CN103130696B - Anthranilamide compound as well as preparation method and application thereof - Google Patents
Anthranilamide compound as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN103130696B CN103130696B CN201310092606.8A CN201310092606A CN103130696B CN 103130696 B CN103130696 B CN 103130696B CN 201310092606 A CN201310092606 A CN 201310092606A CN 103130696 B CN103130696 B CN 103130696B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- aminobenzamide
- substituted
- nitrobenzamide
- compound
- 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.)
- Active
Links
- -1 Anthranilamide compound Chemical class 0.000 title claims abstract description 43
- PXBFMLJZNCDSMP-UHFFFAOYSA-N ortho-aminobenzoylamine Natural products NC(=O)C1=CC=CC=C1N PXBFMLJZNCDSMP-UHFFFAOYSA-N 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 86
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 57
- 239000007787 solid Substances 0.000 claims description 35
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 22
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- 239000003480 eluent Substances 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 238000007445 Chromatographic isolation Methods 0.000 claims description 13
- 238000011097 chromatography purification Methods 0.000 claims description 13
- 238000005406 washing Methods 0.000 claims description 13
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- RHCJFZKQYODIDI-UHFFFAOYSA-N 2-amino-n-(4-chlorophenyl)benzamide Chemical compound NC1=CC=CC=C1C(=O)NC1=CC=C(Cl)C=C1 RHCJFZKQYODIDI-UHFFFAOYSA-N 0.000 claims description 11
- IXZFMVFTKAQKNE-UHFFFAOYSA-N 2-amino-n-(3-bromophenyl)benzamide Chemical compound NC1=CC=CC=C1C(=O)NC1=CC=CC(Br)=C1 IXZFMVFTKAQKNE-UHFFFAOYSA-N 0.000 claims description 10
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N N-phenyl amine Natural products NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims description 10
- 150000001448 anilines Chemical class 0.000 claims description 10
- 239000012074 organic phase Substances 0.000 claims description 9
- 238000001035 drying Methods 0.000 claims description 8
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 7
- 229960000583 acetic acid Drugs 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 239000012362 glacial acetic acid Substances 0.000 claims description 7
- CVDGBBCJEMBUAZ-UHFFFAOYSA-N 2-amino-n-(4-fluorophenyl)benzamide Chemical group NC1=CC=CC=C1C(=O)NC1=CC=C(F)C=C1 CVDGBBCJEMBUAZ-UHFFFAOYSA-N 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- ZWZVWGITAAIFPS-UHFFFAOYSA-N thiophosgene Chemical compound ClC(Cl)=S ZWZVWGITAAIFPS-UHFFFAOYSA-N 0.000 claims description 5
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- LBNSHSUJHXCWON-UHFFFAOYSA-N n-(3-bromophenyl)-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)NC1=CC=CC(Br)=C1 LBNSHSUJHXCWON-UHFFFAOYSA-N 0.000 claims description 4
- XCENMAGLUPDPPI-UHFFFAOYSA-N n-(4-chlorophenyl)-2-nitrobenzamide Chemical compound [O-][N+](=O)C1=CC=CC=C1C(=O)NC1=CC=C(Cl)C=C1 XCENMAGLUPDPPI-UHFFFAOYSA-N 0.000 claims description 4
- JOBMADXPEJVVMY-UHFFFAOYSA-N n-(4-fluorophenyl)-2-nitrobenzamide Chemical group [O-][N+](=O)C1=CC=CC=C1C(=O)NC1=CC=C(F)C=C1 JOBMADXPEJVVMY-UHFFFAOYSA-N 0.000 claims description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 4
- SLAMLWHELXOEJZ-UHFFFAOYSA-N 2-nitrobenzoic acid Chemical compound OC(=O)C1=CC=CC=C1[N+]([O-])=O SLAMLWHELXOEJZ-UHFFFAOYSA-N 0.000 claims description 3
- DHYHYLGCQVVLOQ-UHFFFAOYSA-N 3-bromoaniline Chemical compound NC1=CC=CC(Br)=C1 DHYHYLGCQVVLOQ-UHFFFAOYSA-N 0.000 claims description 3
- QSNSCYSYFYORTR-UHFFFAOYSA-N 4-chloroaniline Chemical compound NC1=CC=C(Cl)C=C1 QSNSCYSYFYORTR-UHFFFAOYSA-N 0.000 claims description 3
- KRZCOLNOCZKSDF-UHFFFAOYSA-N 4-fluoroaniline Chemical group NC1=CC=C(F)C=C1 KRZCOLNOCZKSDF-UHFFFAOYSA-N 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
- 229940041181 antineoplastic drug Drugs 0.000 claims description 3
- 239000000460 chlorine Substances 0.000 claims description 3
- 238000004440 column chromatography Methods 0.000 claims description 3
- 239000012065 filter cake Substances 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 238000007789 sealing Methods 0.000 claims description 3
- 238000010792 warming Methods 0.000 claims description 3
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 2
- 229910052794 bromium Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000006837 decompression Effects 0.000 claims description 2
- 229910052731 fluorine Inorganic materials 0.000 claims description 2
- 239000011737 fluorine Substances 0.000 claims description 2
- 229910052742 iron Inorganic materials 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 claims description 2
- 230000000118 anti-neoplastic effect Effects 0.000 claims 1
- 239000003937 drug carrier Substances 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 235000002639 sodium chloride Nutrition 0.000 claims 1
- 239000003981 vehicle Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 3
- 230000000259 anti-tumor effect Effects 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract description 2
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 47
- 238000005481 NMR spectroscopy Methods 0.000 description 27
- 239000000243 solution Substances 0.000 description 17
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 9
- 229960003966 nicotinamide Drugs 0.000 description 9
- 235000005152 nicotinamide Nutrition 0.000 description 9
- 239000011570 nicotinamide Substances 0.000 description 9
- BLAFVGLBBOPRLP-UHFFFAOYSA-N 2-(pyridin-4-ylmethylamino)-n-[3-(trifluoromethyl)phenyl]benzamide Chemical compound FC(F)(F)C1=CC=CC(NC(=O)C=2C(=CC=CC=2)NCC=2C=CN=CC=2)=C1 BLAFVGLBBOPRLP-UHFFFAOYSA-N 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- VFQXVTODMYMSMJ-UHFFFAOYSA-N isonicotinamide Chemical compound NC(=O)C1=CC=NC=C1 VFQXVTODMYMSMJ-UHFFFAOYSA-N 0.000 description 7
- 230000012010 growth Effects 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VUDZSIYXZUYWSC-DBRKOABJSA-N (4r)-1-[(2r,4r,5r)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]-4-hydroxy-1,3-diazinan-2-one Chemical compound FC1(F)[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)N[C@H](O)CC1 VUDZSIYXZUYWSC-DBRKOABJSA-N 0.000 description 4
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- MSYBLBLAMDYKKZ-UHFFFAOYSA-N hydron;pyridine-3-carbonyl chloride;chloride Chemical compound Cl.ClC(=O)C1=CC=CN=C1 MSYBLBLAMDYKKZ-UHFFFAOYSA-N 0.000 description 4
- QKFJKGMPGYROCL-UHFFFAOYSA-N phenyl isothiocyanate Chemical compound S=C=NC1=CC=CC=C1 QKFJKGMPGYROCL-UHFFFAOYSA-N 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 3
- IHFRMUGEILMHNU-UHFFFAOYSA-N 2-hydroxy-5-nitrobenzaldehyde Chemical compound OC1=CC=C([N+]([O-])=O)C=C1C=O IHFRMUGEILMHNU-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 3
- 108091008605 VEGF receptors Proteins 0.000 description 3
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 150000002611 lead compounds Chemical class 0.000 description 3
- NNDNVJSONPCUHC-UHFFFAOYSA-N n-(3-hydroxyphenyl)-2-nitrobenzamide Chemical compound OC1=CC=CC(NC(=O)C=2C(=CC=CC=2)[N+]([O-])=O)=C1 NNDNVJSONPCUHC-UHFFFAOYSA-N 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- BEOOHQFXGBMRKU-UHFFFAOYSA-N sodium cyanoborohydride Chemical compound [Na+].[B-]C#N BEOOHQFXGBMRKU-UHFFFAOYSA-N 0.000 description 3
