CN102351870B - Method for preparing benzacridine derivative and application of benzacridine derivative as anti-cancer medicine - Google Patents
Method for preparing benzacridine derivative and application of benzacridine derivative as anti-cancer medicine Download PDFInfo
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- CN102351870B CN102351870B CN201110244787.2A CN201110244787A CN102351870B CN 102351870 B CN102351870 B CN 102351870B CN 201110244787 A CN201110244787 A CN 201110244787A CN 102351870 B CN102351870 B CN 102351870B
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- benzacridine
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- JEGZRTMZYUDVBF-UHFFFAOYSA-N Benz[a]acridine Chemical class C1=CC=C2C3=CC4=CC=CC=C4N=C3C=CC2=C1 JEGZRTMZYUDVBF-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 22
- 238000000034 method Methods 0.000 title abstract description 22
- 230000001093 anti-cancer Effects 0.000 title abstract description 5
- 239000000126 substance Substances 0.000 claims abstract description 18
- 229940079593 drug Drugs 0.000 claims abstract description 14
- -1 pyrrolidyl Chemical group 0.000 claims abstract description 11
- 125000005936 piperidyl group Chemical group 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims description 117
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 60
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 58
- 239000002904 solvent Substances 0.000 claims description 41
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 22
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 20
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 18
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 18
- ABDKAPXRBAPSQN-UHFFFAOYSA-N veratrole Chemical compound COC1=CC=CC=C1OC ABDKAPXRBAPSQN-UHFFFAOYSA-N 0.000 claims description 18
- 239000012046 mixed solvent Substances 0.000 claims description 17
- 238000010992 reflux Methods 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 16
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 15
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 14
- 238000011275 oncology therapy Methods 0.000 claims description 13
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 12
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 11
- 150000003053 piperidines Chemical class 0.000 claims description 11
- 239000000047 product Substances 0.000 claims description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 10
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 6
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical class COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims description 5
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000006555 catalytic reaction Methods 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- 239000013067 intermediate product Substances 0.000 claims description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 4
- 229910052763 palladium Inorganic materials 0.000 claims description 4
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- RLOWWWKZYUNIDI-UHFFFAOYSA-N phosphinic chloride Chemical compound ClP=O RLOWWWKZYUNIDI-UHFFFAOYSA-N 0.000 claims description 4
- 229920000137 polyphosphoric acid Polymers 0.000 claims description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001246 bromo group Chemical group Br* 0.000 claims description 3
- 238000006298 dechlorination reaction Methods 0.000 claims description 3
- 230000017858 demethylation Effects 0.000 claims description 3
- 238000010520 demethylation reaction Methods 0.000 claims description 3
- 238000001953 recrystallisation Methods 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 238000005917 acylation reaction Methods 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- JJVNINGBHGBWJH-UHFFFAOYSA-N ortho-vanillin Chemical compound COC1=CC=CC(C=O)=C1O JJVNINGBHGBWJH-UHFFFAOYSA-N 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 claims description 2
- 238000007363 ring formation reaction Methods 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 abstract description 5
- 125000002757 morpholinyl group Chemical group 0.000 abstract description 4
- 125000004193 piperazinyl group Chemical group 0.000 abstract description 4
- 206010028980 Neoplasm Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 3
- 230000002401 inhibitory effect Effects 0.000 abstract description 3
- 108700024542 myc Genes Proteins 0.000 abstract description 2
- 102000053602 DNA Human genes 0.000 abstract 2
- 108020004414 DNA Proteins 0.000 abstract 2
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 abstract 2
- 101100294115 Caenorhabditis elegans nhr-4 gene Proteins 0.000 abstract 1
- 231100000053 low toxicity Toxicity 0.000 abstract 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 abstract 1
- 125000006237 oxymethylenoxy group Chemical group [H]C([H])([*:1])[*:2] 0.000 abstract 1
- 239000007787 solid Substances 0.000 description 37
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 10
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 8
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 230000000452 restraining effect Effects 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 238000011160 research Methods 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- 0 COc(c(*)c1c(Cl)c2CCc3c4)ccc1nc2-c3cc(*)c4I Chemical compound COc(c(*)c1c(Cl)c2CCc3c4)ccc1nc2-c3cc(*)c4I 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 150000004982 aromatic amines Chemical class 0.000 description 4
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 4
- 239000010813 municipal solid waste Substances 0.000 description 4
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000008431 aliphatic amides Chemical class 0.000 description 3
- 229930013930 alkaloid Natural products 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 230000003321 amplification Effects 0.000 description 3
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 238000003199 nucleic acid amplification method Methods 0.000 description 3
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 2
- 101710135898 Myc proto-oncogene protein Proteins 0.000 description 2
- 102100038895 Myc proto-oncogene protein Human genes 0.000 description 2
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 2
- DZBUGLKDJFMEHC-UHFFFAOYSA-N acridine Chemical compound C1=CC=CC2=CC3=CC=CC=C3N=C21 DZBUGLKDJFMEHC-UHFFFAOYSA-N 0.000 description 2
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 2
- 150000003797 alkaloid derivatives Chemical class 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 description 1
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 description 1
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 1
- VEFLKXRACNJHOV-UHFFFAOYSA-N 1,3-dibromopropane Chemical compound BrCCCBr VEFLKXRACNJHOV-UHFFFAOYSA-N 0.000 description 1
- VRWGYMXWYZBBGF-UHFFFAOYSA-M 3,8,13-trimethyl-8h-quino[4,3,2-kl]acridinium methosulfate Chemical compound COS([O-])(=O)=O.C1=C(F)C=C2C3=CC(C)=CC(N(C)C=4C5=CC(F)=CC=4)=C3C5=[N+](C)C2=C1 VRWGYMXWYZBBGF-UHFFFAOYSA-M 0.000 description 1
- MJAPNWJRLLDPAB-UHFFFAOYSA-N BRACO-19 Chemical compound Cl.Cl.Cl.C1=CC(N(C)C)=CC=C1NC1=C(C=CC(NC(=O)CCN2CCCC2)=C2)C2=NC2=CC(NC(=O)CCN3CCCC3)=CC=C12 MJAPNWJRLLDPAB-UHFFFAOYSA-N 0.000 description 1
- YNNJHKOXXBIJKK-UHFFFAOYSA-N COc(cc(CCCC1=O)c1c1)c1OC Chemical compound COc(cc(CCCC1=O)c1c1)c1OC YNNJHKOXXBIJKK-UHFFFAOYSA-N 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- XPYHEGHESSCHSN-UHFFFAOYSA-N N1CCNCC1.[Br] Chemical group N1CCNCC1.[Br] XPYHEGHESSCHSN-UHFFFAOYSA-N 0.000 description 1
- 108700020978 Proto-Oncogene Proteins 0.000 description 1
- 102000052575 Proto-Oncogene Human genes 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 101710150448 Transcriptional regulator Myc Proteins 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000000078 anti-malarial effect Effects 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229930015408 benzyl-isoquinoline alkaloid Natural products 0.000 description 1
- 150000005516 benzylisoquinolines Chemical class 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 210000004671 cell-free system Anatomy 0.000 description 1
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- 231100000135 cytotoxicity Toxicity 0.000 description 1
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- 230000007812 deficiency Effects 0.000 description 1
- FJBFPHVGVWTDIP-UHFFFAOYSA-N dibromomethane Chemical compound BrCBr FJBFPHVGVWTDIP-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
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- 238000009509 drug development Methods 0.000 description 1
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- 239000003112 inhibitor Substances 0.000 description 1
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Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the fields of medicines and chemical industry, and discloses a benzacridine derivative, a method for preparing the benzacridine derivative and application of the benzacridine derivative as an anti-cancer medicine. The benzacridine derivative has a structural formula shown in the specifications, wherein R1 and R2 is CH3O or OCH2O; n is 2 or 3; R3 is NHR4 or NR5; R4 is C1 to C6 alkyl, C3 to C6 naphthenic base, aromatic naphthenic base, aromatic ring base, aromatic heterocyclic radical and the like; and R5 is C1 to C6 alkyl, C3 to C6 naphthenic base, pyrrolidyl, piperidyl, piperazinyl, morpholinyl and the like. The benzacridine derivative has a strong inhibiting effect on deoxyribonucleic acid (DNA) expression of c-myc proto-oncogenes, an obvious inhibiting effect on various cancer cell lines, low toxicity on normal cells, and wide application space in the aspect of preparing the anti-cancer medicine.
