CN1325384A - 邻氨基苯甲酰胺及其作为药物的应用 - Google Patents
邻氨基苯甲酰胺及其作为药物的应用 Download PDFInfo
- Publication number
- CN1325384A CN1325384A CN99813078A CN99813078A CN1325384A CN 1325384 A CN1325384 A CN 1325384A CN 99813078 A CN99813078 A CN 99813078A CN 99813078 A CN99813078 A CN 99813078A CN 1325384 A CN1325384 A CN 1325384A
- Authority
- CN
- China
- Prior art keywords
- group
- halogen
- phenyl
- methyl
- represent
- 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.)
- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 16
- PXBFMLJZNCDSMP-UHFFFAOYSA-N 2-Aminobenzamide Chemical class NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 title abstract description 17
- 201000010099 disease Diseases 0.000 claims abstract description 18
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 18
- 239000013067 intermediate product Substances 0.000 claims abstract description 12
- 239000001257 hydrogen Substances 0.000 claims description 73
- 229910052739 hydrogen Inorganic materials 0.000 claims description 73
- -1 5-chloro-2,3-dihydro indenyl Chemical group 0.000 claims description 69
- 229910052736 halogen Inorganic materials 0.000 claims description 57
- 150000002367 halogens Chemical class 0.000 claims description 57
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 55
- 150000001875 compounds Chemical class 0.000 claims description 49
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 46
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 40
- 125000004076 pyridyl group Chemical group 0.000 claims description 38
- 150000003839 salts Chemical class 0.000 claims description 29
- 150000002431 hydrogen Chemical class 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 25
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 24
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 claims description 22
- 125000001624 naphthyl group Chemical group 0.000 claims description 21
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 21
- 210000004204 blood vessel Anatomy 0.000 claims description 19
- 230000015572 biosynthetic process Effects 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 14
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 11
- 229930192474 thiophene Natural products 0.000 claims description 11
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 8
- 239000005864 Sulphur Substances 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 8
- 230000001537 neural effect Effects 0.000 claims description 8
- 206010003210 Arteriosclerosis Diseases 0.000 claims description 7
- 206010063209 Chronic allograft nephropathy Diseases 0.000 claims description 7
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 7
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 208000010412 Glaucoma Diseases 0.000 claims description 7
- 206010018364 Glomerulonephritis Diseases 0.000 claims description 7
- 206010028980 Neoplasm Diseases 0.000 claims description 7
- 201000004681 Psoriasis Diseases 0.000 claims description 7
- 206010039361 Sacroiliitis Diseases 0.000 claims description 7
- 206010052779 Transplant rejections Diseases 0.000 claims description 7
- 208000011775 arteriosclerosis disease Diseases 0.000 claims description 7
- 208000019425 cirrhosis of liver Diseases 0.000 claims description 7
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 7
- 230000003073 embolic effect Effects 0.000 claims description 7
- 230000003176 fibrotic effect Effects 0.000 claims description 7
- 125000001072 heteroaryl group Chemical group 0.000 claims description 7
- 230000003211 malignant effect Effects 0.000 claims description 7
- 206010062198 microangiopathy Diseases 0.000 claims description 7
- 201000003142 neovascular glaucoma Diseases 0.000 claims description 7
- 201000009925 nephrosclerosis Diseases 0.000 claims description 7
- 230000002062 proliferating effect Effects 0.000 claims description 7
- 206010039073 rheumatoid arthritis Diseases 0.000 claims description 7
- 208000011580 syndromic disease Diseases 0.000 claims description 7
- 208000037816 tissue injury Diseases 0.000 claims description 7
- 206010055031 vascular neoplasm Diseases 0.000 claims description 7
- 125000003118 aryl group Chemical group 0.000 claims description 6
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 230000007246 mechanism Effects 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 239000003112 inhibitor Substances 0.000 claims description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 3
- RFQGAFQKNITSIA-UHFFFAOYSA-N 2-(carboxyamino)benzoic acid Chemical class OC(=O)NC1=CC=CC=C1C(O)=O RFQGAFQKNITSIA-UHFFFAOYSA-N 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 2
- 230000033115 angiogenesis Effects 0.000 abstract 1
- 230000002085 persistent effect Effects 0.000 abstract 1
- 230000001960 triggered effect Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 33
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 33
- 239000002904 solvent Substances 0.000 description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- 239000002585 base Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 23
- 238000000034 method Methods 0.000 description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 20
- 238000006243 chemical reaction Methods 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000002253 acid Substances 0.000 description 14
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 14
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 13
- 238000009835 boiling Methods 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 150000001408 amides Chemical class 0.000 description 11
- 238000001035 drying Methods 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- 235000019441 ethanol Nutrition 0.000 description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- 238000007738 vacuum evaporation Methods 0.000 description 9
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 230000004862 vasculogenesis Effects 0.000 description 8
- 239000003513 alkali Substances 0.000 description 7
- 150000001412 amines Chemical class 0.000 description 7
- 239000012141 concentrate Substances 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000013375 chromatographic separation Methods 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
- 238000006193 diazotization reaction Methods 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
- 238000003810 ethyl acetate extraction Methods 0.000 description 6
- 125000006239 protecting group Chemical group 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 5
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 5
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 5
- 229960000583 acetic acid Drugs 0.000 description 5
- 230000029936 alkylation Effects 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000012362 glacial acetic acid Substances 0.000 description 5
- 239000003999 initiator Substances 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000012074 organic phase Substances 0.000 description 5
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 5
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 5
- 239000007821 HATU Substances 0.000 description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 4
- 229910052786 argon Inorganic materials 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 239000011630 iodine Substances 0.000 description 4
- 229910052740 iodine Inorganic materials 0.000 description 4
- VYFOAVADNIHPTR-UHFFFAOYSA-N isatoic anhydride Chemical compound NC1=CC=CC=C1CO VYFOAVADNIHPTR-UHFFFAOYSA-N 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000006366 phosphorylation reaction Methods 0.000 description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 230000002829 reductive effect Effects 0.000 description 4
- 239000000758 substrate Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 239000003826 tablet Substances 0.000 description 4
- ONDSBJMLAHVLMI-UHFFFAOYSA-N trimethylsilyldiazomethane Chemical compound C[Si](C)(C)[CH-][N+]#N ONDSBJMLAHVLMI-UHFFFAOYSA-N 0.000 description 4
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-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
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 3