- 210000004881 tumor cell Anatomy 0.000 description 3
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- AHJRRCIZGKVLED-UHFFFAOYSA-N 2-amino-n-(3-hydroxyphenyl)benzamide Chemical compound NC1=CC=CC=C1C(=O)NC1=CC=CC(O)=C1 AHJRRCIZGKVLED-UHFFFAOYSA-N 0.000 description 2
- CWLKGDAVCFYWJK-UHFFFAOYSA-N 3-aminophenol Chemical class NC1=CC=CC(O)=C1 CWLKGDAVCFYWJK-UHFFFAOYSA-N 0.000 description 2
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 description 2
- 108091008606 PDGF receptors Proteins 0.000 description 2
- 102000011653 Platelet-Derived Growth Factor Receptors Human genes 0.000 description 2
- 108010053100 Vascular Endothelial Growth Factor Receptor-3 Proteins 0.000 description 2
- 102000009484 Vascular Endothelial Growth Factor Receptors Human genes 0.000 description 2
- 102100033179 Vascular endothelial growth factor receptor 3 Human genes 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 230000010261 cell growth Effects 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- ATBIAJXSKNPHEI-UHFFFAOYSA-N pyridine-3-carbonyl chloride Chemical compound ClC(=O)C1=CC=CN=C1 ATBIAJXSKNPHEI-UHFFFAOYSA-N 0.000 description 2
- 125000004076 pyridyl group Chemical group 0.000 description 2
- 229940124676 vascular endothelial growth factor receptor Drugs 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- BWWHTIHDQBHTHP-UHFFFAOYSA-N 2-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=CC=C1C(Cl)=O BWWHTIHDQBHTHP-UHFFFAOYSA-N 0.000 description 1
- 125000004208 3-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C([H])C(*)=C1[H] 0.000 description 1
- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 206010025652 Malignant melanoma in situ Diseases 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 108010053096 Vascular Endothelial Growth Factor Receptor-1 Proteins 0.000 description 1
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 description 1
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 description 1
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 230000033115 angiogenesis Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229940125773 compound 10 Drugs 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 238000002784 cytotoxicity assay Methods 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000011242 molecular targeted therapy Methods 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 230000005748 tumor development Effects 0.000 description 1
- 230000004614 tumor growth Effects 0.000 description 1
Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to an anthranilamide compound shown in a formula I. The invention further provides a preparation method of the compound and an application of a composition containing the compound in preparation of antitumor medicines.
Description
Technical field
The present invention relates to organic compound and synthesize and medical applications field, relate in particular to anthranilamides and preparation method thereof and pharmaceutical applications.
Background technology
The malignant tumour serious threat mankind's healthy and existence.Along with the further investigation of tumor development mechanism, discovery signals path is brought into play outstanding role in formation of cancer and development, specific effect has been reformed traditional cancer treatment method in the molecular targeted therapy of the required path of growth of tumour cell, the serious toxic side effect that makes patient avoid traditional cellulotoxic chemotherapeutics treatment tumour to bring.In recent years, some occur in order to the medicine of many target spots in Inhibitory signal path, and these many target drugs are blocked several signal paths simultaneously, can in kinds of tumors type, play a role.
AAL993 is the potent vascular endothelial growth factor receptor of highly selective (vascular endothelial growth factor receptor, the VEGFRs) inhibitor of being researched and developed by Novartis of Switzerland.Its action target spot comprises VEGFR-1, VEGFR-2, and VEGFR-3 and platelet derived growth factor receptor (platelet-derived growth factor receptor, PDGFR), have higher selectivity, IC to VEGFR-2 and VEGFR-3
50be respectively 23 ± 6nM, 18 ± 1nM.AAL993 has good physico-chemical property, is easy to permeates cell membranes, can suppress the VEGFR-2 autophosphorylation of VEGF induction, and oral administration biaavailability is high.Melanoma in situ animal model experiment shows, AAL993 can angiogenesis inhibiting, the formation moving of carrying down of the growth of tumor in situ and tumor lympha, and Long-term Oral administration, well-tolerated, without obvious toxic-side effects.Therefore, find the new AAL993 analogue containing anthranilamide and possess good application prospect as antitumor drug.
Summary of the invention
For the deficiencies in the prior art, the invention provides a kind of anthranilamides with anti-tumor activity, the present invention also provides the preparation method of this compound and the purposes in pharmacy.
The present invention is achieved by the following technical solutions:
1, anthranilamides
Anthranilamides of the present invention, structure is as shown in logical formula I:
Wherein, R
1for hydrogen, halogen, cyano group, hydroxyl, trifluoromethyl or amino; X is amino, thioureido, sulfoamido or amide group; R
2for phenyl, substituted-phenyl, substituted benzyl, pyridyl, imidazolyl, substituted imidazole base or picolyl.
Preferably, R
1for fluorine, chlorine, bromine, trifluoromethyl or hydroxyl; X is amino, thioureido, sulfoamido or amide group; R
2for phenyl, cyano group trifluoromethyl di-substituted-phenyl, disubstituted benzyl, methylimidazolyl, pyridyl or picolyl.
Further preferred, anthranilamides of the present invention is one of following:
N-(4-fluorophenyl) 2-(3-(4-cyano group-3-(trifluoromethyl) phenyl) thioureido) benzamide (7a),
N-(4-chloro-phenyl-)-2-(3-(4-cyano group-3-trifluoromethyl) thioureido) benzamide (7b),
N-(3-(trifluoromethyl) phenyl)-2-(3-(4-cyano group-3-(trifluoromethyl) phenyl) thioureido) benzamide (7c),
N-(3-bromophenyl)-2-(3-(4-cyano group-3-(trifluoromethyl) phenyl) thioureido) benzamide (7d),
N-(4-fluorophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8a),
N-(4-chloro-phenyl-)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8b),
N-(3-(trifluoromethyl) phenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8c),
N-(3-bromophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide (8d),
N-(2-((4-chloro-phenyl-) formamyl) phenyl) Isonicotinamide (9a),
N-(2-((3-(trifluoromethyl) phenyl) formamyl) phenyl) Isonicotinamide (9b),
N-(2-((3-bromophenyl) formamyl) phenyl) Isonicotinamide (9c),
N-(2-((4-chloro-phenyl-) formamyl) phenyl) niacinamide (10a),
N-(2-((3-(trifluoromethyl) phenyl) formamyl) phenyl) niacinamide (10b),
N-(2-((3-bromophenyl) formamyl) phenyl) niacinamide (10c),
N-(2-((3-hydroxy phenyl) formamyl) phenyl) niacinamide (10d),
N-(4-chloro-phenyl-)-2-((2-hydroxyl-5-nitrobenzyl) amino) benzamide (11a) or
N-(3-bromophenyl)-2-((2-hydroxyl-5-nitrobenzyl) amino) benzamide (11b).
In bracket after above-mentioned preferred 18 compound titles, be its corresponding code name, for sake of convenience and be concise in expression, the code name in above-mentioned bracket will directly be applied in the following content of this specification sheets.
2, the preparation method of anthranilamides
The preparation method of anthranilamides of the present invention comprises the following steps:
Synthetic route:
Reagent and reaction conditions: (i) thionyl chloride, methylene dichloride, 60 DEG C; (ii) substituted aniline, triethylamine, methylene dichloride; (iii) iron, Glacial acetic acid, ethyl acetate, reflux; (iv) thiophosgene; (v) methylene dichloride, room temperature; (vi) 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE, pyridine, room temperature; (vii) different nicotinoyl chlorine hydrochloride, tetrahydrofuran (THF), room temperature; (viii) nicotinoyl chlorine hydrochloride, tetrahydrofuran (THF), room temperature; (ix) 5-nitrosalicylaldehyde, sodium cyanoborohydride, Glacial acetic acid, methyl alcohol, room temperature.
Concrete steps are as follows:
(i) raw material o-Carboxynitrobenzene is joined in methylene dichloride, under room temperature, fully stir, treat that solid dissolves completely, slowly drip thionyl chloride, drip and finish, be slowly warming up to 60 DEG C, reaction 3-5h, remove solvent and excessive thionyl chloride under reduced pressure and obtain intermediate ortho-nitrophenyl formyl chloride 2, sealed membrane sealing saves backup;
(ii) substituted aniline and triethylamine are dissolved in to methylene dichloride, are placed under condition of ice bath, treat that temperature is down to 0 DEG C, the ortho-nitrophenyl formyl chloride 2 that upper step is made is dissolved in methylene dichloride, is slowly added drop-wise in above-mentioned substituted aniline solution, drips complete room temperature reaction 2h; Question response is complete, filters, and filtrate decompression is steamed and desolventized, and column chromatographic isolation and purification obtains intermediate N substituted-phenyl-2-nitrobenzamide 3, and eluent system is volume ratio sherwood oil: ethyl acetate=8:1;
(iii) the N-substituted-phenyl-2-nitrobenzamide and the reduced iron powder mol ratio 1:10 that upper step are made join in the mixing solutions of Glacial acetic acid and ethyl acetate, reflux 4 hours, be cooled to after completion of the reaction room temperature, filter, filtrate is with saturated NaCl solution washing, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, column chromatographic isolation and purification obtains intermediate N substituted-phenyl-2-aminobenzamide 4, and eluent system is volume ratio sherwood oil: ethyl acetate=6:1;
(iv) thiophosgene is added to the water at 21 DEG C and fully stirs and form nonhomogeneous system, the gradation of 4-amino-2-4-trifluoromethylbenzonitrile is added to above-mentioned nonhomogeneous system, continue fully to stir 1h; React complete, by reaction solution dichloromethane extraction, merge organic phase, saturated sodium-chloride washing, anhydrous MgSO
4dry, filter, remove solvent under reduced pressure, column chromatography obtains intermediate lsothiocyanates 6, and eluent system is volume ratio sherwood oil: ethyl acetate=6:1;
(v) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in to methylene dichloride, under condition of ice bath, slowly drip the dichloromethane solution of 3-itrile group-4-trifluoromethyl lsothiocyanates 6, drip and finish, stirring at room temperature 7h, separate out white solid, filter, a small amount of washed with dichloromethane of filter cake, obtains target compound 7;
(vi) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in anhydrous pyridine, add wherein 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE hydrochloride, under stirring at room temperature, react 15h, add distilled water, room temperature continues to stir 0.5h, and 2M hydrochloric acid adjust pH is to 5-6, with dichloromethane extraction, merge organic phase, saturated NaCl solution washing, anhydrous MgSO
4dry, filter, remove solvent under reduced pressure, column chromatographic isolation and purification obtains target compound 8, and eluent system is volume ratio sherwood oil: ethyl acetate=4:1;
(vii) and (viii) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in anhydrous tetrahydro furan, add wherein triethylamine and different nicotinoyl chlorine hydrochloride or nicotinoyl chlorine hydrochloride, under stirring at room temperature, reaction is spent the night, filter, remove solvent under reduced pressure, the target compound 9 and 10 of column chromatographic isolation and purification;
(ix) N-substituted-phenyl-2-aminobenzamide 4,5-nitrosalicylaldehyde and Glacial acetic acid are added in methyl alcohol, fully stir, under room temperature, react 12h, add in batches sodium cyanoborohydride, room temperature reaction 12-24h; Remove solvent under reduced pressure, methylene dichloride dissolves, saturated sodium bicarbonate washing, and saturated sodium-chloride washing, anhydrous magnesium sulfate drying, column chromatographic isolation and purification obtains target compound 11, and eluent system is volume ratio sherwood oil: ethyl acetate=5:1.
Preferably, above-mentioned steps (ii) in, substituted aniline is 4-fluoroaniline, 4-chloroaniline, 3-5-trifluoromethylaniline, 3-bromaniline, 3-hydroxyanilines.
Preferably, above-mentioned steps (iii) in, N-substituted-phenyl-2-nitrobenzamide is N-(4-fluorophenyl)-2-nitrobenzamide, N-(4-chloro-phenyl-)-2-nitrobenzamide, N-(3-trifluoromethyl)-2-nitrobenzamide, N-(3-bromophenyl)-2-nitrobenzamide, N-(3-hydroxy phenyl)-2-nitrobenzamide.
Preferably, above-mentioned steps is (v) and (vi), N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
Preferably, above-mentioned steps (vii) in, N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
Preferably, above-mentioned steps (viii) in, N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide, N-(3-hydroxy phenyl)-2-aminobenzamide.
Preferably, above-mentioned steps (ix) in, N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide, N-(3-hydroxy phenyl)-2-aminobenzamide.
3, the application of the anthranilamides of general formula I of the present invention
Anthranilamides of the present invention, especially 7a, 7b, 7c, 7d, 11a, 11b, has growth of tumour cell and suppresses active, can be for the preparation of antitumor drug.
Compared with prior art, excellent results of the present invention is: the present invention has synthesized the different compound that is guide based on AAL993 of structure, innovative point is the different fragrant heterocycle of the part of pyridine ring in AAL993 to substitute, obtain having the brand-new compound of structure of inhibition tumor cell growth, wherein compound 7a, 7c, 7d, 11a, 11b has obvious cell growth inhibiting activity to CCL188 HCT-116, simultaneously, compared with lead compound AAL993, compound 7a, 7b, 7c, 7d, 11a, 11b obviously improves (table 1) to the growth inhibitory activity of MDA-MB-231.Growth of tumour cell is suppressed to active evaluation method and adopt conventional MTT cytotoxicity assay method (mtt assay).
Numbering, structural formula and the active testing result of table 1. compound
Activity experiment result shows, anthranilamides of the present invention has obvious cell growth inhibiting activity, compound 7a, 7b, 7c, 7d, 9a, 11a, 11b growth inhibitory activity and the lead compound to HCT116 cell is similar, and compound 7a, 7b, 7c, 7d, 11a, 11b are obviously better than lead compound to the growth inhibitory activity of MDA-MB-231 cell.
Embodiment
Further describe the present invention below in conjunction with embodiment, understand the present invention and advantage and effect in order to more deep, but described embodiment is only for illustrating the present invention instead of restriction the present invention.
Embodiment 1 intermediate 4a-4e's is synthetic
(1) preparation of 2-nitrobenzoyl chloride 2
O-Carboxynitrobenzene (3.76g, 22.5mmol) is added in 35mL methylene dichloride to stirring at room temperature, solid is dissolved completely, add thionyl chloride 5mL, be warming up to 60 DEG C of reaction 4.5h, remove solvent and excessive thionyl chloride under reduced pressure, obtain faint yellow oily matter, sealed membrane sealing saves backup.
(2) preparation of N-substituted-phenyl-2-nitrobenzamide 3
Substituted aniline (22.5mmol), 5.5mL triethylamine are added in 45mL methylene dichloride, and stirring at room temperature mixes.The ortho-nitrophenyl formyl chloride that upper step is made is dissolved in 25mL methylene dichloride, under condition of ice bath, acyl chlorides is slowly added drop-wise in above-mentioned reaction solution, drips and finishes, and stirring at room temperature 2h, removes solvent under reduced pressure after filtration, and column chromatographic isolation and purification, obtains target product.Eluent system is sherwood oil: ethyl acetate (volume ratio)=8:1.
Above-mentioned substituted aniline is 4-fluoroaniline, 4-chloroaniline, 3-5-trifluoromethylaniline, 3-bromaniline, 3-hydroxyanilines.
3a:N-(4-fluorophenyl)-2-nitrobenzamide, white solid, yield 89.7%, mp:167～171 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.04(s,1H),8.16(dd,J=8.4,1.2Hz,1H),7.88(td,J=7.8,1.2Hz,1H),7.78(dd,J=7.8,1.2Hz,1H),7.77(td,J=8.4,1.2Hz,1H),7.21,7.68(A′ABB′,JAB=9.0Hz,4H)。MS(calcd/found)[M+H]
+:261.06/261.2。
3b:N-(4-chloro-phenyl-)-2-nitrobenzamide, white solid, yield 73.9%, mp:185～187 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.81(s,1H),8.17(dd,J=8.1,1.2Hz,1H),7.88(td,J=8.1,1.2Hz,1H),7.79(dd,J=8.1,1.2Hz,1H),7.77(td,J=8.1,1.2Hz,1H),7.69(dd,J=8.7,2.4Hz,2H),7.44(dd,J=8.7,2.4Hz,2H)。MS(calcd/found)[M+H]
+:277.03/277.3。
3c:N-(3-(trifluoromethyl) phenyl)-2-nitrobenzamide, white solid, yield 75.9%, mp:135～137 DEG C.
1HNMR(600MHz,DMSO-d
6)δ11.02(s,1H),8.19(dd,J=8.4Hz,1.2Hz,1H),8.16(s,1H),7.91(td,J=7.8Hz,1.2Hz,1H),7.85(d,J=8.4Hz,1H),7.82(dd,J=7.8Hz,1.2Hz,1H),7.79(td,J=8.4Hz,1.2Hz,1H),7.62(dd,J=8.4Hz,7.5Hz,1H),7.50(d,J=7.5Hz,1H)。MS(calcd/found)[M+H]
+:311.06/311.3.
3d:N-(3-bromophenyl)-2-nitrobenzamide, white solid, yield 89.5%, mp:168～170 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.85(s,1H),8.17(d,J=7.8Hz,1H),8.01(s,1H),7.89(dd,J=7.8Hz,6.9Hz,1H),7.80(d,J=7.8Hz,1H),7.78(dd,J=7.8Hz,6.9Hz,1H),7.57(d,J=8.4Hz,1H),7.32-7.34(m,2H)。MS(calcd/found)[M+H]
+:320.98/321.2。
3e:N-(3-hydroxy phenyl)-2-nitrobenzamide, white solid, yield 32.9%, mp:177～180 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.53(s,1H),9.49(br?s,1H),8.14(d,J=7.80Hz,1H),7.86(t,J=7.20Hz,1H),7.73-7.76(m,2H),7.26(s,1H),7.26(d,J=1.8Hz,1H),7.12(dd,J=8.40Hz,7.8Hz,1H),7.02(d,J=7.80Hz,1H),6.52(dd,J=7.80Hz,1.80Hz,1H)。MS(calcd/found)[M+H]
+:259.23/259.1。
(3) preparation of N-substituted-phenyl-2-aminobenzamide 4
By N-substituted-phenyl-2-this methane amide of nitro (15mmol), reduced iron powder (10eqv.) joins in reaction flask, and adds successively Glacial acetic acid 30mL, ethyl acetate 80mL, heating reflux reaction 4h.React complete, be cooled to room temperature, filter, filtrate is washed with saturated nacl aqueous solution (35mL × 3), and anhydrous sodium sulfate drying filters, and removes solvent under reduced pressure, and column chromatographic isolation and purification obtains target compound.Eluent system is sherwood oil: ethyl acetate (volume ratio)=6:1.
Above-mentioned N-substituted-phenyl-2-nitrobenzamide is N-(4-fluorophenyl)-2-nitrobenzamide, N-(4-chloro-phenyl-)-2-nitrobenzamide, N-(3-trifluoromethyl)-2-nitrobenzamide, N-(3-bromophenyl)-2-nitrobenzamide, N-(3-hydroxy phenyl)-2-nitrobenzamide.
4a:N-(4-fluorophenyl)-2-aminobenzamide, white solid, yield 87.8%, mp:130～132 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.04(s,1H),7.72(AA′of?A′ABB′,2H),7.61(dd,J=7.8Hz,1.2Hz,1H),7.15-7.21(m,3H),6.75(dd,J=7.8Hz,1.2Hz,1H),6.59(td,J=7.8Hz,1.2Hz,1H),6.32(s,2H)。MS(calcd/found)[M+H]
+:231.09/231.3。
4b:N-(4-chloro-phenyl-)-2-aminobenzamide, white solid, yield 83.7%, mp:148～150 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.11(s,1H),7.75(dd,J=7.8Hz,1.5Hz,2H),7.61(dd,J=8.1Hz,1.2Hz,1H),7.38(dd,J=7.8Hz,1.5Hz,2H),7.21(td,J=8.1Hz,1.2Hz,1H),6.75(dd,J=8.1Hz,0.6Hz,1H),6.59(td,J=8.1Hz,0.6Hz,1H),6.33(s,2H)。MS(calcd/found)[M+H]
+:247.06/247.3。
4c:N-(3-(trifluoromethyl) phenyl)-2-aminobenzamide, white solid, yield 85.5%, mp:136～138 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.28(s,1H),8.21(s,1H),7.97(d,J=7.8Hz,1H),7.65(dd,J=8.1Hz,1.5Hz,1H),7.57(t,J=7.8Hz,1H),7.42(d,J=7.8Hz,1H),7.22(td,J=8.1Hz,1.5Hz,1H),6.77(dd,J=8.1Hz,0.6Hz,1H),6.60(td,J=8.1Hz,0.6Hz,1H),6.38(s,2H)。MS(calcd/found)[M+H]
+:281.08/281.3。
4d:N-(3-bromophenyl)-2-aminobenzamide, white solid, yield 79.4%, mp:137～141 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.12(s,1H),8.06(t,J=1.8Hz,1H),7.68(dt,J=7.8Hz,1.8Hz,1H),7.61(dd,J=8.4Hz,1.2Hz,1H),7.30(t,J=7.8Hz,1H),7.26(dt,J=7.8Hz,1.8Hz,1H),7.21(td,J=8.4Hz,1.2Hz,1H),6.76(dd,J=8.4Hz,1.2Hz,1H),6.59(td,J=8.4Hz,1.2Hz,1H),6.35(s,2H)。MS(calcd/found)[M+H]
+:291.01/291.2。
4e:N-(3-hydroxy phenyl)-2-aminobenzamide, light brown solid, yield 63.1%, mp:128～131 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ9.86(s,1H),9.35(s,1H),7.58(dd,J=7.8Hz,1.5Hz,1H),7.28(d,J=2.4Hz,1H),7.19(td,J=7.8Hz,1.5Hz,1H),7.08-7.09(m,2H),6.74(dd,J=7.8Hz,1.2Hz,1H),6.58(td,J=7.8Hz,1.2Hz,1H),6.47(dt,J=6.6Hz,2.4Hz,1H),6.27(s,2H)。MS(calcd/found)[M+H]
+:229.09/229.2。
Embodiment 2 target compound 7a-7d's is synthetic
(1) intermediate 3-trifluoromethyl-4-itrile group thiocarbanil 6 is synthetic
Thiophosgene (1mL, 13mmol) is added in 22mL water and fully stirs and form nonhomogeneous system at 21 DEG C, gradation in 4-amino-2-4-trifluoromethylbenzonitrile (2.23g, 12mmol) is in 15min is added to above-mentioned nonhomogeneous system, continue fully to stir 1h.React complete, by reaction solution dichloromethane extraction, merge organic phase, saturated sodium-chloride washing, anhydrous MgSO
4dry, filter, remove solvent under reduced pressure, column chromatography obtains intermediate 3-trifluoromethyl-4-itrile group thiocarbanil.Eluent system is sherwood oil: ethyl acetate (volume ratio)=6:1.
3-trifluoromethyl-4-itrile group thiocarbanil, off-white color solid, yield 78%.Mp:38～40℃。
1H?NMR(600MHz,DMSO-d
6)δ7.94(dd,J=8.4Hz,1.8Hz,1H),8.11(d,J=1.8Hz,1H),8.25(d,J=8.4Hz,1H)。
(2) N-substituted-phenyl-2-(3-(4-itrile group-3 trifluoromethyl) thioureido) benzamide 7 synthetic
By N-substituted-phenyl-2-amino-benzamide (4,1mmol) be dissolved in 15mL methylene dichloride, under condition of ice bath, the dichloromethane solution that slowly drips 3-trifluoromethyl-4-itrile group thiocarbanil (1mmol), drips and finishes, stirring at room temperature 7h, separate out white solid, filter, filter cake washed with dichloromethane, obtains white solid.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
7a:N-(4-fluorophenyl)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 78.98%, mp:188～191 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.94(s,1H),10.51(s,1H),10.50(s,1H),8.38(d,J=1.8Hz,1H),8.06(d,J=8.7Hz,1H),8.04(dd,J=8.7Hz,1.8Hz,1H),7.79(d,J=8.1Hz,1H),7.71(dd,J=7.2Hz,1.2Hz,1H),7.56(td,J=8.1Hz,1.2Hz,1H),7.37(dd,J=8.1Hz,7.2Hz,1H),7.17,7.70(AA′BB′,J
AB=J
A′B′=9.0Hz,4H)。HRMS(ESI)m/z?calcd?for?C
22H
15F
4N
4OS[M+H]
+:459.0897found459.0899。
7b:N-(4-chloro-phenyl-)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 76.32%, mp:182～185 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.91(s,1H),10.57(s,1H),10.46(s,1H),8.37(d,J=1.8Hz,1H),8.05(d,J=8.4Hz,1H),8.03(dd,J=8.4Hz,1.8Hz,1H),7.69-7.75(m,4H),7.56(dd,J=8.4Hz,7.5Hz,1H),7.39(d,J=8.4Hz,2H),7.37(t,J=7.5Hz,1H).HRMS(ESI)m/z?calcd?for?C
22H
15F
3ClN
4OS[M+H]
+:475.0602,found475.0602。
7c:N-(3-trifluoromethyl)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 80.14%, mp:178～180 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.89(s,1H),10.75(s,1H),10.47(s,1H),8.36(d,J=1.5Hz,1H),8.17(s,1H),8.03(d,J=8.4Hz,1H),8.01(dd,J=8.4Hz,1.5Hz,1H),7.88(d,J=7.8Hz,1H),7.74(d,J=7.8Hz,1H),7.73(d,J=7.2Hz,1H),7.58(dd,J=7.8Hz,7.2Hz,1H),7.57(t,J=7.8Hz,1H),7.44(d,J=7.2Hz,1H),7.39(dd,J=7.8Hz,7.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C
23H
15F
6N
4OS[M+H]
+:509.0865,found509.0869。
7d:N-(3-bromophenyl)-2-(3-(4-itrile group-3-trifluoromethyl) thioureido) benzamide, white solid, yield 81.90%, mp:191～193 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.91(s,1H),10.57(s,1H),10.46(s,1H),8.37(s,1H),8.05(d,J=8.1Hz,1H),8.03(d,J=8.1Hz,1H),7.74(d,J=7.8Hz,1H),7.69-7.21(m,3H),7.55(dd,J=8.4Hz,7.8Hz,1H),7.35-7.39(m,3H)。HRMS(ESI)m/z?calcd?for?C
22H
15F
3BrN
4OS[M+H]
+:519.0097,found519.0099。
Embodiment 3N-substituted-phenyl-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide 8 synthetic
By N-substituted-phenyl-2-aminobenzamide (4,1mmol) be dissolved in anhydrous pyridine, add wherein the hydrochloride (1mmol) of 1-methyl isophthalic acid H-imidazoles-4-SULPHURYL CHLORIDE, stirring at room temperature reaction 15h, add 5ml distilled water, with methylene dichloride (10mL × 4) extraction, merge organic phase, saturated sodium-chloride washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes, column chromatographic isolation and purification.Eluent system is sherwood oil: ethyl acetate=4:1.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
8a:N-(4-fluorophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 71.3%, mp:171～173 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.67(s,1H),10.50(s,1H),7.90(d,J=1.2Hz,1H),7.80(d,J=6.6Hz,1H),7.70-7.73(m,3H),7.59(d,J=8.1Hz,1H),7.50(dd,J=8.1Hz,6.6Hz,1H),7.18-7.24(m,3H),3.62(s,3H)。HRMS(ESI)m/z?calcd?for?C
17H
16FN
4O
3S[M+H]
+:375.0922,found375.0925。
8b:N-(4-chloro-phenyl-)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 74.2%, mp:178～180 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.58(s,1H),10.57(s,1H),7.90(s,1H),7.80(d,J=7.8Hz,1H),7.75(d,J=8.7Hz,2H),7.70(s,1H),7.59(d,J=8.4Hz,1H),7.50(dd,J=8.4Hz,7.2Hz,1H),7.45(d,J=8.7Hz,2H),7.21(dd,J=7.8Hz,7.2Hz,1H),3.62(s,3H)。HRMS(ESI)m/zcalcd?for?C
17H
16ClN
4O
3S[M+H]
+:391.0626.found375.0621。
8c:N-(3-trifluoromethyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 82.1%, mp:168～170 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.74(s,1H),10.52(s,1H),8.18(s,1H),7.97(d,J=7.8Hz,1H),7.90(s,1H),7.81(d,J=6.9Hz,1H),7.70(s,1H),7.63(dd,J=8.4Hz,7.8Hz,1H),7.59(d,J=7.8Hz,1H),7.50-7.53(m,2H),7.22(dd,J=7.8Hz,6.9Hz,1H),3.62(s,3H).HRMS(ESI)m/z?calcd?for?C
18H
16F
3N
4O
3S[M+H]
+:425.0890,found425.0893。
8d:N-(3-bromophenyl)-2-(1-methyl isophthalic acid H-imidazoles-4-sulfoamido) benzamide, white solid, yield 79.37%, mp:157～160 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ10.58(s,1H),10.51(s,1H),8.03(s,1H),7.90(s,1H),7.79(dd,J=7.5Hz,6.6Hz,1H),7.75(d,J=8.7Hz,1H),7.70(s,1H),7.58(d,J=8.1Hz,1H),7.50(dd,J=8.1Hz,7.8Hz,1H),7.45(d,J=7.5Hz,1H),7.35(d,J=6.6Hz,1H),7.21(dd,J=8.7Hz,7.8Hz,1H),3.62(s,3H)。HRMS(ESI)m/z?calcd?for?C
17H
16BrN
4O
3S[M+H]
+:435.0121,found435.0124。
Embodiment 4N-(2-((4-substituted-phenyl) carbamyl) phenyl) Isonicotinamide 9 synthetic
By N-substituted-phenyl-2-aminobenzamide (4,1mmol) be dissolved in methylene dichloride, add wherein 1mL triethylamine, under condition of ice bath, drip the dichloromethane solution of different nicotinoyl chlorine (1mmol) to above-mentioned reaction solution, stirring at room temperature reaction 2h, add saturated sodium bicarbonate solution extremely without bubble formation, divide and get organic phase, methylene dichloride for water (10mL × 4) extraction, merges organic phase, saturated sodium-chloride washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes, and column chromatographic isolation and purification obtains target compound 9.Eluent system is sherwood oil: ethyl acetate=4:1.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
9a:N-(2-((4-chloro-phenyl-) carbamyl) phenyl) Isonicotinamide, white solid, yield 65.3%, Mp:231-233 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.56(s,1H),10.65(s,1H),8.81(dd,J=4.8Hz,1.8Hz,2H),8.29(dd,J=7.8Hz,1.2Hz,1H),7.90(dd,J=7.8Hz,1.8Hz,1H),7.80(dd,J=4.8Hz,1.8Hz,2H),7.75(d,J=9.0Hz,2H),7.64(td,J=7.8Hz,1.8Hz,1H),7.42(d,J=9.0Hz,2H),7.35(td,J=7.8Hz,1.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C
19H
15Cl?N
3O
2[M+H]
+:352.0847found352.0850。
9b:N-(2-((3-trifluoromethyl) carbamyl) phenyl) Isonicotinamide, white solid, yield 53.5%, Mp:229-231 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.38(s,1H),10.78(s,1H),8.80(dd,J=6.0Hz,1.2Hz,2H),8.20(d,J=7.8Hz,1H),8.11(s,1H),8.00(d,J=8.4Hz,1H),7.89(d,J=7.8Hz,1H),7.80(dd,J=6.0Hz,1.2Hz,2H),7.65(t,J=7.8Hz,1H),7.60(dd,J=8.4Hz,7.8Hz,1H),7.47(d,J=7.8Hz,1H),7.37(t,J=7.8Hz,1H)。HRMS(ESI)m/z?calcd?for?C
20H
15F
3N
3O
2[M+H]
+:386.1111found386.1113。
9c:N-(2-((3-bromophenyl) carbamyl) phenyl) Isonicotinamide, white solid, yield 51.7%, Mp:231-233 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.43(s,1H),10.65(s,1H),8.82(d,J=6.0Hz,2H),8.23(d,J=7.8Hz,1H),8.00(s,1H),7.87(d,J=7.8Hz,1H),7.80(d,J=6.0Hz,2H),7.69(d,J=7.2Hz,1H),7.64(t,J=7.8Hz,1H),7.36(t,J=7.8Hz,1H),7.30-7.33(m,2H)。HRMS(ESI)m/z?calcd?forC
19H
15BrN
3O
2[M+H]
+:396.0342found396.0346。
Embodiment 5N-(2-((4-substituted-phenyl) carbamyl) phenyl) niacinamide 10 synthetic
By N-substituted-phenyl-2-aminobenzamide (4,1mmol) be dissolved in methylene dichloride, add wherein 1mL triethylamine, under condition of ice bath, drip the dichloromethane solution of nicotinoyl chlorine (1mmol) to above-mentioned reaction solution, stirring at room temperature reaction 2h, add saturated sodium bicarbonate solution extremely without bubble formation, divide and get organic phase, methylene dichloride for water (10mL × 4) extraction, merges organic phase, saturated sodium-chloride washing, anhydrous magnesium sulfate drying, filter, steaming desolventizes, and column chromatographic isolation and purification obtains target compound 10.Eluent system is sherwood oil: ethyl acetate=4:1.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
10a:N-(2-((4-chloro-phenyl-) carbamyl) phenyl) niacinamide, white solid, yield 55.4%, Mp:207-210 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.47(s,1H),10.63(s,1H),9.07(d,J=1.5Hz,1H),8.78(dd,J=5.1Hz,1.5Hz,1H),8.27(d,J=8.4Hz,1H),8.24(dt,J=7.8Hz,1.5Hz,1H),7.88(d,J=7.8Hz,1H),7.76(d,J=8.4Hz,2H),7.63(dd,J=8.4Hz,7.2Hz,1H),7.60(dd,J=7.8Hz,5.1Hz,1H),7.42(d,J=8.4Hz,2H),7.34(dd,J=7.8Hz,7.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C
19H
15ClN
3O
2[M+H]
+:352.0847found352.0849。
10b:N-(2-((4-trifluoromethyl) carbamyl) phenyl) niacinamide, white solid, yield 63.9%, Mp:218-220 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.30(s,1H),10.78(s,1H),9.08(d,J=1.8Hz,1H),8.77(dd,J=5.4Hz,1.8Hz,1H),8.24(dt,J=8.4Hz,1.8Hz,1H),8.19(d,J=8.4Hz,1H),8.14(s,1H),8.00(d,J=8.4Hz,1H),7.88(d,J=7.8Hz,1H),7.58-7.65(m,3H),7.47(d,J=7.8Hz,1H),7.36(dd,J=7.8Hz,7.2Hz,1H)。HRMS(ESI)m/z?calcd?for?C
20H
15F
3N
3O
2[M+H]
+:386.1111found386.1115。
10c:N-(2-((3-bromophenyl) carbamyl) phenyl) niacinamide, white solid, yield 51.3%, Mp:199-201 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.53(s,1H),10.64(s,1H),9.08(d,J=1.8Hz,1H),8.78(dd,J=4.8Hz,1.8Hz,1H),8.25(dt,J=7.8Hz,1.8Hz,1H),8.21(d,J=8.1Hz,1H),8.02(s,1H),7.86(d,J=8.1Hz,1H),7.69(dd,J=7.2Hz,1.8Hz,1H),7.64(td,J=8.1Hz,1.8Hz,1H),7.60(dd,J=7.8Hz,4.8Hz,1H),7.30-7.36(m,3H)。HRMS(ESI)m/z?calcd?for?C
19H
15BrN
3O
2[M+H]
+:396.0342found396.0348。
10d:N-(2-((3-hydroxy phenyl) carbamyl) phenyl) niacinamide, white solid, yield 52.2%, Mp:207-210 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.61(s,1H),10.41(s,1H),9.45(s,1H),9.08(d,J=1.8Hz,1H),8.79(dd,J=4.8Hz,1.8Hz,1H),8.33(d,J=7.8Hz,1H),8.25(dt,J=7.8Hz,1.8Hz,1H),7.88(d,J=7.8Hz,1H),7.60-7.64(m,2H),7.30-7.34(m,2H),7.09-7.14(m,2H),6.53(dt,J=7.2Hz,1.8Hz,1H)。HRMS(ESI)m/z?calcd?for?C
19H
16N
3O
3[M+H]
+:334.1186found334.1189。
Embodiment 6N-substituted-phenyl-2-(2-hydroxyl-5-nitrobenzyl amido) benzamide 11 synthetic
Be dissolved in 10mL methyl alcohol by N-substituted-phenyl-2-aminobenzamide (4,0.75mmol) with AcOH(2.9mmol), add 2-hydroxyl-5 nitrobenzaldehydes (1mmol), stirring at room temperature reaction 8h.Sodium cyanoborohydride (1mmol) is dissolved in to 10mL methyl alcohol, is slowly added drop-wise to above-mentioned reaction solution, drip and finish, room temperature reaction 24 hours.Remove solvent under reduced pressure, residue dissolves with 15mL methylene dichloride, and with saturated sodium bicarbonate (10mL × 2) washing, saturated sodium-chloride (10mL × 2) washing, anhydrous sodium sulfate drying, filters, and steaming desolventizes, the target compound 11 of column chromatographic isolation and purification.
Above-mentioned N-substituted-phenyl-2-aminobenzamide is N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
11a:N-chloro-phenyl--2-(2-hydroxyl-5-nitrobenzyl amido) benzamide, yellow solid, productive rate 52.7%, Mp:168-169 DEG C.
1H?NMR(600MHz,DMSO-d
6)δ11.41(s,1H),10.28(s,1H),8.08(d,J=3.0Hz,1H),8.04(dd,J=9.0Hz,3.0Hz,1H),7.86(br?t,d=5.4Hz,1H),7.76(d,J=8.7Hz,2H),7.68(d,J=7.8Hz,1H),7.40(d,J=8.7Hz,2H),7.29(dd,J=8.7Hz,7.2Hz,1H),7.01(d,J=8.7Hz,1H),6.63-6.67(m,2H),4.40(d,J=5.4Hz,2H)。HRMS(ESI)m/z?calcd?for?C
20H
17ClN
3O
4[M+H]
+:398.0902found398.0904。
11b:N-bromophenyl-2-(2-hydroxyl-5-nitrobenzyl amido) benzamide, yellow solid, productive rate 55.6%, Mp:146-149 DEG C.
1h NMR (600MHz, DMSO-d
6) δ 11.41 (s, 1H), 10.30 (s, 1H), 8.10 (s, 1H), 8.08 (d, J=2.4Hz, 1H), 8.05 (dd, J=8.7Hz, 2.4Hz, 1H), 7.87 (br t, J=6.0Hz, 1H), 7.69 (d, J=7.8Hz, 1H), 7.68 (d, J=8.4Hz, 1H), 7.27-7.33 (m, 3H), 7.01 (d, J=8.4Hz, 1H), 6.66 (dd, J=7.8Hz, 7.2Hz, 1H), 6.63 (d, J=8.7Hz, H), 4.41 (d, J=6.0Hz, 2H).HRMS(ESI)m/z?calcd?for?C
20H
17BrN
3O
4[M+H]
+:442.0397found442.0399。
Claims (7)
1. anthranilamides, structure as shown in general formula I,
Wherein, R
1for fluorine, chlorine, bromine or trifluoromethyl.
2. the preparation method of compound claimed in claim 1 is as follows:
Synthetic route:
Reagent and reaction conditions: (i) thionyl chloride, methylene dichloride, 60 DEG C; (ii) substituted aniline, triethylamine, methylene dichloride; (iii) iron, Glacial acetic acid, ethyl acetate, reflux; (iv) thiophosgene; (v) methylene dichloride, room temperature;
R
1as claimed in claim 1;
Concrete steps are as follows:
(i) raw material o-Carboxynitrobenzene is joined in methylene dichloride, under room temperature, fully stir, treat that solid dissolves completely, slowly drip thionyl chloride, drip and finish, be slowly warming up to 60 DEG C, reaction 3-5h, remove solvent and excessive thionyl chloride under reduced pressure and obtain intermediate ortho-nitrophenyl formyl chloride 2, sealed membrane sealing saves backup;
(ii) substituted aniline and triethylamine are dissolved in to methylene dichloride, are placed under condition of ice bath, treat that temperature is down to 0 DEG C, the ortho-nitrophenyl formyl chloride 2 that upper step is made is dissolved in methylene dichloride, is slowly added drop-wise in above-mentioned substituted aniline solution, drips complete room temperature reaction 2h; Question response is complete, filters, and filtrate decompression is steamed and desolventized, and column chromatographic isolation and purification obtains intermediate N substituted-phenyl-2-nitrobenzamide, and eluent system is volume ratio sherwood oil: ethyl acetate=8:1;
(iii) the N-substituted-phenyl-2-nitrobenzamide and the reduced iron powder mol ratio 1:10 that upper step are made join in the mixing solutions of Glacial acetic acid and ethyl acetate, reflux 4 hours, be cooled to after completion of the reaction room temperature, filter, filtrate is with saturated NaCl solution washing, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, column chromatographic isolation and purification obtains intermediate N substituted-phenyl-2-aminobenzamide 4, and eluent system is volume ratio sherwood oil: ethyl acetate=6:1;
(iv) thiophosgene is added to the water at 21 DEG C and fully stirs and form nonhomogeneous system, the gradation of 4-amino-2-4-trifluoromethylbenzonitrile is added to above-mentioned nonhomogeneous system, continue fully to stir 1h; React complete, by reaction solution dichloromethane extraction, merge organic phase, saturated sodium-chloride washing, anhydrous MgSO
4dry, filter, remove solvent under reduced pressure, column chromatography obtains intermediate lsothiocyanates 6, and eluent system is volume ratio sherwood oil: ethyl acetate=6:1;
(v) N-substituted-phenyl-2-aminobenzamide 4 is dissolved in to methylene dichloride, under condition of ice bath, slowly drip the dichloromethane solution of 3-itrile group-4-trifluoromethyl lsothiocyanates 6, drip and finish, stirring at room temperature 7h, separate out white solid, filter, a small amount of washed with dichloromethane of filter cake, obtains target compound.
3. the preparation method of compound claimed in claim 2, is characterized in that, step (ii) middle substituted aniline is 4-fluoroaniline, 4-chloroaniline, 3-5-trifluoromethylaniline, 3-bromaniline.
4. the preparation method of compound claimed in claim 2, it is characterized in that, step (iii) in, N-substituted-phenyl-2-nitrobenzamide is N-(4-fluorophenyl)-2-nitrobenzamide, N-(4-chloro-phenyl-)-2-nitrobenzamide, N-(3-trifluoromethyl)-2-nitrobenzamide, N-(3-bromophenyl)-2-nitrobenzamide.
5. the preparation method of compound claimed in claim 2, it is characterized in that, step (v) in, N-substituted-phenyl-2-aminobenzamide is N-(4-fluorophenyl)-2-aminobenzamide, N-(4-chloro-phenyl-)-2-aminobenzamide, N-(3-trifluoromethyl)-2-aminobenzamide, N-(3-bromophenyl)-2-aminobenzamide.
6. an antineoplastic pharmaceutical compositions, comprises compound or its pharmacy acceptable salt and one or more pharmaceutically acceptable carriers or vehicle described in claim 1.
Described in claim 1 compound in the application of preparing in anti-tumor drug.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092606.8A CN103130696B (en) | 2013-03-21 | 2013-03-21 | Anthranilamide compound as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310092606.8A CN103130696B (en) | 2013-03-21 | 2013-03-21 | Anthranilamide compound as well as preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103130696A CN103130696A (en) | 2013-06-05 |
| CN103130696B true CN103130696B (en) | 2014-06-11 |
Family
ID=48491201
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310092606.8A Active CN103130696B (en) | 2013-03-21 | 2013-03-21 | Anthranilamide compound as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103130696B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017123809A1 (en) * | 2016-01-12 | 2017-07-20 | Taipei Medical University | Compounds for inhibiting cancer and virus |
| WO2018102766A2 (en) * | 2016-12-01 | 2018-06-07 | Oregon State University | Small molecule bcl-2 functional converters as cancer therapeutics |
| CN110305045A (en) * | 2018-03-20 | 2019-10-08 | 成都海创药业有限公司 | A kind of amides compound and its purposes in treating cancer |
| CN108863860B (en) * | 2018-07-27 | 2021-08-06 | 温州医科大学 | N-substituted phenyl-3-sulfonyl aminobenzamide compound, preparation thereof and application thereof in resisting breast cancer activity |
| CN113292443B (en) * | 2020-11-24 | 2022-07-19 | 长沙理工大学 | Process for producing amides |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999000121A1 (en) * | 1997-06-26 | 1999-01-07 | Eli Lilly And Company | Antithrombotic agents |
| CN1325384A (en) * | 1998-11-10 | 2001-12-05 | 舍林股份公司 | Anthranilic acid amides and the use thereof as medicaments |
| CN1522244A (en) * | 2001-04-28 | 2004-08-18 | ������ҽҩ�¹�����˾ | Anthranilic acid amides, method for the production thereof, their use as antiarrhythmia agents, and pharmaceutical preparations thereof |
| WO2010019473A1 (en) * | 2008-08-14 | 2010-02-18 | Amgen Inc. | Aurora kinase modulators and methods of use |
-
2013
- 2013-03-21 CN CN201310092606.8A patent/CN103130696B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999000121A1 (en) * | 1997-06-26 | 1999-01-07 | Eli Lilly And Company | Antithrombotic agents |
| CN1325384A (en) * | 1998-11-10 | 2001-12-05 | 舍林股份公司 | Anthranilic acid amides and the use thereof as medicaments |
| CN1522244A (en) * | 2001-04-28 | 2004-08-18 | ������ҽҩ�¹�����˾ | Anthranilic acid amides, method for the production thereof, their use as antiarrhythmia agents, and pharmaceutical preparations thereof |
| WO2010019473A1 (en) * | 2008-08-14 | 2010-02-18 | Amgen Inc. | Aurora kinase modulators and methods of use |
Non-Patent Citations (2)
| Title |
|---|
| Roderick J. Sorenson.Selective N-Arylation of Aminobenzanilides under Mild Conditions Using Triarylbismuthanes.《J. Org. Chem.》.2000,第65卷(第23期),7747-7749. |
| Selective N-Arylation of Aminobenzanilides under Mild Conditions Using Triarylbismuthanes;Roderick J. Sorenson;《J. Org. Chem.》;20001021;第65卷(第23期);第7747-7749页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103130696A (en) | 2013-06-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103130696B (en) | Anthranilamide compound as well as preparation method and application thereof | |
| JP6621486B2 (en) | Pyrido-azaheterocyclic compound and production method and use thereof | |
| TW504508B (en) | Atropisomers of 3-aryl-4(3h)-quinazolinones | |
| ES2454769T3 (en) | Nitrogen ring acylguanidine derivative | |
| CN101323591A (en) | 5- or 6-substited naphthoyl imines compounds and antineoplastic application | |
| CN104341425A (en) | Deuterated acetylenic derivative, pharmaceutical composition and application thereof | |
| CN103370324A (en) | Aromatic alkyne derivative as protein kinase inhibitor and medical use thereof | |
| CN104926788A (en) | Substituted piperidin derivative, and pharmaceutical composition containing substituted piperidin derivative and application thereof in antitumor | |
| CN107286113A (en) | A kind of isoquinolinone derivatives and its production and use | |
| CN104211686A (en) | Quinoline derivatives and treatment use thereof | |
| CN107304211A (en) | A kind of selective FGFR4 kinase inhibitors | |
| CN103130775B (en) | As the dihydroindole ketone derivate of tyrosine kinase inhibitor | |
| CN104230954A (en) | 2,4-diaminopyrimidine compounds and medical applications thereof | |
| CN102633812B (en) | Oxazolone quinazoline derivatives as well as preparation method and application thereof | |
| CN103102352B (en) | Tyrosine kinase inhibitor indolinone derivative | |
| CN104163794A (en) | 2-amino aromatic ring vascular endothelial growth factor receptor (VEGFR) inhibitor, preparation method and use thereof | |
| CN104761482B (en) | 3 (2,2 dimethyl) third cyano group 3 alkane (virtue) base indolones and preparation method thereof | |
| CN106146412B (en) | Quinazoline derivant and its preparation method and application | |
| CN102307861B (en) | Phenylimidazole compounds | |
| Gao et al. | Design, synthesis and biological evaluation of benzyloxyphenyl-methylaminophenol derivatives as STAT3 signaling pathway inhibitors | |
| CN107098884A (en) | The aminopyridines and its preparation and use of one class substitution | |
| CN108929324A (en) | The preparation and application of novel 1,1- cyclopropyl diamide derivatives | |
| CN106117182A (en) | Quinazoline N phenethyl tetrahydroisoquinolicompounds compounds and its preparation method and application | |
| CN103087054A (en) | 4-pyridyl phenyl ether compounds, and preparation method and application thereof | |
| CN107793363A (en) | A kind of substituted aromatic amines base heteroaromatic class compound and its application as antineoplastic |
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 | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170531 Address after: 226400 Rudong chemical industry zone, Jiangsu Patentee after: JIANGSU REPONT PESTICIDE FACTORY Co.,Ltd. Address before: 250012 No. 44 West Wenhua Road, Lixia District, Shandong, Ji'nan Patentee before: Shandong University |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 226400 No. two, No. 18, Haibin Road, Rudong Coastal Economic Development Zone, Nantong, Jiangsu Patentee after: Jiangsu Ruibang agrochemical Co.,Ltd. Address before: 226400 Rudong chemical industry zone, Jiangsu Patentee before: JIANGSU REPONT PESTICIDE FACTORY Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: No. 18 Haiyou Road, Yangkou Town, Rudong County, Nantong City, Jiangsu Province, 226400 Patentee after: Jiangsu Ruibang agrochemical Co.,Ltd. Country or region after: China Address before: 226400 18 Haibin 2nd Road, Rudong Coastal Economic Development Zone, Nantong City, Jiangsu Province Patentee before: Jiangsu Ruibang agrochemical Co.,Ltd. Country or region before: China |