 239000000203 mixture Substances 0.000 description 208
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 142
- 235000019439 ethyl acetate Nutrition 0.000 description 106
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 99
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 90
- 238000006243 chemical reaction Methods 0.000 description 88
- 150000003254 radicals Chemical class 0.000 description 80
- 239000007787 solid Substances 0.000 description 74
- 238000001819 mass spectrum Methods 0.000 description 70
- 239000000243 solution Substances 0.000 description 70
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 69
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 68
- 239000011734 sodium Substances 0.000 description 65
- 125000004432 carbon atom Chemical group C* 0.000 description 54
- 239000012044 organic layer Substances 0.000 description 52
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 52
- 239000012267 brine Substances 0.000 description 51
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 47
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 44
- 235000002639 sodium chloride Nutrition 0.000 description 43
- 238000003818 flash chromatography Methods 0.000 description 41
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 40
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 40
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000000460 chlorine Substances 0.000 description 39
- 239000003921 oil Substances 0.000 description 32
- 235000019198 oils Nutrition 0.000 description 32
- 239000002904 solvent Substances 0.000 description 32
- 210000004027 cell Anatomy 0.000 description 30
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 29
- 229920006395 saturated elastomer Polymers 0.000 description 29
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Substances CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 28
- 239000002253 acid Substances 0.000 description 28
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 28
- 238000010992 reflux Methods 0.000 description 27
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical class NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 26
- 230000008569 process Effects 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 25
- 239000010410 layer Substances 0.000 description 24
- 239000002585 base Substances 0.000 description 23
- 230000002829 reductive effect Effects 0.000 description 22
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 21
- 239000003054 catalyst Substances 0.000 description 21
- 239000013058 crude material Substances 0.000 description 21
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 20
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 18
- 150000001412 amines Chemical class 0.000 description 18
- 239000000741 silica gel Substances 0.000 description 18
- 229910002027 silica gel Inorganic materials 0.000 description 18
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 17
- 125000003545 alkoxy group Chemical group 0.000 description 16
- 239000002246 antineoplastic agent Substances 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 15
- 239000000706 filtrate Substances 0.000 description 15
- 238000009472 formulation Methods 0.000 description 15
- 238000000746 purification Methods 0.000 description 15
- 239000012317 TBTU Substances 0.000 description 13
- CLZISMQKJZCZDN-UHFFFAOYSA-N [benzotriazol-1-yloxy(dimethylamino)methylidene]-dimethylazanium Chemical compound C1=CC=C2N(OC(N(C)C)=[N+](C)C)N=NC2=C1 CLZISMQKJZCZDN-UHFFFAOYSA-N 0.000 description 13
- 229940034982 antineoplastic agent Drugs 0.000 description 13
- 125000006239 protecting group Chemical group 0.000 description 13
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- 241000700159 Rattus Species 0.000 description 12
- 238000001816 cooling Methods 0.000 description 12
- BAVYZALUXZFZLV-UHFFFAOYSA-N mono-methylamine Natural products NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 12
- 239000007858 starting material Substances 0.000 description 12
- 239000000725 suspension Substances 0.000 description 12
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 11
- 239000004480 active ingredient Substances 0.000 description 11
- 150000001408 amides Chemical class 0.000 description 11
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 11