- 238000010934 O-alkylation reaction Methods 0.000 description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 3
- 150000008065 acid anhydrides Chemical class 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 150000001350 alkyl halides Chemical class 0.000 description 3
- 125000000304 alkynyl group Chemical group 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- RWZYAGGXGHYGMB-UHFFFAOYSA-N anthranilic acid Chemical compound NC1=CC=CC=C1C(O)=O RWZYAGGXGHYGMB-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 150000001491 aromatic compounds Chemical class 0.000 description 3
- 125000005605 benzo group Chemical group 0.000 description 3
- 150000001721 carbon Chemical group 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- XTVVROIMIGLXTD-UHFFFAOYSA-N copper(II) nitrate Chemical compound [Cu+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O XTVVROIMIGLXTD-UHFFFAOYSA-N 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 125000004185 ester group Chemical group 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000012467 final product Substances 0.000 description 3
- 125000000623 heterocyclic group Chemical group 0.000 description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 3
- 230000002045 lasting effect Effects 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M nitrite group Chemical group N(=O)[O-] IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 230000035479 physiological effects, processes and functions Effects 0.000 description 3
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 3
- 239000012312 sodium hydride Substances 0.000 description 3
- 229910000104 sodium hydride Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 3
- 230000004614 tumor growth Effects 0.000 description 3
- XBTOSRUBOXQWBO-UHFFFAOYSA-N 1h-indazol-5-amine Chemical compound NC1=CC=C2NN=CC2=C1 XBTOSRUBOXQWBO-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- 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 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-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
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- KWYHDKDOAIKMQN-UHFFFAOYSA-N N,N,N',N'-tetramethylethylenediamine Chemical compound CN(C)CCN(C)C KWYHDKDOAIKMQN-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- SJRJJKPEHAURKC-UHFFFAOYSA-N N-Methylmorpholine Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- WPECQIDVVNFTFV-UHFFFAOYSA-N OS(=O)(=O)C[Na] Chemical compound OS(=O)(=O)C[Na] WPECQIDVVNFTFV-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- 239000007868 Raney catalyst Substances 0.000 description 2
- 229910000564 Raney nickel Inorganic materials 0.000 description 2
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 150000001299 aldehydes Chemical class 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 230000009435 amidation Effects 0.000 description 2
- 238000007112 amidation reaction Methods 0.000 description 2
- 125000004103 aminoalkyl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 description 2
- 238000009395 breeding Methods 0.000 description 2
- 230000001488 breeding effect Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 239000012954 diazonium Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002349 favourable effect Effects 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- 239000008101 lactose Substances 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
- 239000000463 material Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- VAMXMNNIEUEQDV-UHFFFAOYSA-N methyl anthranilate Chemical compound COC(=O)C1=CC=CC=C1N VAMXMNNIEUEQDV-UHFFFAOYSA-N 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 150000002902 organometallic compounds Chemical class 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 229910052763 palladium Inorganic materials 0.000 description 2
- 229910052697 platinum Inorganic materials 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000006722 reduction reaction Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- HJUGFYREWKUQJT-UHFFFAOYSA-N tetrabromomethane Chemical compound BrC(Br)(Br)Br HJUGFYREWKUQJT-UHFFFAOYSA-N 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- 210000002700 urine Anatomy 0.000 description 2
- AMLYFGRCJXYRSH-UHFFFAOYSA-N (2-aminophenyl) trifluoromethanesulfonate Chemical class NC1=CC=CC=C1OS(=O)(=O)C(F)(F)F AMLYFGRCJXYRSH-UHFFFAOYSA-N 0.000 description 1
- BHQCQFFYRZLCQQ-UHFFFAOYSA-N (3alpha,5alpha,7alpha,12alpha)-3,7,12-trihydroxy-cholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 BHQCQFFYRZLCQQ-UHFFFAOYSA-N 0.000 description 1
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- ZXSQEZNORDWBGZ-UHFFFAOYSA-N 1,3-dihydropyrrolo[2,3-b]pyridin-2-one Chemical compound C1=CN=C2NC(=O)CC2=C1 ZXSQEZNORDWBGZ-UHFFFAOYSA-N 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- SIQZJFKTROUNPI-UHFFFAOYSA-N 1-(hydroxymethyl)-5,5-dimethylhydantoin Chemical compound CC1(C)N(CO)C(=O)NC1=O SIQZJFKTROUNPI-UHFFFAOYSA-N 0.000 description 1
- ZGCHLAJIRWDGFE-UHFFFAOYSA-N 1-aminopropane-1,1-diol Chemical compound CCC(N)(O)O ZGCHLAJIRWDGFE-UHFFFAOYSA-N 0.000 description 1
- UPPNJZSFIIFBPQ-UHFFFAOYSA-N 2-(pyridin-4-ylmethylamino)benzoic acid Chemical compound OC(=O)C1=CC=CC=C1NCC1=CC=NC=C1 UPPNJZSFIIFBPQ-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- IFXKXCLVKQVVDI-UHFFFAOYSA-N 2-amino-5-chlorobenzoic acid Chemical compound NC1=CC=C(Cl)C=C1C(O)=O IFXKXCLVKQVVDI-UHFFFAOYSA-N 0.000 description 1
- KJJPLEZQSCZCKE-UHFFFAOYSA-N 2-aminopropane-1,3-diol Chemical compound OCC(N)CO KJJPLEZQSCZCKE-UHFFFAOYSA-N 0.000 description 1
- JKWQUMKCVDUICQ-UHFFFAOYSA-N 2-anilinobenzamide Chemical class NC(=O)C1=CC=CC=C1NC1=CC=CC=C1 JKWQUMKCVDUICQ-UHFFFAOYSA-N 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- JMTMSDXUXJISAY-UHFFFAOYSA-N 2H-benzotriazol-4-ol Chemical compound OC1=CC=CC2=C1N=NN2 JMTMSDXUXJISAY-UHFFFAOYSA-N 0.000 description 1
- LYUQWQRTDLVQGA-UHFFFAOYSA-N 3-phenylpropylamine Chemical compound NCCCC1=CC=CC=C1 LYUQWQRTDLVQGA-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 1
- 102000015427 Angiotensins Human genes 0.000 description 1
- 108010064733 Angiotensins Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 238000007045 Balz-Schiemann reaction Methods 0.000 description 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 description 1
- UZSCFVMBGQQWQY-UHFFFAOYSA-N COS(=O)=O Chemical compound COS(=O)=O UZSCFVMBGQQWQY-UHFFFAOYSA-N 0.000 description 1
- QGJOPFRUJISHPQ-UHFFFAOYSA-N Carbon disulfide Chemical compound S=C=S QGJOPFRUJISHPQ-UHFFFAOYSA-N 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
- 239000004380 Cholic acid Substances 0.000 description 1
- GABQNAFEZZDSCM-RMKNXTFCSA-N Cinnamyl anthranilate Chemical compound NC1=CC=CC=C1C(=O)OC\C=C\C1=CC=CC=C1 GABQNAFEZZDSCM-RMKNXTFCSA-N 0.000 description 1
- 229910021589 Copper(I) bromide Inorganic materials 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 229920000742 Cotton Polymers 0.000 description 1
- QPLDLSVMHZLSFG-UHFFFAOYSA-N CuO Inorganic materials [Cu]=O QPLDLSVMHZLSFG-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000010911 Enzyme Precursors Human genes 0.000 description 1
- 108010062466 Enzyme Precursors Proteins 0.000 description 1
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 238000005863 Friedel-Crafts acylation reaction Methods 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 238000003436 Schotten-Baumann reaction Methods 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 240000008042 Zea mays Species 0.000 description 1
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 1
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 1
- KGHAYBAGTGGGBA-UHFFFAOYSA-N [O--].[O--].[O--].[Na+].[V+5] Chemical compound [O--].[O--].[O--].[Na+].[V+5] KGHAYBAGTGGGBA-UHFFFAOYSA-N 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001409 amidines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000003699 antiulcer agent Substances 0.000 description 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 description 1
- 125000005604 azodicarboxylate group Chemical group 0.000 description 1
- 229910052728 basic metal Inorganic materials 0.000 description 1
- 150000003818 basic metals Chemical class 0.000 description 1
- 229940054066 benzamide antipsychotics Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001718 carbodiimides Chemical class 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- 150000001728 carbonyl compounds Chemical class 0.000 description 1
- 230000006315 carbonylation Effects 0.000 description 1
- 238000005810 carbonylation reaction Methods 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 235000019416 cholic acid Nutrition 0.000 description 1
- 229960002471 cholic acid Drugs 0.000 description 1
- 239000008139 complexing agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- NKNDPYCGAZPOFS-UHFFFAOYSA-M copper(i) bromide Chemical compound Br[Cu] NKNDPYCGAZPOFS-UHFFFAOYSA-M 0.000 description 1
- 235000005822 corn Nutrition 0.000 description 1
- 229960004643 cupric oxide Drugs 0.000 description 1
- 229940045803 cuprous chloride Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- CFBGXYDUODCMNS-UHFFFAOYSA-N cyclobutene Chemical compound C1CC=C1 CFBGXYDUODCMNS-UHFFFAOYSA-N 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 1
- HGCIXCUEYOPUTN-UHFFFAOYSA-N cyclohexene Chemical compound C1CCC=CC1 HGCIXCUEYOPUTN-UHFFFAOYSA-N 0.000 description 1
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 1
- 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 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- KXGVEGMKQFWNSR-UHFFFAOYSA-N deoxycholic acid Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)C(O)C2 KXGVEGMKQFWNSR-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-O diazynium Chemical compound [NH+]#N IJGRMHOSHXDMSA-UHFFFAOYSA-O 0.000 description 1
- NZZFYRREKKOMAT-UHFFFAOYSA-N diiodomethane Chemical compound ICI NZZFYRREKKOMAT-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 150000002240 furans Chemical class 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 150000002337 glycosamines Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910001385 heavy metal Inorganic materials 0.000 description 1
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 description 1
- NAQMVNRVTILPCV-UHFFFAOYSA-N hexane-1,6-diamine Chemical compound NCCCCCCN NAQMVNRVTILPCV-UHFFFAOYSA-N 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- MVFCKEFYUDZOCX-UHFFFAOYSA-N iron(2+);dinitrate Chemical compound [Fe+2].[O-][N+]([O-])=O.[O-][N+]([O-])=O MVFCKEFYUDZOCX-UHFFFAOYSA-N 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 235000015073 liquid stocks Nutrition 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- CNFDGXZLMLFIJV-UHFFFAOYSA-L manganese(II) chloride tetrahydrate Chemical compound O.O.O.O.[Cl-].[Cl-].[Mn+2] CNFDGXZLMLFIJV-UHFFFAOYSA-L 0.000 description 1
- 229910052987 metal hydride Inorganic materials 0.000 description 1
- 150000004681 metal hydrides Chemical class 0.000 description 1
- LVWZTYCIRDMTEY-UHFFFAOYSA-N metamizole Chemical compound O=C1C(N(CS(O)(=O)=O)C)=C(C)N(C)N1C1=CC=CC=C1 LVWZTYCIRDMTEY-UHFFFAOYSA-N 0.000 description 1
- 229930182817 methionine Natural products 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000802 nitrating effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- NXJCBFBQEVOTOW-UHFFFAOYSA-L palladium(2+);dihydroxide Chemical compound O[Pd]O NXJCBFBQEVOTOW-UHFFFAOYSA-L 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- CYQAYERJWZKYML-UHFFFAOYSA-N phosphorus pentasulfide Chemical compound S1P(S2)(=S)SP3(=S)SP1(=S)SP2(=S)S3 CYQAYERJWZKYML-UHFFFAOYSA-N 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 235000007715 potassium iodide Nutrition 0.000 description 1
- 229960004839 potassium iodide Drugs 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 150000003217 pyrazoles Chemical class 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000005932 reductive alkylation reaction Methods 0.000 description 1
- 230000000452 restraining effect Effects 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 231100000241 scar Toxicity 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 229910001958 silver carbonate Inorganic materials 0.000 description 1
- LKZMBDSASOBTPN-UHFFFAOYSA-L silver carbonate Substances [Ag].[O-]C([O-])=O LKZMBDSASOBTPN-UHFFFAOYSA-L 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 150000003556 thioamides Chemical class 0.000 description 1
- HPGGPRDJHPYFRM-UHFFFAOYSA-J tin(iv) chloride Chemical compound Cl[Sn](Cl)(Cl)Cl HPGGPRDJHPYFRM-UHFFFAOYSA-J 0.000 description 1
- VYNCPPVQAZGELS-UHFFFAOYSA-N toluene;trimethylalumane Chemical compound C[Al](C)C.CC1=CC=CC=C1 VYNCPPVQAZGELS-UHFFFAOYSA-N 0.000 description 1
- IMFACGCPASFAPR-UHFFFAOYSA-N tributylamine Chemical compound CCCCN(CCCC)CCCC IMFACGCPASFAPR-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
- C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
- C07C237/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to an acyclic carbon atom of a hydrocarbon radical substituted by oxygen atoms
-
- 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
- C07D401/14—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 three or more hetero rings
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- 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
-
- 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
-
- 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
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
-
- 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
- A61P9/10—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
-
- 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
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
-
- 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
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- 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
- C07D409/12—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 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
Abstract
本发明涉及邻氨基苯甲酰胺及其作为治疗由持续的血管生成引发的疾病的药物的应用,还涉及制备邻氨基苯甲酰胺中的中间产物。
Description
本发明涉及邻氨基苯甲酰胺及其作为药物的应用,其可用于治疗由持续血管生成引发的疾病,还涉及用于制备邻氨基苯甲酰胺的中间产物。
持续血管生成是各种疾病的诱因,如牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病和动脉硬化,或者是可导致这些疾病发展的原因。
直接或间接抑制VEGF受体可用于治疗上述疾病以及VEGF诱导的其他病理性血管生成和血管渗透病症,如肿瘤血管形成。例如,已知用可溶性受体和抗VEGF的抗体可抑制肿瘤的生长。
持续血管生成是由VEGF因子通过其受体诱导的。因此,如果VEGF发挥其作用,VEGF必须结合受体,并产生酪氨酸磷酸化。
已知苯基-邻氨基苯甲酰胺衍生物可用作血管紧张素Ⅱ的拮抗剂(EP 564356)并可作为抗炎剂和抗溃疡化合物(US 3,409,668)。
现在发现通式Ⅰ的化合物及其异构体和盐可阻止酪氨酸磷酸化或持续血管生成,并因此可防止肿瘤的生长和繁殖:其中:A代表基团=NR2;W代表氧、硫、两个氢原子或基团=NR8;Z代表基团=NR10或=N-、-N(R10)-(CH2)q-、支链或直链C1-6烷
基或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、C1-4烷基或基团=NR10,
和/或Ra和/或Rb与Rc和/或Rd形成一个键,或者Rc与Re和/或Rf
形成一个键,或者Ra-Rf中最多有两个可分别闭合最多有3个碳原
子的桥形成R1或R2;X代表基团=NR9或=N-;Y代表基团-(CH2)p;p代表1-4;R1代表未经取代或者任选地在一个或多个位置中被卤素、在一个或多个
位置具有卤素的C1-6烷基取代的C1-6烷基或者是被C1-6烷氧基取
代的芳基或杂芳基,但化合物不包括其中芳基直接键连在A定义中
的=NR2基团上;R2代表氢或C1-6烷基或者与Z中的Ra-Rf形成带有最多3个环原子的
桥或形成R1;R3代表未经取代的或者任选地在一个或多个位置上被卤素、C1-6烷基、
C1-6烷氧基或羟基取代的单环或二环芳基或杂芳基;R4、R5、R6和R7相互独立地是氢、卤素、或者未经取代的或者任选地
在一个或多个位置上被卤素取代的C1-6烷氧基、C1-6烷基或C1-6
如果Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢或C1-4烷基,则Z形成烷基链。
如果Ra和/或Rb与Rc和/或Rd形成一个键,或者Rc与Re和/或Rf形成一个键,则Z代表链烯基或链炔基。
如果Ra-Rf自身形成一个桥,则Z代表环烷基或环烯基。
如果Ra-Rf中最多有两个形成至R1的最多有3个碳原子的桥,则Z与R1一起是苯并-或杂芳基稠合(Ar)的环烷基。
如果Ra-Rf基团中的一个闭合一个桥形成R2,则形成氮杂环,该杂环可由一个基团与R1分开。
例如,它们可以是:
烷基在各种情况下定义为直链或支链烷基,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、戊基、异戊基、或己基,其中C1-4烷基是优选的。
环烷基相应地定义为环丙基、环丁基、环戊基、环己基或环庚基。
环烯基相应地定义为环丁烯基、环戊烯基、环己烯基、环庚烯基,其中连接可发生在双键或单键上。
卤素定义为氟、氯、溴或碘。
链烯基和链炔基取代基在各种情况下定义为直链或支链的,并包含2-6个碳原子,优选为2-4个碳原子。例如,可以是以下基团:乙烯基、丙烯-1-基、丙烯-2-基、丁-1-烯-1-基、丁-1-烯-2-基、丁-2-烯-1-基、丁-2-烯-2-基、2-甲基-丙-2-烯-1-基、2-甲基丙-1-烯-1-基、丁-1-烯-3-基、乙炔基、丙-1-炔-1-基、丁-1-炔-1-基、丁-2-炔-1-基、丁-3-炔-1-基、烯丙基。
在各种情况下,芳基具有6-12个碳原子,例如是萘基、联苯基、特别是苯基。
在各种情况下,杂芳基可以是苯并稠合的。例如可以是5元杂芳香化合物:噻吩、呋喃、恶唑、噻唑、咪唑、吡唑以及它们的苯并衍生物,还可以是6元杂芳香化合物:吡啶、嘧啶、三嗪、喹啉、异喹啉和苯并衍生物,其中如果是苯并稠合的杂芳基,则可连接在杂环以及苯并环上。
在各种情况下,芳基和杂芳基可在1、2或者3个位置上被卤素、C1-4烷氧基、硝基、三氟甲基、三氟甲氧基、氰基、SOqR5或C1-4烷基取代,其中q代表0-2。
如果包括酸性基团,则无机和有机碱的生理相容盐是合适的盐,例如容易溶解的碱金属和碱土金属盐以及N-甲基-葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、1,6-己二胺、乙醇胺、葡糖胺、肌氨酸、丝氨醇、三-羟基-甲基-氨基-甲烷、氨基丙二醇、Sovak碱、1-氨基-2,3,4-丁三醇。
如果包括碱性基团,则无机和有机酸的生理相容盐是合适的盐,例如盐酸、硫酸、磷酸、柠檬酸、酒石酸等。
以下的通式Ⅰ化合物及其异构体和盐证明是特别有效的,其中:A代表基团=NR2;W代表氧、硫、两个氢原子或基团=NR8;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、支链或直链C1-6
烷基或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、C1-4烷基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-(CH2)p;p代表1-4;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、6,7-二甲氧基-1,2,3,4-四氢-2
