CN107311933B - Benzimidazole derivative, preparation method and application thereof - Google Patents
Benzimidazole derivative, preparation method and application thereof Download PDFInfo
- Publication number
- CN107311933B CN107311933B CN201710508016.7A CN201710508016A CN107311933B CN 107311933 B CN107311933 B CN 107311933B CN 201710508016 A CN201710508016 A CN 201710508016A CN 107311933 B CN107311933 B CN 107311933B
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- substituted
- acid
- phenyl
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 39
- 125000003785 benzimidazolyl group Chemical class N1=C(NC2=C1C=CC=C2)* 0.000 title claims abstract 9
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 239000003814 drug Substances 0.000 claims abstract description 23
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 claims abstract description 8
- -1 nitro, sulfonyl Chemical group 0.000 claims description 32
- 238000000034 method Methods 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- 125000003118 aryl group Chemical group 0.000 claims description 8
- 125000005842 heteroatom Chemical group 0.000 claims description 8
- 238000011282 treatment Methods 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 4
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzenecarboxaldehyde Natural products O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910052736 halogen Inorganic materials 0.000 claims description 4
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 238000005904 alkaline hydrolysis reaction Methods 0.000 claims description 2
- 125000002877 alkyl aryl group Chemical group 0.000 claims description 2
- 238000005984 hydrogenation reaction Methods 0.000 claims description 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 230000002194 synthesizing effect Effects 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- TZIHFWKZFHZASV-UHFFFAOYSA-N methyl formate Chemical group COC=O TZIHFWKZFHZASV-UHFFFAOYSA-N 0.000 claims 2
- PWKNBLFSJAVFAB-UHFFFAOYSA-N 1-fluoro-2-nitrobenzene Chemical class [O-][N+](=O)C1=CC=CC=C1F PWKNBLFSJAVFAB-UHFFFAOYSA-N 0.000 claims 1
- 150000003935 benzaldehydes Chemical class 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 7
- 210000004881 tumor cell Anatomy 0.000 abstract description 6
- 206010069755 K-ras gene mutation Diseases 0.000 abstract description 5
- 230000035755 proliferation Effects 0.000 abstract description 5
- 230000002401 inhibitory effect Effects 0.000 abstract description 4
- 239000012453 solvate Substances 0.000 abstract description 4
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 3
- 230000002141 anti-parasite Effects 0.000 abstract description 3
- 230000000840 anti-viral effect Effects 0.000 abstract description 3
- 239000003096 antiparasitic agent Substances 0.000 abstract description 3
- 230000003276 anti-hypertensive effect Effects 0.000 abstract description 2
- 230000008901 benefit Effects 0.000 abstract description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 70
- 239000007787 solid Substances 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 26
- 238000002844 melting Methods 0.000 description 23
- 230000008018 melting Effects 0.000 description 23
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 21
- 239000002994 raw material Substances 0.000 description 21
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 201000011510 cancer Diseases 0.000 description 11
- 201000010099 disease Diseases 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 11
- 239000000243 solution Substances 0.000 description 9
- 101710113436 GTPase KRas Proteins 0.000 description 8
- 150000001263 acyl chlorides Chemical class 0.000 description 8
- 210000004027 cell Anatomy 0.000 description 8
- 238000010626 work up procedure Methods 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 101150105104 Kras gene Proteins 0.000 description 7
- 239000000443 aerosol Substances 0.000 description 7
- 239000012074 organic phase Substances 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 150000002431 hydrogen Chemical group 0.000 description 6
- 108010014186 ras Proteins Proteins 0.000 description 6
- 102000016914 ras Proteins Human genes 0.000 description 6
- 150000001556 benzimidazoles Chemical class 0.000 description 5
- 238000004113 cell culture Methods 0.000 description 5
- 125000000623 heterocyclic group Chemical group 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 4
- 206010064571 Gene mutation Diseases 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 4
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 4
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- 101150040459 RAS gene Proteins 0.000 description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 239000001963 growth medium Substances 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108700042226 ras Genes Proteins 0.000 description 4
- 238000011160 research Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 108700020978 Proto-Oncogene Proteins 0.000 description 3
- 102000052575 Proto-Oncogene Human genes 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 230000004663 cell proliferation Effects 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000007865 diluting Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 239000012065 filter cake Substances 0.000 description 3
- 125000003037 imidazol-2-yl group Chemical group [H]N1C([*])=NC([H])=C1[H] 0.000 description 3
- 230000004807 localization Effects 0.000 description 3
- FKMZNQQOPCCUTD-UHFFFAOYSA-N methyl 3-fluoro-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(F)=C1 FKMZNQQOPCCUTD-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 230000000699 topical effect Effects 0.000 description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 2
- 125000004343 1-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C([H])([H])[H] 0.000 description 2
- NKWCGTOZTHZDHB-UHFFFAOYSA-N 1h-imidazol-1-ium-4-carboxylate Chemical compound OC(=O)C1=CNC=N1 NKWCGTOZTHZDHB-UHFFFAOYSA-N 0.000 description 2
- DEPDDPLQZYCHOH-UHFFFAOYSA-N 1h-imidazol-2-amine Chemical compound NC1=NC=CN1 DEPDDPLQZYCHOH-UHFFFAOYSA-N 0.000 description 2
- ZBNZAJFNDPPMDT-UHFFFAOYSA-N 1h-imidazole-5-carboxamide Chemical compound NC(=O)C1=CNC=N1 ZBNZAJFNDPPMDT-UHFFFAOYSA-N 0.000 description 2
- ANOUKFYBOAKOIR-UHFFFAOYSA-N 3,4-dimethoxyphenylethylamine Chemical compound COC1=CC=C(CCN)C=C1OC ANOUKFYBOAKOIR-UHFFFAOYSA-N 0.000 description 2
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- 102100039788 GTPase NRas Human genes 0.000 description 2
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 2
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 229960000583 acetic acid Drugs 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 2
- 230000024245 cell differentiation Effects 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000015165 citric acid Nutrition 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 238000012258 culturing Methods 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 239000003085 diluting agent Substances 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 239000012894 fetal calf serum Substances 0.000 description 2
- 239000001530 fumaric acid Substances 0.000 description 2
- 235000011087 fumaric acid Nutrition 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960002989 glutamic acid Drugs 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 235000013922 glutamic acid Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 229960000448 lactic acid Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 2
- 239000011976 maleic acid Substances 0.000 description 2
- 239000001630 malic acid Substances 0.000 description 2
- 235000011090 malic acid Nutrition 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- CFYQFTHDHPWCDT-UHFFFAOYSA-N methyl 4-amino-3-(benzylamino)benzoate Chemical compound COC(=O)C1=CC=C(N)C(NCC=2C=CC=CC=2)=C1 CFYQFTHDHPWCDT-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000007923 nasal drop Substances 0.000 description 2
- 229940100662 nasal drops Drugs 0.000 description 2
- 229910017604 nitric acid Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 235000006408 oxalic acid Nutrition 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 235000019260 propionic acid Nutrition 0.000 description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000007921 spray Substances 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 239000011975 tartaric acid Substances 0.000 description 2
- 235000002906 tartaric acid Nutrition 0.000 description 2
- 229960001367 tartaric acid Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RQEUFEKYXDPUSK-SSDOTTSWSA-N (1R)-1-phenylethanamine Chemical compound C[C@@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-SSDOTTSWSA-N 0.000 description 1
- RQEUFEKYXDPUSK-ZETCQYMHSA-N (1S)-1-phenylethanamine Chemical compound C[C@H](N)C1=CC=CC=C1 RQEUFEKYXDPUSK-ZETCQYMHSA-N 0.000 description 1
- IIFVWLUQBAIPMJ-UHFFFAOYSA-N (4-fluorophenyl)methanamine Chemical compound NCC1=CC=C(F)C=C1 IIFVWLUQBAIPMJ-UHFFFAOYSA-N 0.000 description 1
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 1
- UWYVPFMHMJIBHE-OWOJBTEDSA-N (e)-2-hydroxybut-2-enedioic acid Chemical compound OC(=O)\C=C(\O)C(O)=O UWYVPFMHMJIBHE-OWOJBTEDSA-N 0.000 description 1
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide Substances CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 1