Description
Technical field
The invention belongs to medicine and chemical field, relate to a kind of benzacridine derivative and preparation method thereof, with and in the purposes for the preparation of in cancer therapy drug.
Background technology
Cancer is the principal disease that threatens human health and life security, and according to statistics, the whole world every year newly-increased cancer patients reaches 4,000,000 people left and right.The research and development of cancer therapy drug are the focuses that chemist and medicine scholar pay close attention to always.Find efficient, highly selective, cancer therapy drug that toxic side effect is little is one of important directions of drug development research.Take DNA as the synthetic cancer therapy drug of shot design,, for the special higher structure design synthesized micromolecule inhibitor with proto-oncogene DNA such as the telomeric dna of important physiological significance and c-myc, is particularly the important method of Development of Novel cancer therapy drug.
Containing the spread out alkaloid of structure of acridine is the common alkaloid of a class, exist in many pharmaceutical intermediates, and be the primary structure unit of many traditional Chinese medicine ingredients.Many alkaloids that contain acridine structure have antiviral, anti-malarial, and the effect such as antimycotic and antitumor, thereby by extensive concern and research, becomes one of first-selected structure that many scientific researchers pay close attention to.For benzylisoquinoline alkaloid, for the research of target DNA antitumous effect, obtained larger progress in recent years, some take the micromolecular compound that acridine structure is main skeleton, as BRACO-19, RHPS4 etc., aspect the research of target DNA antitumous effect, carried out comparatively deeply, be expected to push in the near future clinical.However, the development research of target DNA cancer therapy drug is still also at the early-stage, therefore has far-reaching theoretical investigation and realistic meaning, has development prospect and potential great market widely.
Summary of the invention
The object of the invention is to for the deficiencies in the prior art, the benzacridine that a kind of toxicity is little, anticancer effect is good derivative is provided.
Another object of the present invention is to provide the preparation method of this benzacridine derivative.
A further object of the invention is to provide the application of this benzacridine derivative.
Invention is achieved through the following technical solutions above-mentioned purpose:
Invention provides a kind of approach of preparing of benzacridine derivative, and its structural formula is:
Wherein each group can be one of following arbitrary combination:
Combination one:
R in formula
1=R
2=CH
3o;
N=2 or 3;
R
3for NHR
4or NR
5;
R
4for C
1-6alkyl, C
3-6cycloalkyl, fragrant alkyl, aromatic ring yl or aromatic heterocyclic;
R
5for C
1-6alkyl, C
3-6cycloalkyl, Pyrrolidine base, piperidyl, N methyl piperazine base, piperazinyl or morpholinyl.
Combination two:
R in formula
1=R
2=OCH
2o; Other as combination one;
The present invention provides the preparation method of this benzacridine derivative simultaneously, and its building-up process is as follows:
Route two, i 1) KMnO
4/ acetone, room temperature, 2 h; 2) Fe, acetic acid/ethanol/water, room temperature, 4 h.
Its synthetic characterization step is as follows:
(1) at AlCl
3under catalysis, take oil of mirbane as solvent, there is acylation reaction in 1,2-dimethoxy benzene and Succinic anhydried, obtain compound at 0 ~ 60 ° of C temperature
, then this compound is at (CH
3cH
2)
3siH and CF
3cO
2under H reflux conditions, deoxidation obtains compound
, then deoxidation products is at polyphosphoric acid and CH
2cl
2reflux conditions ShiShimonoseki ring, obtains compound
, close ring product again through 40 ~ 48% the HBr aqueous solution, under reflux conditions demethylation obtains compound
, last demethylation product, under the catalysis of KF, be take DMF as solvent and CH
2br
2140 ° of C reactions, obtain compound
;
(2) O-VANILLIN be take methylene dichloride as solvent, and under 0 ° of C, through benzenesulfonyl, protection obtains compound
, compound then obtains with concentrated nitric acid is nitrated
, then, in the mixed solvent of acetone/water, under room temperature, use KMnO
4oxidation aldehyde radical, the nitro that reduces under iron powder room temperature condition in acetic acid/ethanol/water mixed solvent obtain compound
;
(3) compound
or
with compound
at POCl
3ring closure reaction under reflux conditions, obtains compound
the condensation compound obtaining is then in the mixed solvent of DMF/ ethanol, DMF/ methyl alcohol, DMF/THF or DMF/ ethyl acetate, under 60 ° of C conditions, with the palladium carbon (Pd/C) that the content of palladium is 5 ~ 10%, slough the chlorine atom in molecule, the dechlorination intermediate product obtaining is in the mixed solvent of dioxane/water or tetrahydrofuran (THF)/water, under 100 ° of C conditions, with sodium hydroxide or potassium hydroxide, the sulfonic group in molecule is hydrolyzed into phenolic hydroxyl group, the phenolic hydroxyl group intermediate product obtaining be take acetonitrile, acetone or DMF as solvent, under 60 ° of C conditions, obtain compound with dibromo alkane reaction
, wherein n is 2 or 3, R
1=R
2for CH
3o or OCH
2o.
When compound be take acetonitrile, acetone or DMF as solvent, under 60 ~ 100 ° of C conditions, bromine atoms is replaced and obtains target compound by aliphatic amide, fatty cyclammonium, aromatic amine, Pyrrolidine, piperidines, N methyl piperazine, morpholine or piperazine
, wherein n is 2 or 3; R
1=R
2for CH
3o or OCH
2o, R
3for NHR
4or NR
5; R
4for C
1-6alkyl, C
3-6cycloalkyl, fragrant alkyl, aromatic ring yl or aromatic heterocyclic etc.; R
5for C
1-6alkyl, C
3-6cycloalkyl, Pyrrolidine base, piperidyl, N methyl piperazine base, piperazinyl or morpholinyl etc.Finally by column chromatography or recrystallization, obtain target product (benzacridine derivative claimed in claim 1).
(4) if compound
take toluene as solvent, under room temperature condition, first through trifluoromethane sulfonic acid methyl esters methyl on N, then take methylene dichloride or chloroform aliphatic amide, fatty cyclammonium, aromatic amine, Pyrrolidine, piperidines, N methyl piperazine, morpholine or piperazine bromine atoms for to be replaced and with anionite-exchange resin general as solvent
-oTf
3be exchanged for
-cl obtains compound
, n=2 or 3; R
1=R
2for CH
3o or OCH
2o, R
3for NHR
4or NR
5; R
4for C
1-6alkyl, C
3-6cycloalkyl, fragrant alkyl, aromatic ring yl and aromatic heterocyclic etc.; R
5for C
1-6alkyl, C
3-6cycloalkyl, Pyrrolidine base, piperidyl, piperazinyl and morpholinyl etc., finally by column chromatography or recrystallization, obtain target product (benzacridine derivative claimed in claim 2).
In above-mentioned preparation process, the AlCl using
3the mol ratio of catalyzer and 1,2-dimethoxy benzene is 2:1 ~ 4:1, and the mol ratio of Succinic anhydried and 1,2-dimethoxy benzene is 1.5:1 ~ 4:1.Temperature of reaction is 0 ~ 60 ° of C, and the amount of substance of 1,2-dimethoxy benzene and the volume ratio of solvent are 1:50 ~ 1:100.
Described compound
with (CH
3cH
2)
3the mol ratio of SiH is 2:1 ~ 4:1, compound
amount of substance and CF
3cO
2the volume ratio of H is 1:5 ~ 1:10.
Described compound
amount of substance and the volume ratio of 40 ~ 48% the HBr aqueous solution be 1:5 ~ 1:10.
Described compound
, CH
2br
2with KF three's mol ratio be 1:1:5 ~ 1:1.2:10.The amount of substance of compound and the volume ratio of solvent are 1:20 ~ 1:40.
Described compound
, KMnO
4with Fe three's mol ratio be 1:1.5:5 ~ 1:2:10.The volume ratio of water and acetone is 1:3 ~ 1:6; The volume ratio of acetic acid/ethanol/water is 5:5:1 ~ 2:2:1.
Described compound
or
with compound
mol ratio be 1:1.5 ~ 1:2.5, with POCl
3amount ratio be 1:5 ~ 1:10(amount of substance: volume).
Described compound
with the mass ratio of the palladium content palladium carbon (Pd/C) that is 5 ~ 10% be 1:0.8 ~ 1:1.2, with the mol ratio of NaOH or KOH be 1:5 ~ 1:10, solvent used is mixed solvent dioxane/water or THF/ water, and in mixed solvent, the volume ratio of two kinds of solvents is 10:1 ~ 5:1; Obtaining the product of sulfonic group hydrolysis and the mol ratio of two bromoalkanes is 1:5 ~ 1:10; Solvent used is mixed solvent DMF/EtOH, DMF/MeOH, DMF/THF or DMF/ ethyl acetate; In described various mixed solvent, the volume ratio of two kinds of solvents is 20:1 ~ 10:1.
Described compound
with the mol ratio of aliphatic amide, fatty cyclammonium, aromatic amine, Pyrrolidine, piperidines, N methyl piperazine, morpholine or piperazine be 1:1.2 ~ 1:10; Solvent used is acetone, DMF or acetonitrile, and the amount of substance of compound and the volume ratio of solvent are 1:5 ~ 1:10.
Described compound
with trifluoromethane sulfonic acid methyl esters (MeOTf
3) mol ratio be 1:1.1 ~ 1:2.0; Compound
amount of substance be 1:8 ~ 1:15 with the ratio of the volume of toluene; The mol ratio of the methylate obtaining and aliphatic amide, fatty cyclammonium, aromatic amine, Pyrrolidine, piperidines, N methyl piperazine, morpholine or piperazine is 1:1.2 ~ 1:10, and the amount of substance of methylate and the volume ratio of solvent are 1:3 ~ 1:8.
The present invention discloses simultaneously and has protected this benzacridine derivative in the purposes of preparing on cancer therapy drug; And the cancer therapy drug that contains this benzacridine derivative.
Compared with prior art, the present invention has following beneficial effect:
(1) experimental results show that, novel benzacridine derivative disclosed in this invention has very strong interaction with the c-myc proto-oncogene DNA that is rich in guanine, demonstration has very strong restraining effect to the expression of proto-oncogene c-myc, show significant antitumous effect, can be used for preparation and there is selectivity cancer therapy drug.
(2) further experiment proves, the benzacridine derivative the present invention relates to has stronger restraining effect to multiple JEG-3, and little to normal cytotoxicity, has wide application space preparing on cancer therapy drug.
Embodiment
By specific embodiment, further illustrate technical scheme of the present invention below.
embodiment mono-:compound
3synthetic
Under 0 ° of C, by 2.65 mol AlCl
3in 0.5 hour, join the 1,2-dimethoxy benzene that is dissolved in 1.5 L oil of mirbane in batches
1in, then by the 1.27 mol Succinic anhydrieds that are dissolved in 1 L oil of mirbane
2in 1 hour, gradation joins in above-mentioned solution, and in insulated and stirred after 10 minutes, reaction system is transferred in the oil bath of 60 ° of C and continues reaction 3 hours.Then reaction solution is slowly joined in trash ice, will separate out solid filtering, dry, re-crystallizing in ethyl acetate obtains shallow white solid
3.
Productive rate: 24%;
1h NMR (400 MHz, CDCl
3) δ: 7.61 (dd,
j=2 Hz,
j=2 Hz, 1H), 7.53 (d,
j=1.6 Hz, 1H), 6.89 (d,
j=8.4 Hz, 1H), 3.94 (s, 3H), 3.92 (s, 3H), 3.28 (t,
j=6.8 Hz, 2H), 2.79 (t,
j=6.8 Hz, 2H); MM-ES+APCI m/z:237.1[M-H]
-.
embodiment bis-:compound
4synthetic
By 0.19 mol compound
3join in 140 mL trifluoracetic acids, and add the triethyl silicane of 0.78 mol, reaction system 2 h that reflux.After having reacted, spin off solvent, residuum is slowly poured in trash ice, by the solid suction filtration of separating out, dry, obtain albescent solid
4.
Productive rate: 97.7%;
1h NMR (400 MHz, CDCl
3) δ: 6.79 (d,
j=7.6 Hz, 1H), 6.73 (d,
j=1.6 Hz, 1H), 6.71 (s, 1H), 3.87 (s, 3H), 3.85 (3,3H), 2.62 (t,
j=7.6 Hz, 2H), 2.38 (t,
j=7.6 Hz, 2H), 1.99-19.91 (m, 2H); MM-ES+APCI m/z:223.1 [M-H]
-.
embodiment tri-:compound
5synthetic
By 0.19 mol compound
4join in 50 mL methylene dichloride, and add 210 g polyphosphoric acid, mixture system refluxes 2 hours, spins off solvent, residuum is slowly joined in trash ice, by saturated sodium bicarbonate solution regulator solution pH value to 7-8.By the solid suction filtration of separating out, dry, obtain albescent solid
5.
Productive rate: 93.3%;
1h NMR (400 MHz, CDCl
3) δ: 7.51 (s, 1H), 6.67 (s, 1H), 3.93 (s, 3H), 3.91 (s, 3H), 2.89 (t,
j=6 Hz, 2H), 2.60 (t,
j=6.4 Hz, 2H), 2.15-2.09 (m, 2H);
13c NMR (101 MHz, CDCl
3) δ: 197.10,153.51,147.96,139.27,125.79,110.22,108.57,55.98,38.50,29.44,23.61.
embodiment tetra-:compound
6synthetic
By 0.19 mol compound
5join in 48% HBr of 500 mL, reaction system refluxes 4 hours, and quiet putting is cooled to room temperature.Crystallize out filters, dry, obtains dun crystal
6.
Productive rate: 84.8%;
1h NMR (400 MHz, CDCl
3) δ: 7.67 (s, 1H), 7.16 (s, 1H), 6.75 (s, 1H), 6.23 (s, 1H), 2.85 (t,
j=6.4 Hz, 2H), 2.59 (t,
j=6.4 Hz, 2H), 2.12-2.06 (m, 2H); MM-ES+APCI m/z:177.1 [M-H]
-.
embodiment five:compound
7synthetic
By 0.14 mol compound
6, 1.24 mol KF and 0.17 mol methylene bromide join 300 mL DMF, in 145 ℃, at enclosed system, react 6 hours.After having reacted, suction filtration removes solid residue.Spin off solvent after washing residuum, ethyl acetate is extracted water layer 3 times, and ester layer is dry, and 200-300 order silica gel column chromatography obtains white solid
7.