-萘基,或者代表在-个或多个位置上被C1-4烷基、C1-4烷氧基、
羟基、卤素或三氟甲基取代的苯基或吡啶基,或者代表以下基团:
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或C1-6烷基或者与Z中的Ra-Rf形成带有最多3个环原子的
桥或形成R1;R3代表未经取代的或者任选地在一个或多个位置上被卤素、C1-6烷基、
C1-6烷氧基或羟基取代的单环或二环芳基或者单环或二环杂芳
基;R4、R5、R6和R7相互独立地是氢、卤素、或者是未经取代的或者任选
地在一个或多个位置上被卤素取代的C1-6烷氧基或C1-6烷基,或
以下的通式Ⅰ化合物及其异构体和盐也是特别优选的:其中:A代表基团=NR2;W代表氧、硫或两个氢原子;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、6,7-二甲氧基-1,2,3,4-四氢-2
-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧基、
羟基、卤素或三氟甲基取代的苯基或吡啶基,或者代表以下基团:
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
代的苯基、吡啶基或1,2,3,4-四氢萘基,或者代表以下基团:R5和R6相互独立地是氢、卤素、甲基、甲氧基或三氟甲基;R4和R7相互独立地是氢或卤素;R9代表氢;R10代表氢或甲基。
以下的通式Ⅰ化合物及其异构体和盐已证明特别有效的,其中:A代表基团=NR2;W代表氧;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、6,7-二甲氧基-1,2,3,4-四氢-2
-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧基、
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
以下的通式Ⅰ化合物及其异构体和盐也证明特别有效的,其中:A代表基团=NR2;W代表硫;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、6,7-二甲氧基-1,2,3,4-四氢-2
-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧基、
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
以下的通式Ⅰ化合物及其异构体和盐也是特别优选的,其中:A代表基团=NR2;W代表两个氢原子;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、6,7-二甲氧基-1,2,3,4-四氢-2
-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧基、
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上:R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
根据本发明的化合物可防止磷酸化,也就是说选择性地抑制某些酪氨酸激酶,由此终止持续的血管生成。因此,抑制例如肿瘤的生长和繁殖。
根据本发明的通式Ⅰ化合物还包括可能的互变异构体,并包括E-和Z-异构体,或者如果存在手性中心,则还包括外消旋体和对映体。
式Ⅰ的化合物及其生理相容的盐可基于它们相对于VEGF受体的磷酸化作用的抑制活性用作药物。根据它们的作用模式,根据本发明的化合物适合用于治疗由持续的血管生成导致的疾病。
因为式Ⅰ的化合物已确定为酪氨酸激酶KDR和FLT的抑制剂,所以它们特别适合于治疗那些由持续的血管生成导致的疾病,而持续的血管生成是由VEGF受体或血管渗透性增加引发的。
本发明还涉及根据本发明的化合物作为酪氨酸激酶KDR和FLT的抑制剂的应用。
因此,本发明还包括用于治疗肿瘤的药物。
根据本发明的化合物可单独或者配制成药剂的形式使用,来治疗牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病、动脉硬化以及神经组织损伤。
根据本发明的化合物还可用于抑制球管治疗后、血管修复或者使血管敞开的机械装置如支架后的血管再闭合。
在治疗神经组织损伤时,用本发明的化合物可防止损伤部位处的快速疤痕形成,也就是说防止疤痕在轴突相互重新连接在一起之前形成。因此有利于重新构建神经连接。
用本发明的化合物还可抑制患者中腹水的形成。也可抑制VEGF诱导的浮肿。
此等药物、它们的制剂以及应用也包括在本发明中。
本发明还涉及通式Ⅰ的化合物在制备用于治疗以下疾病的药物中的应用:肿瘤、牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病、动脉硬化、神经组织损伤、以及抑制球管治疗后、血管修复或者使血管敞开的机械装置如支架后的血管再闭合。
为以药物的形式使用通式Ⅰ的化合物,可将其配制成药物制剂,其除活性成分外为进行肠道或非胃肠道给药还包括合适的无机或有机惰性药物载体,如水、明胶、阿拉伯胶、乳糖、淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇等。药物制剂可为固体形式,例如片剂、包衣片、栓剂、胶囊剂,或者为液体形式,例如溶液剂、混悬剂或乳剂。另外,它们可任选包括辅剂,如防腐剂、稳定剂、湿润剂或乳化剂、用于改变渗透压的盐或缓冲剂。
在非胃肠道使用时,特别是以注射溶液或混悬液使用时,在多羟基乙氧基化蓖麻油中的活性化合物水溶液是特别合适的。
作为载体系统,也可使用表面活性辅剂,如胆酸的盐或者动物或植物磷脂、它们的混合物以及脂质体或其组成。
在口服使用时,片剂、包衣片或胶囊是特别合适的,其中含有滑石和/或烃载体或粘合剂如乳糖、玉米或马铃薯淀粉。该应用也可以液体形式来进行,例如汁液,其中任选添加甜味剂。
活性成分的剂量可根据给药方法、患者的年龄和体重、待治疗疾病的类型和严重程度、以及类似的因素而变化。日剂量为0.5-1000mg,优选为50-200mg,其中该剂量可以单剂量一次性给药,或者分成2个或更多个日剂量给药。
上述制剂和剂型也包括在本发明的范围中。
根据本发明的化合物可根据本领域己知的方法来制备。例如式Ⅰ的化合物可如下制备:(a)式Ⅱ的化合物其中R4-R7与上述定义相同,而T是H或者保护基,A是卤素或OR13,其中R13代表氢原子、C1-4烷基或C1-4酰基,或者与T连接成环,首先使N烷基化,然后将COA转化为酰胺,接着任选地断裂保护基,或者首先转化为酰胺,然后进行N烷基化,或者(b)式Ⅲ的化合物其中R4-R7与上述定义相同,而T是H或者保护基,使其邻位金属化,然后通过亲电子攻击转化为酰胺,接着断裂保护基,并使氨基烷基化,或者(c)式Ⅳ的化合物其中R4-R7与上述定义相同,而T是H或者保护基,B代表卤素或O-Troflate、O-甲苯磺酸或O-甲磺酸基,将其转化为酰胺,然后断裂保护基,并使氨基烷基化。
上述步骤顺序在所有三种情况中都是可以相反的。
根据本领域已知的方法进行酰胺的形成。
对于酰胺的形成,起始物可由相应的酯制备。根据J.Org.Chem.1995,S414使酯与三甲基铝和相应的胺在溶剂如甲苯中反应,温度为0℃-溶剂的沸点。该方法也可用于未经保护的邻氨基苯甲酸酯。如果分子包含两个酯基,则将它们都转化为相同的酰胺。
如果使用腈代替酯,则在类似的条件下得到脒。
但是对于酰胺的形成,也可使用肽化学中已知的所有方法。例如,相应的酸在非质子极性溶剂如二甲基甲酰胺中于经活化的酸衍生物上反立,该经活化的酸衍生物可例如用羟基苯并三唑和碳化二亚胺如二异丙基碳化二亚胺或者用预先形成的试剂如HATU(Chem.Comm.1994,201)或者BTU得到,温度为0℃-溶剂的沸点,优选为80℃,在HATU中用胺时优选在室温下。这些方法也可用于未经保护的邻氨基苯甲酸。对于酰胺的形成,该方法也可通过使用混合酸酐、咪唑或叠氮化物来进行。在所有情况中,预先保护氨基如酰胺并不是必须的,但可使反应有利地进行。靛红酸酐是特别优选的起始物,在该物质中同时存在氨基的保护和酸官能团的活化。
如果胺已经转化为BOC保护的化合物,则邻位可通过与有机金属化合物的反应来金属化,所述有机金属化合物例如是正丁基锂,然后用异氰酸酯或异硫氰酸酯攻击,形成邻氨基苯甲酰胺或邻氨基苯甲酸硫代酰胺。在邻位的溴或碘取代基有利于通过卤素-金属交换进行邻位金属化。作为溶剂,醚如乙醚或四氢呋喃或者烃如己烷是合适的,但也可使用它们的混合物。添加络合剂如四甲基乙二胺(TMEDA)是有利的。温度可在-78℃至室温之间变化。BOC-酰胺的断裂可用酸处理来进行,例如三氟乙酸,可用溶剂如二氯甲烷或不用溶剂,温度为0℃-溶剂的沸点,或者用盐酸,优选1N盐酸,溶剂为乙醇或二恶烷,温度为室温-溶剂的沸点。
酰胺基团也可通过羰基化来引入。为此目的,起始物由相应的式Ⅳ化合物(o-碘、o-溴或者o-triflyloxyanilines)制备,其在常压或者略微升高的压力下与一氧化碳反应,然后在过度金属催化剂如氯化钯(Ⅱ)或乙酸钯(Ⅱ)或者四(三苯基膦)钯存在下在溶剂如二甲基甲酰胺中与胺反应。添加配位体如三苯基磷以及添加碱如三丁基胺也可以是有利的(例如参见:J.Org.Chem.1974,3327;J.Org.Chem.1996,7482;Synth.Comm.1997,367,Tetr.Lett 1998,2835)。
如果要在分子中引入各种酰胺基团,则必须例如在产生第一个酰胺基团后在分子中引入第二个酯基,然后必须酰胺化,或者分子中一个基团是酯基而另一个是酸,然后根据各种方法顺序地对两个基团进行酰胺化。
硫代酰胺可根据Bull Soc.Chim.Belg.87,229,1978的方法由邻氨基苯甲酰胺通过与二磷二硫烷(diphosphadithianes)的反应或者在溶剂如吡啶中或者没有溶剂的情况下于0-200℃的温度下通过与五硫化二磷反应来制备。
对于富电子芳香化合物,产物也可进行亲电子芳香取代反应。该取代反应可在邻位或对位进行,形成二个氨基或者其中一个氨基。因此其可在Friedel-Crafts催化剂如三氯化铝存在下在溶剂如硝基甲烷、二硫化碳、二氯甲烷或硝基苯中于0℃-溶剂的沸点、优选在室温下通过Friedel-Crafts酰化反应而被酰化。
根据本领域已知的方法可引入一个或多个硝基,例如在没有溶剂时用硝化酸、各种浓度的硝酸,或者在极性溶剂如乙醇或冰醋酸或者乙酸酐中用硝酸金属盐如硝酸铜(Ⅱ)或硝酸铁(Ⅲ)。
可根据本领域已知的方法引入卤素,例如在极性溶剂如四氢呋喃、乙腈、二氯甲烷、冰醋酸或二甲基甲酰胺中通过与溴、N-溴、或N-碘琥珀酰亚胺或乌洛托品hydrotribromide的反应。
硝基的还原反应是在极性溶剂中于室温或升高的温度下进行。对于还原反应的催化剂,金属如Raney镍或贵金属催化剂如钯或铂或任选在载体上的氢氧化钯是合适的。替代氢,也可按已知的方法使用甲酸铵、环己烯、或肼。还原剂如氯化锡(Ⅱ)和氯化钛(Ⅲ)也可使用,以及氢化金属复合物,任选有重金属盐存在。也可使用铁作为还原剂。该反应在有酸如乙酸或氯化铵存在下进行,任选添加溶剂如水、甲醇等。如果延长反应时间,氨基的酰化可在该变化方案中发生。
如果希望氨基进行烷基化,则可根据常规使用的方法进行烷基化反应,例如用烷基卤化物,或者根据Mitsunobu的方法通过在例如三苯基膦和偶氮二羧酸酯存在下与醇的反应来进行。胺也可用醛或酮进行还原性烷基化,其中在有还原剂如氰基硼氢化钠存在下在合适的惰性溶剂如乙醇中进行反应,温度为0℃-溶剂的沸点。如果起始物由伯氨基制备,反应可任选地连续用两个不同的羰基化合物进行,由此得到混合衍生物(文献例如是:Verardo等人,Synthesis(1993),121;Synthesis(1991),447;Kawaguchi,Synthesis(1985),701;Micovic等人.Synthesis(1991),1043)。
通过醛与胺在溶剂如乙醇或甲醇中的反应,可有利地形成Schiff碱,可任选地添加辅剂如冰醋酸,然后仅添加还原剂如氰基硼氢化钠。
分子中烯基或炔基的氢化可用例如催化氢化反应按照常规方法来进行。作为催化剂,可使用重金属如钯或铂,任选在载体上,或者用Raney镍。作为溶剂,醇如乙醇是合适的。反应温度为0℃-溶剂的沸点,压力最高至20bar,但优选在室温和常压下。使用催化剂时,例如Lindlar催化剂,三键被部分氢化为双键,由此优选形成Z-构型。
氨基的酰化按照常规方法用例如酰卤或酸酐进行,任选存在碱如二甲基氨基吡啶,溶剂例如为二氯甲烷、四氢呋喃或吡啶,根据Schotten-Baumann法在含水溶液中于弱碱性pH条件下,或者在冰醋酸中通过与酸酐的反应。
通过氨基引入卤素氯、溴、碘或叠氮基团也可根据例如Sandmeyer的方法通过重氮化盐来进行,该重氮化盐是在相应酸如盐酸或氢溴酸存在下亚硝酸盐与氯化亚铜(Ⅰ)或溴化亚铜(Ⅰ)反应或者与碘化钾反应而形成的中间产物。
如果使用有机亚硝酸盐,卤素可通过添加二碘甲烷或四溴甲烷引入在溶剂如二甲基甲酰胺中。氨基的脱除可通过在四氢呋喃中与有机亚硝酸盐的反应或者通过重氮化反应以及重氮化盐与例如磷酸的还原性煮浓来实现,或者可任选添加氧化铜(Ⅰ)。
氟的引入可通过四氟硼酸重氮盐的Balz-Schiemann反应或者根据J.Fluor.Chem.76,1996,59-62在HFx吡啶存在通过重氮化反应、然后任选在氟离子源如四丁基氟化铵存在下煮浓来实现。
叠氮基的引入可在重氮化反应后通过在室温下与叠氮化钠的反应来进行。
醚断裂可根据文献中已知的方法来进行。在此情况下,也可在分子中存在的几个基团中进行选择性断裂。此时,醚在溶剂如二氯甲烷中于-100℃至溶剂沸点、优选-78℃的温度下用例如三溴化硼来处理。但是也可在溶剂如二甲基甲酰胺中用硫代甲基钠断裂醚。温度在室温-溶剂沸点之间,优选在150℃。
酰胺的N-或O-烷基化如吡啶-2-酮或2-羟基吡啶可根据文献中己知的方法来进行。N-烷基化可用碱如氢化钠或碳酸钾在溶剂如二甲基甲酰胺中实现,然后用烷基卤化物如碘甲烷进行烷基化。O-烷基化是用碱如碳酸银在溶剂如四氢呋喃或甲苯或优选它们的混合物中用烷基卤化物如碘甲烷进行。O-烷基化也可通过在惰性溶剂如二氯甲烷中用三烷基氧四氟硼酸盐的转化来得到。N-和O-烷基衍生物的混合物可在溶剂如甲醇或甲苯、优选它们的混合物中,在室温-溶剂沸点、优选室温的温度下,在与重氮甲烷或三甲基甲硅烷基重氮甲烷的反应中得到。该方法可相对于苯甲酰胺对吡啶酮进行选择性的烷基化。
根据常规使用的方法,如结晶、色谱或形成盐,可将异构体混合物分离成对映体或E/Z-异构体。
盐的制备是按照常规方法进行的,其中式Ⅰ化合物的溶液与等量或过量的碱或酸混合,所述碱或酸任选为溶液,然后分离沉淀,或者按常规方法处理溶液。
如果没有描述起始物的制备,则其是已知的或者可类似于已知化合物或者根据在此描述的方法进行制备。
本发明还包括通式Ⅴ的N-羧氨基苯甲酸衍生物及其异构体和盐,其是制备根据本发明的通式Ⅰ化合物的重要中间产物:其中R3-R7、X、Y和W与以上通式Ⅰ的定义相同,A代表基团=NR2或氧,而Z和R1一起形成连接于X上的=C=O基团。
通式Ⅴ的中间产物中特别有价值的是以下化合物及其异构体和盐,其中:A和W代表氧;Z和R1一起形成连接于X上的=C=O基团;X代表基团=NR9或=N-;Y代表基团-CH2-;R3代表吡啶基或者被羟基、溴、甲基、或甲氧基取代的苯基或1,2,3,
4-四氢萘基;R5和R6代表氢、氯、甲基、甲氧基或三氟甲基;R4和R7代表氢;R9代表氢。
该中间产物本身具有部分活性,因此可制备用于治疗以下疾病的药物:肿瘤、牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病、动脉硬化、神经组织损伤、以及抑制球管治疗后、血管修复或者使血管敞开的机械装置如支架后的血管再闭合。
以下实施例将阐述本发明化合物的制备,但本发明并不限于这些实施例中。实施例1.0制备N-(4-吡啶基甲基)-邻氨基苯甲酸甲酯
在氮气氛下,使7.5g邻氨基苯甲酸甲酯和8.6g吡啶-4-甲醛在300ml甲醇中的混合物与3ml乙酸混合,在室温下搅拌12小时。反应混合物与5.7g的氰基硼氢化钠(85%)混合,在室温下再搅拌3小时。此后,再添加1.14g的氰基硼氢化钠(85%),并在室温下搅拌12小时。蒸发浓缩反应混合物。残留物在乙酸乙酯中处理,用饱和碳酸氢钠溶液以及饱和氯化钠溶液洗涤。经干燥的有机相进行蒸发浓缩,残留物用硅胶柱色谱进行纯制,其中使用己烷/乙酸乙酯(1+1)洗脱。
得到10.2g的标题化合物,其熔点为85.6℃。实施例2.0制备N-(3-苯基丙-1-基)-N2-(4-吡啶基甲基)-邻氨基苯甲酰胺
将242mg的N-(4-吡啶基甲基)-邻氨基苯甲酸甲酯引入在3.5ml甲苯中,与202mg的3-苯基丙基胺混合,然后在0℃下与0.75ml的2M三甲基铝甲苯溶液快速混合。反应混合物在室温下加热1小时,然后回流1小时。冷却后,反应混合物添加在饱和碳酸氢钠溶液中,并用乙酸乙酯萃取。有机相洗涤、干燥、过滤并真空蒸发浓缩。残留物用乙酸乙酯重结晶。
得到265mg的标题化合物,其熔点为117.4℃。
将425mg的N-(4-甲氧基苄基)靛红酸酐溶解在20ml的四氢呋喃(p.A)中,与234mg的4-氯苄基胺混合并回流4小时。反应溶液真空蒸发浓缩,用乙酸乙酯处理,洗涤,干燥,过滤,然后真空蒸发浓缩。残留物用乙醇重结晶。得到标题化合物,其熔点为130.5℃。
类似地制备以下化合物:
在氮气氛下将71mg的N-[2-(4-氯苯基)乙基]-N2-(4-甲氧基苄基)-邻氨基苯甲酰胺溶解在2ml的纯二甲基甲酰胺中,并与76mg的硫代甲基钠混合。反应混合物回流1.5小时。冷却后,与30ml的水混合,然后用乙酸乙酯萃取。有机相洗涤,干燥,过滤,然后真空蒸发至干燥。残留物在硅胶上用己烷+乙酸乙酯(7+3)作为洗脱剂进行色谱分离。
得到23mg的标题化合物,其熔点为103-105℃。实施例5.0制备2-[(2-氯吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺
使300mg的2-(氨基)-N-(异喹啉-3-基)苯甲酰胺在6ml的甲醇中与0.06ml的冰醋酸和523mg的39%2-氯-4-吡啶甲醛在二氯甲烷和乙酸乙酯中的溶液混合,然后在氩气中于室温下搅拌20小时。然后添加96mg的氰基硼氢化钠,并在室温下搅拌6小时。真空蒸发浓缩后,残留物在30ml的碳酸氢钠稀水溶液中处理,并用乙酸乙酯萃取。乙酸乙酯相用水洗涤,干燥,过滤,然后蒸发浓缩。残留物在硅胶上用乙酸乙酯作为洗脱剂进行色谱分离。合并相应的馏分并蒸发浓缩后,得到56mg的2-[(2-氯吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺。
类似地制备以下化合物: 实施例6.0制备2-[[(1,2-二氢-1-甲基-2-氧吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺
使在2ml二甲基甲酰胺中的80mg的2-[[(1,2-二氢-2-氧吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺在氩气氛中与10mg的氢化钠(80%)混合,然后在60℃下加热30分钟。滴加0.015ml的碘甲烷在0.5ml二甲基甲酰胺中的溶液,并在60℃下加热1小时。冷却后,反应物添加在碳酸氢钠溶液中,并用乙酸乙酯萃取。乙酸乙酯相洗涤,干燥,并蒸发浓缩,残留物在硅胶上用二氯甲烷∶乙醇=97∶3作为洗脱剂进行色谱分离。得到30mg的2-[[(1,2-二氢-1-甲基-2-氧吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺。
类似地制备以下化合物: 实施例7.0制备2-[(2-甲氧基吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺和2-[[(1,2-二氢-1-甲基-2-氧吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺
将130mg的2-[[(1,2-二氢-2-氧比啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺引入在4ml的甲苯∶甲醇=1∶3.5混合物中,并与0.2ml的2M三甲基甲硅烷基重氮甲烷在己烷中的溶液混合,然后在室温下搅拌8小时。重复添加0.2ml的三甲基甲硅烷基重氮己烷溶液并搅拌1小时后,将反应物蒸发至干燥,然后在硅胶上用二氯甲烷∶乙醇=97∶3作为洗脱剂进行色谱分离。得到20mg的2-[(2-甲氧基吡啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺和10mg的2-[[(1,2-二氢-1-甲基-2-氧比啶-4-基)甲基]氨基]-N-(异喹啉-3-基)苯甲酰胺。
在氩气氛和无水气的条件下将228mg的N-(4-吡啶基甲基)-邻氨基苯甲酸引入在10ml的二甲基甲酰胺中。添加266mg的5-氨基吲唑、0.27ml的甲基吗啉和456mg的O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基六氟磷酸尿(HATU)。在室温下搅拌混合物4小时。然后与碳酸氢钠稀溶液混合,并用乙酸乙酯萃取三次。合并的有机相用水洗涤,干燥,过滤,然后真空蒸发浓缩。残留物在硅胶上用乙酸乙酯作为洗脱剂进行色谱分离。
用丙酮进行吸附沉淀,得到245mg的标题化合物,其熔点为209.8℃。
以下实施例阐述本发明中间产物的制备,但不是用于限制本发明的范围。实施例9.0制备用于制备本发明最终产物的中间产物N-(4-甲氧基苄基)靛红酸酐
在氮气氛下在冰浴中冷却由5g的靛红酸酐和1000ml的N,N-二甲基乙酰胺组成的溶液,然后分批地与1.35g的氢化钠(油,约60%)混合。反应混合物在室温下搅拌30分钟,然后在60℃的浴温下再搅拌30分钟。冷却至室温后,滴加5ml的4-甲氧基苯甲醛并同时搅拌,然后在室温下搅拌过夜。反应混合物真空蒸发浓缩,并倾倒在100ml的冰/水上。分离沉淀物,在50ml的二氯甲烷中处理,洗涤,干燥,过滤,然后真空蒸发浓缩。残留物用醇重结晶。
得到3.4g的标题化合物,其熔点为143℃。
将2g的N-(4-吡啶基甲基)-邻氨基苯甲酸甲酯溶解在15ml的甲醇中,与16ml的1N氢氧化钠溶液混合,然后回流1小时。冷却后,真空蒸除甲醇,残留物与20ml的水和20ml的1N柠檬酸溶液混合。抽滤出结晶,用水洗涤并干燥。
得到1.7g的标题化合物,其熔点为208.0℃。实施例11.0制备用于制备本发明最终产物的中间产物N-(吲唑-5-基)-5-氯邻氨基苯甲酰胺
将在氩气氛和无水气的条件下将171mg的5-氯邻氨基苯甲酸引入在10ml的二甲基甲酰胺中,然后顺序地与253mg的甲基吗啉、266mg的5-氨基吲唑和456mg的O-(7-氮杂苯并三唑-1-基)-N,N,N′,N′-四甲基六氟磷酸尿(HATU)混合,并在室温下搅拌4小时。过夜放置后,与50ml的水混合,并用30ml的乙酸乙酯萃取。有机相用水洗涤,干燥,过滤,然后真空蒸发浓缩。残留物在硅胶上用乙酸乙酯作为洗脱剂进行色谱分离。得到266mg的N-(吲唑-5-基)-5-氯邻氨基苯甲酰胺。
以下样品应用说明根据本发明的化合物的生理作用和用途,但并不是对本发明范围的限制。实验所用的溶液原料液原料液A:3mmol的ATP,在水中,pH7.0(约70℃)原料液B:g-33P-ATP1mCi/100μl原料液C:聚-(Glu4Tyr)10mg/ml,在水中用于稀释的溶液底物溶剂:10mmol的DTT,10mmol的氯化锰,100mmol的氯化镁酶溶液:120mmol的tris/HCl,pH7.5,10μm的氧化钒钠样品应用1在本发明化合物存在时对KDR-和FLT-1激酶活性的抑制作用
在向下尖的微量滴定板(无蛋白结合)中添加10μl的底物化合物(10μl体积的ATP原料液A+25μCi的g-33p-ATP(约2.5μl的原料液B)+30μl的聚-(Glu4Tyr)原料液C+1.21ml的底物溶剂)、10μl的抑制剂溶液(相当于稀释液的物质,DMSO在底物溶剂中3%,作为对照)、以及10μl的酶溶液(11.25μg的酶原料液(KDR或FLT-1激酶)在4℃下稀释于1.25ml的酶溶液中)。彻底混合,并在室温下温育10分钟。然后添加10μl的终止溶液(250mmol的EDTA,pH7.0),混合,并将10μl的溶液转移至P81磷酸纤维素过滤器上。在0.1M磷酸中洗涤几次。干燥滤纸,用Meltilex涂敷,并在microbeta计数器中测量。
由抑制剂浓度测定IC50值,其必须是在除去空白读数(EDTA终止反应)后将磷酸掺入抑制在未被抑制的掺入的50%。
激酶抑制作用IC50(μmol)的结果见以下表所示。
实施例号 | VEGFR1(FLT) | VEGFRⅡ(KDR) |
2.0 | 0.05 | 0.05 |
2.1 | 0.01 | 0.3 |
2.2 | 0.1 | 0.5 |
2.3 | 0.02 | 0.02 |
2.4 | 0.02 | 0.1 |
2.5 | 1 | 10 |
2.6 | 0.2 | 2 |
2.8 | 0.5 | 0.1 |
2.9 | 5 | 1 |
2.10 | 3 | 10 |
2.11 | 0.02 | 0.2 |
2.12 | 0.7 | 3 |
2.13 | 0.7 | 3 |
2.14 | 0.5 | 0.3 |
2.15 | 1.0 | KH |
2.16 | 0.1 | 0.2 |
2.17 | 0.4 | 0.5 |
2.18 | 0.3 | 0.5 |
2.19 | >10 | >10 |
2.20 | 4 | KH |
2.21 | 2 | 0.3 |
实施例号 | VEGFR1(FLT) | VEGFRⅡ(KDR) |
2.23 | 0.02 | 0.67 |
2.24 | 0.5 | >1 |
2.25 | 0.3 | 0.2 |
2.26 | 0.2 | 0.2 |
2.27 | 0.02 | 0.02 |
2.28 | 1 | 2 |
2.29 | 2 | 3 |
2.30 | 0.005 | 0.02 |
2.31 | 0.1 | 0.27 |
2.32 | 0.02 | 0.02 |
2.33 | 1 | 2 |
2.34 | 2 | 0.1 |
2.35 | 0.098 | 0.02 |
2.36 | 0.05 | 0.2 |
2.37 | 0.2 | |
2.38 | 7 | 0.2 |
2.39 | 0.05 | 0.03 |
2.40 | 0.5 | |
2.41 | 1 | 0.3 |
2.42 | 0.5 | 0.1 |
2.43 | 0.02 | 0.05 |
2.44 | 0.3 | 0.2 |
2.45 | 0.1 | 1 |
2.46 | 0.04 | 0.05 |
2.47 | 0.02 | 1 |
2.48 | 0.1 | 0.5 |
2.49 | 0.08 | 0.05 |
2.50 | KH | KH |
实施例号 | VEGFR1(FLT) | VEGFRⅡ(KDR) |
2.51 | ||
2.52 | 0.05 | |
2.53 | 0.02 | 0.02 |
2.54 | 0.02 | 0.005 |
2.55 | 0.3 | 0.2 |
2.56 | 0.04 | 0.02 |
2.57 | KH | KH |
2.58 | 0.5 | 5 |
2.59 | 50 | KH |
2.60 | 0.5 | 0.7 |
2.61 | 10 | 10 |
2.63 | 0.0003 | |
2.64 | 0.04 | 0.04 |
2.65 | 0.0002 | |
2.74 | 1 | KH |
2.75 | 0.3 | 5 |
3.0 | KH | 3.0 |
3.2 | 2.0 | 2.0 |
4.0 | 0.5 | 0.2 |
8.0 | 0.04 | 0.04 |
8.2 | 0.2 | 0.2 |
8.3 | 0.05 | 0.04 |
8.8 | 0.05 | 0.02 |
8.9 | 0.5 | 0.5 |
8.10 | 0.02 | 0.02 |
8.11 | 0.2 | 1 |
8.12 | 0.2 | 0.1 |
8.13 | 0.5 | 0.5 |
8.14 | 0.5 | 0.2 |
实施例号 | VEGFR1(FLT) | VEGFRⅡ(KDR) |
8.15 | 0.2 | 0.2 |
8.16 | 0.2 | 0.3 |
8.17 | 0.05 | |
8.18 | 0.05 |
Claims (15)
1、通式Ⅰ的化合物及其异构体和盐:其中:A代表基团=NR2;W代表氧、硫、两个氢原子或基团=NR8;Z代表基团=NR10或=N-、-N(R10)-(CH2)q-、支链或直链C1-6烷
和/或Ra和/或Rb与Rc和/或Rd形成一个键,或者Rc与Re和/或Rf
形成一个键,或者Ra-Rf中最多有两个可分别闭合最多有3个碳原
子的桥形成R1或R2;X代表基团=NR9或=N-;Y代表基团-(CH2)p;p代表1-4;R1代表未经取代或者任选地在一个或多个位置中被卤素、在一个或多个
位置具有卤素的C1-6烷基取代的C1-6烷基或者是被C1-6烷氧基取
代的芳基或杂芳基,但化合物不包括其中芳基直接键连在A定义中
的=NR2基团上;R2代表氢或C1-6烷基或者与Z中的Ra-Rf形成带有最多3个环原子的
桥或形成R1;R3代表未经取代的或者任选地在一个或多个位置上被卤素、C1-6烷基、
C1-6烷氧基或羟基取代的单环或二环芳基或杂芳基;R4、R5、R6和R7相互独立地是氢、卤素、或是未经取代的或者任选地
在一个或多个位置上被卤素取代的C1-6烷氧基、C1-6烷基或C1-6
2、如权利要求1所述的通式Ⅰ化合物及其异构体和盐,其中:A代表基团=NR2;W代表氧、硫、两个氢原子或基团=NR8;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、支链或直链C1-6
烷基或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、C1-4烷基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-(CH2)p;p代表1-4;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、或6,7-二甲氧基-1,2,3,4-四氢
-2-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧
基、羟基、卤素或三氟甲基取代的苯基或吡啶基,或者代表以下基
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或C1-6烷基或者与Z中的Ra-Rf形成带有最多3个环原子的
桥或形成R1;R3代表未经取代的或者任选地在一个或多个位置上被卤素、C1-6烷基、
C1-6烷氧基或羟基取代的单环或二环芳基或者单环或二环杂芳
基;R4、R5、R6和R7相互独立地是氢、卤素、或者是未经取代的或者任选
地在一个或多个位置上被卤素取代的C1-6烷氧基或C1-6烷基,或
3、如权利要求1或2所述的通式Ⅰ化合物及其异构体和盐,其中:A代表基团=NR2;W代表氧、硫或两个氢原子;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、或6,7-二甲氧基-1,2,3,4-四氢
-2-萘基,或者代表在-个或多个位置上被C1-4烷基、C1-4烷氧
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在-个或多个位置上被羟基、卤素、甲基或甲氧基取
4、如权利要求1-3之一所述的通式Ⅰ化合物及其异构体和盐,其中:A代表基团=NR2;W代表氧;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、或6,7-二甲氧基-1,2,3,4-四氢
-2-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧
基、羟基、卤素或三氟甲基取代的苯基或吡啶基,或者代表以下基
团:
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
5、如权利要求1-3之一所述的通式Ⅰ化合物及其异构体和盐,其中:A代表基团=NR2;W代表硫;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、苯并-1,2,5-恶二唑、或6,7-二甲氧基-1,2,3,4-四氢-2-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧基、羟基、卤素或三氟甲基取代的苯基或吡啶基,或者代表以下基团:
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
6、如权利要求1-3之一所述的通式Ⅰ化合物及其异构体和盐,其中:A代表基团=NR2;W代表两个氢原子;Z代表基团=NR10或=N-、或-N(R10)-(CH2)q-、或以下基团:或者A、Z和R1一起形成以下基团:m、n和o代表0-3;q代表1-6;Ra、Rb、Rc、Rd、Re、Rf相互独立地代表氢、甲基或基团=NR10;X代表基团=NR9或=N-;Y代表基团-CH2-;R1代表苯基、吡啶基、5-氯-2,3-二氢茚基、2,3-二氢茚基、噻
吩基、6-氟-1H-吲哚-3-基、萘基、1,2,3,4-四氢萘基、
苯并-1,2,5-恶二唑、或6,7-二甲氧基-1,2,3,4-四氢
-2-萘基,或者代表在一个或多个位置上被C1-4烷基、C1-4烷氧
其中苯基、取代苯基或萘基不直接连接在A定义中的=NR2基团上;R2代表氢或甲基;R3代表吡啶基或者在一个或多个位置上被羟基、卤素、甲基或甲氧基取
7、如权利要求1-6之一所述的化合物在制备用于治疗以下疾病的药物中的应用:肿瘤、牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病、动脉硬化、神经组织损伤、以及抑制球管治疗后、血管修复或者使血管敞开的机械装置如支架后的血管再闭合。
8、一种药物,其包含至少一种如权利要求1-6之一所述的化合物。
9、如权利要求8所述的化合物,其是用于治疗肿瘤、牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病、动脉硬化、神经组织损伤、以及抑制球管治疗后、血管修复或者使血管敞开的机械装置如支架后的血管再闭合。
10、具有合适配方和载体的如权利要求1-6之一所述的化合物以及如权利要求7-9所述的药物。
11、如权利要求1-6之一所述的通式Ⅰ化合物作为酪氨酸激酶KDR和FLT抑制剂的应用。
12、如权利要求1-6之一所述的通式Ⅰ化合物在肠道、非胃肠道和口服给药的药物制剂方面的应用。
14、通式Ⅴ的中间产物及其异构体和盐,其是制备通式Ⅰ化合物的中间产物,其中:A和W代表氧;Z和R1一起形成连接于X上的=C=O基团;X代表基团=NR9或=N-;Y代表基团-CH2-;R3代表吡啶基或者被羟基、溴、甲基、或甲氧基取代的苯基或1,2,3,
4-四氢萘基;R5和R6代表氢、氯、甲基、甲氧基或三氟甲基;R4和R7代表氢;R9代表氢。
15、如权利要求13或14所述的通式Ⅴ化合物在制备用于治疗以下疾病的药物中的应用:肿瘤、牛皮癣、关节炎如类风湿关节炎、血管瘤、血管纤维瘤、眼病如糖尿病性视网膜病、新血管性青光眼、肾病如肾小球性肾炎、糖尿病性肾病、恶性肾硬化、栓塞性微血管病综合症、移植物排斥反应和肾小球病、纤维变性疾病如肝硬变、肾小球细胞增殖性疾病、动脉硬化、神经组织损伤、以及抑制球管治疗后、血管修复或者使血管敞开的机械装置如支架后的血管再闭合。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GBGB9824579.8A GB9824579D0 (en) | 1998-11-10 | 1998-11-10 | Organic compounds |
GB9824579.8 | 1998-11-10 | ||
DE19910396.8 | 1999-03-03 | ||
DE1999110396 DE19910396C2 (de) | 1999-03-03 | 1999-03-03 | Anthranilsäureamide und deren Verwendung als Arzneimittel |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1325384A true CN1325384A (zh) | 2001-12-05 |
CN1151133C CN1151133C (zh) | 2004-05-26 |
Family
ID=26052266
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB998130788A Expired - Fee Related CN1151133C (zh) | 1998-11-10 | 1999-11-09 | 邻氨基苯甲酰胺及其用于制备药物的应用 |
Country Status (23)
Country | Link |
---|---|
US (1) | US7122547B1 (zh) |
EP (1) | EP1129074A2 (zh) |
JP (1) | JP2002529452A (zh) |
KR (2) | KR100777476B1 (zh) |
CN (1) | CN1151133C (zh) |
AU (1) | AU771180B2 (zh) |
BG (1) | BG65371B1 (zh) |
BR (1) | BR9915553A (zh) |
CA (1) | CA2350208A1 (zh) |