- 239000012298 atmosphere Substances 0.000 description 10
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 238000001914 filtration Methods 0.000 description 10
- 239000003112 inhibitor Substances 0.000 description 10
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- 239000012299 nitrogen atmosphere Substances 0.000 description 10
- 239000002244 precipitate Substances 0.000 description 10
- 239000011541 reaction mixture Substances 0.000 description 10
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical class [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 description 10
- DTQVDTLACAAQTR-UHFFFAOYSA-N trifluoroacetic acid Substances OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000003981 vehicle Substances 0.000 description 10
- 239000003039 volatile agent Substances 0.000 description 10
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 9
- 108010050904 Interferons Proteins 0.000 description 9
- 102000014150 Interferons Human genes 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 9
- 229940079322 interferon Drugs 0.000 description 9
- 125000004430 oxygen atom Chemical group O* 0.000 description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 101100030361 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) pph-3 gene Proteins 0.000 description 8
- 229910004298 SiO 2 Inorganic materials 0.000 description 8
- 239000013543 active substance Substances 0.000 description 8
- 239000002671 adjuvant Substances 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 230000012010 growth Effects 0.000 description 8
- 125000005844 heterocyclyloxy group Chemical group 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Inorganic materials [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 8
- 239000000843 powder Substances 0.000 description 8
- 238000010898 silica gel chromatography Methods 0.000 description 8
- 229910000104 sodium hydride Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 229910052717 sulfur Inorganic materials 0.000 description 8
- 125000004434 sulfur atom Chemical group 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 7
- 239000005711 Benzoic acid Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 125000003282 alkyl amino group Chemical group 0.000 description 7
- 239000003995 emulsifying agent Substances 0.000 description 7
- 125000006517 heterocyclyl carbonyl group Chemical group 0.000 description 7
- 238000005984 hydrogenation reaction Methods 0.000 description 7
- 125000003387 indolinyl group Chemical group N1(CCC2=CC=CC=C12)* 0.000 description 7
- 125000002911 monocyclic heterocycle group Chemical group 0.000 description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 229910052760 oxygen Inorganic materials 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 238000003786 synthesis reaction Methods 0.000 description 7
- MKDCJAPHKZPKOU-UHFFFAOYSA-N 1-nitro-2,3-dihydroindole Chemical compound C1=CC=C2N([N+](=O)[O-])CCC2=C1 MKDCJAPHKZPKOU-UHFFFAOYSA-N 0.000 description 6
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 6
- 206010030113 Oedema Diseases 0.000 description 6
- 125000003277 amino group Chemical group 0.000 description 6
- 150000005840 aryl radicals Chemical class 0.000 description 6
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Classifications
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- 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
- C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
- C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
-
- 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
- C07D403/12—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 chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Public Health (AREA)
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- Endocrinology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Indole Compounds (AREA)
- Other In-Based Heterocyclic Compounds (AREA)
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| US39514402P | 2002-07-09 | 2002-07-09 | |
| US60/395,144 | 2002-07-09 | ||
| US10/615,809 | 2003-07-08 | ||
| US10/615,809 US7307088B2 (en) | 2002-07-09 | 2003-07-08 | Substituted anthranilic amide derivatives and methods of use |
| PCT/US2003/021601 WO2004005279A2 (en) | 2002-07-09 | 2003-07-09 | Substituted anthranilic amide derivatives and methods of use |
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| AU2003256481A1 AU2003256481A1 (en) | 2004-01-23 |
| AU2003256481B2 true AU2003256481B2 (en) | 2007-08-09 |
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| CA (1) | CA2489166A1 (enExample) |
| MX (1) | MXPA05000120A (enExample) |
| PL (1) | PL375586A1 (enExample) |
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| DE10023484A1 (de) * | 2000-05-09 | 2001-11-22 | Schering Ag | Anthranylamide und deren Verwendung als Arzneimittel |
| US7615565B2 (en) * | 2002-07-31 | 2009-11-10 | Bayer Schering Pharma Aktiengesellschaft | VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines |
| US7202260B2 (en) * | 2003-06-13 | 2007-04-10 | Schering Ag | VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridones |
| KR101254371B1 (ko) | 2003-07-18 | 2013-05-02 | 암젠 프레몬트 인코포레이티드 | 간세포 성장인자에 결합하는 분리된 항체 |
| US20050130986A1 (en) * | 2003-11-21 | 2005-06-16 | Eklund Kari K. | Treatment of spondylarthropathies |
| US7507748B2 (en) * | 2004-07-22 | 2009-03-24 | Amgen Inc. | Substituted aryl-amine derivatives and methods of use |
| US7906533B2 (en) * | 2004-11-03 | 2011-03-15 | Bayer Schering Pharma Ag | Nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors |
| EP1657241A1 (en) * | 2004-11-03 | 2006-05-17 | Schering Aktiengesellschaft | Novel anthranilamide pyridinureas as VEGF receptor kinase inhibitors |
| EP1655295A1 (en) * | 2004-11-03 | 2006-05-10 | Schering Aktiengesellschaft | Anthranilamide pyridinureas as VEGF receptor kinase inhibitors |
| JP2008521900A (ja) | 2004-11-30 | 2008-06-26 | アムジエン・インコーポレーテツド | キノリン及びキナゾリン類似体並びにがん治療のための医薬としてのその使用 |
| US7906511B2 (en) | 2005-03-31 | 2011-03-15 | Santen Pharmaceutical Co., Ltd. | Cyclic compound having pyrimidinylalkylthio group |
| JP4834441B2 (ja) * | 2005-03-31 | 2011-12-14 | 参天製薬株式会社 | ピリミジニルアルキルチオ基を有する新規環式化合物 |
| US8247556B2 (en) * | 2005-10-21 | 2012-08-21 | Amgen Inc. | Method for preparing 6-substituted-7-aza-indoles |
| KR20080071562A (ko) * | 2005-11-30 | 2008-08-04 | 아스텔라스세이야쿠 가부시키가이샤 | 2-아미노벤즈아미드 유도체 |
| US20080108664A1 (en) | 2005-12-23 | 2008-05-08 | Liu Belle B | Solid-state form of AMG 706 and pharmaceutical compositions thereof |
| AR059066A1 (es) | 2006-01-27 | 2008-03-12 | Amgen Inc | Combinaciones del inhibidor de la angiopoyetina -2 (ang2) y el inhibidor del factor de crecimiento endotelial vascular (vegf) |
| CA2641713C (en) | 2006-02-10 | 2011-11-22 | Amgen Inc. | Hydrate forms of amg706 |
| US8217177B2 (en) | 2006-07-14 | 2012-07-10 | Amgen Inc. | Fused heterocyclic derivatives and methods of use |
| PE20121506A1 (es) | 2006-07-14 | 2012-11-26 | Amgen Inc | Compuestos triazolopiridinas como inhibidores de c-met |
| US7687522B2 (en) | 2006-12-20 | 2010-03-30 | Amgen Inc. | Substituted pyridines and pyrimidines and their use in treatment of cancer |
| CA2673652A1 (en) | 2007-01-09 | 2008-07-17 | Amgen Inc. | Bis-aryl amide derivatives and methods of use |
| US8314087B2 (en) | 2007-02-16 | 2012-11-20 | Amgen Inc. | Nitrogen-containing heterocyclyl ketones and methods of use |
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- 2003-07-08 US US10/615,809 patent/US7307088B2/en not_active Expired - Lifetime
- 2003-07-09 JP JP2004520114A patent/JP2006502112A/ja active Pending
- 2003-07-09 CA CA002489166A patent/CA2489166A1/en not_active Abandoned
- 2003-07-09 MX MXPA05000120A patent/MXPA05000120A/es not_active Application Discontinuation
- 2003-07-09 EP EP03763451A patent/EP1519921A2/en not_active Withdrawn
- 2003-07-09 WO PCT/US2003/021601 patent/WO2004005279A2/en not_active Ceased
- 2003-07-09 PL PL03375586A patent/PL375586A1/xx unknown
- 2003-07-09 AU AU2003256481A patent/AU2003256481B2/en not_active Ceased
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Also Published As
| Publication number | Publication date |
|---|---|
| CA2489166A1 (en) | 2004-01-15 |
| PL375586A1 (en) | 2005-11-28 |
| MXPA05000120A (es) | 2005-04-08 |
| JP2006502112A (ja) | 2006-01-19 |
| AU2003256481A1 (en) | 2004-01-23 |
| WO2004005279A3 (en) | 2004-03-11 |
| WO2004005279A2 (en) | 2004-01-15 |
| US7307088B2 (en) | 2007-12-11 |
| EP1519921A2 (en) | 2005-04-06 |
| US20040087568A1 (en) | 2004-05-06 |
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