Productive rate: 54%;
1h NMR (400 MHz, CDCl
3) δ: 7.45 (s, 1H), 6.65 (s, 1H), 5.99 (s, 2H), 2.86 (t,
j=6 Hz, 2H), 2.58 (t,
j=6.4 Hz, 2H), 2.11-2.05 (m, 2H),
13c NMR (101 MHz, CDCl
3) δ: 196.53,151.99,146.91,141.35,127.47,107.91,106.23,101.52,38.61,30.02,23.46.
embodiment six:compound
9synthetic
Under room temperature condition, to the 0.22 mol compound that is dissolved in 300 mL acetone
8(synthesize and see Press, J. B.et al,
j. Heterocyclic. Chem.1986,
23, 1821) in, gradation adds the 0.33 mol KMnO being dissolved in 100 mL water
4.Reaction system stirred after 2 hours, added wherein the Virahol of 20 mL, and reaction system continues to stir 1 h.Then reaction system is passed through to diatomite suction filtration, spin off solvent, the white solid obtaining is directly used in next step.
It is that 2:2:1 and cumulative volume are in acetic acid/ethanol/water mixed solvent of 500 mL that white solid is dissolved in to volume ratio.The Fe powder of 3.4 mol is joined in reaction system in batches, stirring at room 4 hours, the white solid suction filtration of separating out, and be dissolved in the NaOH solution of 100 mL 5 M, by the solution of gained through diatomite suction filtration, filtrate is with dilute hydrochloric acid adjust pH to 5-6, and the white solid suction filtration of separating out, obtains compound
9.
Productive rate: 41.7%;
1h NMR (400 MHz, CDCl
3) δ: 7.89 (d,
j=7.6 Hz, 2H), 7.65 (t,
j=7.6 Hz, 1H), 7.52 (t,
j=7.6 Hz, 2H), 6.92 (d,
j=8.8 Hz, 1H), 6.59 (d,
j=9.2 Hz, 1H), 3.38 (s, 3H),
13c NMR (101 MHz, DMSO-d
6) δ: 167.31,143.96,142.16,136.34,136.26,134.35,129.21,128.10,118.54,115.50,110.79,56.07; MM-ES+APCI m/z 324 [M+H]
+.
embodiment seven:compound
11synthetic
By 9.7 mmol compounds
5with 15.5 mmol compounds
9join in the phosphorus oxychloride of 30 mL and reflux 8 hours.Question response system is chilled to after room temperature, and it is slowly joined in trash ice, and by the solid suction filtration of separating out, dry, 200-300 order silica gel column chromatography obtains flaxen solid
11.
Productive rate: 49%;
1h NMR (400 MHz, CDCl
3) δ: 8.20 (s, 1H), 8.09 (s, 1H), 7.88 (d,
j=0.8 Hz, 1H), 7.86 (d,
j=1.6 Hz, 1H), 7.66 (t,
j=7.6 Hz, 1H), 7.53 (t,
j=8 Hz, 2H), 7.33 (d,
j=9.2 Hz, 1H), 6.76 (s, 1H), 4.06 (s, 3H), 3.96 (s, 3H), 3.43 (s, 3H), 3.27 (t,
j=7.6 Hz, 2H), 2.95 (t,
j=7.6 Hz, 2H);
13c NMR (101 MHz, CDCl
3) δ: 151.51,151.03,150.38,148.51; 143.17,137.86,135.89,133.55; 132.57,130.99,130.80,129.99; 128.60,128.49,126.06,121.49; 115.89,110.42,108.73,56.18; 55.98,55.96,27.01,26.08; MM-ES+APCI m/z 512.1 [M+H]
+.
embodiment eight:compound
10synthetic
Method is with embodiment seven, and difference is to use compound
7replace compound
5, obtain faint yellow solid
10.
Productive rate: 64%;
1h NMR (400 MHz, CDCl
3) δ: 8.08 (d,
j=8.0 Hz, 1H), 8.00 (s, 1H), 7.87 (d,
j=7.6 Hz, 2H), 7.66 (t,
j=7.6 Hz, 1H), 7.53 (t,
j=8.0 Hz, 2H), 7.32 (d,
j=9.2 Hz, 1H), 6.73 (s, 1H), 6.01 (s, 2H), 3.43 (s, 3H), 3.24 (t,
j=7.6 Hz, 2H), 2.91 (t,
j=7.6 Hz, 2H);
13c NMR (101 MHz, CDCl
3) δ: 151.39,150.35,149.35,147.31; 143.15,137.83,135.78,134.19; 133.57,130.87,130.76,130.12; 128.61,128.49,127.63,121.50; 115.86,107.78,106.15,101.25; 55.91,27.48,26.02; MM-ES+APCI m/z 496.0 [M+H]
+.
embodiment nine:compound
12synthetic
By 2 mmol compounds
10being dissolved in cumulative volume is in 50ml DMF/ ethanol (V/V=46:4), and toward wherein adding 1 g 10% Pd/C, hydrogen is saturated, is incubated 60 ° of C, reacts 3 hours.Reaction solution is passed through to diatomite suction filtration, spin off solvent, add wherein 30 mL dioxane, and add the NaOH solution of 2 mL 5 M, reflux after 2 hours, spin off solvent, pH value of solution is adjusted to 6-7, and room temperature is placed, crystallize out suction filtration, dry, the product of gained is joined in 30 mL anhydrous acetonitriles, and add 828 mg anhydrous K
2cO
3, 0.87 mL glycol dibromide.Reaction system stirs 3 hours in 60 ° of C.After question response completes, spin off solvent, washing, dichloromethane extraction, dry, 200-300 order silica gel column chromatography obtains faint yellow solid
12.
Productive rate: 30%;
1h NMR (400 MHz, CDCl3) δ: 8.31 (s, 1H), 8.02 (s, 1H), 7.87 (d,
j=9.2 Hz, 1H), 7.41 (d,
j=9.2 Hz, 1H), 6.73 (s, 1H), 6.00 (s, 2H), 4.50 (t,
j=6.0 Hz, 2H), 4.00 (s, 3H), 3.73 (t,
j=6.0 Hz, 2H), 3.11 (t,
j=7.6 Hz, 2H), 2.91 (t,
j=7.6 Hz, 2H); MM-ES+APCI m/z 428.0 [M+H]
+.
embodiment ten:compound
13synthetic
Method is with embodiment nine, and difference is to replace glycol dibromide with 1,3-dibromopropane, obtains faint yellow solid
13.
Productive rate: 35%;
1h NMR (400 MHz, CDCl3) δ: 8.74 (s, 1H), 8.55 (d,
j=9.6 Hz, 1H), 8.09 (s, 1H), 7.71 (d,
j=9.2 Hz, 1H), 6.83 (s, 1H), 6.14 (s, 2H), 4.36 (t,
j=5.6,2H), 4.05 (s, 3H), 3.78 (t,
j=5.6 Hz, 2H), 3.19 (t,
j=7.6 Hz, 2H), 3.00 (t,
j=7.6 Hz, 2H), 2.45-2.39 (m, 2H); MM-ES+APCI m/z 442.1 [M+H]
+.
embodiment 11:compound
14synthetic
Method is with embodiment 10, and difference is to use compound
11replace compound
10, obtain faint yellow solid
14.
Productive rate: 57.6%;
1h NMR (400 MHz, CDCl3) δ: 8.17 (s, 1H), 8.08 (s, 1H), 7.89 (d,
j=8.8 Hz, 1H), 7.41 (d,
j=9.2 Hz, 1H), 6.76 (s, 1H), 4.28 (t,
j=6.0 Hz, 2H), 4.06 (s, 3H), 4.00 (s, 3H), 3.95 (s, 3H), 3.78 (t,
j=6.4 Hz, 2H), 3.13 (t,
j=7.6 Hz, 2H), 2.95 (t,
j=7.6 Hz, 2H), 2.45-2.39 (m, 2H); MM-ES+APCI m/z 458.1 [M+H]
+.
embodiment 12:compound
15asynthetic
By 0.14 mmol compound
12, 0.42 mmol anhydrous K
2cO
3join in 20 mL acetonitriles with 1.4 mmol diethylamine, reaction mixture stirs 6 h at 60 ° of C.After question response completes, spin off solvent, washing residuum, dichloromethane extraction, dry, 200-300 order silica gel column chromatography obtains pale solid
15a.
Productive rate: 30%;
1h NMR (400 MHz, CDCl
3) δ: 8.26 (s, 1H), 8.01 (s, 1H), 7.83 (d,
j=9.2 Hz, 1H), 7.41 (d,
j=9.2 Hz, 1H), 6.73 (s, 1H), 6.00 (s, 2H), 4.25 (t,
j=6.0 Hz, 2H), 3.99 (s, 3H), 3.09 (t,
j=7.2 Hz, 2H), 3.00 (s, 2H), 2.90 (t,
j=7.6 Hz, 2H), 2.73 (s, 4H), 1.12 (t,
j=6.8 Hz, 6H);
13c NMR (101 MHz, CDCl
3) δ: 151.61,148.66,148.02,147.19; 143.37,140.82,134.21,129.94; 128.97,127.67,125.21,123.41; 116.84,107.97,105.95,101.07; 71.49,56.74,52.84,47.44; 29.26,28.55,11.72; HRMS
m/z: 421.2122 [M+H]
+.
embodiment 13:compound
15bsynthetic
Method is with embodiment 12, and difference is to replace diethylamine with Pyrrolidine, obtains canescence look solid
15b.
Productive rate: 46.7%;
1h NMR (400 MHz, CDCl
3) δ: 8.20 (s, 1H), 7.95 (s, 1H), 7.78 (d,
j=9.2 Hz, 1H), 7.35 (d,
j=9.2 Hz, 1H), 6.67 (s, 1H), 5.94 (s, 2H), 4.21 (t,
j=5.6 Hz, 2H), 3.93 (s, 3H), 3.02 (t,
j=7.6 Hz, 2H), 2.92 (s, 2H), 2.84 (t,
j=7.6 Hz, 2H), 2.62 (s, 4H), 1.80 (s, 4H);
13c NMR (101 MHz, CDCl
3) δ: 151.62,148.70,148.18,147.24; 143.48,140.96,134.21,129.92; 129.06,127.72,125.30,123.58; 117.04,107.97,106.01,101.07; 72.09,56.85,55.95,54.52; 29.30,28.61,23.61; HRMS
m/z: 419.1969 [M+H]
+.
embodiment 14:compound
16asynthetic
Method is with embodiment 12, and difference is to use compound
13replace
12, obtain pale solid
16a.
Productive rate: 90.2%;
1h NMR (400 MHz, CDCl
3) δ: 8.16 (s, 1H), 8.01 (s, 1H), 7.83 (d,
j=9.2 Hz, 1H), 7.40 (d,
j=9.2 Hz, 1H), 6.72 (s, 1H), 5.99 (s, 2H), 4.19 (t,
j=6.4 Hz, 2H), 3.98 (s, 3H), 3.09 (t,
j=7.6 Hz, 2H), 2.90 (t,
j=7.6 Hz, 2H), 2.83 (t,
j=8.0 Hz, 2H), 2.67 (q,
j=7.2 Hz 4H), 2.12-2.05 (m, 2H), 1.11 (t,
j=7.2 Hz, 6H);
13c NMR (101 MHz, CDCl
3) δ: 151.59,148.69,148.04,147.22; 143.51,140.98,134.18,129.90; 128.99,127.42,125.16,123.41; 117.13,107.95,105.98,101.06; 72.18,56.84,49.79,46.92; 29.28,28.56,27.71,11.41; HRMS
m/z: 435.2279 [M+H]
+.
embodiment 15:compound
17asynthetic
Method is with embodiment 14, and difference is to use
14replace
13, must understand pale solid
17a.
Productive rate 34.2%.
1H?NMR?(400?MHz,?CDCl
3)?δ:?8.14?(s,?1H),?8.06?(s,?1H),?7.86?(d,?
J?=?9.2?Hz,?1H),?7.40?(d,?
J?=?9.2?Hz,?1H),?6.75?(s,?1H),?4.20?(t,?
J?=?6.0?Hz,?2H),?4.05?(s,?3H),?3.98?(s,?3H),?3.94?(s,?3H),?3.11?(t,?
J?=?6.8?Hz,?2H),?2.99-2.92?(m,?4H),?2.82-2.77?(m,?4H),?2.16?(t,?
J?=?7.6?Hz,?2H),?1.19?(t,?
J?=?7.2?Hz,?6H);?
13C?NMR?(101?MHz,?CDCl
3)?δ:?151.73,?150.30,?148.39,?147.93,?143.41,?140.67,?132.64,?130.14,?127.37,?127.35,?125.22,?123.26,?116.79,?110.63,?108.34,?71.70,?56.73,?56.11,?55.93,?49.66,?46.82,?29.37,?28.03,?26.95,?10.67;?ESI-HRMS?
m/z:?calcd?for?C
27H
34N
2O
4?[M+H]
+?451.2591,?found?451.2596。
embodiment 16:compound
17csynthetic
Method is with embodiment 14, and difference is to use
14replace
13, with piperidines, replace diethylamine simultaneously, must understand white solid
17c.
Productive rate: 40%;
1h NMR (400 MHz, CDCl
3) δ: 8.15 (s, 1H), 8.08 (s, 1H), 7.86 (d,
j=9.2 Hz, 1H), 7.40 (d,
j=9.2 Hz, 1H), 6.75 (s, 1H), 4.20 (t,
j=6.4 Hz, 2H), 4.06 (s, 3H), 3.99 (s, 2H), 3.95 (s, 3H), 3.12 (t,
j=7.2 Hz, 2H), 2.94 (t,
j=7.6 Hz, 2H), 2.68 (s, 2H), 2.49 (s, 4H), 2.13 (s, 2H), 1.66 (s, 4H), 1.48 (s, 2H);
13c NMR (101 MHz, CDCl
3) δ: 151.71,150.33,148.45,148.05,143.54; 140.96,132.58,130.03,127.52,127.49; 125.16,123.42,117.05,110.70; 108.46,72.06,56.86,56.15; 56.04,55.97,54.21,29.41; 28.09,27.49,25.58,24.18; HRMS
m/z: 463.2588 [M+H]
+.
embodiment 17:compound
18synthetic
By 0.94 mmol compound
12be dissolved in dry toluene, under room temperature condition, drip 1.15 mmol trifluoromethanesulfonic acid methyl esters, after 5 minutes, have a large amount of faint yellow solids to separate out.Reaction mixture continues to stir 1 h, and by solid suction filtration, absolute ethanol washing, is dried to obtain faint yellow solid compound
18.
Productive rate: 91%;
1h NMR (400 MHz, CDCl
3) δ: 9.04 (s, 1H), 8.31 (d,
j=9.2 Hz, 1H), 7.87 (d,
j=9.6 Hz, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 6.16 (s, 2H), 4.74 (s, 3H), 4.65 (t,
j=5.6 Hz, 2H), 4.08 (s, 3H), 3.75 (t,
j=6.8 Hz, 2H), 3.10 (t,
j=7.2 Hz, 2H), 2.96 (t,
j=7.6 Hz, 2H); MM-ES+APCI m/z 442.1 [M-OTf
3]
+.
embodiment 18:compound
19synthetic
Method is with embodiment 17, and difference is to use compound
13replace
12,obtain faint yellow solid
19.
Productive rate: 64%;
1h NMR (400 MHz, CDCl
3) δ: 8.80 (s, 1H), 8.28 (d,
j=9.2 Hz, 1H), 7.86 (d,
j=9.2 Hz, 1H), 7.43 (s, 1H), 6.94 (s, 1H), 6.15 (s, 2H), 4.73 (s, 3H), 4.38 (t,
j=5.6 Hz, 2H), 4.08 (s, 3H), 3.76 (t,
j=6.4 Hz, 2H), 3.10 (t,
j=7.6 Hz, 2H), 2.96 (t,
j=7.6 Hz, 2H), 2.46-2.40 (m, 2H); MM-ES+APCI m/z 456.1 [M-OTf
3]
+.
embodiment 19:compound
20synthetic
Method is with embodiment 17, and difference is to use
14replace
12, obtain faint yellow solid
20.
Productive rate: 50%;
1h NMR (400 MHz, CDCl
3) δ: 8.77 (s, 1H), 8.27 (d,
j=9.6 Hz, 1H), 7.82 (d,
j=10.0 Hz, 1H), 7.57 (s, 1H), 6.93 (s, 1H), 4.79 (s, 3H), 4.37 (t,
j=6.0 Hz, 1H), 4.07 (s, 3H), 4.03 (s, 6H), 3.76 (t,
j=6.4 Hz, 2H), 3.10 (t,
j=7.2 Hz, 2H), 2.96 (t,
j=7.2 Hz, 2H), 2.45-2.40 (m, 2H); MM-ES+APCI m/z 472.1 [M-OTf
3]
+.
embodiment 20:compound
21bsynthetic
By the compound of 0.37 mmol
18, 0.6 mmol Pyrrolidine and 1.11 mmol anhydrous K
2cO
3join in 20 mL methylene dichloride, and add the KI of catalytic amount, reaction system stirs 2 days under room temperature condition.Then by reaction system washing, dry, first use 200 ~ 300 order silica gel column chromatographies, then will with anionite-exchange resin
-oTf
3be exchanged for
-cl, then use 200 ~ 300 order Al
2o
3column chromatography, obtains faint yellow solid
21b.
Productive rate: 31.6%;
1h NMR (400 MHz, CDCl
3) δ: 9.02 (s, 1H), 8.71 (d,
j=9.6 Hz, 1H), 7.92 (d,
j=9.6 Hz, 1H), 7.66 (s, 1H), 6.92 (s, 1H), 6.14 (s, 2H), 4.95 (s, 3H), 4.34 (t,
j=5.6 Hz, 2H), 4.05 (s, 3H), 3.03 (t,
j=8.0 Hz, 2H), 2.93-2.88 (m, 4H), 2.61 (s, 4H), 1.82 (s, 4H);
13c NMR (101 MHz, CDCl
3) δ: 153.08,152.48,150.66,147.62; 141.23,141.01,135.99,134.99; 133.43,123.96,121.76,119.64; 117.00,111.09,109.00,102.69; 72.44,56.72,55.63,54.20; 46.53,29.06,28.84,23.56; HRMS
m/z: 433.2125 [M-Cl]
+.
embodiment 21:compound
22asynthetic
Method is with embodiment 20, and difference is to use
19replace
18, and replace Pyrrolidine with diethylamine, obtain faint yellow solid
22a.
Productive rate: 25%;
1h NMR (400 MHz, CDCl
3) δ: 8.79 (s, 1H), 8.71 (d,
j=9.6 Hz, 1H), 7.92 (d,
j=9.6 Hz, 1H), 7.66 (s, 1H), 6.92 (s, 1H), 6.14 (s, 2H), 4.96 (s, 3H), 4.27 (t,
j=6.4 Hz, 2H), 4.05 (s, 3H), 3.06 (t,
j=7.2 Hz, 2H), 2.92 (t,
j=7.2 Hz, 2H), 2.70 (t,
j=7.6 Hz, 2H), 2.59 (q,
j=7.2 Hz, 4H), 2.08-1.99 (m, 2H), 1.05 (t,
j=7.2 Hz, 6H);
13c NMR (101 MHz, CDCl
3) δ: 153.12,152.54,150.46,147.66,141.43; 141.01,135.31,135.14,133.59; 123.64,121.94,119.64,116.92; 111.14,109.00,102.71,73.00; 56.74,49.36,46.81,46.75; 29.11,28.83,27.88,11.55; HRMS
m/z: 449.2432 [M-Cl]
+.
embodiment 22:compound
22bsynthetic
Method is with embodiment 21, and difference is to replace diethylamine with Pyrrolidine, obtains faint yellow solid
22b.
Productive rate: 37.5%;
1h NMR (400 MHz, CDCl
3) δ 8.83 (s, 1H), 8.30 (d,
j=9.6 Hz, 1H), 7.84 (d,
j=9.6 Hz, 1H), 7.45 (s, 1H), 6.94 (s, 1H), 6.15 (s, 2H), 4.75 (s, 3H), 4.33 (t,
j=6.4 Hz, 2H), 4.06 (s, 3H), 3.08 (t,
j=7.2 Hz, 2H), 2.94 (t,
j=7.2 Hz, 2H), 2.77 (t,
j=7.2 Hz, 2H), 2.62 (s, 4H), 2.17-2.09 (m, 2H), 1.83 (s, 4H);
13c NMR (101 MHz, CDCl
3) δ: 153.17,152.56,150.48,147.67,141.43; 141.09,135.49,135.13,133.71; 123.69,121.87,119.66,116.81; 111.11,109.02,102.73,72.60; 56.76,54.17,52.75,46.64; 29.45,29.08,28.85,23.46; HRMS
m/z: 447.2275 [M-Cl]
+.
embodiment 23:compound
22csynthetic
Method is with embodiment 21, and difference is to replace diethylamine with piperidines, obtains faint yellow solid
22c.
Productive rate: 18.4%;
1h NMR (400 MHz, D
2o) δ: 8.41 (s, 1H), 7.85 (d,
j=9.6 Hz, 1H), 7.70 (d,
j=10 Hz, 1H), 7.21 (s, 1H), 6.97 (s, 1H), 6.04 (s, 2H), 4.39 (s, 3H), 3.97 (t,
j=6.4 Hz, 2H), 3.91 (s, 3H), 2.89 (t,
j=7.6 Hz, 2H), 2.78 (t,
j=6.8 Hz, 2H), 2.41-2.33 (m, 6H), 1.86-1.79 (m, 2H), 1.49-1.44 (m, 4H), 1.35 (s, 2H);
13c NMR (101 MHz, D
2o) δ: 153.81,151.99,150.02,146.75,142.44; 140.56,134.87,134.56,134.47,123.20; 120.85,119.49,115.14,110.11; 109.09,102.73,73.45,56.41; 55.12,53.61,44.71,28.45; 27.94,26.17,24.67,23.30; HRMS
m/z: 461.2432 [M-Cl]
+.
embodiment 24:compound
22dsynthetic
Method is with embodiment 21, and difference is to replace diethylamine with N methyl piperazine, obtains faint yellow solid
22d.
Productive rate: 16%;
1h NMR (400 MHz, CDCl
3) δ 8.75 (s, 1H), 8.64 (d,
j=9.6 Hz, 1H), 7.91 (d,
j=9.6 Hz, 1H), 7.65 (s, 1H), 6.93 (s, 1H), 6.14 (s, 2H), 4.93 (s, 3H), 4.28 (t,
j=6.4 Hz, 2H), 4.05 (s, 3H), 3.07 (t,
j=7.6 Hz, 2H), 2.93 (t,
j=7.2 Hz, 2H), 2.65 (t,
j=7.6 Hz, 2H), 2.55 (s, 4H), 2.32 (s, 3H), 2.1-2.04 (m, 6H);
13c NMR (101 MHz, CDCl
3) δ: 153.24,152.58,150.44,147.69,141.34; 141.07,135.18,135.16,133.67,123.64; 121.88,119.66,116.80,111.14; 109.02,102.73,72.64,56.75; 54.85,54.82,52.95,46.60; 45.82,29.18,28.83,27.55; HRMS
m/z: 476.2541 [M-Cl]
+.
embodiment 25:compound
22esynthetic
Method is with embodiment 21, and difference is to replace diethylamine with hexahydroaniline, and the mol ratio of hexahydroaniline and compound 19 is increased to 10:1.Obtain yellow solid
22e.
Productive rate: 51.6%;
1h NMR (400 MHz, CDCl
3) δ: 8.79 (s, 1H), 8.69 (d,
j=9.6 Hz, 1H), 7.92 (d,
j=10 Hz, 1H), 7.65 (s, 1H), 6.92 (s, 1H), 6.14 (s, 2H), 4.94 (s, 3H), 4.30 (t,
j=6.4 Hz, 2H), 4.05 (s, 3H), 3.07 (t,
j=7.2 Hz, 2H), 2.94-2.89 (m, 4H), 2.52-2.45 (m, 1H), 2.10-2.05 (m, 2H), 1.93 (d,
j=10.4 Hz, 2H), 1.73 (d,
j=12.8 Hz, 2H), 1.31-1.21 (m, 4H), 1.14-1.06 (m, 2H);
13c NMR (101 MHz, CDCl
3) δ: 153.17,152.51,150.40,147.60,141.37; 141.18,135.48,135.05,133.81,123.64; 121.81,119.59,116.75,111.03,109.03; 102.70,72.76,56.98,56.75; 46.61,43.36,32.92,30.44; 29.03,28.81,25.92,24.98; HRMS
m/z: 475.2589 [M-Cl]
+.
embodiment 26:compound
22fsynthetic
Method is with embodiment 21, and difference is to replace diethylamine with benzylamine, and by benzylamine and compound
19mol ratio be increased to 10:1.Obtain yellow solid
22f.
Productive rate: 16%;
1h NMR (400 MHz, CDCl
3) δ: 8.81 (s, 1H), 8.71 (d,
j=9.6 Hz, 1H), 7.90 (d,
j=9.6 Hz, 1H), 7.65 (s, 1H), 7.37 (d,
j=6.8 Hz, 2H), 7.32 (t,
j=6.8 Hz, 2H), 7.24 (d,
j=6.0 Hz, 1H), 6.92 (s, 1H), 6.14 (s, 2H), 4.96 (s, 3H), 4.32 (t,
j=6.4 Hz, 2H), 4.01 (s, 3H), 3.88 (s, 2H), 3.02-2.98 (m, 2H), 2.95 (t,
j=6.8 Hz, 2H), 2.90-2.87 (m, 2H);
13c NMR (101 MHz, CDCl
3) δ: 153.38,152.58,150.41,147.66,141.60; 141.39,138.95,135.66,135.17,133.95; 128.48,128.46,127.28,123.77,121.87; 119.70,116.24,110.96,109.07,102.72; 72.70,56.80,53.72,46.25; 45. 95,30.04,29.03,28.85; HRMS
m/z: 483.2279 [M-Cl]
+.
embodiment 27:compound
23bsynthetic
Method is with embodiment 21, and difference is to use compound
20replace
18, and replace diethylamine with Pyrrolidine, obtain yellow solid
23b.
Productive rate 26.3%.
1H?NMR?(400?MHz,?CDCl
3)?δ:?8.79?(s,?1H),?8.22?(d,?
J?=?9.6?Hz,?1H),?7.80?(d,?
J?=?9.6?Hz,?1H),?7.52?(s,?1H),?6.93?(s,?1H),?4.76?(s,?3H),?4.31?(t,?
J?=?6.4?Hz,?2H),?4.04?(s,?3H),?4.01?(s,?6H),?3.08?(t,?
J?=?6.8?Hz,?2H),?2.95?(t,?
J?=?6.8?Hz,?2H),?2.76?(t,?
J?=?7.6?Hz,?2H),?2.61?(s,?4H),?2.14-2.07?(m,?2H),?1.82?(s,?4H);?
13C?NMR?(101?MHz,?CDCl
3)?δ:?154.01,?153.70,?150.37,?148.53,?141.69,?139.10,?135.41,?135.12,?133.92,?123.72,?121.37,?118.59,?115.68,?113.83,?111.05,?72.77,?57.02,?56.71,?56.37,?54.21,?52.79,?45.57,?29.53,?29.12,?28.25,?23.46;?ESI-HRMS?
m/z:?calcd?for?C
28H
35N
2O
4?[M-Cl]
+463.2591,?found?463.2585。
embodiment 28:compound
23csynthetic
Method is with embodiment 21, and difference is to use compound
20replace
18, and replace diethylamine with piperidines, obtain yellow solid
23c.
Productive rate is 44.3%:
1h NMR (400 MHz, CDCl
3) δ: 8.71 (s, 1H), 8.54 (d,
j=9.6 Hz, 1H), 8.01 (s, 1H), 7.83 (d,
j=9.6 Hz, 1H), 6.90 (s, 1H), 5.12 (s, 3H), 4.27 (t,
j=6.4 Hz, 2H), 4.14 (s, 3H), 4.04 (s, 3H), 4.02 (s, 3H), 3.07 (t,
j=6.8 Hz, 2H), 2.94 (t,
j=6.8 Hz, 2H), 2.57 (t,
j=7.6 Hz, 2H), 2.44 (s, 4H), 2.10-2.03 (m, 2H), 1.64-1.58 (m, 4H), 1.48-1.43 (m, 2H);
13c NMR (101 MHz, CDCl
3) δ: 153.98,153.64,150.33,148.75,141.55; 138.39,135.42,134.83,133.78,123.71; 121.63,118.90,116.72,114.99,110.81; 72.90,57.93,56.74,56.32; 55.63,54.66,46.73,29.20; 28.37,27.71,25.93,24.34; HRMS
m/z: 477.2743 [M-Cl]
+.
embodiment 29:the restraining effect of benzacridine derivative to the amplification of C-myc promoter DNA described in this patent
Select the compound of part of representative, the C-myc promoter DNA polymerase chain amplification that adopts PCR-stop method to carry out cell-free system suppresses experiment.By a certain amount of rTaq polysaccharase, after Nucleotide dNTP and medicament mixed to be measured, carry out PCR reaction, result utilizes fluorescence gel imager to detect, and result is as shown in table 1.Result shows, the compound described in this patent has obvious restraining effect to rTaq polysaccharase in vitro.Therefore novel benzacridine derivative of the present invention can be used for preparation and take the cancer therapy drug that C-myc promoter DNA is target spot.
Table
1the IC of the compound effect that amplification suppresses to C-myc promoter DNA
50(μ M)
| Embodiment | 12 | 13 | 14 | 15 | 16 | 21 | 22 |
| IC50(μM) | > 50 | > 50 | > 50 | > 50 | > 50 | 12.0 | 10.8 |
| Embodiment | 23 | 24 | 25 | 26 | 28 | ? | ? |
| IC50(μM) | 15.2 | 21.7 | 16.5 | ?8.7 | ?9.1 | ? | ? |
embodiment 30:the restraining effect of benzacridine derivative to growth of tumour cell described in this patent
Select the compound of part of representative, with the strain of two kinds of tumor cell line hela(human cervical carcinoma cells), CNE-2(people's snuff JEG-3), adopt mtt assay to carry out cell in vitro poison and measure.Logarithmic phase cell adds the novel benzacridine derivative of different concns, acts on after 96 hours, measures its absorbancy.Compound concentration when calculating respectively cell growth inhibiting and reaching 50%, with IC
50value representation, result is as shown in table 2.Result shows described in this patent that compound all has stronger restraining effect to these two kinds of tumor cell lines in vitro.Therefore benzacridine derivative of the present invention can be used for preparing anticancer medicine.
Table
2restraining effect (the IC of part of compounds to tumor cell line growth
50/ μ M)
| Embodiment | 12 | 13 | 14 | 15 | 20 | 21 | 23 |
| hela | 5.26 | 15.1 | 6.14 | 40.63 | - | 43.75 | 46.11 |
| CNE-2 | 5.57 | 7.29 | 4.66 | 41.38 | 7.29 | - | 39.43 |
| Embodiment | 23 | 24 | 26 | ? | ? | ? | ? |
| hela | - | 17.67 | 43.14 | ? | ? | ? | ? |
| CNE-2 | 38 | 7.93 | 19.83 | ? | ? | ? | ? |
Claims (1)
1. a benzacridine derivative, is characterized in that structural formula is:
R in formula
1=R
2for CH
3o or OCH
2o;
N=2 or 3;
R
3for NHR
4or NR
5;
R
4for C
3-6cycloalkyl; NR
5for Pyrrolidine base, piperidyl, N methyl piperazine base.
2. a benzacridine derivative, is characterized in that structural formula is:
R in formula
1=R
2for CH
3o or OCH
2o;
N=2 or 3;
R
3for NHR
4or NR
5;
R
4for C
3-6cycloalkyl; NR
5for Pyrrolidine base, piperidyl, N methyl piperazine base.
3. a preparation method for benzacridine derivative as claimed in claim 1 or 2, is characterized in that:
Its preparation method comprises the following steps: at AlCl
3under catalysis, take oil of mirbane as solvent, there is acylation reaction in 1,2-dimethoxy benzene and Succinic anhydried, obtain compound at 0 ~ 60 ° of C temperature
, then this product is at (CH
3cH
2)
3siH and CF
3cO
2under H reflux conditions, its deoxidation is obtained to compound
, then at polyphosphoric acid and CH
2cl
2reflux conditions ShiShimonoseki ring, obtains compound
, compound is again through the HBr aqueous solution containing 40 ~ 48%, and under reflux conditions demethylation obtains compound
, last under the catalysis of KF, take DMF as solvent and CH
2br
2140 ° of C reactions, obtain compound
;
Meanwhile, O-VANILLIN be take methylene dichloride as solvent, and under 0 ° of C, through benzenesulfonyl, protection obtains compound
, compound then obtains with concentrated nitric acid is nitrated
, then, in the mixed solvent of acetone/water, under room temperature, use KMnO
4oxidation aldehyde radical, the nitro that reduces under iron powder room temperature condition in acetic acid/ethanol/water mixed solvent obtain compound
,
Compound
or
with compound
at POCl
3ring closure reaction under reflux conditions, obtains compound
compound is then in the mixed solvent of DMF/ ethanol, DMF/ methyl alcohol, DMF/THF or DMF/ ethyl acetate, under 60 ° of C conditions, with the palladium carbon that the content of palladium is 5 ~ 10%, slough the chlorine atom in molecule, the dechlorination intermediate product obtaining is in the mixed solvent of dioxane/water or tetrahydrofuran (THF)/water, under 100 ° of C conditions, with sodium hydroxide or potassium hydroxide, the sulfonic group in molecule is hydrolyzed into phenolic hydroxyl group, the phenolic hydroxyl group intermediate product obtaining be take acetonitrile, acetone or DMF as solvent, under 60 ° of C conditions, obtain compound with dibromo alkane reaction
, wherein n is 2 or 3, R
1=R
2for CH
3o or OCH
2o;
When compound be take acetonitrile, acetone or DMF as solvent, under 60 ~ 100 ° of C conditions, bromine atoms is directly by Pyrrolidine, piperidines, N methyl piperazine or NHR
4during replacement, obtain target compound
, n=2 or 3 wherein; R
1=R
2for CH
3o or OCH
2o, R
3for NHR
4or NR
5; R
4for C
3-6cycloalkyl; NR
5for Pyrrolidine base, piperidyl, N methyl piperazine base;
Work as compound
take toluene as solvent, under room temperature condition, first through trifluoromethane sulfonic acid methyl esters methyl on N, then take methylene dichloride or chloroform as solvent is again by Pyrrolidine, piperidines, N methyl piperazine or NHR for bromine atoms
4replace and with anionite-exchange resin by OTf
3 -be exchanged for Cl
-obtain target compound
, n=2 or 3 wherein; R
1=R
2for CH
3o or OCH
2o, R
3for NHR
4or NR
5; R
4for C
3-6cycloalkyl; NR
5for Pyrrolidine base, piperidyl, N methyl piperazine base.
4. preparation method as claimed in claim 3, is characterized in that used AlCl
3the mol ratio of catalyzer and 1,2-dimethoxy benzene is 2:1 ~ 4:1, and the mol ratio of Succinic anhydried and 1,2-dimethoxy benzene is 1.5:1 ~ 4:1, and temperature of reaction is 0 ~ 60 ° of C, and the amount of substance of 1,2-dimethoxy benzene and the volume ratio of solvent are 1:50 ~ 1:100; Compound
with (CH
3cH
2)
3the mol ratio of SiH is 2:1 ~ 4:1, the amount of substance of compound and CF
3cO
2the volume ratio of H is 1:5 ~ 1:10; Compound
amount of substance and the volume ratio of 40 ~ 48% the HBr aqueous solution be 1:5 ~ 1:10, compound
, CH
2br
2with KF three's mol ratio be 1:1:5 ~ 1:1.2:10, the amount of substance of compound and the volume ratio of solvent are 1:20 ~ 1:40.
5. preparation method as claimed in claim 3, is characterized in that described compound
, KMnO
4with Fe three's mol ratio be 1:1.5:5 ~ 1:2:10, the volume ratio of water and acetone is 1:3 ~ 1:6; The volume ratio of acetic acid/ethanol/water is 5:5:1 ~ 2:2:1.
6. preparation method as claimed in claim 3, is characterized in that described compound
or
with compound
mol ratio be 1:1.5 ~ 1:2.5, the amount of substance of compound and POCl
3volume ratio be 1:5 ~ 1:10.
7. preparation method as claimed in claim 3, is characterized in that described compound
with the mass ratio of the palladium content palladium carbon that is 5 ~ 10% be 1:0.8 ~ 1:1.2, solvent used is mixed solvent DMF/EtOH, DMF/MeOH, DMF/THF or DMF/ ethyl acetate, in mixed solvent, the volume ratio of two kinds of solvents is 20:1 ~ 10:1; The dechlorination product obtaining and the mol ratio of NaOH or KOH are 1:5 ~ 1:10, and solvent used is mixed solvent dioxane/water or THF/ water, and in mixed solvent, the volume ratio of two kinds of solvents is 10:1 ~ 5:1; Obtaining the product of sulfonic group hydrolysis and the mol ratio of two bromoalkanes is 1:5 ~ 1:10, and solvent used is acetone, acetonitrile or DMF; Compound
with Pyrrolidine, piperidines, N methyl piperazine or NHR
4the ratio replacing is 1:1.2 ~ 1:10, wherein R
4for C
3-6cycloalkyl; Solvent used is DMF, acetone or acetonitrile, and the amount of substance of compound and the volume ratio of solvent are 1:5 ~ 1:10.
8. preparation method as claimed in claim 3, is characterized in that described compound
with the mol ratio of trifluoromethane sulfonic acid methyl esters be 1:1.1 ~ 1:2.0, with the ratio of the amount of substance of compound and the volume of toluene be 1:8 ~ 1:15; The methylate obtaining and Pyrrolidine, piperidines, N methyl piperazine or NHR
4mol ratio be 1:1.2 ~ 1:10, wherein R
4for C
3-6cycloalkyl, the amount of substance of methylate and the volume ratio of solvent are 1:3 ~ 1:8.
9. preparation method as claimed in claim 3, is characterized in that obtained target compound obtains sterling through column chromatography or recrystallization.
10. the purposes of the benzacridine derivative described in claim 1 or 2 in preparing cancer therapy drug.
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