CZ (1) | CZ20011631A3 (zh) |
EA (1) | EA004701B1 (zh) |
EE (1) | EE200100258A (zh) |
HK (1) | HK1041882A1 (zh) |
HR (1) | HRP20010402A2 (zh) |
HU (1) | HUP0104425A3 (zh) |
NO (1) | NO320647B1 (zh) |
NZ (1) | NZ511413A (zh) |
PL (1) | PL348349A1 (zh) |
SK (1) | SK6072001A3 (zh) |
TR (1) | TR200101307T2 (zh) |
UA (1) | UA71587C2 (zh) |
WO (1) | WO2000027819A2 (zh) |
YU (1) | YU31801A (zh) |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603729A (zh) * | 2012-01-12 | 2012-07-25 | 贵州大学 | N-(2-(取代苯并噻唑-2-氨基甲酰基)-取代苯基)吡啶甲酰胺类衍生物 |
CN103130696A (zh) * | 2013-03-21 | 2013-06-05 | 山东大学 | 邻氨基苯甲酰胺类化合物及其制备方法与应用 |
CN103405434A (zh) * | 2013-08-22 | 2013-11-27 | 中国药科大学 | Vegfr-2抑制剂及其用途 |
CN104163794A (zh) * | 2013-10-17 | 2014-11-26 | 中国药科大学 | 2-氨基芳环类血管内皮生长因子受体(vegfr)抑制剂及其制备方法和用途 |
WO2022222890A1 (en) * | 2021-04-19 | 2022-10-27 | Shanghai Yao Yuan Biotechnology Co., Ltd. | Benzothiazole and quinoline derivatives for use in treating kawasaki disease |
Families Citing this family (148)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1140903B1 (en) * | 1998-12-23 | 2004-08-04 | Eli Lilly And Company | Aromatic amides |
DE10023485A1 (de) * | 2000-05-09 | 2001-11-22 | Schering Ag | Anthranylalkyl- und -cycloalkylamide und deren Verwendung als Arzneimittel |
DE10023484A1 (de) | 2000-05-09 | 2001-11-22 | Schering Ag | Anthranylamide und deren Verwendung als Arzneimittel |
DE10023486C1 (de) | 2000-05-09 | 2002-03-14 | Schering Ag | Ortho substituierte Anthranilsäureamide und deren Verwendung als Arzneimittel |
AU8181701A (en) * | 2000-06-21 | 2002-01-02 | Hoffmann La Roche | Benzothiazole derivatives |
JP2004521878A (ja) * | 2000-12-07 | 2004-07-22 | スィーヴィー セラピューティクス インコーポレイテッド | Abca−1を上昇させる化合物 |
US20030134836A1 (en) | 2001-01-12 | 2003-07-17 | Amgen Inc. | Substituted arylamine derivatives and methods of use |
US7102009B2 (en) * | 2001-01-12 | 2006-09-05 | Amgen Inc. | Substituted amine derivatives and methods of use |
US6995162B2 (en) * | 2001-01-12 | 2006-02-07 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
US6878714B2 (en) | 2001-01-12 | 2005-04-12 | Amgen Inc. | Substituted alkylamine derivatives and methods of use |
US7105682B2 (en) | 2001-01-12 | 2006-09-12 | Amgen Inc. | Substituted amine derivatives and methods of use |
US20020147198A1 (en) * | 2001-01-12 | 2002-10-10 | Guoqing Chen | Substituted arylamine derivatives and methods of use |
CN104116738A (zh) | 2001-02-19 | 2014-10-29 | 诺华股份有限公司 | 癌症的治疗 |
US6864255B2 (en) | 2001-04-11 | 2005-03-08 | Amgen Inc. | Substituted triazinyl amide derivatives and methods of use |
JP2004528379A (ja) * | 2001-05-08 | 2004-09-16 | シエーリング アクチエンゲゼルシャフト | Vegfr−2およびvegfr−3インヒビターとしての選択的アントラニルアミドピリジンアミド |
DE10123587B4 (de) * | 2001-05-08 | 2005-04-07 | Schering Ag | Cyanoanthranylamid-Derivate und deren Verwendung als Arzneimittel |
DE10123573B4 (de) * | 2001-05-08 | 2005-06-02 | Schering Ag | N-Oxidanthranylamid-Derivate und deren Verwendung als Arzneimittel |
US7459470B2 (en) | 2001-05-08 | 2008-12-02 | Schering Ag | N-oxide anthranylamide derivatives and their use as medicaments |
WO2003000678A1 (de) * | 2001-05-08 | 2003-01-03 | Schering Aktiengesellschaft | Cyanoanthranylamid-derivate und deren verwendung als arzneimittel |
AU2002342335B2 (en) | 2001-05-16 | 2006-02-02 | Novartis Ag | Combination comprising N-{5-[4-(4-methyl-piperazino-methyl)-benzoylamido]-2-methylphenyl}-4-(3-pyridyl)-2pyrimidine-amine and a chemotherapeutic agent |
US7199147B2 (en) | 2001-06-12 | 2007-04-03 | Dainippon Sumitomo Pharma Co., Ltd. | Rho kinase inhibitors |
TWI315982B (en) | 2001-07-19 | 2009-10-21 | Novartis Ag | Combinations comprising epothilones and pharmaceutical uses thereof |
JP4445262B2 (ja) | 2001-10-09 | 2010-04-07 | アムジェン インコーポレイテッド | 抗炎症剤としてのイミダゾール誘導体 |
GB0126902D0 (en) * | 2001-11-08 | 2002-01-02 | Novartis Ag | Organic compounds |
GB0206215D0 (en) | 2002-03-15 | 2002-05-01 | Novartis Ag | Organic compounds |
EP1944026B1 (en) | 2002-05-16 | 2013-06-26 | Novartis AG | Use of EDG receptor binding agents in cancer |
US7307088B2 (en) | 2002-07-09 | 2007-12-11 | Amgen Inc. | Substituted anthranilic amide derivatives and methods of use |
US7094789B2 (en) | 2002-07-22 | 2006-08-22 | Asahi Kasei Pharma Corporation | 5-substituted isoquinoline derivatives |
US7615565B2 (en) | 2002-07-31 | 2009-11-10 | Bayer Schering Pharma Aktiengesellschaft | VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridines |
DE10235690A1 (de) * | 2002-07-31 | 2004-02-19 | Schering Ag | VEGFR-2 und VEGFR-3 inhibitorische Anthranylamidpyridinamide |
US7338956B2 (en) | 2002-08-07 | 2008-03-04 | Sanofi-Aventis Deutschland Gmbh | Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals |
EP1388341A1 (en) * | 2002-08-07 | 2004-02-11 | Aventis Pharma Deutschland GmbH | Acylamino-substituted heteroaromatic compounds and their use as pharmaceuticals |
DE60329030D1 (de) * | 2002-12-04 | 2009-10-08 | Ore Pharmaceuticals Inc | Melanocortin-rezeptormodulatoren |
US7696225B2 (en) | 2003-01-06 | 2010-04-13 | Osi Pharmaceuticals, Inc. | (2-carboxamido)(3-Amino) thiophene compounds |
TWI299664B (en) | 2003-01-06 | 2008-08-11 | Osi Pharm Inc | (2-carboxamido)(3-amino)thiophene compounds |
US7087761B2 (en) | 2003-01-07 | 2006-08-08 | Hoffmann-La Roche Inc. | Cyclization process for substituted benzothiazole derivatives |
US20040192728A1 (en) * | 2003-02-03 | 2004-09-30 | Ellen Codd | Quinoline-derived amide modulators of vanilloid VR1 receptor |
EP1606289B1 (en) | 2003-02-14 | 2009-12-02 | Glaxo Group Limited | Carboxamide derivatives |
US7534802B2 (en) | 2003-03-07 | 2009-05-19 | Santen Pharmaceutical Co., Ltd. | Compounds having 4-pyridylalkylthio group as substituent |
AR044402A1 (es) | 2003-05-19 | 2005-09-14 | Irm Llc | Compuestos heterociclicos y su uso como inmunodepresores. composiciones farmaceuticas que los contienen. |
MY150088A (en) | 2003-05-19 | 2013-11-29 | Irm Llc | Immunosuppressant compounds and compositions |
US20050004133A1 (en) * | 2003-06-05 | 2005-01-06 | Makings Lewis R. | Modulators of VR1 receptor |
US7202260B2 (en) * | 2003-06-13 | 2007-04-10 | Schering Ag | VEGFR-2 and VEGFR-3 inhibitory anthranilamide pyridones |
DE10327719A1 (de) * | 2003-06-13 | 2005-01-20 | Schering Ag | VEGFR-2 und VEGFR-3 Inhibitorische Anthranylamidpyridone |
US8309562B2 (en) | 2003-07-03 | 2012-11-13 | Myrexis, Inc. | Compounds and therapeutical use thereof |
WO2006074147A2 (en) | 2005-01-03 | 2006-07-13 | Myriad Genetics, Inc. | Nitrogen containing bicyclic compounds and therapeutical use thereof |
ES2380201T3 (es) * | 2003-07-11 | 2012-05-09 | Merck Patent Gmbh | Derivados de benzimidazol |
GB0326601D0 (en) * | 2003-11-14 | 2003-12-17 | Novartis Ag | Organic compounds |
UA89035C2 (ru) | 2003-12-03 | 2009-12-25 | Лео Фарма А/С | Эфиры гидроксамовых кислот и их фармацевтическое применение |
KR101179840B1 (ko) | 2004-02-17 | 2012-09-04 | 산텐 세이야꾸 가부시키가이샤 | 치환 또는 무치환 아미노기를 도입한 4-피리딜알킬티오기를갖는 신규 고리형 화합물 |
DE102004009238A1 (de) * | 2004-02-26 | 2005-09-08 | Merck Patent Gmbh | Arylamid-Derivate |
EP1568368A1 (en) * | 2004-02-26 | 2005-08-31 | Schering Aktiengesellschaft | Pharmaceutical combination comprising a CDK inhibitor and a VEGF receptor inhibitor |
WO2005085188A2 (en) * | 2004-03-02 | 2005-09-15 | Compass Pharmaceuticals Llc | Compounds and methods for anti-tumor therapy |
US7427390B2 (en) * | 2004-03-10 | 2008-09-23 | Schering Ag | Radiohalogenated benzamide derivatives and their use in tumor diagnosis and tumor therapy |
DE102004011720B4 (de) * | 2004-03-10 | 2008-04-03 | Bayer Schering Pharma Aktiengesellschaft | Radiohalogenierte Benzamidderivate und deren Verwendung in der Tumordiagnostik und Tumortherapie |
EA011279B1 (ru) | 2004-05-24 | 2009-02-27 | Ф. Хоффманн-Ля Рош Аг | (4-метокси-7-морфолин-4-илбензотиазол-2-ил)-амид 4-гидрокси-4-метилпиперидин-1-карбоновой кислоты |
DE102004039876A1 (de) * | 2004-06-23 | 2006-01-26 | Lanxess Deutschland Gmbh | Herstellung von fluorierten 1,3-Benzodioxanen |
GB0512324D0 (en) | 2005-06-16 | 2005-07-27 | Novartis Ag | Organic compounds |
BRPI0515594B8 (pt) | 2004-09-22 | 2021-05-25 | Janssen Pharmaceutica Nv | compostos inibidores da interação entre mdm2 e p53,composição farmacêutica, processo para a preparação desta composição farmacêutica, usos dos compostos, suas combinações e processo para a preparação destes compostos |