- LCFXRSKBJWQHON-UHFFFAOYSA-N 1-benzyl-2-phenylbenzimidazole Chemical class C=1C=CC=CC=1C1=NC2=CC=CC=C2N1CC1=CC=CC=C1 LCFXRSKBJWQHON-UHFFFAOYSA-N 0.000 description 1
- ALOCUZOKRULSAA-UHFFFAOYSA-N 1-methylpiperidin-4-amine Chemical compound CN1CCC(N)CC1 ALOCUZOKRULSAA-UHFFFAOYSA-N 0.000 description 1
- 125000004484 1-methylpiperidin-4-yl group Chemical group CN1CCC(CC1)* 0.000 description 1
- NMIZONYLXCOHEF-UHFFFAOYSA-N 1h-imidazole-2-carboxamide Chemical compound NC(=O)C1=NC=CN1 NMIZONYLXCOHEF-UHFFFAOYSA-N 0.000 description 1
- ITRNQMJXZUWZQL-UHFFFAOYSA-N 2-(2-bromophenyl)ethanamine Chemical compound NCCC1=CC=CC=C1Br ITRNQMJXZUWZQL-UHFFFAOYSA-N 0.000 description 1
- AUCVZEYHEFAWHO-UHFFFAOYSA-N 2-(3-fluorophenyl)ethanamine Chemical compound NCCC1=CC=CC(F)=C1 AUCVZEYHEFAWHO-UHFFFAOYSA-N 0.000 description 1
- JWYUFVNJZUSCSM-UHFFFAOYSA-N 2-aminobenzimidazole Chemical compound C1=CC=C2NC(N)=NC2=C1 JWYUFVNJZUSCSM-UHFFFAOYSA-N 0.000 description 1
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 1
- IGPFOKFDBICQMC-UHFFFAOYSA-N 3-phenylmethoxyaniline Chemical compound NC1=CC=CC(OCC=2C=CC=CC=2)=C1 IGPFOKFDBICQMC-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- HVBSAKJJOYLTQU-UHFFFAOYSA-N 4-aminobenzenesulfonic acid Chemical compound NC1=CC=C(S(O)(=O)=O)C=C1 HVBSAKJJOYLTQU-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- CAOCEOAUKSPUPN-UHFFFAOYSA-N 4-ethylpiperazine-1-carbaldehyde Chemical compound CCN1CCN(C=O)CC1 CAOCEOAUKSPUPN-UHFFFAOYSA-N 0.000 description 1
- 125000004176 4-fluorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1F)C([H])([H])* 0.000 description 1
- XJEVFFNOMKXBLU-UHFFFAOYSA-N 4-methylsulfonylaniline Chemical compound CS(=O)(=O)C1=CC=C(N)C=C1 XJEVFFNOMKXBLU-UHFFFAOYSA-N 0.000 description 1
- ZCVAGTPWBAZXAL-UHFFFAOYSA-N 4-nitro-2,1,3-benzoxadiazole Chemical compound [O-][N+](=O)C1=CC=CC2=NON=C12 ZCVAGTPWBAZXAL-UHFFFAOYSA-N 0.000 description 1
- WOYZXEVUWXQVNV-UHFFFAOYSA-N 4-phenoxyaniline Chemical compound C1=CC(N)=CC=C1OC1=CC=CC=C1 WOYZXEVUWXQVNV-UHFFFAOYSA-N 0.000 description 1
- DUKKRSPKJMHASP-UHFFFAOYSA-N 6-chloropyrimidin-4-amine Chemical compound NC1=CC(Cl)=NC=N1 DUKKRSPKJMHASP-UHFFFAOYSA-N 0.000 description 1
- 102100033793 ALK tyrosine kinase receptor Human genes 0.000 description 1
- 201000004384 Alopecia Diseases 0.000 description 1
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- 125000000172 C5-C10 aryl group Chemical group 0.000 description 1
- PCBZRNYXXCIELG-WYFCWLEVSA-N COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 Chemical compound COC1=CC=C(C[C@H](NC(=O)OC2CCCC3(C2)OOC2(O3)C3CC4CC(C3)CC2C4)C(=O)N[C@@H]2[C@@H](CO)O[C@H]([C@@H]2O)N2C=NC3=C2N=CN=C3N(C)C)C=C1 PCBZRNYXXCIELG-WYFCWLEVSA-N 0.000 description 1
- 102100033211 Centromere protein W Human genes 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 1
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 1
- 102100030708 GTPase KRas Human genes 0.000 description 1
- 101000779641 Homo sapiens ALK tyrosine kinase receptor Proteins 0.000 description 1
- 101000944447 Homo sapiens Centromere protein W Proteins 0.000 description 1
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 1
- 101000946040 Homo sapiens Lysosomal-associated transmembrane protein 4B Proteins 0.000 description 1
- 101001030211 Homo sapiens Myc proto-oncogene protein Proteins 0.000 description 1
- 101000692455 Homo sapiens Platelet-derived growth factor receptor beta Proteins 0.000 description 1
- 101000579425 Homo sapiens Proto-oncogene tyrosine-protein kinase receptor Ret Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 description 1
- 101000691578 Homo sapiens Zinc finger protein PLAG1 Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 229940124785 KRAS inhibitor Drugs 0.000 description 1
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical compound NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 102100034726 Lysosomal-associated transmembrane protein 4B Human genes 0.000 description 1
- 108010050345 Microphthalmia-Associated Transcription Factor Proteins 0.000 description 1
- 102000013760 Microphthalmia-Associated Transcription Factor Human genes 0.000 description 1
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 1
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 102100028286 Proto-oncogene tyrosine-protein kinase receptor Ret Human genes 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100037486 Reverse transcriptase/ribonuclease H Human genes 0.000 description 1
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
- 102000044209 Tumor Suppressor Genes Human genes 0.000 description 1
- 108700025716 Tumor Suppressor Genes Proteins 0.000 description 1
- 102000010989 Type 6 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037638 Type 6 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 102100026200 Zinc finger protein PLAG1 Human genes 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 229940025084 amphetamine Drugs 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 229960005261 aspartic acid Drugs 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- 229940092714 benzenesulfonic acid Drugs 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960004365 benzoic acid Drugs 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 239000000227 bioadhesive Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008827 biological function Effects 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000006189 buccal tablet Substances 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 231100000504 carcinogenesis Toxicity 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 239000006184 cosolvent Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 150000002169 ethanolamines Chemical class 0.000 description 1
- 150000003947 ethylamines Chemical class 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 230000006126 farnesylation Effects 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 229940013688 formic acid Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 201000005787 hematologic cancer Diseases 0.000 description 1
- 208000024200 hematopoietic and lymphoid system neoplasm Diseases 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000007529 inorganic bases Chemical class 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 229940045996 isethionic acid Drugs 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000012423 maintenance Methods 0.000 description 1
- 229940098895 maleic acid Drugs 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- OZKCNRYXLXLSBG-UHFFFAOYSA-N methyl 3-(benzylamino)-4-nitrobenzoate Chemical compound COC(=O)C1=CC=C([N+]([O-])=O)C(NCC=2C=CC=CC=2)=C1 OZKCNRYXLXLSBG-UHFFFAOYSA-N 0.000 description 1
- 150000003956 methylamines Chemical class 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 1
- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- RWIVICVCHVMHMU-UHFFFAOYSA-N n-aminoethylmorpholine Chemical compound NCCN1CCOCC1 RWIVICVCHVMHMU-UHFFFAOYSA-N 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 239000007922 nasal spray Substances 0.000 description 1
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Substances [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000000668 oral spray Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 229960003104 ornithine Drugs 0.000 description 1
- WLJNZVDCPSBLRP-UHFFFAOYSA-N pamoic acid Chemical compound C1=CC=C2C(CC=3C4=CC=CC=C4C=C(C=3O)C(=O)O)=C(O)C(C(O)=O)=CC2=C1 WLJNZVDCPSBLRP-UHFFFAOYSA-N 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000003071 parasitic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 229950000244 sulfanilic acid Drugs 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- LFKDJXLFVYVEFG-UHFFFAOYSA-N tert-butyl carbamate Chemical compound CC(C)(C)OC(N)=O LFKDJXLFVYVEFG-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- AOCSUUGBCMTKJH-UHFFFAOYSA-N tert-butyl n-(2-aminoethyl)carbamate Chemical compound CC(C)(C)OC(=O)NCCN AOCSUUGBCMTKJH-UHFFFAOYSA-N 0.000 description 1
- MUUHXGOJWVMBDY-UHFFFAOYSA-L tetrazolium blue Chemical compound [Cl-].[Cl-].COC1=CC(C=2C=C(OC)C(=CC=2)[N+]=2N(N=C(N=2)C=2C=CC=CC=2)C=2C=CC=CC=2)=CC=C1[N+]1=NC(C=2C=CC=CC=2)=NN1C1=CC=CC=C1 MUUHXGOJWVMBDY-UHFFFAOYSA-L 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 238000013519 translation Methods 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229950002929 trinitrophenol Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07D235/30—Nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses benzimidazole derivatives shown as a formula I, pharmaceutically acceptable salts and solvates thereof, a preparation method thereof and application of the benzimidazole derivatives in preparing medicaments for treating tumors, antiviral medicaments, antibacterial medicaments, antiparasitic medicaments, antihypertensive medicaments and the like. The compound has the advantages of remarkable proliferation capacity for inhibiting tumor cells with kras mutation, stable structure, simple and convenient preparation and potential for developing novel antitumor drugs.
Description
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to benzimidazole derivatives, a preparation method thereof and application of the benzimidazole derivatives as medicaments for treating tumors, antiviral medicaments, antibacterial medicaments, antiparasitic medicaments, antihypertensive medicaments and the like.
Background
Malignant tumors are serious diseases threatening human life and health. According to the statistics of the world health organization, about 1400 million new cancer cases exist in the world in 2012, compared with 2008, the cancer patients and the mortality rate all have an increasing trend in the world, and the number of new cancer cases is estimated to increase by about 70% in the next twenty years. Cancer is the second leading cause of death in 880 ten thousand people in 2015 as the second leading cause of death in the world, with the highest incidence of lung, liver, colorectal, gastric and breast cancers. Approximately 70% of cancer deaths occur in low and medium income countries, with new cancer cases and deaths occurring in China at the top of the world.
The existing organic small-molecule anticancer drugs easily cause toxic and side effects such as bone marrow suppression, gastrointestinal tract effect, rash, alopecia and the like, and the curative effect also needs to be improved. The activation of protooncogenes and the inactivation of cancer suppressor genes are important reasons for causing tumors, and the research of novel targeted anticancer drugs is a new strategy for finding high-efficiency and low-toxicity antitumor drugs according to the abnormality of protooncogenes and related molecules involved in the process of generating tumors.
Malignant tumor is a multifactorial disease, gene mutation is an important cause of tumor, and more than 100 kinds of tumor-inducing protooncogenes are known, mainly including MYC, Ras, HER2, BRAF, MET, BCR-ABL, PDGFR, KTT, FGFR3, ALK, RET, MITF, CUG2, FAM83, LAPTM4B, PLAG1, etc. Among them, about 1/3 of cancers are associated with Ras gene mutations, which are involved in about 50% of colorectal cancers, 30% of lung cancers and 20% of blood cancer induction.
The 36 genes in the human Ras gene family with tumor associated three characteristic genes are H-Ras, K-Ras and N-Ras, respectively, responsible for encoding H-Ras, K-Ras4A, K-Ras4B and N-Ras four Ras proteins. Among them, K-Ras gene mutation is most closely related to tumors, because of the extremely strong affinity of K-Ras protein and substrate GTP (pmol. L)-1Grade), there is a great challenge to design inhibitors of kras protein, and therefore, there is no effective Ras-targeting therapeutic agent clinically.
Ras protein synthesized by Ras gene translation is a protein precursor, and a biological function needs to be obtained through farnesylation modification. The activated Ras protein is a small GTP hydrolase, is positioned in the cell intima, stimulates a downstream signal path to transmit mitotic signals, and plays an important role in regulating and controlling the growth, proliferation and differentiation of cells and the conduction of other signals. PDE (phosphodiesterase) is a subtype of phosphodiesterase 6, has an isoprene binding pocket in the spatial structure, can selectively recognize farnesylated Ras protein, regulates the intimal localization of the Ras protein, and has the action mechanism mainly comprising the maintenance of the spatial structure of K-Ras, the assistance of the localization of the palmitylated K-Ras to a cell membrane, and the transportation of the K-Ras to a golgi after the K-Ras is subjected to the action and is subjected to the debalmitylation, so that the retentization and the membrane localization are promoted, and the circulation of the K-Ras between a GTP activated state and a GDP inactivated state is fully ensured.
Blocking the interaction of kras and PDE can provide a new treatment strategy for tumors caused by K-Ras mutation.
Disclosure of Invention
According to one aspect of the present invention there is provided a benzimidazole derivative of formula I, a pharmaceutically acceptable salt, solvate thereof:
wherein A is selected from a substituted or unsubstituted five to ten membered heterocyclic group containing 1 to 3 heteroatoms selected from S, N and O, or-NH-R4.
When a is a substituted or unsubstituted five-to ten-membered heterocyclic group containing 1 to 3 heteroatoms selected from S, N and O, it is preferably a substituted or unsubstituted five-to seven-membered heterocyclic group containing 1 to 3 heteroatoms selected from S, N and O;
when a is-NH-R4, wherein R4 is selected from substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C5-C10 aryl, substituted or unsubstituted C6-C12 alkylaryl, substituted or unsubstituted five-to ten-membered heterocyclyl containing 1 to 3 heteroatoms selected from S, N and O, substituted or unsubstituted eight-to ten-membered heterocyclylcyclyl containing 1 to 3 heteroatoms selected from S, N and O;
preferably, R4 is selected from the group consisting of substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted C5-C8 aryl, substituted or unsubstituted C6-C10 alkylaryl, substituted or unsubstituted five to eight membered heterocyclyl containing 1 to 3 heteroatoms selected from S, N and O, substituted or unsubstituted eight to ten membered fused cyclic containing 1 to 3 heteroatoms selected from S, N and O;
wherein the term "substituted" refers to C1-C6 alkoxy substituted with 1 to 3 same or different substituents selected from the group consisting of hydroxy, amino, halogen, nitro, carboxy, sulfonyl, C1-C6 alkoxy, C5-C7 aryl, C5-C7 aryl.
R2 is selected from hydrogen, C1-C6 alkyl, Ar is selected from C5-10 aromatic ring group, preferably, R2 is selected from hydrogen, C1-C3 alkyl, Ar is selected from C5-C7 aromatic ring group, more preferably, R2 is selected from hydrogen, methyl and ethyl, and Ar is selected from C5-C6 aromatic ring group.
R3 is selected from hydrogen, alkyl of C1-C6, preferably, R2 is selected from hydrogen, alkyl of C1-C3, more preferably, R3 is selected from hydrogen, methyl, ethyl.
The halogen is selected from F, Cl, Br or I, preferably F, Cl or Br.
The benzimidazole derivatives of formula I according to the present invention are more preferably the following compounds:
the pharmaceutically acceptable salt is a conventional non-toxic salt formed by reacting the compound with the general formula (I) and an inorganic acid or an organic acid. For example, the conventional non-toxic salts can be prepared by reacting the compound of formula (I) with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, or organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or sodium salt, potassium salt, calcium salt, aluminum salt or ammonium salt formed by the compound of the general formula (I) and propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid after forming ester and then forming inorganic base; or the methylamine salt, ethylamine salt or ethanolamine salt formed by the compound of the general formula (I) and organic base; or the compound of the general formula (I) forms ester with lysine, arginine and ornithine and then forms corresponding inorganic acid salt with hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid or forms corresponding organic acid salt with formic acid, acetic acid, picric acid, methanesulfonic acid and ethanesulfonic acid.
According to another aspect of the present invention, the present invention also provides a method for synthesizing a compound represented by formula I, wherein the reaction scheme is as follows:
step 1) carbomethoxy-substituted o-nitrofluorobenzene and corresponding amine compound
The compound of formula 2 can be obtained by condensation under the specific reaction conditions described in the references (Organic Letters,17(19), 4734-4737);
step 2) the compound of formula 2 is subjected to hydrogenation reduction to obtain the compound of formula 3, and the specific reaction conditions can be referred to in the literature (Organic & Biomolecular Chemistry,7(24), 5173-5183);
step 3) reaction of the compound of formula 3 with a substituted benzaldehyde
Condensation to obtain the compound of formula 4, wherein the specific reaction conditions can be found in literature (Tetrahedron,71(4), 532-538);
step 4) carrying out alkaline hydrolysis on the compound of the formula 4 to obtain a compound of a formula 5, wherein the specific reaction conditions can be referred to documents (ChemMedChem,1(9), 955-958);
step 5) condensing the compound of formula 5 with corresponding amine compound, wherein the specific reaction conditions can be referred to in the literature (Journal of Medicinal Chemistry,47(26),6451-6454), to obtain the target product compound of formula I.
Wherein substituent A, R2、R3And Ar is as defined above.
According to another aspect of the invention, the invention also provides the use of the compound shown in the formula I for preparing medicaments such as tumor treatment medicaments, antiviral medicaments, antibacterial medicaments, antiparasitic medicaments and/or blood pressure lowering medicaments.
Another aspect of the present invention is to provide a pharmaceutical composition comprising a compound represented by formula I, a pharmaceutically acceptable salt or solvate thereof as an active ingredient. The pharmaceutical composition comprises a therapeutically effective amount of the compound shown in the formula I, pharmaceutically acceptable salts or solvates thereof and pharmaceutical excipients. The term "effective amount" can refer to an amount effective at dosages and for periods of time necessary to achieve the desired effect. This effective amount may vary depending on factors such as the type of disease or the condition of the disease being treated, the particular target organ being administered, the size of the individual patient, or the severity of the disease or symptoms. One of ordinary skill in the art can empirically determine the effective amount of a particular compound without undue experimentation. The "pharmaceutical excipients" refer to various excipients conventionally used in medicines, such as excipients, controlled release agents, stabilizers, etc., which are within the conventional knowledge of those skilled in the art.
Preferably, the pharmaceutical composition comprising the compound represented by formula I according to the present invention can be used for the treatment of viral related diseases, bacterial related diseases, parasitic related diseases, atherosclerosis related diseases, thrombosis related diseases, hypertension related diseases.
The pharmaceutical composition according to the invention may be in the following dosage form: tablets such as, but not limited to, plain tablets, immediate release tablets, sustained release tablets, controlled release tablets, film coated tablets, sugar coated tablets, buccal tablets, sublingual tablets, bioadhesive tablets and the like; capsules such as, but not limited to, hard capsules, soft capsules, and the like; injections such as, but not limited to, sterile or bacteriostatic aqueous injections, oily injections, lyophilized injections, microspheres for injection, etc.; sprays such as, but not limited to, oral sprays, nasal sprays, topical skin sprays, and the like; aerosols such as, but not limited to, aerosols for pulmonary inhalation, topical skin aerosols, and the like; nasal drops such as, but not limited to, nasal drops gels, and the like; powder aerosols such as, but not limited to, powder aerosols for the cavity, powder aerosols for the nasal cavity, powder aerosols for the topical skin, and the like; suppository, patch, and gel for other body cavities such as vagina, rectum, and ear cavity. The preparation of these formulations is carried out by the person skilled in the art on the basis of the available knowledge or with reference to relevant textbooks or tool books or literature.
Advantageous effects
The kras-based drug research is a research difficulty of tumor treatment drugs, no successful drug is available on the market at present, and the compound provided by the invention has the advantages of remarkable proliferation capacity for inhibiting kras mutant tumor cells, stable structure, simple preparation and potential for developing novel antitumor drugs.
Detailed Description
Hereinafter, the present invention will be described in detail. Before the description is made, it should be understood that the terms used in the present specification and the appended claims should not be construed as limited to general and dictionary meanings, but interpreted based on the meanings and concepts corresponding to technical aspects of the present invention on the basis of the principle that the inventor is allowed to define terms appropriately for the best explanation. Accordingly, the description proposed herein is just a preferable example for the purpose of illustrations only, not intended to limit the scope of the invention, so it should be understood that other equivalents and modifications could be made thereto without departing from the spirit and scope of the invention.
The invention relates to 1-benzyl-2-phenyl benzimidazole derivatives have no literature report, the compounds shown in formula I according to the invention can selectively kill cancer cells with Ras gene mutation or inhibit the proliferation of the cancer cells; the mechanism of action of the agents of formula I includes, but is not limited to, inhibition of the interaction of kras protein with PDE.
The experimental procedures in the following examples are conventional unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
EXAMPLE 1 preparation of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-formylmorpholine (ZXY8008-1)
The synthetic route of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-formylmorpholine is shown below.
Step a: preparation of 3-benzylamino-4-nitro-benzoic acid methyl ester
9.9g (0.05mol) of methyl 3-fluoro-4-nitrobenzoate (10) was dissolved in 50ml of DMF, and 8.3g (0.06mol) of potassium carbonate and 6.4g (0.06mol) of benzylamine were added to react at 50 ℃ until the starting material disappeared, the reaction solution was poured into water, and a red-orange solid was obtained by filtration, 13.5g, yield: 94.6 percent.1H-NMR(400MHz,DMSO-d6)(ppm):8.73-8.70(t,1H,J＝5.72Hz),8.19-8.17(d,1H,J＝8.68Hz),7.43-7.43(d,1H,J＝1.68Hz),7.39-7.33(m,4H),7.28-7.24(m,1H),7.14-7.12(dd,1H,J＝8.68,1.68Hz),4.67-4.65(d,2H,J＝5.88Hz),3.81(s,3H)。
Step b: preparation of 3-benzylamino-4-amino-benzoic acid methyl ester
14.3g (0.05mol) of 3-benzylamino-4-nitro-methyl benzoate is placed in a 500ml reaction kettle, 3.6g (wet weight) of catalyst Raney nickel is taken and added into 200ml of methanol, the methanol is poured into the reaction kettle while stirring, hydrogen is introduced to react for 3 to 5 hours at 65 ℃, reaction liquid is filtered (a filter cake is washed by proper amount of methanol, the reaction liquid is decompressed and concentrated to obtain light yellow oily liquid, off-white solid is separated out by ether ultrasonic, and the white solid is filtered, dried and obtained by 11.5g, and the yield is 89.5%.1H-NMR(400MHz,CDCl3)(ppm):7.50-7.48(dd,1H,J＝8.12,1.96Hz),7.43-7.41(m,3H),7.39-7.35(m,2H),7.33-7.31(m,1H),6.72-6.70(d,1H,J＝8.16Hz),4.33(s,2H),3.86(s,3H),3.70(s,2H)。
Step c: preparation of 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxylic acid methyl ester
9.3g (0.04mol) of 3-benzylamino-4-amino-benzoic acid methyl ester are dissolved in 100ml of ethanol, 4.3g (0.04mol) of benzaldehyde are added, the mixture is refluxed until the raw materials disappear, the mixture is concentrated under reduced pressure, and the solid crude product is treated with ethanol: sonication with water 7:3, filtration and drying of the filter cake gave 11.5g of white solid, yield: 92.6 percent. 1H-NMR (400MHz, CDCl)3)(ppm):8.05-8.02(dd,1H,J＝8.44,1.4Hz),8.00-7.99(d,1H,J＝0.84Hz),7.88-7.86(d,1H,J＝8.4Hz),7.70-7.68(m,2H),7.50-7.43(m,3H),7.36-7.30(m,3H),7.09-7.07(dd,2H,J＝8.16,1.68Hz),5.501(s,2H),3.897(s,3H)。
Step d: preparation of 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxylic acid
11.5g (0.03mol) of 1-benzyl-2-phenyl-1H-benzo [ d ] are taken]Dissolving imidazole-6-carboxylic acid methyl ester in 300ml methanol, adding 1mol/L sodium hydroxide solution 65ml, reacting overnight at 65 ℃, acidifying the reaction solution with dilute hydrochloric acid until the pH value is about 4, precipitating a large amount of white solid, filtering,the filter cake was washed with water (25 ml. times.2) and dried to give 10.9g of a white solid, yield: 98.5 percent.1H-NMR(400MHz,DMSO-d6)(ppm):12.92(s,1H),8.09-8.08(d,1H,J＝1.12Hz),7.92-7.90(dd,1H,J＝8.4,1.4Hz),7.83-7.81(d,1H,J＝8.68Hz),7.78-7.76(m,2H),7.59-7.53(m,3H),7.33-7.24(m,3H),7.03-7.02(d,2H,J＝6.72Hz),5.70(s,2H)。
Step e: preparation of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-formylmorpholine
263mg (0.80mmol) of 1-benzyl-2-phenyl-1H-benzo [ d ] are taken]Imidazole-6-carboxylic acid and 77mg (0.88mmol) of morpholine are dissolved in 4ml of DMF and 184mg (0.96mmol) of EDCI, 130mg (0.96mmol) of HOBt, 30mg (0.24mmol) of DMAP are added and reacted at 50 ℃ overnight. The raw material disappears, the heating is stopped, the light brown oily matter is obtained by decompression and concentration, the crude product is separated and purified by column chromatography to obtain white solid, and the yield is as follows: 76.9%, melting point: 149-151 ℃ is adopted. ESI-HRMS (M/z) 398.1864[ M + H]+,1H-NMR(400MHz,CDCl3)(ppm):7.90-7.89(d,1H,J＝1.12Hz),7.70-7.68(m,2H),7.51-7.45(m,3H),7.38-7.31(m,4H),7.27-7.24(d,1H,J＝8.96Hz),7.10-7.08(dd,2H,J＝7.84,1.68Hz),5.48(s,2H),3.73(s,8H),13C-NMR(400MHz,CDCl3)(ppm):170.8,162.6,156.0,144.4,136.0,135.8,130.4,129.8,129.6,129.3,129.3,129.0,128.1,126.1,122.1,120.0,110.6,67.0,48.7。
Example 2 preparation of N- (3- (benzyloxy) -phenyl) 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8008-3)
With reference to the preparation and conditions of example 1, 3-benzyloxyaniline and 1-benzyl-2-phenyl-1H-benzo [ d ] were used]Performing amide condensation with imidazole-6-carboxylic acid as raw material, stopping heating, concentrating under reduced pressure to remove solvent, adding 20ml water into the concentrated oily liquid, ultrasonic treating for 15-20 min, precipitating solid, and drying to obtain white solidSolid, yield: 91.0%, melting point: 168-170 ℃. ESI-HRMS (M/z) 510.2176[ M + H]+,1H-NMR(400MHz,DMSO-d6)(ppm):10.20(s,1H),8.15(s,1H),7.95-7.92(dd,1H,J＝8.68,1.4Hz),7.87-7.85(d,1H,J＝8.4Hz),7.77-7.75(m,2H),7.57-7.52(m,4H),7.47-7.45(m,2H),7.42-7.23(m,8H),7.02-7.01(d,2H,J＝7Hz),6.77-6.75(dd,1H,J＝8.12,2.24Hz),5.69(s,2H),5.10(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):165.6,158.5,155.6,145.0,140.5,137.1,136.8,129.4,129.3,129.1,128.9,128.9,128.5,127.8,127.7,127.6,126.0,122.0,118.9,113.0,111.3,109.9,107.1,69.1,47.6。
EXAMPLE 3 preparation of tert-butyl (2- (1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamido) ethyl) carbamate (ZXY8011-1)
Referring to the experimental conditions and post-treatment method of example 2, N-Boc-ethylenediamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 90.2%, melting point: 179-182 ℃. ESI-HRMS (M/z) 471.2390[ M + H]+,1H-NMR(400MHz,CDCl3)(ppm):7.91(s,1H),7.86-7.84(d,1H,J＝8.4Hz),7.72-7.67(m,3H),7.52-7.44(m,3H),7.33-7.28(m,4H),7.06-7.05(d,2H),5.49(s,2H),5.06(m,1H),3.57-3.53(m,2H),3.40-3.39(m,2H),1.41(s,9H),13C-NMR(400MHz,CDCl3)(ppm):168.0,157.6,156.3,145.5,136.2,136.1,130.4,129.7,129.4,129.3,129.2,129.0,128.0,126.0,121.3,119.7,110.8,80.0,48.5,42.2,40.1,28.5。
EXAMPLE 4 preparation of N- (1H-benzo [ d ] imidazol-2-yl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8011-5)
With reference to the experimental conditions and work-up procedure of example 2, 2-amino-benzimidazole and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid is used as raw material to obtainWhite solid, yield: 87.1%, melting point: 250-253 ℃. ESI-HRMS (M/z) 444.1819[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.22(s,2H),8.43(s,1H),8.13-8.11(d,1H,J＝8.4Hz),7.86-7.84(d,1H,J＝8.4Hz),7.77-7.75(dd,2H,J＝7.56,2.24Hz),7.56-7.55(m,3H),7.46-7.44(dd,2H,J＝5.88,3.36Hz),7.35-7.25(m,3H),7.13-7.11(dd,2H,J＝5.88,3.12Hz),7.07-7.06(d,2H,J＝7Hz),5.67(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):155.8,145.6,136.8,135.8,130.3,129.7,129.1,129.0,128.9,128.4,127.7,126.1,122.9,121.5,119.0,113.4,111.8,47.8。
EXAMPLE 5 preparation of N- (3, 4-Dimethoxyphenethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazolecarboxamide (ZXY8013-1)
With reference to the experimental conditions and work-up procedure of example 2, 3, 4-dimethoxyphenethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to prepare a white solid with a yield: 90.8%, melting point: 164-166 ℃. ESI-HRMS (M/z) 492.2281[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.55-8.52(t,1H,J＝5.6Hz),8.04(s,1H),7.82-7.77(m,2H),7.75-7.72(dd,2H,J＝7.04,1.68Hz),7.55-7.51(m,3H),7.33-7.26(m,3H),7.01-6.99(d,2H,J＝7.04Hz),6.84-6.82(d,2H,J＝8.12Hz),6.74-6.72(dd,1H,J＝8.12,1.68Hz),5.63(s,2H),3.70(s,3H),3.68(s,3H),3.49-3.44(m,2H),2.79-2.76(t,2H,J＝7.28Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.2,155.3,148.6,147.2,144.7,136.8,135.8,132.1,129.1,129.0,128.9,127.6,125.9,121.6,120.5,118.8,112.5,111.8,110.6,55.5,55.3,47.6,41.3,34.8。
EXAMPLE 6 preparation of N- (4-phenoxyphenyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8013-2)
Reference to the implementationExample 2 Experimental conditions and work-up procedure 4-amino-diphenyl ether and 1-benzyl-2-phenyl-1H-benzo [ d ]]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 79.0%, melting point: 216-218 ℃. ESI-HRMS (M/z) 496.2020[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):10.3(s,1H),8.16(d,1H,J＝1.12Hz),7.96-7.94(dd,1H,J＝8.4,1.68Hz),7.87-7.85(d,1H,J＝8.4Hz),7.79-7.45(m,4H),7.56-7.52(m,3H),7.40-7.36(m,2H),7.33-7.23(m,3H),7.13-7.09(m,1H),7.05-6.98(m,6H),5.69(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):165.4,157.3,155.6,152.1,145.0,136.8,130.0,129.1,128.9,128.9,127.6,126.0,123.0,122.2,122.0,119.3,118.9,118.0,111.2,47.6。
Example 7 preparation of N- (4-fluorobenzyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8013-3)
With reference to the experimental conditions and the work-up procedure of example 2, p-fluorobenzylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 80.5%, melting point: 139 to 141 ℃. ESI-HRMS (M/z) 436.1820[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):9.07-9.04(t,1H,J＝5.6Hz),8.10(s,1H),7.88-7.86(d,1H,J＝8.4Hz),7.81-7.79(d,1H,J＝8.4Hz),7.74-7.72(m,2H),7.57-7.51(m,3H),7.37-7.23(m,5H),7.17-7.12(m,2H),7.01-6.99(d,2H,J＝7.28Hz),5.64(s,2H),4.47-4.46(d,2H,J＝5.6Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.2,162.64,155.4,144.8,136.8,136.0,135.9,130.2,129.8,129.3,129.202,129.1,128.9,128.9,128.8,127.6,125.9,121.6,118.8,115.1,114.9,110.8,47.6,42.1。
EXAMPLE 8 preparation of (S) -N- (1-phenylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-1)
Referring to the experimental conditions and post-treatment method of example 2, R (+) -alpha-phenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 92.5%, melting point: 177-178 ℃. ESI-HRMS (M/z) 432.2070[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.792-8.772(d,1H,J＝7.84Hz),8.079(s,1H),7.91-7.89(d,1H,J＝8.4Hz),7.80-7.78(d,1H,J＝8.4Hz),7.75-7.73(d,2H,J＝5.6Hz),7.59-7.52(m,3H),7.40-7.38(m,2H),7.33-7.19(m,6H),7.00-6.99(d,2H,J＝7.32Hz),5.65(s,2H),5.23-5.17(m,1H),1.50-1.48(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):165.5,155.3,145.1,144.8,136.8,135.9,130.2,129.8,129.1,128.9,128.9,128.3,127.6,126.6,126.1,126.0,121.8,118.7,110.9,48.6,47.6,22.3。
EXAMPLE 9 preparation of (R) -N- (1-phenylpropyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-2)
Referring to the experimental conditions and post-treatment method of example 2, R (+) -1-amphetamine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 92.1%, melting point: 178-181 ℃. ESI-HRMS (M/z) 446.2227[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.72-8.70(d,2H,J＝8.4Hz),8.05(s,1H),7.904-7.88(dd,1H,J＝8.4,1.4Hz),7.80-7.78(d,1H,J＝8.4Hz),7.75-7.73(m,2H),7.55-7.51(m,3H),7.40-7.38(d,2H,J＝7.28Hz),7.33-7.19(m,6H),7.01-6.99(d,2H,J＝7Hz),5.64(s,2H)4.96-4.92(m,1H),1.90-1.78(m,2H),0.92-0.88(t,3H,J＝7.28Hz),13C-NMR(400MHz,DMSO-d6)(ppm):165.93,155.3,144.7,144.2,136.8,135.8,130.2,129.8,129.1,129.1,128.9,128.2,127.6,126.6,126.0,121.7,118.7,111.0,55.0,47.6,29.0,11.5。
EXAMPLE 10 preparation of (R) -N- (1-phenylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-3)
Referring to the experimental conditions and post-treatment method of example 2, S (-) -alpha-phenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d-]Imidazole-6-carboxylic acid is used as a raw material to obtain a light yellow solid, and the yield is as follows: 95.9%, melting point: 191-193 ℃. ESI-HRMS (M/z) 432.2071[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.81-8.79(d,1H,J＝7.56Hz),8.09(s,1H),7.92-7.90(d,1H,J＝8.4Hz),7.81-7.79(d,1H,J＝8.4Hz),7.75-735(d,2H,J＝5.0Hz),7.53(s,3H),7.40-7.38(d,2H,J＝7Hz),7.33-7.21(m,6H),7.01-6.99(d,2H,J＝6.72Hz),5.65(s,2H),5.22-5.18(m,1H),1.50-1.48(d,3H,J＝6.44Hz),13C-NMR(400MHz,CDCl3)(ppm):166.7,156.4,143.4,136.3,136.0,130.5,129.6,129.4,129.3,129.2,129.0,128.8,128.0,127.5,126.4,126.0,120.9,119.6,111.1,49.5,48.5,21.9。
EXAMPLE 11 preparation of (R) -N- (1- (1H-benzo [ d ] imidazol-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-4)
With reference to the experimental conditions and the work-up procedure of example 2, the (R) - (+) -2- (. alpha. -methylamine) -1H-benzo [ d ] compound was prepared]Imidazole and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 85.7%, melting point: 290-292 deg.C. ESI-HRMS (M/z) 472.2132[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.28(s,1H),8.98-8.96(d,1H,J＝7.84Hz),8.19(s,1H),7.99-7.96(dd,1H,J＝8.44,1.12Hz),7.83-7.81(d,1H,J＝8.68Hz),7.75-7.73(m,2H),7.54-7.50(m,5H),7.32-7.22(m,3H),7.15-7.12(dd,2H,J＝5.88,3.08Hz),7.00-6.98(d,2H,J＝7.28Hz),5.66(s,2H),5.49-5.41(m,1H),1.66-1.65(d,3H,J＝7Hz)。
EXAMPLE 12 preparation of N- (2-bromophenylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8015-5)
With reference to the experimental conditions and work-up procedure of example 2, o-bromophenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 91.7%, melting point: 147-149 ℃. ESI-HRMS (M/z) 512.1161[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.84-7.82(d,1H,J＝8.4Hz),7.81-7.81(d,1H,J＝1.12Hz),7.69-7.67(dd,2H,J＝8.4,1.12Hz),7.60-7.57(dd,1H,J＝8.4,1.4Hz),7.54-7.52(dd,1H,J＝8.12,1.12Hz),7.50-7.43(m,3H),7.35-7.29(m,3H),7.26-7.18(m,2H),7.10-7.05(m,3H),6.35-6.32(m,1H),5.49(s,2H),3.75-3.70(m,2H),3.10-3.07(t,2H,J＝6.72Hz),13C-NMR(400MHz,CDCl3)(ppm):167.8,156.3,138.5,133.0,131.1,130.4,129.5,129.3,129.2,128.9,128.4,128.0,127.7,125.9,121.1,119.6,110.7,48.4,40.1,35.7。
Example 13 preparation of N- (3H-1,2, 4-Triazol-3-yl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8020-2)
To 263mg (0.80mmol) of 1-benzyl-2-phenyl-1H-benzo [ d]Adding 5ml of toluene and 0.5ml of thionyl chloride into imidazole-6-carboxylic acid, reacting for 2-3 hours at 80 ℃, concentrating under reduced pressure to remove the thionyl chloride, dissolving 75mg (0.88mmol) of 3-amino-1, 2,4 triazole in 5ml of dichloromethane, adding 0.5ml of pyridine, diluting the newly prepared acyl chloride with dichloromethane at 0 ℃, and slowly dropping the diluted acyl chloride into an amine solution. After the reaction, the reaction solution was transferred to a separatory funnel, the organic phase (15ml × 2) was washed with water, the aqueous phases were combined and extracted with 10ml dichloromethane, the organic phases were combined, washed with saturated sodium chloride, dried, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain a white solid, yield: 74.8%, melting point: 200-203 ℃. ESI-HRMS (M/z) 395.1615[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):8.318(s,1H),8.06-8.02(dd,1H,J＝8.68,1.4Hz),7.86-7.56(m,9H),7.32-7.25(m,3H),7.05-7.03(d,2H,J＝7Hz),5.66(s,2H),13C-NMR(400MHz,DMSO-d6)(ppm):167.7,158.4,156.5,151.2,146.0,136.4,135.1,130.4,129.5,129.2,128.9,127.7,126.3,125.8,125.3,118.5,115.2,47.8。
Example 14 preparation of (R) -N- (1- (3H-imidazo [4,5-c ] pyridin-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8022)
With reference to the experimental conditions and the work-up procedure of example 2, the reaction mixture was prepared with (R) - (+) -2- (. alpha. -methylamine) -1H-pyridoimidazole and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-6-carboxylic acid as a raw material to obtain a white solid with a yield: 70.0%, melting point: 270-273 ℃. ESI-HRMS (M/z) 473.2082[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.68(s,1H),9.01-8.99(d,1H,J＝7.56Hz),8.85(s,1H),8.27-8.26(d,1H,J＝3.92Hz),8.17(s,1H),7.98-7.96(d,1H,J＝8.12Hz),7.83-7.81(d,1H,J＝8.68Hz),7.75-7.73(d,2H,J＝5.36Hz),7.54(s,3H),7.47(s,1H),7.30-7.24(m,3H),7.00-6.98(d,2H,J＝6.72Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.0,155.4,144.9,136.8,135.8,130.2,129.7,129.0,128.9,128.8,128.4,127.6,125.9,122.1,118.7,111.0,47.5,44.1,19.3。
Example 15 preparation of N- (4- (methylsulfonyl) phenyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8024)
With reference to the experimental conditions and working up procedure of example 13, 4-methanesulfonylaniline and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 77.8%, melting point: 287-289 deg.C. ESI-HRMS (M/z) 482.1533[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):10.63(s,1H),8.20-8.19(d,1H,J＝1.28Hz),8.06-8.04(m,2H),7.99-7.96(dd,1H,J＝8.72,1.68Hz),7.92-7.88(m,3H),7.78-7.76(m,2H),7.57-7.53(m,3H),7.33-7.25(m,3H),7.03-7.01(d,2H,J＝7Hz),5.71(s,2H),3.19(s,3H),13C-NMR(400MHz,DMSO-d6)(ppm):166.1,155.8,145.3,143.9,136.7,135.9,134.9,130.3,129.6,129.1,128.9,128.7,128.1,127.6,126.0,122.2,120.1,119.0,111.6,47.6,43.8。
Example 16 preparation of N- (2- (dimethylamino) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8026-3)
With reference to the experimental conditions and working up procedure of example 13, 2-aminoimidazole and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 91.7%, melting point: 125-128 ℃. ESI-HRMS (M/z) 399.2179[ M + H]+,1H-NMR(400MHz,DMSO-d6)(ppm):8.42-8.39(t,1H,J＝5.6Hz),8.04(m,1H),7.83-7.72(m,4H),7.55-7.50(m,3H),7.33-7.23(m,3H),7.01-6.99(d,2H,J＝7.04Hz),5.64(s,2H),3.39-3.34(m,2H),2.43-2.39(t,2H,J＝7Hz),2.18(s,6H),13C-NMR(400MHz,DMSO-d6)(ppm):166.1,155.3,144.7,136.8,135.8,130.2,129.8,129.1,129.0,128.9,127.6,125.9,121.5,118.7,110.7,58.3,47.5,45.3,37.5。
Example 17 preparation of (1-benzyl-2-phenyl-1H-benzo [ d ] imidazol-6-yl) (4-ethylpiperazin-1-yl) methanone (ZXY8026-4)
With reference to the experimental conditions and working up procedure of example 13, 4-amino-6-chloropyrimidine and 1-benzyl-2-phenyl-1H-benzo [ d ] was used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 93.3%, melting point: 126-128 ℃. ESI-HRMS (M/z) 425.2336[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):7.78-7.74(m,3H),7.56-7.54(m,3H),7.51(s,1H),7.30-7.22(m,4H),7.01-6.99(d,2H,J＝7.28Hz),5.63(s,2H),3.58-3.27(m,5H),2.35-2.30(m,6H),1.01-0.97(t,3H,J＝7.28Hz)。
EXAMPLE 18 preparation of N- (1-methylpiperidin-4-yl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY5049-1)
With reference to the experimental conditions and work-up procedure of example 13, 4-amino-1-methylpiperidine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 79.9%, melting point: 222-224 ℃. ESI-HRMS (M/z) 425.2336[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.86-7.83(m,2H),7.69-7.67(m,2H),7.63-7.61(d,1H,J＝8.44Hz),7.51-7.44(m,3H),7.32-7.28(m,3H),7.06-7.04(d,2H,J＝6.44Hz),6.18-6.16(d,1H,J＝7Hz),5.49-5.48(m,2H),3.99-3.97(m,1H),2.83-2.80(d,2H),2.30-2.30(s,3H),2.17-2.12(m,2H),2.04-2.01(m,2H),1.62-1.54(m,2H),13C-NMR(400MHz,CDCl3)(ppm):167.0,156.2,145.4,136.1,136.0,130.3,129.6,129.2,129.1,128.8,127.9,125.9,120.9,119.5,110.8,54.6,48.3,46.8,46.3,32.3。
EXAMPLE 19 preparation of N- (3-fluorophenethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY5049-2)
With reference to the experimental conditions and working up procedure of example 13, 3-fluorophenylethylamine and 1-benzyl-2-phenyl-1H-benzo [ d ] amine]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 83.8%, melting point: 176-178 ℃. ESI-HRMS (M/z) 450.1975[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.83-7.80(m,2H),7.69-7.67(m,2H),7.56-7.53(dd,1H,J＝8.4,1.4Hz),7.54-7.43(m,3H),7.34-7.21(m,4H),7.06-7.04(dd,2H,J＝7.84,1.96Hz),6.99-6.98(d,1H,J＝7.56Hz),6.94-6.90(m,2H),6.35-6.32(t,1H,J＝5.6Hz),5.48(s,2H),3.71-3.66(m,2H),2.93-2.90(t,2H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):167.7,164.2,161.7,156.3,130.4,129.4,129.2,129.2,128.9,128.0,125.9,124.5,121.0,119.6,115.8,115.5,110.7,48.4,41.1,35.5。
EXAMPLE 20 preparation of N- (2-morpholinylethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY5049-3)
With reference to the experimental conditions and working up procedure of example 13, N- (2-aminoethyl) morpholine and 1-benzyl-2-phenyl-1H-benzo [ d ] is used]Imidazole-6-carboxylic acid is used as a raw material, a white solid is prepared by an acyl chloride method, and the yield is as follows: 83.8%, melting point: 169-171 ℃. ESI-HRMS (M/z) 441.2286[ M + H]+；1H-NMR(400MHz,CDCl3)(ppm):7.89-7.87(d,1H,J＝8.44Hz),7.86-7.85(d,1H,J＝1.12Hz),7.71-7.69(m,2H),7.66-7.64(dd,1H,J＝8.68,1.68Hz),7.53-7.44(m,3H),7.35-7.29(m,3H),7.09-7.07(dd,2H,J＝8.12,1.96Hz),6.90(s,1H),5.51(s,2H),3.71-3.69(t,4H,J＝4.48Hz),3.57-5.33(m,2H),2.62-2.5(t,4H,J＝5.88Hz),2.50(s,4H),13C-NMR(400MHz,CDCl3)(ppm):167.5,156.4,145.5,136.2,136.0,130.4,129.6,129.5,129.3,129.2,129.0,128.0,125.9,120.9,119.7,110.8,67.1,56.9,53.3,48.5,36.2。
Example 21 preparation of N- (2- ((7-nitrobenzo [ c ] [1,2,5] oxadiazole) -4-amino) ethyl) 1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-6-carboxamide (ZXY8027)
400mg of (2- (1-benzyl-2-phenyl-1H-benzo [ d ] are taken]Imidazole-6-formamido) ethyl) carbamic acid tert-butyl ester is added with 5ml of 4mol/L hydrochloric acid and 5ml of dichloromethane, stirred overnight at room temperature, the next day, adjusted pH to 7-8 by 1mol/L sodium hydroxide, the water layer is extracted by dichloromethane (15ml multiplied by 2), the organic phases are combined, washed by saturated sodium chloride, dried by the organic phase, filtered and concentrated under reduced pressure to obtain white solid. 223mg (0.6mmol) and 120mg (0.6mmol) of 4-chloro-7-nitrobenzene are weighed out from the mixtureAnd 2-oxa-1, 3-diazole was dissolved in 10ml of dichloromethane, 0.5ml of triethylamine was added thereto, and the reaction was carried out at room temperature for 3 hours. Transferring the reaction solution to a separating funnel, washing twice (10ml multiplied by 2), extracting the water phase with 10ml dichloromethane, combining the organic phases, washing with saturated sodium chloride, drying the organic phases, filtering, concentrating the organic phases under reduced pressure, and separating and purifying the crude product by column chromatography to obtain a dark brown solid 91mg, yield: 48.8 percent. ESI-HRMS (M/z) 534.1885[ M + H]+,1H-NMR(400MHz,DMSO-d6)(ppm):9.56(s,1H),8.74-8.72(m,1H),8.52-8.50(d,1H,J＝8.96Hz),8.011(s,1H),7.79(s,2H),7.74-7.72(m,2H),7.56-7.51(m,3H),7.32-7.23(m,3H),6.99-6.97(d,2H,J＝6.72Hz),6.52-6.49(d,1H,J＝8.96Hz),5.63(s,2H),3.68-3,58(m,4H)。
EXAMPLE 22 preparation of N-1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-5-formylmorpholine
Using 1-benzyl-2-phenyl-1H-benzo [ d ]]Imidazole-5-carboxylic acid was synthesized using an amide condensation method analogous to step e of the synthetic method in example 1, with morpholine and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-5-carboxylic acid is used as a raw material to prepare a target compound, and the target compound is separated and purified by column chromatography to obtain a white solid, wherein the yield is as follows: 77.9%, melting point: 147-150 ℃. ESI-HRMS (M/z) 398.1863[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):7.78(s,1H),7.75-7.73(m,2H),7.56-7.52(m,4H),7.32-7.24(m,4H),7.02-7.00(d,2H,J＝8.12Hz),5.62(s,2H),3.61(s,8H),13C-NMR(400MHz,DMSO-d6)(ppm):169.6,154.6,142.0,136.7,136.6,130.1,129.8,129.7,129.1,128.8,127.6,126.2,122.1,118.3,111.2,66.1,47.6。
EXAMPLE 23 preparation of (S) -N- (1- (1H-benzo [ d ] imidazol-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-5-carboxamide
Preparation of 1-benzyl-2-phenyl Using the above method-1H-benzo [ d]Imidazole-5-carboxylic acid with (R) - (+) -2- (. alpha. -methylamine) -1H-benzimidazole and 1-benzyl-2-phenyl-1H-benzo [ d]Imidazole-5-carboxylic acid was used as starting material to prepare the title compound in a similar manner to example 11, giving a white solid in yield: 85.1%, melting point: 250-252 ℃. ESI-HRMS (M/z) 472.2132[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.26(s,1H),9.01-8.99(d,1H,J＝7.84Hz),8.43(s,1H),7.91-7.88(dd,1H,J＝8.4,1.12Hz),7.76-7.74(dd,2H,J＝7.56,3.92Hz),7.60-7.52(m,6H),7.30-7.23(m,3H),7.15-7.13(m,2H),6.98-6.96(d,2H,J＝7Hz),5.65(s,2H),5.50-5.43(m,1H),1.68-1.66(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.4,156.3,154.8,138.0,136.7,130.1,129.1,128.9,128.8,128.6,127.6,126.6,122.7,121.4,119.2,110.7,47.6,44.1,19.7。
EXAMPLE 24 preparation of (S) -N- (1- (3H-imidazo [4,5-c ] pyridin-2-yl) ethyl) -1-benzyl-2-phenyl-1H-benzo [ d ] imidazole-5-carboxamide
With (R) - (+) -2- (. alpha. -methylamine) -1H-pyridoimidazole (24) and 1-benzyl-2-phenyl-1H-benzo [ d ]]Imidazole-5-carboxylic acid was used as starting material and the title compound was prepared in analogy to example 14, giving a white solid in yield: 77.3%, melting point: 155-157 ℃. ESI-HRMS (M/z) 473.2084[ M + H]+；1H-NMR(400MHz,DMSO-d6)(ppm):12.71(s,1H),9.07～9.05(d,1H,J＝7.6Hz),8.86(s,1H),8.43～8.43(d,1H,J＝1.12Hz),8.28～8.26(d,1H,J＝5.6Hz),7.9～7.87(dd,1H,J＝8.4,1.4Hz),7.76～7.73(m,2H),7.60～7.58(d,1H,J＝8.4Hz),7.57～7.49(m,3H),7.30～7.23(m,3H),6.98～6.96(d,2H,J＝8.4Hz),5.65(s,2H),5.51～5.44(m,1H),1.70～1.68(d,3H,J＝7Hz),13C-NMR(400MHz,DMSO-d6)(ppm):166.5,154.9,138.1,136.8,129.8,129.1,128.9,128.9,128.5,127.6,126.1,122.8,119.2,110.8,47.7,44.2,19.4。
Test example 1: antitumor Activity test
The Kras gene mutation leads to the enhancement of the function of Kras protease, and further leads to the uncontrolled proliferation and differentiation of cells, so that tumor cell strains positive to Kras mutation are more sensitive to the cytotoxicity of the Kras inhibitor. Based on this, we performed biological activity tests, and selected Panc-tu-1 positive for kras mutation and Panc-1 negative for kras mutation for comparative study to determine cytotoxicity. The results are given in table 1 below.
Table 1 partial compound cytotoxicity test results
Test example 2: test for antitumor Activity of Compound
The tested cells comprise MDA-MB-231 and LM 3; the cell culture and experiment method comprises inoculating cells into DMEM cell culture solution containing 10% fetal calf serum (supplemented with streptomycin stock solution 5ml/500ml), and placing at 37 deg.C and containing 5% CO2In the cell culture chamber, the medium was changed every 1 to 2 days, digested with 0.25% trypsin, passaged and collected. Cells in logarithmic growth phase are prepared into cell suspension with proper concentration by DMEM cell culture solution containing 10% fetal calf serum, 2500-4000 cells (100 mu l) per well are added into a 96-well cell culture plate, after overnight culture, 100 mu l of culture medium containing different concentrations of test substances is added into each well, and 4 parallel wells are arranged for each concentration. And (3) adding the cell into the culture medium for culturing for 72 hours, then discarding the supernatant, adding 100 mu l of newly-configured serum-free culture solution of 0.5-0.55mg/ml tetrazolium blue (MTT) into each hole, culturing for 4 hours at 37 ℃, then discarding the supernatant, adding 200 mu l of DMSO-soluble formazan into each hole, and measuring the absorbance value by an enzyme-labeling instrument at the wavelength of 570 nm. Preparing the medicine: taking the guiding of the guiding principle discussion draft of antitumor drug efficacy and the guiding principle of non-clinical research technology of cytotoxic antitumor compounds as guidance, diluting a tested compound to 20mg/ml by using a cosolvent DMSO according to the result of a preliminary test, taking 10 mul of diluent, then adding 990 mul of culture medium for preliminary dilution, further diluting the diluent to different concentrations of the tested compound by using the culture medium according to the required concentration, and additionally arranging a blank control group. Data processing, wherein the data is expressed by +/-S; inhibition rate (control group OD value-administration group OD value)/control group OD value × 100%; index of Effect of CompoundThe half concentration (IC50) was used to represent the measured maximum inhibition ratio (Imax). The half-effect concentration (IC50, μ g/ml) was determined by plotting using Origin software and fitting a four parameter Logistic program in the software to the tumor cell growth curve. The results are shown in Table 2 below.
TABLE 2 Experimental results of the inhibition of tumor cell proliferation by the compounds
On the basis of primary screening, the representative compound is tested in tumor cell strains MDA-MB-231 and LM3 with high malignancy degree, the IC50 for inhibiting cell proliferation is nM grade, the capability of inhibiting tumor cell proliferation is very strong, and good development potential of antitumor drugs is shown.
Claims (5)
1. A benzimidazole derivative represented by formula I, pharmaceutically acceptable salts thereof:
wherein A is-NH-R4;
wherein R4 is selected from the group consisting of substituted or unsubstituted C5-C8 aryl, substituted or unsubstituted C6-C10 alkylaryl, substituted or unsubstituted eight to ten membered fused ring group containing 1 to 3 heteroatoms selected from S, N and O;
r2 is selected from hydrogen, Ar is phenyl,
r3 is selected from the group consisting of hydrogen,
wherein "substituted" means substituted with 1 to 3 substituents which may be the same or different, selected from the group consisting of amino, halogen, nitro, sulfonyl, C1-C6 alkoxy, C5-C7 aryl-substituted C1-C6 alkoxy, C5-C7 aryl;
the halogen is selected from F, Cl or Br.
2. Benzimidazole derivatives and pharmaceutically acceptable salts thereof, wherein the benzimidazole derivatives are selected from the following compounds:
3. a method for synthesizing benzimidazole derivatives represented by formula I and pharmaceutically acceptable salts thereof according to claim 1, wherein the reaction scheme is as follows:
step 1) condensing methyl formate substituted o-nitrofluorobenzene and a corresponding amine compound to obtain a compound shown in a formula 2;
step 2) carrying out hydrogenation reduction on the compound of the formula 2 to obtain a compound of a formula 3;
step 3) condensing the compound of the formula 3 with substituted benzaldehyde to form a ring to obtain a compound of a formula 4;
step 4), carrying out alkaline hydrolysis on the compound of the formula 4 to obtain a compound of a formula 5;
step 5) condensing the compound of the formula 5 with a corresponding amine compound to obtain a target product, namely a compound of a formula I;
wherein substituent A, R2、R3And Ar is as defined in claim 1.
4. Use of a benzimidazole derivative of formula I or 2 according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of tumors.
5. A pharmaceutical composition comprising a therapeutically effective amount of a benzimidazole derivative of formula I or of claim 2, or a pharmaceutically acceptable salt thereof, according to claim 1, and a pharmaceutical adjuvant.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710508016.7A CN107311933B (en) | 2017-06-28 | 2017-06-28 | Benzimidazole derivative, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710508016.7A CN107311933B (en) | 2017-06-28 | 2017-06-28 | Benzimidazole derivative, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107311933A CN107311933A (en) | 2017-11-03 |
| CN107311933B true CN107311933B (en) | 2020-12-22 |
Family
ID=60179609
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710508016.7A Active CN107311933B (en) | 2017-06-28 | 2017-06-28 | Benzimidazole derivative, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107311933B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3833439B1 (en) * | 2018-08-08 | 2023-07-12 | Bristol-Myers Squibb Company | Benzimidazole inhibitors of pad enzymes |
| CN114671858B (en) * | 2022-03-07 | 2023-08-08 | 华中师范大学 | A kind of benzimidazole compound and its preparation method and application |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0508586B1 (en) * | 1991-03-08 | 1995-05-31 | Fgn, Inc. | Substituted indenyl compounds |
| CN1211238A (en) * | 1995-12-28 | 1999-03-17 | 藤泽药品工业株式会社 | Benzimidazole derivatives |
| US6211177B1 (en) * | 1998-11-24 | 2001-04-03 | Cell Pathways, Inc. | Method for treating neoplasia by exposure to substituted 2-aryl-benzimidazole derivatives |
| EP1214330A1 (en) * | 1999-09-21 | 2002-06-19 | LION Bioscience AG | Benzimidazole derivatives and combinatorial libraries thereof |
| WO2003053938A1 (en) * | 2001-12-20 | 2003-07-03 | Novo Nordisk A/S | Benzimidazols and indols as glucagon receptor antagonists/inverse agonisten |
| WO2005066151A2 (en) * | 2003-12-19 | 2005-07-21 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| WO2007043653A1 (en) * | 2005-10-13 | 2007-04-19 | Taisho Pharmaceutical Co., Ltd. | Benzimidazole-5-carboxamide derivative |
-
2017
- 2017-06-28 CN CN201710508016.7A patent/CN107311933B/en active Active
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0508586B1 (en) * | 1991-03-08 | 1995-05-31 | Fgn, Inc. | Substituted indenyl compounds |
| CN1211238A (en) * | 1995-12-28 | 1999-03-17 | 藤泽药品工业株式会社 | Benzimidazole derivatives |
| US6211177B1 (en) * | 1998-11-24 | 2001-04-03 | Cell Pathways, Inc. | Method for treating neoplasia by exposure to substituted 2-aryl-benzimidazole derivatives |
| EP1214330A1 (en) * | 1999-09-21 | 2002-06-19 | LION Bioscience AG | Benzimidazole derivatives and combinatorial libraries thereof |
| WO2003053938A1 (en) * | 2001-12-20 | 2003-07-03 | Novo Nordisk A/S | Benzimidazols and indols as glucagon receptor antagonists/inverse agonisten |
| WO2005066151A2 (en) * | 2003-12-19 | 2005-07-21 | Takeda San Diego, Inc. | Histone deacetylase inhibitors |
| WO2007043653A1 (en) * | 2005-10-13 | 2007-04-19 | Taisho Pharmaceutical Co., Ltd. | Benzimidazole-5-carboxamide derivative |
Non-Patent Citations (4)
| Title |
|---|
| "Quality control in combinatorial chemistry: determination of the quantity, purity, and quantitative purity of compounds in combinatorial libraries";Yan, Bing, et al.;《Journal of combinatorial chemistry》;20031231;第5卷(第5期);547-559 * |
| "Synthesis of some new benzimidazolecarboxamides and evaluation of their antimicrobial activity";Göker, Hakan, et al.;《IL farmaco》;19981231;第53卷(第1期);415-420 * |
| "Synthesis, characterization and evaluation of benzimidazole derivative and its precursors as inhibitors of MDA-MB-231 human breast cancer cell proliferation.";Thimmegowda, N. R., et al.;《Bioorganic & medicinal chemistry letters》;20081231;第18卷(第1期);432-435 * |
| "Traceless solid-phase synthesis of substituted benzimidazoles via a base-cleavable linker.";Tumelty, David, Kathy Cao, and Christopher P. Holmes.;《Organic letters》;20011231;第3卷(第1期);83-86 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107311933A (en) | 2017-11-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8084454B2 (en) | Compounds with anti-cancer activity | |
| JP7026787B2 (en) | A novel heteroarylamide derivative as a selective inhibitor of histone deacetylase 1 and / or 2 (HDAC1-2) | |
| WO2019042444A1 (en) | Compound for inhibiting and degrading tyrosine protein kinase alk | |
| WO2010139180A1 (en) | Naphthalene carboxamide derivatives as inhibitors of protein kinase and histone deacetylase, preparation methods and uses thereof | |
| AU2013326850B2 (en) | Novel compounds, their preparation and their uses | |
| WO2011043359A1 (en) | Pharmaceutical product containing aromatic heterocyclic compound | |
| CN113444069B (en) | 2-aryl-4- (1H-pyrazol-3-yl) pyridine LSD1/HDAC double-target inhibitor | |
| WO2020221006A1 (en) | Bet inhibitor, and preparation method and use thereof | |
| CN109574936B (en) | A kind of hydroxamic acid compound with HDAC6 inhibitory activity and its application | |
| CN117651552A (en) | Therapeutic or prophylactic agent for covd-19 | |
| CN114957383A (en) | Peptide-like compound, preparation method thereof, pharmaceutical composition and application | |
| CN113620930A (en) | Compound containing sulfonamide structure, preparation method and application thereof, and pharmaceutical composition and application thereof | |
| CN107311933B (en) | Benzimidazole derivative, preparation method and application thereof | |
| CN117580831A (en) | GRK2 inhibitors and uses thereof | |
| JP6987125B2 (en) | New 2,4,6-trisubstituted s-triazine compound and its production method and use | |
| WO2023091565A1 (en) | Nsd2-targeted chemical degraders and compositions and methods of use thereof | |
| CN108069954A (en) | The quinazolinones of the donor containing NO | |
| CN113880772A (en) | A class of CDK kinase inhibitors and their applications | |
| CN116348114A (en) | Thiobenzimidazole derivatives or pharmaceutically acceptable salts thereof and use thereof | |
| WO2012130159A1 (en) | Aminopyridine derivatives and uses thereof | |
| CN106496132B (en) | N- (4-substituted phenyl) -2-substituted acetamide compound and application thereof as SIRT2 protein inhibitor | |
| CN117946165A (en) | Novel structural compound AXL inhibitor and application thereof | |
| WO2017097215A1 (en) | Wnt pathway inhibitor embedded with ureas structure | |
| CN117486813A (en) | N-disubstituted phenyl acrylamide compounds and pharmaceutical compositions and uses thereof | |
| WO2014190872A1 (en) | Selenium-containing compounds and pharmaceutical use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |