CN113816903A - 一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用 - Google Patents
一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用 Download PDFInfo
- Publication number
- CN113816903A CN113816903A CN202111118063.3A CN202111118063A CN113816903A CN 113816903 A CN113816903 A CN 113816903A CN 202111118063 A CN202111118063 A CN 202111118063A CN 113816903 A CN113816903 A CN 113816903A
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- China
- Prior art keywords
- tetrahydroisoquinoline
- pharmaceutically acceptable
- acid
- compound
- cells
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
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- -1 Tetrahydroisoquinoline stilbene compound Chemical class 0.000 title claims abstract description 40
- UWYZHKAOTLEWKK-UHFFFAOYSA-N tetrahydro-isoquinoline Natural products C1=CC=C2CNCCC2=C1 UWYZHKAOTLEWKK-UHFFFAOYSA-N 0.000 title claims abstract description 20
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 title claims abstract description 19
- 235000021286 stilbenes Nutrition 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 230000000694 effects Effects 0.000 claims abstract description 13
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 5
- 210000004881 tumor cell Anatomy 0.000 claims abstract description 5
- 210000004027 cell Anatomy 0.000 claims description 35
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 201000005202 lung cancer Diseases 0.000 claims description 5
- 208000020816 lung neoplasm Diseases 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 229910052783 alkali metal Inorganic materials 0.000 claims description 4
- 150000001340 alkali metals Chemical class 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims description 4
- 150000007522 mineralic acids Chemical class 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 3
- 229910052736 halogen Inorganic materials 0.000 claims description 3
- 150000002367 halogens Chemical class 0.000 claims description 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 3
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000002246 antineoplastic agent Substances 0.000 claims description 2
- 229940041181 antineoplastic drug Drugs 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- 239000011976 maleic acid Substances 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 239000011591 potassium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 9
- 229940079593 drug Drugs 0.000 abstract description 7
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 230000000144 pharmacologic effect Effects 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 36
- 238000006243 chemical reaction Methods 0.000 description 23
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- 238000003786 synthesis reaction Methods 0.000 description 15
- 239000007787 solid Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 229960001338 colchicine Drugs 0.000 description 9
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 8
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 229930012538 Paclitaxel Natural products 0.000 description 5
- 229960001592 paclitaxel Drugs 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- 102000004243 Tubulin Human genes 0.000 description 4
- 108090000704 Tubulin Proteins 0.000 description 4
- YHESWIOKPVFEEN-VAWYXSNFSA-N [6,7-dimethoxy-1-(4-methylphenyl)-3,4-dihydro-1H-isoquinolin-2-yl]-[4-[(E)-2-phenylethenyl]phenyl]methanone Chemical compound CC1=CC=C(C(C(C(CC2)=C3)=CC(OC)=C3OC)N2C(C2=CC=C(/C=C/C3=CC=CC=C3)C=C2)=O)C=C1 YHESWIOKPVFEEN-VAWYXSNFSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- IAGXTPCOGVFRSQ-VOTSOKGWSA-N 4-[(e)-2-phenylethenyl]benzoic acid Chemical compound C1=CC(C(=O)O)=CC=C1\C=C\C1=CC=CC=C1 IAGXTPCOGVFRSQ-VOTSOKGWSA-N 0.000 description 3
- NQUVCRCCRXRJCK-UHFFFAOYSA-N 4-methylbenzoyl chloride Chemical compound CC1=CC=C(C(Cl)=O)C=C1 NQUVCRCCRXRJCK-UHFFFAOYSA-N 0.000 description 3
- YGLKVQPJAUSVRD-UHFFFAOYSA-N 6,7-dimethoxy-1-(4-methylphenyl)-3,4-dihydroisoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCN=C1C1=CC=C(C)C=C1 YGLKVQPJAUSVRD-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- JXLYSJRDGCGARV-WWYNWVTFSA-N Vinblastine Natural products O=C(O[C@H]1[C@](O)(C(=O)OC)[C@@H]2N(C)c3c(cc(c(OC)c3)[C@]3(C(=O)OC)c4[nH]c5c(c4CCN4C[C@](O)(CC)C[C@H](C3)C4)cccc5)[C@@]32[C@H]2[C@@]1(CC)C=CCN2CC3)C JXLYSJRDGCGARV-WWYNWVTFSA-N 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000003744 tubulin modulator Substances 0.000 description 3
- 229960003048 vinblastine Drugs 0.000 description 3
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 3
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 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
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- MAHCADRFWTWORG-UHFFFAOYSA-N 6,7-dimethoxy-1-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline Chemical compound C1=2C=C(OC)C(OC)=CC=2CCNC1C1=CC=C(C)C=C1 MAHCADRFWTWORG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 229940122803 Vinca alkaloid Drugs 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 230000032823 cell division Effects 0.000 description 2
- 229940125782 compound 2 Drugs 0.000 description 2
- 229940125898 compound 5 Drugs 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 239000010410 layer Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- PIXQPCRMVZPSFH-UHFFFAOYSA-N n-[2-(3,4-dimethoxyphenyl)ethyl]-4-methylbenzamide Chemical compound C1=C(OC)C(OC)=CC=C1CCNC(=O)C1=CC=C(C)C=C1 PIXQPCRMVZPSFH-UHFFFAOYSA-N 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 description 2
- LPNBBFKOUUSUDB-UHFFFAOYSA-N p-toluic acid Chemical compound CC1=CC=C(C(O)=O)C=C1 LPNBBFKOUUSUDB-UHFFFAOYSA-N 0.000 description 2
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 238000010025 steaming Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 2
- MQLACMBJVPINKE-UHFFFAOYSA-N 10-[(3-hydroxy-4-methoxyphenyl)methylidene]anthracen-9-one Chemical compound C1=C(O)C(OC)=CC=C1C=C1C2=CC=CC=C2C(=O)C2=CC=CC=C21 MQLACMBJVPINKE-UHFFFAOYSA-N 0.000 description 1
- ILUSBJDVXKZYEP-UHFFFAOYSA-N 4-(aminomethyl)oxan-4-ol;hydrochloride Chemical compound Cl.NCC1(O)CCOCC1 ILUSBJDVXKZYEP-UHFFFAOYSA-N 0.000 description 1
- FTGYTJSRQLHCTD-VOTSOKGWSA-N 4-[(e)-2-phenylethenyl]benzoyl chloride Chemical compound C1=CC(C(=O)Cl)=CC=C1\C=C\C1=CC=CC=C1 FTGYTJSRQLHCTD-VOTSOKGWSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- PJANXHGTPQOBST-QXMHVHEDSA-N Cistacarpin Natural products C=1C=CC=CC=1/C=C\C1=CC=CC=C1 PJANXHGTPQOBST-QXMHVHEDSA-N 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102000029749 Microtubule Human genes 0.000 description 1
- 108091022875 Microtubule Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 229940122429 Tubulin inhibitor Drugs 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229960002708 antigout preparations Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- CZNGTXVOZOWWKM-UHFFFAOYSA-N methyl 4-bromobenzoate Chemical compound COC(=O)C1=CC=C(Br)C=C1 CZNGTXVOZOWWKM-UHFFFAOYSA-N 0.000 description 1
- 210000004688 microtubule Anatomy 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000003463 organelle Anatomy 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000007939 sustained release tablet Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
- C07D217/12—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring
- C07D217/14—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals
- C07D217/16—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with radicals, substituted by hetero atoms, attached to carbon atoms of the nitrogen-containing ring other than aralkyl radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
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Abstract
本发明涉及药物技术领域，具体涉及一种四氢异喹啉二苯乙烯类化合物及其应用。该化合物或其药学上可接受的盐具有如通式I和通式II所示的结构。药理研究表明，本发明提供的四氢异喹啉二苯乙烯类化合物对A549、MCF‑7、HT29肿瘤细胞的活性具有显著的抑制作用，可用于肿瘤的治疗。
Description
技术领域
本发明涉及药物技术领域，具体涉及一种四氢异喹啉二苯乙烯类化合物及其制备方法、应用。
背景技术
微管蛋白为微管的基本结构单位，其作为一种异二聚体蛋白，不仅能调节细胞分裂，还具有维持细胞形态、维持细胞器的空间分布、参与细胞内物质的运输等功能。以微管蛋白为靶点的抗肿瘤药物可通过抑制微管蛋白聚合或解离，以干扰细胞的有丝分裂，影响细胞的正常生理功能，使细胞分裂停留在M期。
按微管蛋白抑制剂与微管蛋白结合的位点不同，分为长春碱位点、紫杉醇位点和秋水仙碱位点。长春碱、紫杉醇类微管蛋白抑制剂虽已被用于临床治疗多种肿瘤，但仍存在生物利用度低，毒副作用大等缺点，尤其多重耐药糖蛋白的出现，导致其临床治疗效果受限。另外长春碱、紫杉醇类微管蛋白抑制剂多为天然大分子化合物，合成较困难，来源受限，限制了该类抑制剂进一步开发。相对于长春碱、紫杉醇位点，秋水仙碱位点空腔体积小，相应抑制剂的分子结构简单，代表化合物为秋水仙碱、Combretastatin A-4(CA4)，秋水仙碱为临床抗痛风药，也被应用于肿瘤的治疗，但在体内的代谢物二秋水仙碱具有极强毒性，对消化道刺激性较强，限制了其临床应用；CA4为天然顺式二苯乙烯类化合物，具有明显抑制微管蛋白聚合作用，但因其水溶性差，生物利用度低，易转化为活性低的反式构型，限制了其开发和临床应用。
针对于此，以微管蛋白为靶向，开发高效、低毒、抗耐药，作用于秋水仙碱位点的抑制剂具有十分重要的意义。
发明内容
本发明以CA4为先导化合物，依据分子片段理论和拼合原理设计合成了一类四氢异喹啉二苯乙烯类化合物，该类化合物不仅抗肿瘤活性显著，且结构简单、合成方便，具有良好的开发前景。
本发明第一个目的是提供如通式I和通式II所示的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐：
其中，R1选自甲基、甲氧基、卤素、硝基；R2选自氢、甲氧基、甲基。
优选地，所述化合物选自：
优选地，所述盐为药学上可接受的碱金属、无机酸或有机酸形成的盐。
更优选地，所述碱金属为钠或钾；所述无机酸为盐酸、硫酸或磷酸；所述有机酸为马来酸、枸橼酸、酒石酸、富马酸或醋酸。
本发明第二个目的是提供一种上述四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
优选地，所述四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐能够抑制能够抑制肿瘤细胞活性。
更优选地，所述肿瘤细胞为肺癌A549细胞、人乳腺癌MCF-7细胞、人结肠癌HT-29细胞。
本发明还提供一种药物组合物，其包括上述四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐，及药学上可接受的载体或辅料。
对比现有技术，本发明的有益效果为：
本发明提供的化合物中对A549、MCF-7和HT-29细胞的生长均具有一定的抑制作用，其中部分化合物对A549、MCF-7和HT-29细胞抑制作用均强于阳性对照秋水仙碱。
具体实施方式
下面结合具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。
本发明提供如通式I和通式II所示的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐：
其中，R1选自甲基、甲氧基、卤素、硝基；R2选自氢、甲氧基、甲基。
上述四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐能够用于制备抗肿瘤的药物。
本发明还提供一种药物组合物，其包括上述四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐，及药学上可接受的载体或辅料。
该药物组合物可以按照药学上可接受的方法制备成普通片剂、胶囊、缓释片剂、口服液、注射剂等制剂学上常规的制剂形式。
一般地，本发明的化合物用于治疗时，人用剂量范围为1mg～1000mg/天。也可根据剂型的不同和疾病严重程度，使用剂量超出该范围。
下面列举具体实施例对本发明提供的化合物进行详细说明。
实施例1
化合物1：(E)-(6,7-二甲氧基-1-(对甲苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮(BY-1)的合成
S1、N-(3,4-二甲氧基苯乙基)-4-甲基苯甲酰胺的合成：
将甲苯50mL、4-甲基苯甲酸(4g,29.4mmol)、二氯亚砜20mL依次加入一圆底烧瓶，加热升温至75℃搅拌反应4h，TLC[V(氯仿)：V(甲醇)＝5:1]检测反应完全，减压浓缩，用无水甲苯带蒸3次(20mL/次)，得4-甲基苯甲酰氯，用20mL二氯甲烷溶解备用；
将二氯甲烷60mL、3,4–二甲氧基苯乙胺(5.3g,29.3mmol)、三乙胺6mL加入一圆底烧瓶中，冰浴条件下，将4-甲基苯甲酰氯溶液缓慢加入，加毕后继续反应2.5h，TLC[V(乙酸乙酯)：V(石油醚)＝2:1]检测反应完全，分别用3mol·L-1盐酸(40mL×3)、1mol·L-1氢氧化钠(40mL×3)、饱和氯化钠(50mL×3)洗涤，有机层用无水硫酸钠干燥，抽滤，浓缩，无水CH3CH2OH重结晶，得灰色固体N-(3,4-二甲氧基苯乙基)-4-甲基苯甲酰胺7.1g，收率81.1％；
S2、6,7-二甲氧基-1-(对甲苯基)-1,2,3,4-四氢异喹啉的合成：
将甲苯50mL、N-(3,4-二甲氧基苯乙基)-4-甲基苯甲酰胺(3.0g,10.0mmol)加入一三颈烧瓶，升温至85℃，搅拌下，缓慢加入三氯氧磷(7.0mL,24.2mmol)，加毕后升温至115℃反应7h，TLC[V(乙酸乙酯)：V(石油醚)＝2:1]检测反应完全，浓缩，用乙酸乙酯60mL稀释，转移到分液漏斗，水提(50mL×3)，合并水层，在冰浴条件下用浓氨水调pH＝9～10，静置10min，用CH2Cl2萃取(40mL×3)，CH2Cl2层用饱和NaCl洗涤3次(60mL×3)，无水硫酸钠干燥，抽滤，浓缩CH2Cl2，得黄色油状物6,7-二甲氧基-1-(对甲苯基)-3,4-二氢异喹啉2.4g，收率85.2％；
将6,7-二甲氧基-1-(对甲苯基)-3,4-二氢异喹啉(2.4g,8.5mmol)、40mL无水甲醇加入一圆底烧瓶，冰浴下搅拌，待6,7-二甲氧基-1-(对甲苯基)-3,4-二氢异喹啉完全溶解后，分批加入NaBH4(0.4g,19.2mmol)，加毕后继续反应4h，TLC[V(乙酸乙酯)：V(石油醚)＝2:1]检测反应完全，浓缩，用CH2Cl230mL溶解，水洗涤(50mL×2)，无水硫酸钠干燥，抽滤，浓缩，甲醇重结晶，得白色固体6,7-二甲氧基-1-(对甲苯基)-1,2,3,4-四氢异喹啉1.8g，收率75.0％；
S3、(E)-4-苯乙烯基苯甲酸的合成：
将对溴苯甲酸甲酯(0.4g,1.9mmol)、苯乙烯(0.3g,2.9mmol)、醋酸耙(9.0mg,0.04mmol)、三(邻甲基苯基)磷(24.3mg,0.08mmol)、2mL三乙胺和20mL N,N-二甲基甲酰胺加入一圆底烧瓶中，氮气保护下，100℃反应4h,TLC[V(石油醚)：V(乙酸乙酯)＝10:1为展开剂]显示反应基本完全。将反应液降至室温，倒入100mL冰水中，经乙酸乙酯(50mLx3)萃取，合并有机相，用饱和氯化钠溶液洗涤(100mL×2)，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离，无水乙醇重结晶，得白色固体化合物(E)-4-苯乙烯基苯甲酸乙酯0.3g，收率72.7％；
将化合物(E)-4-苯乙烯基苯甲酸乙酯(0.3g，1.3mmol)、85％的甲醇30mL、NaOH(0.1g,2.5mmol)加入在一圆底烧瓶中，常温反应8h，TLC[V(氯仿)：V(甲醇)＝8:1]检测反应完全，用浓盐酸调pH＝2～3，浓缩，经CH2Cl2(20mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤(60mL×2)，无水硫酸钠干燥，过滤，浓缩，经硅胶柱分离，得白色固体化合物(E)-4-苯乙烯基苯甲酸0.23g，收率79.3％；
S4、(E)-(6,7-二甲氧基-1-(对甲苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮(BY-1)的合成：
将甲苯10mL、化合物(E)-4-苯乙烯基苯甲酸(0.23g，1.0mmol)、二氯亚砜0.6mL加入一圆底烧瓶，加热升温至75℃搅拌反应6h，TLC[V(氯仿)：V(甲醇)＝8:1]检测反应完全，减压浓缩，用无水甲苯带蒸3次(20mL/次)，得化合物(E)-4-苯乙烯基苯甲酰氯，用10mLCH2Cl2溶解备用；
将化合物6,7-二甲氧基-1-(对甲苯基)-1,2,3,4-四氢异喹啉(0.3g,1.0mmol)、0.3mL三乙胺、20mL CH2Cl2加入一圆底烧瓶中，冰浴条件下，将(E)-4-苯乙烯基苯甲酰氯溶液缓慢加入，加毕后继续反应4h，TLC[V(乙酸乙酯)：V(石油醚)＝1:1]检测反应完全，分别用3mol·L-1盐酸(15mL×3)、1mol·L-1氢氧化钠(15mL×3)饱和氯化钠(10mL×3)洗涤，有机层用无水硫酸钠干燥，抽滤，浓缩，经硅胶柱分离，得白色固体化合物(E)-(6,7-二甲氧基-1-(对甲苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮0.3g，收率61.3％。m.p.：97.3-98.6。1H NMR(400MHz,CDCl3)δ:7.46(d,J＝7.2Hz,3H,Ar-H),7.31(d,J＝7.6Hz,3H,Ar-H),7.22(d,J＝7.2Hz,1H,Ar-H),7.18-7.12(m,4H,Ar-H,Ar-CH＝CH-Ar),7.06(d,J＝6.8Hz,4H,Ar-H),6.92(s,1H,Ar-H),6.59(s,1H,Ar-H),6.49(s,1H,CHN),3.83(s,3H,OCH3),3.70(s,3H,OCH3),3.62-3.57(m,1H,NCH2CH2),3.27-3.21(m,1H,NCH2CH2),2.93-2.86(m,1H,NCH2CH2),2.61-2.52(m,1H,NCH2CH2),2.27(s,3H,CH3)；13C-NMR(100MHz,CDCl3)δ:168.9,147.1,146.7,138.6,137.6,136.3,135.9,134.3,128.9,128.0,127.7,127.5,127.3,127.2,127.1,127.0,126.9,126.7,126.1,125.6,125.5,125.3,125.1,110.2,110.1,66.3,54.9,53.5,39.6,27.9,20.1；ESI-MS for C33H31NO3:m/z(M+H)+490.15。
实施例2
化合物2：(E)-(6,7-二甲氧基-1-(对甲氧苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(6,7-二甲氧基-1-(对甲氧苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮(BY-2)白色固体，收率53.4％。m.p.：98.4-99.3。1H NMR(400MHz,CDCl3)δ:7.46(d,J＝7.2Hz,2H,Ar-H),7.37-7.30(m,4H,Ar-H),7.22-7.15(m,3H,Ar-H),7.13-7.05(m,4H,Ar-H,Ar-CH＝CH-Ar),6.90-6.75(m,3H,Ar-H),6.59(d,J＝8.8Hz,1H,Ar-H),6.48(d,J＝11.2Hz,1H,CHN),3.83(s,3H,OCH3),3.73(s,3H,OCH3),3.70(s,3H,OCH3),3.61-3.51(m,1H,NCH2CH2),3.32-3.17(m,1H,NCH2CH2),2.94-2.85(m,1H,NCH2CH2),2.65-2.53(m,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:169.9,159.0,148.2,147.8,1138.6,136.9,130.3,130.0,129.6,129.1,128.8,128.6,128.4，128.3,128.2,128.1,128.0,127.7,127.1,126.9,126.7,126.5,126.4,113.7,111.3,67.4,55.9,55.3,40.5,28.9；ESI-MS for C33H31NO4:m/z(M+H)+506.17。
实施例3
化合物3：(E)-(6,7-二甲氧基-1-(对氯苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(6,7-二甲氧基-1-(对氯苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮(BY-3)白色固体，收率50.6％。m.p.：101.7-103.2。1H NMR(400MHz,CDCl3)δ:7.48(m,3H,Ar-H),7.31(d,J＝7.2Hz,3H,Ar-H),7.22-7.13(m,7H,Ar-H,Ar-CH＝CH-Ar),7.07(d,J＝8.4Hz,2H,Ar-H),6.90(s,1H,Ar-H),6.60(s,1H,Ar-H),6.45(s,1H,CHN),3.83(s,3H,OCH3),3.70(s,3H,OCH3),3.65-3.56(m,1H,NCH2CH2),3.23-3.17(m,1H,NCH2CH2),2.93-2.88(m,1H,NCH2CH2),2.62-2.52(m,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:170.1,148.5,148.0,138.9,136.9,135.0,133.6,130.4,130.2,129.0,128.7,128.5,128.2,128.0,127.7,127.1,126.7,126.6,126.1,111.4,111.3,67.3,56.0,54.3,40.7,28.8；ESI-MS for C32H28ClNO3:m/z(M+H)+510.14。
实施例4
化合物4：(E)-(6,7-二甲氧基-1-(3,4二甲氧苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(6,7-二甲氧基-1-(3,4二甲氧苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮(BY-4)白色固体，收率58.4％。m.p.：93.5-95.6。1H NMR(400MHz,CDCl3)δ:7.46(t,J＝8.0Hz,3H,Ar-H),7.32(d,J＝7.2Hz,3H,Ar-H),7.23(d,J＝7.2Hz,1H,Ar-H),7.19(s,1H,Ar-H),7.13-7.01(m,4H,Ar-H,Ar-CH＝CH-Ar),6.90(s,1H,Ar-H),6.70(d,J＝8.0Hz,1H,Ar-H),6.60(s,2H,Ar-H),6.51(s,1H,CHN),3.84(s,3H,OCH3),3.79(s,6H,OCH3),3.71(s,3H,OCH3),3.64-3.60(m,1H,NCH2CH2),3.28-3.22(m,1H,NCH2CH2),2.94-2.86(m,1H,NCH2CH2),2.61(d,J＝1.6Hz,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:170.0,148.9,148.5,148.2,147.7,138.7,136.9,135.3,130.1,128.8,128.6,128.4,128.3,128.2,128.0,127.7,127.1,126.7,126.6,126.5,121.4,112.3,111.3,111.1,110.4,67.0,55.9,54.6,40.6,29.0；ESI-MS for C32H28N2O5:m/z(M+H)+521.18。
实施例5
化合物5：(E)-(6,7-二甲氧基-1-(对硝基苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(6,7-二甲氧基-1-(对硝基苯基)-3,4-二氢异喹啉-2(1H)-基)(4-苯乙烯基苯基)甲酮(BY-5)白色固体，收率54.7％。m.p.：92.7-94.1。1H NMR(400MHz,CDCl3)δ:8.18(d,J＝6.8Hz,2H,Ar-H),7.57(d,J＝7.2Hz,3H,Ar-H),7.53(d,J＝8.0Hz,2H,Ar-H),7.40-7.29(m,4H,Ar-H,),7.22-6.99(m,5H,Ar-H,Ar-CH＝CH-Ar),6.72(s,1H,Ar-H),6.51(s,1H,CHN),4.14-4.09(m,1H,NCH2CH2),3.91(s,3H,OCH3),3.77(s,3H,OCH3),3.29-3.16(m,1H,NCH2CH2),3.11-2.93(m,1H,NCH2CH2),2.74-2.66(m,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:168.9,147.9,147.4,145.8,145.2,137.7,135.8,134.2,134.1,129.0,127.7,127.5,127.4,127.2,127.1,127.0,126.6,126.0,125.6,125.5,120.3,111.3,109.3,107.5,107.2,100.0,66.0,54.8,39.5,28.4；ESI-MSfor C34H33NO5:m/z(M+H)+536.19。
实施例6
化合物6：(E)-(4-苯乙烯基苯基)(5-(对甲苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(4-苯乙烯基苯基)(5-(对甲苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮(BY-6)白色固体，收率64.8％。m.p.：98.5-101.2。1H NMR(400MHz,CDCl3)δ:7.46(d,J＝7.2Hz,3H,Ar-H),7.31(d,J＝7.2Hz,3H,Ar-H),7.22(d,J＝7.6Hz,1H,Ar-H),7.18-7.12(m,4H,Ar-H,Ar-CH＝CH-Ar),7.06(d,J＝7.2Hz,4H,Ar-H),6.86(s,1H,Ar-H),6.57(s,1H,Ar-H),6.46(s,1H,CHN),5.87(s,2H,OCH2O),3.64-3.50(m,1H,NCH2CH2),3.29-3.18(m,1H,NCH2CH2),2.93-2.86(m,1H,NCH2CH2),2.59-2.50(m,1H,NCH2CH2),2.27(s,3H,CH3)；13C-NMR(100MHz,CDCl3)δ:168.8,145.8,145.3,138.5,137.6,136.3,135.9,134.2,129.0,128.0,127.7,127.5,127.3,127.2,127.1,127.0,126.7,126.1,125.6,125.5,107.5,107.2,99.9,53.9,39.6,28.4,20.1；ESI-MS for C32H27NO3:m/z(M+H)+474.15。
实施例7
化合物7：(E)-(4-苯乙烯基苯基)(5-(对甲氧苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(4-苯乙烯基苯基)(5-(对甲氧苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮(BY-7)白色固体，收率59.6％。m.p.：100.5-102.1。1H NMR(400MHz,CDCl3)δ:7.45(d,J＝6.8Hz,3H,Ar-H),7.31(d,J＝7.2Hz,3H,Ar-H),7.22-7.11(m,4H,Ar-H,Ar-CH＝CH-Ar),7.06(d,J＝7.2Hz,2H,Ar-H),6.84(s,1H,Ar-H),6.78(d,J＝7.2Hz,3H,Ar-H),6.56(s,1H,Ar-H),6.45(s,1H,CHN),5.86(s,2H,OCH2O),3.71(s,3H,OCH3),3.59-3.57(m,1H,NCH2CH2),3.27-3.16(m,1H,NCH2CH2),2.94-2.86(m,1H,NCH2CH2),2.58-2.49(m,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:170.1,147.1,146.5,141.0,138.9,136.9,134.9,133.6,130.5,130.2,128.8,128.6,128.3,128.2,128.1,127.6,127.2,126.7,126.6,108.4,101.2,67.0,54.7,40.7,29.3；ESI-MSfor C32H27NO4:m/z(M+H)+490.12。
实施例8
化合物8：(E)-(4-苯乙烯基苯基)(5-(对氯苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(4-苯乙烯基苯基)(5-(对氯苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮(BY-8)白色固体，收率55.1％。m.p.：125.4-127.1。1H NMR(400MHz,CDCl3)δ:7.45(d,J＝7.6Hz,3H,Ar-H),7.30(d,J＝6.4Hz,3H,Ar-H),7.22(d,J＝8.8Hz,5H,Ar-H),7.11-7.00(m,4H,Ar-H,Ar-CH＝CH-Ar),6.83(s,1H,Ar-H),6.57(s,1H,Ar-H),6.42(s,1H,CHN),5.86(s,2H,OCH2O),3.61-3.53(m,1H,NCH2CH2),3.22-3.11(m,1H,NCH2CH2),2.88-2.75(m,1H,NCH2CH2),2.58-2.50(m,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:168.8,158.0,145.8,137.6,135.9,134.2,129.2,129.0,128.1,127.7,127.5,127.4,127.1,127.0,126.7,126.1,125.6,125.5,112.6,107.2,100.0,54.2,39.5,28.4；ESI-MS for C31H24ClNO3:m/z(M+H)+494.10。
实施例9
化合物9：(E)-(4-苯乙烯基苯基)(5-(3,4-二甲氧苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮的合成
合成反应步骤：按实施例1方法操作制得(E)-(4-苯乙烯基苯基)(5-(3,4-二甲氧苯基)-7,8-二氢-[1,3]二氧杂环[4,5-g]异喹啉-6(5H)-基)甲酮(BY-9)白色固体，收率60.5％。m.p.：98.9-100.4。1H NMR(400MHz,CDCl3)δ:7.53(t,J＝7.6Hz,3H,Ar-H),7.36(t,J＝7.2Hz,4H,Ar-H),7.29-7.26(m,1H,Ar-H),7.19-7.08(m,4H,Ar-H,Ar-CH＝CH-Ar),6.91(s,1H,Ar-H),6.75(s,1H,Ar-H),6.64(brs,2H,Ar-H),6.55(s,1H,CHN),5.95(s,2H,OCH2O),3.86(s,6H,OCH3),3.77-3.66(m,1H,NCH2CH2),3.35-3.26(m,1H,NCH2CH2),3.02-2.93(m,1H,NCH2CH2),2.73-2.58(m,1H,NCH2CH2)；13C-NMR(100MHz,CDCl3)δ:169.9,149.0,148.5,146.9,138.7,136.9,135.2,130.1,128.8,128.6,128.5,128.3,128.2,127.7,127.1,126.7,121.4,112.3,110.4,108.6,108.3,101.0,67.0,55.9,55.0,40.6,29.4；ESI-MS for C33H29NO5:m/z(M+H)+520.16。
下面是本发明化合物的药效学试验及结果：
实验方法：SRB法检测。
细胞株：肺癌A549细胞、人乳腺癌MCF-7细胞、人结肠癌HT-29细胞。
具体操作步骤：分别将对数生长期的各细胞消化后，吹打成单细胞悬液，以1×105cells/孔接种于96孔板，置于37℃，5％CO2条件下培养，直至细胞80％融合后，用无血清的MEM培养基孵育2h使细胞同步化。随后，弃去上清，加入待测化合物(浓度为：0μM,0.1μM,1μM,10μM,100μM,200μM)的MEM完全培养基(10％FBS)孵育72h，孵育后在培养液表面每孔轻轻加入50μl预冷的50％的三氯醋酸(TCA)固定，静置5分钟后，再将培养板移至4℃放置1小时。倒掉固定液，每孔用去离子水洗5遍，甩干，空气干燥。每孔加入100μlSRB液，在室温放置10分钟，未与蛋白质结合的SRB用1％醋酸洗5遍，空气干燥。结合的SRB用150μl 10mmol/L非缓冲Tris碱液(pH 10.5)振荡溶解。细胞振荡仪上振荡10min，待结晶物充分溶解后用酶标仪测定OD540。抑制率＝(无药细胞对照孔OD值-用药孔OD值)/无药细胞对照孔OD值×100％。以mean±SD表示，根据抑制率通过GraphPad Prism 6得出IC50。同时，以秋水仙碱作为对照。本发明化合物对肺癌A549细胞、人乳腺癌MCF-7细胞、人结肠癌HT-29细胞增殖抑制活性见表1。
表1本发明化合物对肺癌A549细胞、人乳腺癌MCF-7细胞、人结肠癌HT-29细胞增殖抑制活性
结果显示，本发明提供的化合物中对A549、MCF-7和HT-29生长均表现出一定的抑制作用。其中化合物5对A549、MCF-7和HT-29细胞抑制作用均强于阳性对照秋水仙碱；化合物2、化合物7对MCF-7细胞抑制作用亦强于阳性对照秋水仙碱。
以上公开的仅为本发明的几个具体实施例，但是，本发明实施例并非局限于此，任何本领域的技术人员能思之的变化都应落入本发明的保护范围。
Claims (8)
1.如通式I和通式II所示的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐：
其中，R1选自甲基、甲氧基、卤素、硝基；R2选自氢、甲氧基、甲基。
2.根据权利要求1所述的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐，其特征在于，所述化合物选自：
3.根据权利要求1或2所述的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐，其特征在于，所述盐为药学上可接受的碱金属、无机酸或有机酸形成的盐。
4.根据权利要求3所述的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐，其特征在于，所述碱金属为钠或钾；所述无机酸为盐酸、硫酸或磷酸；所述有机酸为马来酸、枸橼酸、酒石酸、富马酸或醋酸。
5.一种权利要求1所述的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐在制备抗肿瘤药物中的用途。
6.根据权利要求5所述的用途，其特征在于，所述四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐能够抑制肿瘤细胞活性。
7.根据权利要求6所述的用途，其特征在于，所述肿瘤细胞为肺癌A549细胞、人乳腺癌MCF-7细胞、人结肠癌HT-29细胞。
8.一种药物组合物，其特征在于，其包括权利要求1或2所述的四氢异喹啉二苯乙烯类化合物或其药学上可接受的盐，及药学上可接受的载体或辅料。
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