US7906533B2 (en) * | 2004-11-03 | 2011-03-15 | Bayer Schering Pharma Ag | Nicotinamide pyridinureas as vascular endothelial growth factor (VEGF) receptor kinase inhibitors |
EP1655297A1 (en) * | 2004-11-03 | 2006-05-10 | Schering Aktiengesellschaft | 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 |
EP1812392B1 (en) | 2004-11-05 | 2008-07-09 | F.Hoffmann-La Roche Ag | Process for preparation of isonicotinic acid derivatives |
US8258145B2 (en) | 2005-01-03 | 2012-09-04 | Myrexis, Inc. | Method of treating brain cancer |
WO2006093253A1 (ja) * | 2005-03-03 | 2006-09-08 | Santen Pharmaceutical Co., Ltd. | キノリルアルキルチオ基を有する新規環式化合物 |
BRPI0609719B8 (pt) | 2005-03-23 | 2021-05-25 | Hoffmann La Roche | derivados de acetilenil-pirazol-pirimidina como antagonistas de mgbur2 |
WO2006106914A1 (ja) | 2005-03-31 | 2006-10-12 | Santen Pharmaceutical Co., Ltd. | ピリミジニルアルキルチオ基を有する新規環式化合物 |
GB0510390D0 (en) | 2005-05-20 | 2005-06-29 | Novartis Ag | Organic compounds |
CN101273040B (zh) | 2005-09-27 | 2011-11-09 | 弗·哈夫曼-拉罗切有限公司 | 作为mglur2拮抗剂的*二唑基吡唑并嘧啶类化合物 |
RU2008116314A (ru) | 2005-09-27 | 2009-11-10 | Новартис АГ (CH) | Соединения карбоксамина и их применение для лечения hdac-зависимых заболеваний |
US8247556B2 (en) * | 2005-10-21 | 2012-08-21 | Amgen Inc. | Method for preparing 6-substituted-7-aza-indoles |
CA2933875C (en) | 2005-11-21 | 2018-06-26 | Novartis Ag | 40-o-(2-hydroxyethyl)-rapamycin for use as a sole drug substance in the treatment of carcinoid tumors arising from the foregut, midgut, or hindgut |
JP5169220B2 (ja) * | 2005-11-30 | 2013-03-27 | アステラス製薬株式会社 | 2−アミノベンズアミド誘導体 |
CA2644649C (en) | 2006-03-22 | 2014-06-17 | Janssen Pharmaceutica N.V. | Cyclic-alkylaminederivatives as inhibitors of the interaction between mdm2 and p53 |
CA2644643C (en) | 2006-03-22 | 2015-05-19 | Janssen Pharmaceutica N.V. | Inhibitors of the interaction between mdm2 and p53 |
KR20140019032A (ko) | 2006-04-05 | 2014-02-13 | 노파르티스 아게 | 암을 치료하기 위한 치료제의 조합물 |
KR20090007635A (ko) | 2006-05-09 | 2009-01-19 | 노파르티스 아게 | 철 킬레이터 및 항-신생물 약제를 포함하는 조합물 및 그의용도 |
GB0612721D0 (en) | 2006-06-27 | 2006-08-09 | Novartis Ag | Organic compounds |
ATE502943T1 (de) | 2006-09-29 | 2011-04-15 | Novartis Ag | Pyrazolopyrimidine als pi3k-lipidkinasehemmer |
WO2008077809A1 (en) * | 2006-12-22 | 2008-07-03 | F. Hoffmann-La Roche Ag | Process for the manufacture of 7-oxa-bicyclo derivatives |
JP5216341B2 (ja) | 2007-01-29 | 2013-06-19 | 参天製薬株式会社 | 血管新生阻害活性を有する新規オキサジアゾール誘導体およびチアジアゾール誘導体 |
US20100069458A1 (en) | 2007-02-15 | 2010-03-18 | Peter Wisdom Atadja | Combination of lbh589 with other therapeutic agents for treating cancer |
EP1975166A1 (en) * | 2007-03-30 | 2008-10-01 | Bayer Schering Pharma AG | Synthesis of anthranilamides |
TW200922557A (en) | 2007-08-06 | 2009-06-01 | Janssen Pharmaceutica Nv | Substituted phenylenediamines as inhibitors of the interaction between MDM2 and p53 |
KR101252349B1 (ko) | 2008-03-26 | 2013-04-08 | 노파르티스 아게 | 데아세틸라제 b의 히드록사메이트-기재 억제제 |
CA2734551A1 (en) | 2008-08-27 | 2010-03-04 | Leo Pharma A/S | Pyridine derivatives as vegfr-2 receptor and protein tyrosine kinase inhibitors |
EP2344161B1 (en) | 2008-10-16 | 2018-12-19 | Celator Pharmaceuticals, Inc. | Combinations of a liposomal water-soluble camptothecin with cetuximab or bevacizumab |
MY152669A (en) | 2008-12-18 | 2014-10-31 | Novartis Ag | Hemifumarate salt of 1-[4-[1-(4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl]-azetidine-3-carboxylic acid |
US8173634B2 (en) | 2008-12-18 | 2012-05-08 | Novartis Ag | Polymorphic form of 1-(4-{1-[(E)-4-cyclohexyl-3-trifluoromethyl-benzyloxyimino]-ethyl}-2-ethyl-benzyl)-azetidine-3-carboxylic |
BRPI0922466A2 (pt) | 2008-12-18 | 2018-10-23 | Novartis Ag | sais |
TW201031406A (en) | 2009-01-29 | 2010-09-01 | Novartis Ag | Substituted benzimidazoles for the treatment of astrocytomas |
NZ594186A (en) | 2009-02-04 | 2012-12-21 | Janssen Pharmaceutica Nv | Indole derivatives as anticancer agents |
SG176105A1 (en) | 2009-06-26 | 2011-12-29 | Novartis Ag | 1, 3-disubstituted imidazolidin-2-one derivatives as inhibitors of cyp 17 |
US8389526B2 (en) | 2009-08-07 | 2013-03-05 | Novartis Ag | 3-heteroarylmethyl-imidazo[1,2-b]pyridazin-6-yl derivatives |
AU2010283806A1 (en) | 2009-08-12 | 2012-03-01 | Novartis Ag | Heterocyclic hydrazone compounds and their uses to treat cancer and inflammation |
CA2771532C (en) | 2009-08-17 | 2021-03-23 | Intellikine, Inc. | Heterocyclic compounds and uses thereof |
AU2010284972A1 (en) | 2009-08-20 | 2012-03-08 | Novartis Ag | Heterocyclic oxime compounds |
IN2012DN01693A (zh) | 2009-08-26 | 2015-06-05 | Novartis Ag | |
CA2773661A1 (en) | 2009-09-10 | 2011-03-17 | Novartis Ag | Ether derivatives of bicyclic heteroaryls |
KR101398772B1 (ko) | 2009-11-04 | 2014-05-27 | 노파르티스 아게 | Mek 억제제로서 유용한 헤테로시클릭 술폰아미드 유도체 |
JP2013512215A (ja) | 2009-11-25 | 2013-04-11 | ノバルティス アーゲー | 二環式ヘテロアリールのベンゼン縮合6員酸素含有ヘテロ環誘導体 |
EA201200823A1 (ru) | 2009-12-08 | 2013-02-28 | Новартис Аг | Гетероциклические производные сульфонамидов |
US8440693B2 (en) | 2009-12-22 | 2013-05-14 | Novartis Ag | Substituted isoquinolinones and quinazolinones |
CU24130B1 (es) | 2009-12-22 | 2015-09-29 | Novartis Ag | Isoquinolinonas y quinazolinonas sustituidas |
US20130090342A1 (en) | 2010-06-17 | 2013-04-11 | Novartis Ag | Biphenyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives |
US20130085161A1 (en) | 2010-06-17 | 2013-04-04 | Novartis Ag | Piperidinyl substituted 1,3-dihydro-benzoimidazol-2-ylideneamine derivatives |
US20130102477A1 (en) | 2010-06-23 | 2013-04-25 | Ryan D. Morin | Biomarkers for non-hodgkin lymphomas and uses thereof |
US9175331B2 (en) | 2010-09-10 | 2015-11-03 | Epizyme, Inc. | Inhibitors of human EZH2, and methods of use thereof |
CA2810998C (en) | 2010-09-10 | 2024-04-09 | Robert Allen Copeland | Inhibitors of human ezh2, and methods of use thereof |
CN103108871B (zh) | 2010-09-16 | 2014-09-10 | 诺华股份有限公司 | 17α-羟化酶/C17,20-裂合酶抑制剂 |
US20130324526A1 (en) | 2011-02-10 | 2013-12-05 | Novartis Ag | [1,2,4] triazolo [4,3-b] pyridazine compounds as inhibitors of the c-met tyrosine kinase |
WO2012116237A2 (en) | 2011-02-23 | 2012-08-30 | Intellikine, Llc | Heterocyclic compounds and uses thereof |
EP2681216B1 (en) | 2011-02-28 | 2017-09-27 | Epizyme, Inc. | Substituted 6,5-fused bicyclic heteroaryl compounds |
EP2683722A1 (en) | 2011-03-08 | 2014-01-15 | Novartis AG | Fluorophenyl bicyclic heteroaryl compounds |
TWI598336B (zh) | 2011-04-13 | 2017-09-11 | 雅酶股份有限公司 | 經取代之苯化合物 |
JO3438B1 (ar) | 2011-04-13 | 2019-10-20 | Epizyme Inc | مركبات بنزين مستبدلة بأريل أو أريل غير متجانس |
MX359399B (es) | 2011-04-28 | 2018-09-27 | Novartis Ag | Inhibidores de 17alfa-hidroxilasa/c17-20-liasa. |
KR20140034898A (ko) | 2011-06-09 | 2014-03-20 | 노파르티스 아게 | 헤테로시클릭 술폰아미드 유도체 |
US8859535B2 (en) | 2011-06-20 | 2014-10-14 | Novartis Ag | Hydroxy substituted isoquinolinone derivatives |
WO2012175487A1 (en) | 2011-06-20 | 2012-12-27 | Novartis Ag | Cyclohexyl isoquinolinone compounds |
ES2691650T3 (es) | 2011-09-15 | 2018-11-28 | Novartis Ag | 3-(quinolin-6-il-tio)-[1,2,4]-triazolo-[4,3-a]-piridinas 6-sustituidas como inhibidores de tirosina quinasa c-Met |
WO2013080141A1 (en) | 2011-11-29 | 2013-06-06 | Novartis Ag | Pyrazolopyrrolidine compounds |
EA201491259A1 (ru) | 2011-12-23 | 2014-11-28 | Новартис Аг | Соединения и композиции для ингибирования взаимодействия bcl2 с партнерами связывания |
EA201491260A1 (ru) | 2011-12-23 | 2014-11-28 | Новартис Аг | Соединения и композиции для ингибирования взаимодействия bcl2 с партнерами по связыванию |
CA2859862A1 (en) | 2011-12-23 | 2013-06-27 | Novartis Ag | Compounds for inhibiting the interaction of bcl2 with binding partners |
CN104136429A (zh) | 2011-12-23 | 2014-11-05 | 诺华股份有限公司 | 用于抑制bcl2与结合配偶体相互作用的化合物 |
AU2012355623A1 (en) | 2011-12-23 | 2014-07-17 | Novartis Ag | Compounds for inhibiting the interaction of BCL2 with binding partners |
US8815926B2 (en) | 2012-01-26 | 2014-08-26 | Novartis Ag | Substituted pyrrolo[3,4-D]imidazoles for the treatment of MDM2/4 mediated diseases |
WO2013138753A1 (en) | 2012-03-16 | 2013-09-19 | Fox Chase Chemical Diversity Center, Inc. | Prodrugs of riluzole and their method of use |
US20150297604A1 (en) | 2012-04-03 | 2015-10-22 | Novartis Ag | Combination Products with Tyrosine Kinase Inhibitors and their Use |
MX362339B (es) | 2012-04-13 | 2019-01-11 | Epizyme Inc | Forma de sal de un inhibidor de histona metiltransferasa humana ezh2. |
CN104321325B (zh) | 2012-05-24 | 2016-11-16 | 诺华股份有限公司 | 吡咯并吡咯烷酮化合物 |
BR112015008480A2 (pt) | 2012-10-15 | 2017-07-04 | Epizyme Inc | compostos de benzeno substituído |
WO2014115077A1 (en) | 2013-01-22 | 2014-07-31 | Novartis Ag | Substituted purinone compounds |
US9556180B2 (en) | 2013-01-22 | 2017-01-31 | Novartis Ag | Pyrazolo[3,4-d]pyrimidinone compounds as inhibitors of the P53/MDM2 interaction |
JP2016512835A (ja) | 2013-03-15 | 2016-05-09 | インテリカイン, エルエルシー | キナーゼ阻害剤の組み合わせ及びそれらの使用 |
WO2014155268A2 (en) | 2013-03-25 | 2014-10-02 | Novartis Ag | Fgf-r tyrosine kinase activity inhibitors - use in diseases associated with lack of or reduced snf5 activity |
WO2015022664A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
WO2015022663A1 (en) | 2013-08-14 | 2015-02-19 | Novartis Ag | Compounds and compositions as inhibitors of mek |
US9227969B2 (en) | 2013-08-14 | 2016-01-05 | Novartis Ag | Compounds and compositions as inhibitors of MEK |
MX2016004703A (es) | 2013-10-16 | 2017-02-28 | Epizyme Inc | Forma salina de hidrocloruro para la inhibicion de ezh2. |
WO2015084804A1 (en) | 2013-12-03 | 2015-06-11 | Novartis Ag | Combination of mdm2 inhibitor and braf inhibitor and their use |
JP6526789B2 (ja) | 2014-07-31 | 2019-06-05 | ノバルティス アーゲー | 組み合わせ療法 |
US20210128615A1 (en) | 2017-10-18 | 2021-05-06 | Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus | Methods and compounds for improved immune cell therapy |
JP7021356B2 (ja) | 2017-12-21 | 2022-02-16 | ヘフェイ インスティテューツ オブ フィジカル サイエンス, チャイニーズ アカデミー オブ サイエンシーズ | ピリミジン誘導体系キナーゼ阻害剤類 |
EP4058465A1 (en) | 2019-11-14 | 2022-09-21 | Cohbar Inc. | Cxcr4 antagonist peptides |
AU2020417293A1 (en) | 2020-01-03 | 2022-09-01 | Berg Llc | Polycyclic amides as UBE2K modulators for treating cancer |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3226394A (en) * | 1964-06-16 | 1965-12-28 | Shulton Inc | Pyridylethylated anthranilamides and derivatives thereof |
US3409668A (en) | 1964-11-07 | 1968-11-05 | Palazzo Giuseppe | Substituted anthranilamides and process for the preparation thereof |
JPS5744672B2 (zh) | 1974-05-24 | 1982-09-22 | ||
DE2652144A1 (de) | 1976-11-16 | 1978-05-18 | Merck Patent Gmbh | Neue chinazolindione |
US4568687A (en) | 1983-02-28 | 1986-02-04 | American Cyanamid Company | N-[2-4-(1H-Imidazol-1-yl)alkyl]-arylamides and pharmaceutical compositions |
EP0117462A3 (en) | 1983-02-28 | 1986-08-20 | American Cyanamid Company | N-(2-4-(1h-imidazol-1-yl)alkyl)arylamides |
FR2689508B1 (fr) * | 1992-04-01 | 1994-06-17 | Fournier Ind & Sante | Derives de l'imidazole, leur procede de preparation et leur application en therapeutique. |
CN1118595A (zh) * | 1993-12-27 | 1996-03-13 | 卫材株式会社 | 氨茴酸衍生物 |
DE59710417D1 (de) * | 1996-03-15 | 2003-08-14 | Novartis Ag | N-7 HETEROCYCLYL-PYRROLO[ 2,3-d]PYRIMIDINE UND IHRE VERWENDUNG |
-
1999
- 1999-09-11 UA UA2001063917A patent/UA71587C2/uk unknown
- 1999-11-09 PL PL99348349A patent/PL348349A1/xx not_active Application Discontinuation
- 1999-11-09 CA CA002350208A patent/CA2350208A1/en not_active Abandoned
- 1999-11-09 US US09/831,506 patent/US7122547B1/en not_active Expired - Fee Related
- 1999-11-09 WO PCT/EP1999/008478 patent/WO2000027819A2/de not_active Application Discontinuation
- 1999-11-09 KR KR1020017005800A patent/KR100777476B1/ko not_active IP Right Cessation
- 1999-11-09 KR KR1020077015852A patent/KR100855396B1/ko not_active IP Right Cessation
- 1999-11-09 TR TR2001/01307T patent/TR200101307T2/xx unknown
- 1999-11-09 EE EEP200100258A patent/EE200100258A/xx unknown
- 1999-11-09 AU AU10454/00A patent/AU771180B2/en not_active Ceased
- 1999-11-09 CZ CZ20011631A patent/CZ20011631A3/cs unknown
- 1999-11-09 SK SK607-2001A patent/SK6072001A3/sk unknown
- 1999-11-09 BR BR9915553-2A patent/BR9915553A/pt not_active Application Discontinuation
- 1999-11-09 NZ NZ511413A patent/NZ511413A/en unknown
- 1999-11-09 YU YU31801A patent/YU31801A/sh unknown
- 1999-11-09 EA EA200100524A patent/EA004701B1/ru not_active IP Right Cessation
- 1999-11-09 EP EP99953967A patent/EP1129074A2/de not_active Withdrawn
- 1999-11-09 HU HU0104425A patent/HUP0104425A3/hu unknown
- 1999-11-09 CN CNB998130788A patent/CN1151133C/zh not_active Expired - Fee Related
- 1999-11-09 JP JP2000580999A patent/JP2002529452A/ja not_active Withdrawn
-
2001
- 2001-05-07 NO NO20012245A patent/NO320647B1/no unknown
- 2001-05-25 HR HR20010402A patent/HRP20010402A2/hr not_active Application Discontinuation
- 2001-06-11 BG BG105588A patent/BG65371B1/bg unknown
-
2002
- 2002-05-14 HK HK02103628A patent/HK1041882A1/xx not_active IP Right Cessation
Cited By (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102603729A (zh) * | 2012-01-12 | 2012-07-25 | 贵州大学 | N-(2-(取代苯并噻唑-2-氨基甲酰基)-取代苯基)吡啶甲酰胺类衍生物 |
CN103130696A (zh) * | 2013-03-21 | 2013-06-05 | 山东大学 | 邻氨基苯甲酰胺类化合物及其制备方法与应用 |
CN103130696B (zh) * | 2013-03-21 | 2014-06-11 | 山东大学 | 邻氨基苯甲酰胺类化合物及其制备方法与应用 |
CN103405434A (zh) * | 2013-08-22 | 2013-11-27 | 中国药科大学 | Vegfr-2抑制剂及其用途 |
CN104163794A (zh) * | 2013-10-17 | 2014-11-26 | 中国药科大学 | 2-氨基芳环类血管内皮生长因子受体(vegfr)抑制剂及其制备方法和用途 |
WO2022222890A1 (en) * | 2021-04-19 | 2022-10-27 | Shanghai Yao Yuan Biotechnology Co., Ltd. | Benzothiazole and quinoline derivatives for use in treating kawasaki disease |
Also Published As
Publication number | Publication date |
---|---|
BG105588A (en) | 2002-04-30 |
WO2000027819A3 (de) | 2000-08-17 |
HRP20010402A2 (en) | 2003-10-31 |
YU31801A (sh) | 2003-12-31 |
AU1045400A (en) | 2000-05-29 |
NZ511413A (en) | 2004-01-30 |
UA71587C2 (uk) | 2004-12-15 |
KR20070087027A (ko) | 2007-08-27 |
NO20012245D0 (no) | 2001-05-07 |
KR20010075689A (ko) | 2001-08-09 |
TR200101307T2 (tr) | 2002-05-21 |
JP2002529452A (ja) | 2002-09-10 |
HK1041882A1 (en) | 2002-07-26 |
EA200100524A1 (ru) | 2002-02-28 |
US7122547B1 (en) | 2006-10-17 |
BR9915553A (pt) | 2001-08-14 |
EA004701B1 (ru) | 2004-06-24 |
AU771180B2 (en) | 2004-03-18 |
CA2350208A1 (en) | 2000-05-18 |
HUP0104425A3 (en) | 2003-05-28 |
NO20012245L (no) | 2001-07-10 |
BG65371B1 (bg) | 2008-04-30 |
PL348349A1 (en) | 2002-05-20 |
EE200100258A (et) | 2002-12-16 |
CN1151133C (zh) | 2004-05-26 |
KR100855396B1 (ko) | 2008-08-29 |
SK6072001A3 (en) | 2002-01-07 |
EP1129074A2 (de) | 2001-09-05 |
CZ20011631A3 (cs) | 2001-10-17 |
WO2000027819A2 (de) | 2000-05-18 |
HUP0104425A2 (hu) | 2002-03-28 |
KR100777476B1 (ko) | 2007-11-16 |
NO320647B1 (no) | 2006-01-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1325384A (zh) | 邻氨基苯甲酰胺及其作为药物的应用 | |
CN1285578C (zh) | 取代苯甲酸酰胺及其在抑制血管生成中的应用 | |
CN1237062C (zh) | 邻取代的邻氨基苯甲酸酰胺及其作为药物的应用 | |
CN1429200A (zh) | 邻氨基苯甲酸酰胺及其作为药物的应用 | |
KR101692705B1 (ko) | 암 및 면역 질환의 치료를 위한 Bcl2선택적 아폽토시스-유도제로서의 설폰아미드 유도체 | |
JP5484568B2 (ja) | プロテインキナーゼおよびヒストンデアセチラーゼの阻害剤としてのナフタレンカルボキサミド誘導体、その製造方法および用途 | |
CN1281590C (zh) | 具有抑制血管生成活性的六员氨基酰胺类衍生物 | |
CN1237177A (zh) | 稠合的二环嘧啶衍生物 | |
CN1211252A (zh) | 用作拓扑异构酶抑制剂的甲氧檗因类似物 | |
Chessari et al. | Structure-based design of potent and orally active isoindolinone inhibitors of MDM2-p53 protein–protein interaction | |
US6818661B2 (en) | Anthranylalkyl and cycloalkyl amides and use thereof as VEGF receptor inhibitors | |
CN1839130A (zh) | N-取代的吡唑基-酰胺基-苯并咪唑基的c-kit抑制剂 | |
CN1133634C (zh) | 抑制因子Xa的杂环衍生物 | |
CN1169149A (zh) | 止痛组合物 | |
CN1300113C (zh) | 邻氨基苯甲酰胺和其作为vegf受体酪氨酸激酶抑制剂的用途 | |
JP4343681B2 (ja) | シアノアントラニルアミド誘導体およびそれらの薬剤としての使用 | |
CN101056870A (zh) | 作为血管内皮生长因子(vegf)受体激酶抑制剂的新的烟酰胺吡啶脲 | |
CN1013864B (zh) | 抗精神病的γ-咔啉的制备方法 | |
CN1541219A (zh) | 三环咪唑并吡啶 | |
CN1147485C (zh) | 用作5-ht-2c受体拮抗剂的二氢吲哚衍生物 | |
CN1313766A (zh) | 新的切割dna的抗肿瘤剂 | |
CN1044241C (zh) | 氧代吡啶基喹喔啉衍生物及含有它们的药物组合物 | |
CN1824665A (zh) | 芳杂环基咪唑并萘酰亚胺类化合物及其应用 | |
CN1046726C (zh) | 咪唑并吡啶-吡咯烷酮、其制法和药用 | |
KR101789934B1 (ko) | 상피세포성장인자수용체 변이체를 가진 종양 진단 및 종양 성장 억제 활성을 갖는 신규 화합물 및 이를 포함하는 의학적 용도 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C19 | Lapse of patent right due to non-payment of the annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |