CN103910739B - 一种双苄基异喹啉甜菜碱及其制备方法和在制备抗肿瘤药物中的应用 - Google Patents
一种双苄基异喹啉甜菜碱及其制备方法和在制备抗肿瘤药物中的应用 Download PDFInfo
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- CN103910739B CN103910739B CN201410116550.XA CN201410116550A CN103910739B CN 103910739 B CN103910739 B CN 103910739B CN 201410116550 A CN201410116550 A CN 201410116550A CN 103910739 B CN103910739 B CN 103910739B
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- Prior art keywords
- acid
- sodium
- potassium
- iodine
- bromine
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- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- KWIUHFFTVRNATP-UHFFFAOYSA-N glycine betaine Chemical compound C[N+](C)(C)CC([O-])=O KWIUHFFTVRNATP-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960003237 betaine Drugs 0.000 title claims abstract description 36
- 239000002246 antineoplastic agent Substances 0.000 title claims abstract description 6
- 229940041181 antineoplastic drug Drugs 0.000 title claims abstract description 6
- 229910052740 iodine Inorganic materials 0.000 claims abstract description 62
- 239000002904 solvent Substances 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 18
- 206010009944 Colon cancer Diseases 0.000 claims abstract description 12
- 208000029742 colonic neoplasm Diseases 0.000 claims abstract description 12
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 6
- 208000014018 liver neoplasm Diseases 0.000 claims abstract description 4
- 201000007270 liver cancer Diseases 0.000 claims abstract description 3
- 239000000047 product Substances 0.000 claims description 84
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 72
- 239000000460 chlorine Substances 0.000 claims description 57
- 229910052794 bromium Inorganic materials 0.000 claims description 56
- 239000011630 iodine Substances 0.000 claims description 56
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 51
- 229910052801 chlorine Inorganic materials 0.000 claims description 46
- 150000001875 compounds Chemical class 0.000 claims description 37
- -1 2-bromo-butyric acid potassium Chemical compound 0.000 claims description 26
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000002253 acid Substances 0.000 claims description 23
- 238000003756 stirring Methods 0.000 claims description 21
- 239000011591 potassium Substances 0.000 claims description 19
- 229910052700 potassium Inorganic materials 0.000 claims description 19
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 18
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 17
- 239000011734 sodium Substances 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- 229910052708 sodium Inorganic materials 0.000 claims description 12
- 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 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 10
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 9
- MONMFXREYOKQTI-UHFFFAOYSA-N 2-bromopropanoic acid Chemical compound CC(Br)C(O)=O MONMFXREYOKQTI-UHFFFAOYSA-N 0.000 claims description 8
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 claims description 8
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 8
- 229940071870 hydroiodic acid Drugs 0.000 claims description 8
- NFRKUDYZEVQXTE-UHFFFAOYSA-N 2-chloropentane Chemical compound CCCC(C)Cl NFRKUDYZEVQXTE-UHFFFAOYSA-N 0.000 claims description 7
- HZYCAKGEXXKCDM-UHFFFAOYSA-N Methyl 2-(methylthio)acetate Chemical compound COC(=O)CSC HZYCAKGEXXKCDM-UHFFFAOYSA-N 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 7
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 claims description 7
- 229940082004 sodium laurate Drugs 0.000 claims description 7
- 229940045870 sodium palmitate Drugs 0.000 claims description 7
- GGXKEBACDBNFAF-UHFFFAOYSA-M sodium;hexadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCC([O-])=O GGXKEBACDBNFAF-UHFFFAOYSA-M 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 6
- QCEDORUJSTYXSJ-UHFFFAOYSA-N [Na].C(CCCCCCCC)(=O)O Chemical compound [Na].C(CCCCCCCC)(=O)O QCEDORUJSTYXSJ-UHFFFAOYSA-N 0.000 claims description 6
- PXYVJNSUJSWPHW-UHFFFAOYSA-N heptanoic acid;potassium Chemical compound [K].CCCCCCC(O)=O PXYVJNSUJSWPHW-UHFFFAOYSA-N 0.000 claims description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 6
- HIDKSOTTZRMUML-UHFFFAOYSA-M potassium;dodecanoate Chemical compound [K+].CCCCCCCCCCCC([O-])=O HIDKSOTTZRMUML-UHFFFAOYSA-M 0.000 claims description 6
- ANBFRLKBEIFNQU-UHFFFAOYSA-M potassium;octadecanoate Chemical compound [K+].CCCCCCCCCCCCCCCCCC([O-])=O ANBFRLKBEIFNQU-UHFFFAOYSA-M 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 6
- NMTDPTPUELYEPL-UHFFFAOYSA-M sodium;heptanoate Chemical compound [Na+].CCCCCCC([O-])=O NMTDPTPUELYEPL-UHFFFAOYSA-M 0.000 claims description 6
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 5
- DBJFFHKFYVGAMQ-UHFFFAOYSA-N [K].C(CCCCCCC)C(=O)O Chemical compound [K].C(CCCCCCC)C(=O)O DBJFFHKFYVGAMQ-UHFFFAOYSA-N 0.000 claims description 5
- 229910052731 fluorine Inorganic materials 0.000 claims description 5
- 125000004785 fluoromethoxy group Chemical group [H]C([H])(F)O* 0.000 claims description 5
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000001257 hydrogen Substances 0.000 claims description 5
- 238000006386 neutralization reaction Methods 0.000 claims description 5
- QDIGBJJRWUZARS-UHFFFAOYSA-M potassium;decanoate Chemical compound [K+].CCCCCCCCCC([O-])=O QDIGBJJRWUZARS-UHFFFAOYSA-M 0.000 claims description 5
- 229960005480 sodium caprylate Drugs 0.000 claims description 5
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 5
- 229910003204 NH2 Inorganic materials 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 4
- QKRAOTCLMXZGQF-UHFFFAOYSA-N [Na].BrCC(=O)O Chemical compound [Na].BrCC(=O)O QKRAOTCLMXZGQF-UHFFFAOYSA-N 0.000 claims description 4
- 235000011054 acetic acid Nutrition 0.000 claims description 4
- RXQNHIDQIJXKTK-UHFFFAOYSA-N azane;pentanoic acid Chemical compound [NH4+].CCCCC([O-])=O RXQNHIDQIJXKTK-UHFFFAOYSA-N 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- ADCUQUUDYDDLQY-UHFFFAOYSA-N pentanoic acid;potassium Chemical compound [K].CCCCC(O)=O ADCUQUUDYDDLQY-UHFFFAOYSA-N 0.000 claims description 4
- 229940096992 potassium oleate Drugs 0.000 claims description 4
- MLICVSDCCDDWMD-KVVVOXFISA-M potassium;(z)-octadec-9-enoate Chemical compound [K+].CCCCCCCC\C=C/CCCCCCCC([O-])=O MLICVSDCCDDWMD-KVVVOXFISA-M 0.000 claims description 4
- RLEFZEWKMQQZOA-UHFFFAOYSA-M potassium;octanoate Chemical compound [K+].CCCCCCCC([O-])=O RLEFZEWKMQQZOA-UHFFFAOYSA-M 0.000 claims description 4
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 claims description 4
- 239000001117 sulphuric acid Substances 0.000 claims description 4
- 235000011149 sulphuric acid Nutrition 0.000 claims description 4
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 3
- OHDTTZKQAZNALA-UHFFFAOYSA-N ClC(C(=O)O)CC.[Na] Chemical compound ClC(C(=O)O)CC.[Na] OHDTTZKQAZNALA-UHFFFAOYSA-N 0.000 claims description 3
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical compound CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- PFRCKXSROVSDPW-UHFFFAOYSA-N [K].ClC(C(=O)O)C Chemical compound [K].ClC(C(=O)O)C PFRCKXSROVSDPW-UHFFFAOYSA-N 0.000 claims description 3
- ZZVJHGFDCBUXGQ-UHFFFAOYSA-N [K].IC(C(=O)O)C Chemical compound [K].IC(C(=O)O)C ZZVJHGFDCBUXGQ-UHFFFAOYSA-N 0.000 claims description 3
- MFVGNZLVTFSJGU-UHFFFAOYSA-N [Na].CCC(Br)C(O)=O Chemical compound [Na].CCC(Br)C(O)=O MFVGNZLVTFSJGU-UHFFFAOYSA-N 0.000 claims description 3
- DTKXHLMEFBSBSD-UHFFFAOYSA-N azane;2-bromoacetic acid Chemical compound N.OC(=O)CBr DTKXHLMEFBSBSD-UHFFFAOYSA-N 0.000 claims description 3
- YTGUVFOCFQHBPT-UHFFFAOYSA-N azanium 2-iodopropanoate Chemical compound CC(C(=O)[O-])I.[NH4+] YTGUVFOCFQHBPT-UHFFFAOYSA-N 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 235000019253 formic acid Nutrition 0.000 claims description 3
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 3
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 3
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical class ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- XWVXXVQCDFVDMW-UHFFFAOYSA-N 2-chloropropanoic acid;sodium Chemical compound [Na].CC(Cl)C(O)=O XWVXXVQCDFVDMW-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 2
- DLSVSQFAZAUYAE-UHFFFAOYSA-N [K].ClC(C(=O)O)CC Chemical compound [K].ClC(C(=O)O)CC DLSVSQFAZAUYAE-UHFFFAOYSA-N 0.000 claims description 2
- AXYBKGMHGWHWTA-UHFFFAOYSA-N [K].ICC(=O)O Chemical compound [K].ICC(=O)O AXYBKGMHGWHWTA-UHFFFAOYSA-N 0.000 claims description 2
- VFTMJKIWWFRRHF-UHFFFAOYSA-N [Na].IC(C(=O)O)C Chemical compound [Na].IC(C(=O)O)C VFTMJKIWWFRRHF-UHFFFAOYSA-N 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims description 2
- BBHMODQMZQGIAS-UHFFFAOYSA-N azanium 2-bromobutanoate Chemical compound [NH4+].CCC(Br)C([O-])=O BBHMODQMZQGIAS-UHFFFAOYSA-N 0.000 claims description 2
- YTGWCBFIZZKMFO-UHFFFAOYSA-N azanium 2-bromohexanoate Chemical compound CCCCC(C(=O)[O-])Br.[NH4+] YTGWCBFIZZKMFO-UHFFFAOYSA-N 0.000 claims description 2
- OVXIFFOJLCARJG-UHFFFAOYSA-N azanium 2-chlorobutanoate Chemical compound CCC(C(=O)[O-])Cl.[NH4+] OVXIFFOJLCARJG-UHFFFAOYSA-N 0.000 claims description 2
- XHOIUYRDJMVPQB-UHFFFAOYSA-N azanium 2-chloropropanoate Chemical compound CC(C(=O)[O-])Cl.[NH4+] XHOIUYRDJMVPQB-UHFFFAOYSA-N 0.000 claims description 2
- VRURHMQGJUTBLH-UHFFFAOYSA-N azanium 2-iodoacetate Chemical compound ICC(=O)[O-].[NH4+] VRURHMQGJUTBLH-UHFFFAOYSA-N 0.000 claims description 2
- YNTQKXBRXYIAHM-UHFFFAOYSA-N azanium;butanoate Chemical compound [NH4+].CCCC([O-])=O YNTQKXBRXYIAHM-UHFFFAOYSA-N 0.000 claims description 2
- 239000003560 cancer drug Substances 0.000 claims description 2
- 239000007795 chemical reaction product Substances 0.000 claims description 2
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 claims description 2
- 229940089960 chloroacetate Drugs 0.000 claims description 2
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 125000001421 myristyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 235000006408 oxalic acid Nutrition 0.000 claims description 2
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 claims description 2
- 238000003805 vibration mixing Methods 0.000 claims description 2
- FBUKVWPVBMHYJY-UHFFFAOYSA-N nonanoic acid Chemical compound CCCCCCCCC(O)=O FBUKVWPVBMHYJY-UHFFFAOYSA-N 0.000 claims 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims 2
- 239000005711 Benzoic acid Substances 0.000 claims 1
- 235000010233 benzoic acid Nutrition 0.000 claims 1
- 238000005660 chlorination reaction Methods 0.000 claims 1
- SKHOVAPWIYEIAZ-UHFFFAOYSA-N decanoic acid;potassium Chemical compound [K].CCCCCCCCCC(O)=O SKHOVAPWIYEIAZ-UHFFFAOYSA-N 0.000 claims 1
- 235000011087 fumaric acid Nutrition 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- RWSZDLPYUAAMDO-UHFFFAOYSA-N pentanoic acid;sodium Chemical compound [Na].CCCCC(O)=O RWSZDLPYUAAMDO-UHFFFAOYSA-N 0.000 claims 1
- 235000011056 potassium acetate Nutrition 0.000 claims 1
- WVTKBKWTSCPRNU-KYJUHHDHSA-N (+)-Tetrandrine Chemical class C([C@H]1C=2C=C(C(=CC=2CCN1C)OC)O1)C(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2C[C@@H]2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-KYJUHHDHSA-N 0.000 abstract description 38
- 230000000694 effects Effects 0.000 abstract description 11
- 230000002401 inhibitory effect Effects 0.000 abstract description 10
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- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 26
- 210000004027 cell Anatomy 0.000 description 26
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- 238000002441 X-ray diffraction Methods 0.000 description 23
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
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- 239000003513 alkali Substances 0.000 description 19
- WVTKBKWTSCPRNU-UHFFFAOYSA-N rac-Tetrandrin Natural products O1C(C(=CC=2CCN3C)OC)=CC=2C3CC(C=C2)=CC=C2OC(=C2)C(OC)=CC=C2CC2N(C)CCC3=CC(OC)=C(OC)C1=C23 WVTKBKWTSCPRNU-UHFFFAOYSA-N 0.000 description 17
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- INYYVPJSBIVGPH-UHFFFAOYSA-N 14-episinomenine Natural products C1CN(C)C2CC3=CC=C(OC)C(O)=C3C31C2C=C(OC)C(=O)C3 INYYVPJSBIVGPH-UHFFFAOYSA-N 0.000 description 10
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- INYYVPJSBIVGPH-QHRIQVFBSA-N Sinomenine Chemical compound C([C@@H]1N(CC2)C)C3=CC=C(OC)C(O)=C3[C@@]32[C@@H]1C=C(OC)C(=O)C3 INYYVPJSBIVGPH-QHRIQVFBSA-N 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
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- 241000335053 Beta vulgaris Species 0.000 description 7
- 239000007832 Na2SO4 Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 230000001629 suppression Effects 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000003463 adsorbent Substances 0.000 description 6
- 229910021529 ammonia Inorganic materials 0.000 description 6
- 230000015572 biosynthetic process Effects 0.000 description 6
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- 238000010025 steaming Methods 0.000 description 6
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Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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Abstract
本发明涉及一种双苄基异喹啉甜菜碱及其制备方法和在制备抗肿瘤药物中的应用,结构式如通式(Ⅰ)所示,式中取代基如说明书所示,双苄基异喹啉或取代物在溶剂中与卤代脂肪酸盐‑20℃~300℃反应制得。双苄基异喹啉甜菜碱化学结构,提高了对受体的亲和力,对人肝癌细胞株HepG2增殖具有较高的抑制活性,对人结肠癌细胞HT29增殖也具有较高的抑制活性。比现有的粉防己碱类化合物抗肝癌活性提高20多倍,在临床上可以减少药剂用量,从而可以减轻药物的毒副作用。
Description
技术领域
本发明涉及一种双苄基异喹啉甜菜碱及其制备方法和在药物中的应用,属于药物合成技术领域。
背景技术
双苄基异喹啉化合物(bisBenzylisoquinoline compounds)具有抗癌、抗菌、抗炎、降压、肌肉松弛、调节免疫功能等名方面的作用,其中比较重要的天然双苄基异喹啉化合物包括粉防己碱、防己诺林碱、小檗胺、千金藤素、轮环藤宁、箭毒碱等,如粉防己碱(Tetrandrine),又称汉防己碱或汉防己甲素,属双苄基异喹啉类化合物,临床上主要用于风湿痛、关节痛、神经痛,亦用于矽肺病。汉肌松(碘化二甲基粉防己碱,是粉防己碱的季铵盐)是一种横纹肌松弛药,临床上可用于外科手术中使横纹肌松弛。实验研究证明,汉防己碱在抗肺癌、慢性粒细胞白血病、肝癌、神经母细胞瘤、乳腺癌等方面都有一定作用,其机制与逆转多药耐药、诱导细胞凋亡、放疗增敏、抑制肿瘤血管形成有关。通过体外实验证明(徐萌,等.汉防己甲素逆转肺癌化疗耐药和凋亡抗性的实验研究[J].新中医,2006,38(6):90),汉防己碱作用于耐药肺癌细胞后,耐药指数(RF)由用阿霉素时的5.43降至1.89,说明汉防己碱可以逆转GLC-82/ADR耐药肺癌细胞对阿霉素的耐药。汉防己碱可以诱导细胞凋亡(①荆绪斌,等.汉防己甲素诱导肝癌细胞氧化损伤的实验研究[J].临床肝胆病杂志,2002,8(6):366;②Quan ri Jin,et al.etrandrine cytotoxicity and its dual effect onoxidative stress-induced apoptosis through modulating cellular redox statesin Neuro-2a mouse neuroblastoma cells[J].Life Sciences,2002,71(17):2053;③李巍松,等.汉防己甲素诱导神经母细胞瘤株TGW凋亡作用的实验研究[J].临床儿科杂志,2006,24(6):512)。已申请专利的汉防己碱主要有如下几种,汉防己碱在制备防治肝脏损伤的药物中的用途(CN101199529),汉防己碱和汉防己碱化合物合成和应用(CN1720232),含有粉防己碱的眼用制剂及其在制备治疗眼科疾病的含有粉防己碱的眼用制剂中的应用(CN1785192),粉防己碱在制备预防和/或治疗抑郁症药物中的应用(CN102274227A),粉防己碱在制备抑制肝星状细胞迁移的药物中的应用(201110274644.6),汉防己碱和汉防己碱化合物合成和应用(CN1328280C),粉防己碱有机酸盐及制备方法和应用(CN1504469),含有粉防己碱及粉防己碱类衍生物和组蛋白去乙酰化酶抑制剂的药物组合物及其应用(200910129319.3),5-取代粉防己碱类化合物及其在制备抗癌药增敏剂中的用途(CN102875560A),一种汉防己甲素的没食子酸盐、其药物组合物、其制备方法及其用途(CN102898433A),双苄基异喹啉类生物碱及其制备方法和药物组合物(CN1293196),双苄基异喹啉-(7-0-11')-单醚键生物碱衍生物及类似物在治疗纤维化有关疾病中的用途(03136949.9),双苄基异喹啉化合物及制备方法和应用(200810061688.9),双苄基异喹啉类生物碱的新用途(200810223901.1),双苄基异喹啉衍生物及其制备和用途(200910272626.7),双苄基异喹啉衍生物及其制备和用途(201010542104.7),双苄基异喹啉类化合物或其在药学上可接受的盐在制备改善睡眠的药品或保健品中的应用(201110066105.3),通式Ⅰ所述的双苄基异喹啉生物碱衍生物或类似物的新用途(201210061676.2)。现有双苄基异喹啉类化合物的研究主要围绕粉防己碱,对抗癌性能的研究也不多。
有关甜菜碱及其衍生物的专利文献有:一种混合脂肪酸酰胺丙基甜菜碱及其制备方法(CN103524370A),一种混合脂肪酸酰胺丙基甜菜碱复合物及应用(CN103525390A),一种高纯度甜菜碱磷酸盐的制备方法(CN103387503A),一种N,N-二甲基-N-脂肪醇聚氧乙烯醚基羧甲基甜菜碱的制备方法(CN102964260A),一种十二烷基二甲基甜菜碱(CN102924307A),一种甜菜碱盐酸盐的制备方法(CN102807499A),甜菜碱的制备方法(CN103242184A),甜菜碱的制备方法(CN102838500A),甜菜碱硝酸盐的制备方法(CN102838499A),一种制备盐酸甜菜碱的方法(CN102267918A),一种甜菜碱盐酸盐的制备方法(CN102827011A),一种盐酸甜菜碱的制备方法(CN102617374A),无溶剂季铵化制备高含量α-烷基甜菜碱的方法(CN102126964A),甜菜碱的制备方法(CN102070474A),无水甜菜碱的制造方法(CN102311354A),一种金刚烷基甜菜碱型两性表面活性剂及其制备方法(CN101721942A),生产γ-丁基甜菜碱酯的方法(CN101538215A),一种双长链烷基甜菜碱表面活性剂的制备及其应用(CN101549266A),一种合成甜菜碱的方法(CN101531604A),一种甜菜碱、甜菜碱盐酸盐的合成方法(CN101323581A),含甜菜碱的结构化组合物(CN101332162A),含甜菜碱的结构化组合物的制备和使用方法(CN101332161A),一种长链羧基甜菜碱表面活性剂及其制备方法(CN101618302A),一种α-烷基甜菜碱两性表面活性剂的制备方法(CN101249399A),N-氨基取代的羧酸型甜菜碱表面活性剂及其合成方法(CN101050187A),甜菜碱磷酸盐及其生产方法与应用(CN101121672A),甜菜碱磷酸盐及其生产方法与应用(CN101121672A),甜菜碱水杨酸盐的合成及其生物学和药理学作用(CN1733704A),用于抗血栓形成的甘氨酸甜菜碱(CN1342071A),甜菜碱产品,其生产方法及应用(CN1258229A),提取盐酸甜菜碱工艺(CN1117967A),合成三甲铵乙内酯(甜菜碱)的方法(CN1084505A),从甜菜糖蜜发酵废液中制取甜菜碱(CN1049333A)。但现有的甜菜碱多作为表面活性剂使用。
结、直肠癌是常见的消化道恶性肿瘤之一,严重威胁着人类的健康,全世界结、直肠癌的发病率处于恶性肿瘤的第三位,每年约有120万例新增患者。目前主要的治疗方法为(1)外科手术治疗,(2)化疗。对于初始不可切除的结、直肠癌,需在术前接受化疗,使局部肿瘤缩小,控制转移率,有利于手术操作。目前,主要药物有5-氟尿嘧啶,奥沙利铂和伊立替康。分子靶向药物主要以抗血管生成(VEGF)的贝伐单抗和抗表皮生长因子受体(EGFR)的西妥昔单抗。结、直肠癌患者中只有K-RAS基因为野生型的病例对西妥昔单抗敏感,患者在接受西妥昔单抗治疗前需要进行基因检测。因此,目前临床上应用于结、直肠癌治疗的药物品种少且疗效不佳,因此,研究开发新疗效更好的抗结、直肠癌瘤药物是非常有必要的。
肝癌是我国常见恶性肿瘤之一,成年人发病率高,发现时多为晚期,病死率高,俗称“癌中之王”。我国大陆每年约11万人死于肝癌,占全世界肝癌死亡人数的45%。目前我国肝癌的治疗有很大进,使肝癌由过去的“不治之症”转变为“部分可治”,5年生存率也由2.6%提高到20.6%。目前主要的治疗方法为(1)外科手术治疗,(2)化疗或和放射治疗,(3)肝移植等。其中,分子药物靶向治疗是利用肿瘤细胞与正常细胞之间分子细胞生物学上的差异,采用封闭受体、抑制血管生成、阻断信号传导通路等方法作用于肿瘤细胞特定的靶点,特异性地抑制肿瘤细胞的生长,促使肿瘤细胞凋亡。药物进入体内后,会特异地选择致癌位点,使肿瘤细胞特异性死亡,而不波及其周围的正常组织细胞。这类药物有索拉非尼(sorafenib,商品名:nexavar,多吉美),PI-88(澳大利亚Progen公司开发,通过半合成得到的高度硫酸化的甘露五糖磷酸,属于硫酸肝素类似物),酪丝亮肽(tyroserleutide,深圳市康哲药业有限公司从猪脾脏水解液中分离纯化得到的活性超短肽,其化学结构为L-酪氨酰-L-丝氨酰-L-亮氨酸,已全人工合成,其纯度在98%以上)等。尽管如此,目前我国临床上应用于肝癌治疗的药物大多数疗效都难尽人意,因此,研究开发新疗效更好的抗肝肿瘤药物是非常有必要的。
发明内容
本发明的目的是提供一种双苄基异喹啉甜菜碱及其制备方法。本发明的另一目的是提供该种双苄基异喹啉甜菜碱在制备抗肿瘤药物中的应用。
本发明采取的技术方案为:
一种双苄基异喹啉甜菜碱,结构式如通式(Ⅰ)所示:
式中:
X选自氢、羟基、卤素取代基、氨基、烷氧基、卤代烷氧基、氧乙酰基;
R选自氢、C1-C16的烷烃基。
上述化合物中,
X优选自H,OH,I,Br,Cl,F,NH2,OCH3,OC2H5,OC3H7,OC4H9,OCH2Cl,OCH2Br,OCH2F,OCH2I,OCOCH3;进一步优选自OH,OCH3,OCOCH3。
R优选自H,CH3,C2H5,C3H7,C4H9,C5H11,C6H13,C7H15,C8H17,C10H21,C12H25,C14H29,C16H33,C16H31;进一步优选自H,CH3。
所述双苄基异喹啉甜菜碱的制备方法:将通式(Ⅱ)化合物溶于溶剂中,加入卤代脂肪酸盐Y,通式(Ⅱ)化合物与卤代脂肪酸盐Y摩尔配比为1:0.5~10.0;搅拌或振荡混合,控制温度-20℃~300℃,在碱性或中性条件下反应0.1h~72h,中和反应产物,再经过分离纯化制得目的产物。
其中通式(Ⅱ)化合物为:
式中X为H、OH、I、Br、Cl、F、NH2、OCH3、OC2H5、OC3H7、OC4H9、OCH2Cl、OCH2Br、OCH2F、OCH2I或OCOCH3。
结构通式(Ⅱ)化合物为从植物防己科汉防己(Stephania tetrandra S.Moore)、毛茛科狭序唐松草(Thalictrum atriplex)、小檗科狭叶十大功劳(Mahonia fortunei)、防己科毛叶轮环藤(Cyclea barbata)中经提取、分离制得或者分离提取后的化合物卤代制得。提取、分离为现有技术,即中药采用乙酸乙酯等有机溶剂,加热回流提取,然后采用层析分离或根据生物碱溶解度的差异进行分离制得,参见资料《生物碱类天然药物的提取及生产工艺》(科学出版社:2009年10月第1版),卤代方法也为现有技术,直接卤代或在三卤氧磷下卤素取代酚羟基或甲醛、卤化氢与羟基的卤甲基化制得。
所述的卤代脂肪酸盐Y为2-氯乙酸钠或2-溴乙酸钠或2-碘乙酸钠或2-氯乙酸钾或2-溴乙酸钾或2-碘乙酸钾或2-氯乙酸铵或2-溴乙酸铵或2-碘乙酸铵或2-氯丙酸钠或2-溴丙酸钠或2-碘丙酸钠或2-氯丙酸钾或2-溴丙酸钾或2-碘丙酸钾或2-氯丙酸铵或2-溴丙酸铵或2-碘丙酸铵或2-氯丁酸钠或2-溴丁酸钠或2-碘丁酸钠或2-氯丁酸钾或2-溴丁酸钾或2-碘丁酸钾或2-氯丁酸铵或2-溴丁酸铵或2-碘丁酸铵或2-氯戊酸钠或2-溴戊酸钠或2-碘戊酸钠或2-氯戊酸钾或2-溴戊酸钾或2-碘戊酸钾或2-氯戊酸铵或2-溴戊酸铵或2-碘戊酸铵或2-氯己酸钠或2-溴己酸钠或2-碘己酸钠或2-氯己酸钾或2-溴己酸钾或2-碘己酸钾或2-氯己酸铵或2-溴己酸铵或2-碘己酸铵或2-氯庚酸钠或2-溴庚酸钠或2-碘庚酸钠或2-氯庚酸钾或2-溴庚酸钾或2-碘庚酸钾或2-氯辛酸钠或2-溴辛酸钠或2-碘辛酸钠或2-氯辛酸钾或2-溴辛酸钾或2-碘辛酸钾或2-氯壬酸钠或2-溴壬酸钠或2-碘壬酸钠或2-氯壬酸钾或2-溴壬酸钾或2-碘壬酸钾或2-氯癸酸钠或2-溴癸酸钠或2-碘癸酸钠或2-氯癸酸钾或2-溴癸酸钾或2-碘癸酸钾或2-氯十二酸钠或2-溴十二酸钠或2-碘十二酸钠或2-氯十二酸钾或2-溴十二酸钾或2-碘十二酸钾或2-氯十四酸钠或2-溴十四酸钠或2-碘十四酸钠或2-氯十四酸钾或2-溴十四酸钾或2-碘十四酸钾或2-氯十六酸钠或2-溴十六酸钠或2-碘十六酸钠或2-氯十六酸钾或2-溴十六酸钾或2-碘十六酸钾或2-氯十八酸钠或2-溴十八酸钠或2-碘十八酸钠或2-氯十八酸钾或2-溴十八酸钾或2-碘十八酸钾或2-氯油酸钠或2-溴油酸钠或2-碘油酸钠或2-氯油酸钾或2-溴油酸钾或2-碘油酸钾。
上述双苄基异喹啉衍生物可以是盐酸盐或氢溴酸盐或氢碘酸盐或硫酸盐或硫酸氢盐或硝酸盐或甲酸盐或乙酸盐或苯甲酸盐或草酸盐或富马酸盐。
上述制备所用的溶剂为水或甲醇或乙醇或丙醇或丁醇或戊醇或二氯甲烷或三氯甲烷或四氯化碳或苯或甲苯或二甲苯或1,4-二氧六环或1,2-二氯乙烷或四氢呋喃或N,N-二甲基甲酰胺或二甲基亚砜。每摩尔通式(Ⅱ)的化合物溶于10~100L溶剂。
所需碱性条件时,需加入的化学成分为γ-Al2O3-Na碱或γ-Al2O3-K碱或γ-Al2O3-NaOH-Na碱或γ-Al2O3-NaOH-K碱或γ-Al2O3-KOH-Na碱或γ-Al2O3-KOH-K碱或甲醇钠或乙醇钠或丙醇钠或丁醇钠或氨基钠或金属钠或氢氧化钠或氢氧化钾或氢氧化钙或碳酸钾或碳酸钠或碳酸氢钾或碳酸氢钠或氨水或乙胺或二乙胺或三乙胺或甲胺或二甲胺或三甲胺或苯胺或甲基苯胺或二甲基苯胺或乙基苯胺或二乙基苯胺或吡啶或哌啶。碱的用量摩尔配比为结构通式(Ⅱ)的化合物:碱=1:0.1~5。
中和所用的酸是盐酸或氢溴酸或氢碘酸或硫酸或硝酸或甲酸或乙酸或草酸或苯甲酸或富马酸。所述的分离与纯化是过滤或树脂处理或水洗或蒸馏或萃取或活性炭处理或分子筛处理或层析。
本发明制得的双苄基异喹啉甜菜碱,结构表征数据或参数见实例。
本发明制得的双苄基异喹啉甜菜碱在制备抗肿瘤药物中的应用,特别是在制备抗肝癌、结肠癌药物中的应用。双苄基异喹啉甜菜碱化学结构,提高了对受体的亲和力,对人肝癌细胞株HepG2增殖具有较高的抑制活性,对人结肠癌细胞HT29增殖也具有较高的抑制活性。现有粉防己碱类化合物虽然有抗肝癌活性,但其有效剂量通常在8ug/mL以上,对正常细胞的毒性较大;本发明制得的双苄基异喹啉甜菜碱,在0.6ug/mL即显示很强的对人肝癌细胞株HepG2和人结肠癌细胞HT29的抑制活性,因此,在临床上可以减少对正常细胞的毒害,减轻药物的毒副作用。
具体实施方式
下面结合实施例进一步说明。
实施例1
称取双苄基异喹啉(通式ⅡX=H)5.92g、2-氯乙酸钠2.50g和氢氧化钠0.20g,加入500mL三口烧瓶中,溶于200mL乙醇,搅拌加热回流,并保温反应8h,减压蒸出溶剂,降温至室温,10%HCl中和至中性,加水50mL并用氯仿萃取3次(60mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥8h,回收氯仿,固体物在60℃下干燥4h,即得黄色粉末状的产物3.35g。目的产物的熔点:156-157℃,飞行时间质谱:M/e(326.1576),分子式为C39H43O7N2Cl,13CNMR显示有一个δ=167.01羰基峰,X-ray衍射单晶结构,即表1中的化合物1。
实施例2
称取7-羟基双苄基异喹啉(通式ⅡX=OH)6.60g、2-溴乙酸钠10.00g和氢氧化钾0.20g溶于150mL正丁醇中,加入500mL三口烧瓶中,搅拌加热至沸,并保温搅拌反应4h,减压蒸出溶剂,降温至室温,5%HBr中和至中性,加水50mL并用丙酮萃取3次(60mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥8h,回收丙酮,固体物在60℃下干燥4h,即得黄色粉末状的产物4.25g。目的产物的熔点:151-152℃,飞行时间质谱:M/e(334.1550),分子式为C39H43O8N2Br,13C NMR(75MHz,DMSO-d6):δ21.61(C-4),23.12(C-4’),35.63(C-15),41.67(C-15’),3.48(NCH3),54.12(N’CH3),56.16(C-3),56.24(C-3’),59.70(6-OCH3),59.74(6’-OCH3),59.84(12-OCH3),61.88(C-1),62.78(C-1’),70.25(N*CH2COO),107.21(C-5),112.69(C-5’),113.55(C-13),115.75(C-10),120.80(C-8’),121.13(C-13’),122.85(C-11’),123.59(C-14),124.50(C-8a),128.50(C-4a),130.09(C-4a’),131.68(C-8a’),132.19(C-14’),132.78(C-10’),133.25(C-9),134.74(C-9’),137.70(C-7’),144.90(C-7),147.37(C-12),148.14(C-8),149.22(C-6’),150.65(C-11),151.63(C-6),154.44(C-12’),165.33(NCH2*COO),即表1中的化合物2。
实施例3
称取7-氯双苄基异喹啉(通式ⅡX=Cl)6.26g,2-氯乙酸钠3.00g,无水碳酸钠2.10g,溶于100mL水,加入500mL三口烧瓶中,搅拌冷冻至10℃,并保温搅拌反应24h,升至室温后用10%HCl中和至中性,减压蒸出水至液体体积减少至一半,常温结晶过夜,过滤,制得的固体物在60℃下干燥4h,即得黄色粉末状的产物2.12g。目的产物的熔点:162-163℃,飞行时间质谱:M/e(343.1381),分子式为C39H42O7N2Cl2,13CNMR显示有一个δ=167.71羰基峰,X-ray衍射单晶结构,即表1中的化合物3。
实施例4
称取7-溴双苄基异喹啉(通式ⅡX=Br)6.50g,2-溴乙酸钠2.20g,碳酸钾2.20g,溶于200mL甲醇,加入500mL三口烧瓶中,搅拌冷冻至-20℃,并保温搅拌反应48h,升至室温后用5%HBr中和至中性,减压蒸出溶剂,200g氧化铝柱层析,二氯甲烷-甲醇(10:1)洗脱,TLC追踪反应与产物的分离纯化过程,收集并合并产品流分,用旋转蒸发仪蒸60℃下蒸出溶剂,即得淡黄色粉末状的产物2.71g。目的产物的熔点:167-168℃,飞行时间质谱:M/e(365.1128),分子式为C39H42O7N2Br2,13CNMR显示有一个δ=166.24羰基峰,X-ray衍射单晶结构,即表1中的化合物5。
实施例5
称取7-碘双苄基异喹啉(通式ⅡX=I)7.17g,2-碘乙酸钠3.20g,碳酸氢钠6.50g,溶于200mL95%乙醇,加入500mL三口烧瓶中,搅拌冷冻至-5℃,并保温搅拌反应24h,升至室温后用2%氢碘酸中和至中性,减压蒸出溶剂至液体体积减少至1/3,常温下结晶过夜,过滤,制得的固体物在60℃下干燥4h,即得淡黄色粉末状的产物1.34g。目的产物的熔点:169-170℃,飞行时间质谱:M/e(389.1059),C39H42O7N2I2,13CNMR显示有一个δ=167.43羰基峰,X-ray衍射单晶结构,即表1中的化合物6。
实施例6
称取7-氨基双苄基异喹啉(通式ⅡX=NH2)6.22g和2-溴乙酸铵3.50g,加乙醇200mL和三甲胺10mL,加入500mL三口烧瓶中,一起搅拌混合冷冻至0℃,保温搅拌反应72h,升温至室温,用5%氢溴酸10mL中和,回收溶剂后加水200mL溶解,用500g的D-101型大孔吸附树脂处理,水洗后95%乙醇洗脱,TLC追踪反应与产物的分离纯化过程,回收乙醇流分,减压蒸出乙醇后制得固体物,固体物在60℃下干燥4h,即得黄色粉末状的产物2.33g。目的产物的熔点:154-155℃,飞行时间质谱:M/e(333.6630),分子式为C39H44O7N3Br,13CNMR显示有一个δ=166.45羰基峰,X-ray衍射单晶结构,即表1中的化合物7。
实施例7
称取7-甲氧基双苄基异喹啉(通式ⅡX=OCH3)6.22g和2-溴乙酸钾1.32g,加三氯甲烷200mL和甲醇钠0.10g,加入500mL三口烧瓶中,一起搅拌混合加热至沸腾,并保温搅拌反应0.1h,减压蒸出溶剂,降温至室温,5%HBr中和至中性,加水200mL溶解后,用500g5A分子筛吸附树脂处理,水洗后无水醇洗脱,TLC追踪反应与产物的分离纯化过程,回收乙醇流分,减压蒸出乙醇得固体物,固体物在60℃下干燥4h,即得淡黄色粉末状的产物0.95g。目的产物的熔点:165-166℃,飞行时间质谱:M/e(341.1628),分子式为C40H45O8N2Br,13C-NMR(DMSO-d6,75MHz,ppm):δ21.51(C-4),23.39(C-4’),35.63(C-15’),42.37(C-15),43.72(NCH3),44.98(N’CH3),53.37(C-3),53.94(C-3’),54.26(6-OCH3),56.12(6’-OCH3),56.32(12-OCH3),59.84(7-OCH3),61.92(C-1),65.32(C-1’),68.93(N’-*CH2COO-),107.18(C-5),112.66(C-5’),113.38(C-13),115.61(C-10),120.93(C-8’),122.12(C-13’),122.29(C-11’,C-14),123.52(C-8a),124.94(C-4a,C-4a’),132.14(C-8a’,C-14’,C-10’),133.28(C-9,C-9’),137.58(C-7),144.96(C-7’),147.31(C-12),148.23(C-8),149.26(C-6’),150.65(C-11),151.59(C-6),154.38(C-12’),167.84(-*COO-),X-ray衍射单晶结构,即表1中的化合物8。
实施例8
称取7-乙氧基双苄基异喹啉(通式ⅡX=OC2H5)6.35g和2-碘乙酸钠2.00g,加N,N-二甲基甲酰胺100mL和乙醇钠0.15g,加入500mL三口烧瓶中,一起搅拌混合加热至90℃,并保温搅拌反应0.6h,减压蒸出溶剂,降温至室温,加水200mL溶解后,用500g的H型732型阳离子树脂处理,水洗后2%氢碘酸洗脱,TLC追踪反应与产物的分离纯化过程,收集产物溜分,浓缩至液体体积减至一半,常温下结晶过夜,过滤,固体物在60℃下干燥4h,即得淡黄色粉末状的产物2.05g。目的产物的熔点:163-164℃,飞行时间质谱:M/e(348.1707),分子式为C41H47O8N2I,13CNMR显示有一个δ=165.23羰基峰,X-ray衍射单晶结构,即为表1中的化合物9。
实施例9
称取7-氯甲氧基双苄基异喹啉(通式ⅡX=OCH2Cl)6.56g和2-氯乙酸钾1.30g,加DMSO100mL和5mL的三乙胺,加入250mL密闭反应器中,加热至沸腾并保温搅拌反应2h,少量10%盐酸中和,加丙酮200mL溶解后,加入活性炭2g搅拌0.5h,过滤除杂质,滤液蒸出3/4体积后冷却结晶过夜,过滤,固体物在60℃下干燥4h,即得淡红黄粉末状的产物4.51g。目的产物的熔点:167-168℃,飞行时间质谱:M/e(358.1433),分子式为C40H43ClN2O8,13CNMR显示有一个δ=165.62羰基峰,X-ray衍射单晶结构,即为表1中的化合物12。
实施例10
称取7-氧乙酰基双苄基异喹啉(通式ⅡX=OCOCH3)6.05g和2-碘乙酸钠1.00g,加水100mL和2.50g的K2CO3,加入250mL密闭反应器中,加热至300℃并保温反应4h,常温下用少量2%氢碘酸中和,减压加热蒸馏分离出溶剂,固体物加丙酮100mL重结晶,过滤,固体物在60℃下干燥4h,即得淡黄色粉末状的产物3.23g。目的产物的熔点:170-171℃,飞行时间质谱:M/e(355.1603),分子式为C41H44N2O9,13CNMR显示有δ=175.55和δ=164.24两个羰基峰,X-ray衍射单晶结构,即为表1中的化合物16。
实施例11
称取双苄基异喹啉(通式ⅡX=H)6.06g、2-氯丙酸钾2.60g和乙醇钠1.60g,溶于100mL无水醇中,加热搅拌至沸,并保温搅拌反应8h,减压蒸出溶剂,降温至室温,20%醋酸中和至中性,加水50mL并用二氯甲烷萃取3次(50mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥过夜,回收二氯甲烷,固体物在50℃下干燥4h,即得黄色粉末状的产物6.12g。目的产物的熔点:157-158℃,飞行时间质谱:M/e(333.1654),分子式为C42H48O9N2,13CNMR显示有δ=175.34和δ=165.22两个羰基峰,X-ray衍射单晶结构,即为表1中的化合物17。
实施例12
称取7-羟基双苄基异喹啉(通式ⅡX=OH)6.22g、2-溴丙酸钠2.50g和氢氧化钠0.20g,溶于100mL异丙醇中,加入500mL三口烧瓶中,加热搅拌至沸,并保温搅拌反应6h,减压蒸出溶剂,降温至室温,少量10%甲酸中和至中性,加水50mL并用氯仿萃取3次(60mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥8h,回收氯仿,固体物在60℃下干燥4h,即得淡黄色粉末状的产物3.91g。目的产物的熔点:148-149℃,飞行时间质谱:M/e(341.1628),分子式为C41H46O10N2,13CNMR显示有δ=176.11和δ=164.24两个羰基峰,X-ray衍射单晶结构,即为表1中的化合物18。
实施例13
称取7-氯双苄基异喹啉(通式ⅡX=Cl)6.40g、2-碘丙酸铵4.50g,乙酸乙酯50mL,γ-Al2O3-Na碱0.20g,加入500mL三口烧瓶中,搅拌加热至70℃,并保温搅拌反应72h,降至室温后过滤,滤液用少量2%氢碘酸中和,减压蒸出溶剂至液体体积减少至1/4,5℃结晶过夜,过滤,固体物在60℃下干燥4h,即得淡黄色粉末状的产物4.55g。目的产物的熔点:145-146℃,飞行时间质谱:M/e(350.1459),分子式为C40H43ClN2O7,13CNMR显示有一个δ=167.64羰基峰,X-ray衍射单晶结构,即为表1中的化合物19。
实施例14
称取7-甲氧基双苄基异喹啉(通式ⅡX=OC4H9)8.40g和2-碘丙酸钾4.10g,加1,2-二氯乙烷200mL和甲醇钠0.30g,加入500mL三口烧瓶中,一起搅拌混合加热至沸腾,并保温搅拌反应36h,减压蒸出溶剂,降温至室温,少量2%氢碘酸中和,加水200mL溶解后,用500g的D-101型大孔吸附树脂处理,水洗后95%乙醇洗脱,TLC追踪反应与产物的分离纯化过程,回收乙醇部分,减压蒸出乙醇得固体物,固体物在60℃下干燥6h,即得淡黄色粉末状的产物5.00g。目的产物的熔点:141-142℃,飞行时间质谱:M/e(369.1941),分子式为C44H52N2O8,13CNMR显示有一个δ=166.22羰基峰,X-ray衍射单晶结构,即为表1中的化合物27。
实施例15
称取7-溴甲氧基双苄基异喹啉(通式ⅡX=OCH2Br)7.80g和2-溴丙酸钾3.50g,加甲苯100mL和0.30g的KOH,加入500mL三口烧瓶中,在-10℃条件下一起搅拌混合,并保温搅拌反应72h,减压加热蒸馏分离出溶剂,加水200mL溶解后,用500g的H型732型阳离子树脂处理,水洗后稀氨水洗脱,减压蒸出氨和部分水,冷却结晶过夜,过滤,固体物在60℃下干燥4h,即得淡黄色粉末状的产物3.22g。目的产物的熔点:142-143℃,飞行时间质谱:M/e(387.1259),分子式为C41H45BrN2O8,13CNMR显示有一个δ=165.35羰基峰,X-ray衍射单晶结构,即为表1中的化合物29。
实施例16
称取7-氧乙酰基双苄基异喹啉(通式ⅡX=OCOCH3)6.05g和2-溴丙酸钠3.50g,加戊醇100mL和0.40g的KOH,加入500mL三口烧瓶中,在混合搅拌下加热至100℃,并保温搅拌反应24h,少量5%氢溴酸中和,减压加热蒸馏分离出溶剂戊醇,固体物加丙酮100mL重结晶,过滤,固体物在60℃下干燥4h,即得淡黄色粉末状的产物5.71g。目的产物的熔点:145-146℃,飞行时间质谱:M/e(362.1681),分子式为C42H46N2O9,13CNMR显示有δ=174.55和δ=165.34两个羰基峰,X-ray衍射单晶结构,即为表1中的化合物32。
实施例17
称取双苄基异喹啉(通式ⅡX=H)6.06g、2-氯丁酸钠3.50g和10%氨水150mL,加入500mL三口烧瓶中,密闭加热搅拌至沸,并保温搅拌反应8h,减压蒸出溶剂,降温至室温,10%盐酸中和至中性,加水50mL并用乙酸乙酯萃取3次(50mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥8h,回收乙酸乙酯,固体物在60℃下干燥4h,即得淡黄色粉末状的产物4.20g。目的产物的熔点:141-142℃,飞行时间质谱:M/e(340.1732),分子式为C41H47O7N2Cl,13CNMR显示有一个δ=167.33羰基峰,X-ray衍射单晶结构,即为表1中的化合物33。
实施例18
称取7-溴双苄基异喹啉(通式ⅡX=Br)6.85g,2-溴丁酸钠4.50g溶于N,N-二甲基甲酰胺100mL,γ-Al2O3-K碱0.50g,加入500mL三口烧瓶中,搅拌混合,冷却至-10℃,并保温搅拌反应24h后,过滤,滤液用少量5%氢溴酸中和,减压蒸出溶剂,200g氧化铝柱层析,乙酸乙酯-乙醇(5:1)洗脱,TLC追踪反应与产物的分离纯化过程,收集并合并产品流分,用旋转蒸发仪蒸60℃下蒸出溶剂,即得淡黄色粉末状的产物5.20g。目的产物的熔点:146-147℃,飞行时间质谱:M/e(379.1285),分子式为C41H45BrN2O7,13CNMR显示有一个δ=166.54羰基峰,X-ray衍射单晶结构,即为表1中的化合物37。
实施例19
称取7-乙氧基双苄基异喹啉(通式ⅡX=OC2H5)6.50g和2-碘丁酸钠6.20g,加N,N-二甲基甲酰胺50mL和乙醇钠0.30g,加入500mL三口烧瓶中,一起搅拌混合加热至80℃,并保温搅拌反应60h,减压蒸出溶剂,降温至室温,用少量2%氢碘酸中和,200g200目硅胶柱层析,二氯甲烷-甲醇(10:1)洗脱,TLC追踪反应与产物的分离纯化过程,收集并合并产品流分,用旋转蒸发仪蒸60℃下蒸出溶剂,即得淡黄色粉末状的产物4.13g。目的产物的熔点:147-148℃,飞行时间质谱:M/e(362.1863),分子式为C43H50N2O8,13CNMR显示有一个δ=165.11羰基峰,X-ray衍射单晶结构,即为表1中的化合物41。
实施例20
称取双苄基异喹啉(通式ⅡX=H)6.06g、2-氯戊酸钾5.50g和乙醇钠0.60g,溶于100mL无水醇中,加入500mL三口烧瓶中,加热搅拌至沸,并保温搅拌反应8h,减压蒸出溶剂,降温至室温,用少量10%HCl中和,加水50mL并用二氯甲烷萃取3次(50mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥过夜,回收二氯甲烷,固体物在50℃下干燥4h,即得淡红色粉末状的产物5.05g。目的产物的熔点:145-146℃,飞行时间质谱:M/e(347.1811),分子式为C42H48N2O7,13CNMR显示有一个δ=167.45羰基峰,X-ray衍射单晶结构,即为表1中的化合物45。
实施例21
称取双苄基异喹啉(通式ⅡX=H)6.06g、2-溴十四酸钾6.50g和叔丁醇钠0.50g,溶于100mL叔丁醇中,加热搅拌至沸,并保温搅拌反应6h,降温至室温,用少量5%HBr中和,减压蒸出溶剂,加水50mL并用四氯化碳萃取3次(50mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用分子筛干燥过夜,回收四氯化碳,固体物在50℃下干燥4h,即得淡黄色粉末状的产物2.53g。目的产物的熔点:123-124℃,飞行时间质谱:M/e(410.2515),分子式为C51H66N2O7,13CNMR显示有一个δ=167.56羰基峰,X-ray衍射单晶结构,即为表1中的化合物50。
实施例22
称取7-羟基双苄基异喹啉(通式ⅡX=OH)6.22g、2-氯己酸钾4.50g和氢氧化钾0.30g,溶于100mL正丁醇中,加入500mL三口烧瓶中,加热搅拌至110℃,并保温搅拌反应6h,减压蒸出溶剂,降温至室温,用少量10%HCl中和,加水50mL并用丙酮萃取3次(60mL×3),TLC追踪反应与产物的分离纯化过程,萃取液用无水Na2SO4干燥8h,回收丙酮,固体物在60℃下干燥4h,即得淡黄色粉末状的产物5.00g。目的产物的熔点:135-136℃,飞行时间质谱:M/e(362.1863),分子式为C43H50N2O8,13CNMR显示有一个δ=164.42羰基峰,X-ray衍射单晶结构,即为表1中的化合物54。
实施例23
称取7-羟基双苄基异喹啉(通式ⅡX=OH)6.22g和2-碘十六酸钠9.50g,加1,4-二氧六环300mL,加入500mL三口烧瓶中,在60℃条件下一起搅拌混合,并保温搅拌反应72h,减压蒸出溶剂,加水300mL溶解后,用500g的H型732型阳离子树脂处理,水洗后稀氨水洗脱,TLC追踪反应与产物的分离纯化过程,减压蒸出氨和部分水,冷却结晶过夜,过滤,固体物在60℃下干燥4h,即得淡黄色粉末状的产物1.50g。目的产物的熔点:114-115℃,飞行时间质谱:M/e(432.2646),分子式为C53H70N2O8,13CNMR显示有一个δ=165.34羰基峰,X-ray衍射单晶结构,即为表1中的化合物59。
实施例24
称取7-甲氧基双苄基异喹啉(通式ⅡX=OCH3)6.36g和2-溴辛酸钠5.50g,加1,2-二氯乙烷200mL和甲醇钠0.40g,加入500mL三口烧瓶中,一起搅拌混合加热至沸腾,并保温搅拌反应36h,减压蒸出溶剂,降温至室温,用少量5%氢溴酸中和,加水200mL溶解后,用500g的D-101型大孔吸附树脂处理,水洗后95%乙醇洗脱,TLC追踪反应与产物的分离纯化过程,回收乙醇流分,减压蒸出乙醇得固体物,固体物在60℃下干燥6h,即得淡黄色粉末状的产物4.25g。目的产物的熔点:130-131℃,飞行时间质谱:M/e(383.2098),分子式为C46H56N2O8,13CNMR显示有一个δ=166.51羰基峰,X-ray衍射单晶结构,即为表1中的化合物63。
实施例25
称取7-甲氧基双苄基异喹啉(通式ⅡX=OCH3)6.36g和2-溴十八酸钠9.50g,加DMF200mL和甲醇钠0.50g,加入500mL三口烧瓶中,一起搅拌混合加热至50℃,并保温搅拌反应72h,减压蒸出溶剂,降温至室温,用少量5%氢溴酸中和,加水200mL溶解后,用500g的D-101型大孔吸附树脂处理,水洗后95%乙醇洗脱,TLC追踪反应与产物的分离纯化过程,回收乙醇流分,减压蒸出乙醇得固体物,固体物在60℃下干燥6h,即得淡黄色粉末状的产物1.05g。目的产物的熔点:101-102℃,飞行时间质谱:M/e(453.2880),分子式为C56H76N2O8,13CNMR显示有一个δ=167.14羰基峰,X-ray衍射单晶结构,即为表1中的化合物68。
实施例26
称取7-氧乙酰基双苄基异喹啉(通式ⅡX=OCOCH3)6.05g和2-碘癸酸钠7.50g,加丙醇200mL和0.80g的丙醇钠,加入500mL三口烧瓶中,在混合搅拌下加热至沸,并保温搅拌反应48h,用少量10%盐酸中和,静止沉淀4h,过滤去除沉淀物,滤液减压加热蒸馏分离出溶剂丙醇,固体物加无水乙醇100mL重结晶,过滤,固体物在60℃下干燥2h,即得淡黄色粉末状的产物3.50g。目的产物的熔点:127-128℃,飞行时间质谱:M/e(411.2229),分子式为C49H60N2O9,13CNMR显示有δ=175.56和δ=165.74两个羰基峰,X-ray衍射单晶结构,即为表1中的化合物72。
实施例27
称取7-氧乙酰基双苄基异喹啉(通式ⅡX=OCOCH3)6.05g和2-碘十二酸钠8.50g,DMSO100mL和0.90g的丙醇钠,加入500mL三口烧瓶中,在混合搅拌下加热至沸,并保温搅拌反应8h,用少量10%盐酸中和,静止沉淀4h,过滤去除沉淀物,滤液减压加热蒸馏分离出溶剂DMSO,固体物加无水乙醇100mL重结晶,过滤,固体物在60℃下干燥4h,即得淡红黄粉末状的产物2.20g。目的产物的熔点:122-123℃,飞行时间质谱:M/e(425.2385),分子式为C51H64N2O9,13CNMR显示有δ=176.11和δ=164.23两个羰基峰,X-ray衍射单晶结构,即为表1中的化合物73。
实施例28
称取7-甲氧基双苄基异喹啉(通式ⅡX=OCH3)6.36g和2-溴油酸钠9.00g,加DMF200mL和叔丁醇钠1.00g,加入500mL三口烧瓶中,一起搅拌混合加热至60℃,并保温搅拌反应24h,减压蒸出溶剂,降温至室温,用少量5%氢溴酸中和,加水200mL溶解后,用500g的D-101型大孔吸附树脂处理,水洗后95%乙醇洗脱,TLC追踪反应与产物的分离纯化过程,回收乙醇流分,减压蒸出乙醇得固体物,固体物在60℃下干燥6h,即得淡黄色粉末状的产物1.50g。目的产物的熔点:97-98℃,飞行时间质谱:M/e(452.2802),分子式为C56H74O8N2,13CNMR显示有一个δ=165.51羰基峰,X-ray衍射单晶结构,即表1中的化合物81。
本发明典型实例所制备的化合物列于表1,其化学结构如通式(Ⅰ)化合物。
表1合成的典型化合物的化学结构
抗癌试验
(一)对人肝癌细胞株HepG2增殖的抑制活性实验
取对数生长期生长状态良好的HepG2细胞以2×103/0.1mL/孔的密度接种于96孔培养板,每组设5个平行孔,在37℃,5%CO2培养箱中培养,在含10%小牛血清的培养液中培养24h后,分别换为表1中化合物1-81[浓度分别为0.2ug/mL,0.6ug/mL,1.0ug/mL]的培养液中继续培养,空白对照组加培养基。培养24h后,加MTT20uL(5mg/mL)再培养4h,弃上清,加入100uL二甲亚砜(DMSO),振荡10分钟,待其沉淀物完全溶解后,于酶联检测分析仪上570nm波长,空白调零,测定各孔OD值,上述每组重复3次。
抑制率=(对照组OD-实验组OD)/对照组OD×100%
所合成的典型化合物1至化合物81,对人肝癌细胞株HepG2增殖的抑制活性实验结果见表2。由实验结果可以看出,化合物1至化合物44在0.6ug/mL浓度下对人肝癌细胞株HepG2增殖抑制率超过35%,其中化合物8、化合物9等则超过了45%,其余化合物大部分超过了30%;化合物1至化合物43在1.0ug/mL浓度下对人肝癌细胞株HepG2增殖抑制率超过了60%,其余的化合物大部分超过了30%。与已报道的文献(如粉防己碱有机酸盐及制备方法和应用CN101423519)比较,所合成的典型化合物1至化合物81使用剂量约为已报道文献的1/20,表明化合物1至化合物81对人肝癌细胞株HepG2具有优秀的抑制活性。
(二)对人结肠癌细胞HT29增殖的抑制活性实验
取对数生长期生长状态良好的人结肠癌细胞HT29以2×103/0.1mL/孔的密度接种于96孔培养板,每组设5个平行孔,在37℃,5%CO2培养箱中培养,在含10%小牛血清的培养液中培养24h后,分别换为表1中化合物1-81[浓度分别为0.2ug/mL,0.6ug/mL,1.0ug/mL]的培养液中继续培养48h,空白对照组加培养基。药物试剂每天加一次,连续2次,对照组加等量相同培养液,空白组不含细胞。培养44h后,加MTT20uL(5mg/mL)再培养4h,弃上清,加入100uL二甲亚砜(DMSO),振荡10分钟,待其沉淀物完全溶解后,于酶联检测分析仪上570nm波长,空白调零,测定各孔OD值,上述每组重复3次。
抑制率=(对照组OD-实验组OD)/对照组OD×100%
所合成的典型化合物1至化合物81,对人结肠癌细胞HT29增殖的抑制活性实验结果见表2。由实验结果可以看出,化合物1至化合物19在0.6ug/mL浓度下对人结肠癌细胞HT29增殖抑制率超过45%,其余化合物大部分超过30%;化合物1至化合物19在1.0ug/mL浓度下对人结肠癌细胞HT29增殖抑制率超过了74%;化合物20至化合物44中大部分超过了63%,其余化合物大部分超过45%。因此,化合物1至化合物81对人结肠癌细胞HT29增殖有优异的抑制活性。
表2对人肝癌细胞株HepG2和人结肠癌细胞HT29增殖的抑制率
Claims (7)
1.一种双苄基异喹啉甜菜碱及其可接受的药用盐,结构式如通式(Ⅰ)所示:
式中:X选自H,OH,I,Br,Cl,F,NH2,OCH3,OC2H5,OC3H7,OC4H9,OCH2Cl,OCH2Br,OCH2F,OCH2I,OCOCH3;
R选自氢、C1-C16的烷烃基。
2.根据权利要求1所述的一种双苄基异喹啉甜菜碱及其可接受的药用盐,其特征是,
X选自OH,I,Br,Cl,F,OCH3,OC2H5,OCH2Cl,OCH2Br,OCH2F,OCH2I,OCOCH3;
R选自H,CH3,C2H5,C3H7,C4H9,C5H11,C6H13,C7H15,C8H17,C10H21,C12H25,C14H29,C16H33,C16H31。
3.根据权利要求1所述的一种双苄基异喹啉甜菜碱及其可接受的药用盐,其特征是,
X选自OH,OCH3,OCOCH3;
R选自H,CH3。
4.根据权利要求1-3任一项所述的一种双苄基异喹啉甜菜碱的制备方法,其特征是,步骤为:将通式(Ⅱ)化合物溶于溶剂中,加入卤代脂肪酸盐Y,通式(Ⅱ)化合物与卤代脂肪酸盐Y摩尔配比为1:0.5~10.0;搅拌或振荡混合,控制温度-20℃~300℃,在碱性或中性条件下反应0.1h~72h,中和反应产物,再经过分离纯化制得目的产物,
其中通式(Ⅱ)化合物为:
式中X为H、OH、I、Br、Cl、F、NH2、OCH3、OC2H5、OC3H7、OC4H9、OCH2Cl、OCH2Br、OCH2F、OCH2I或OCOCH3;
所述的卤代脂肪酸盐Y为2-氯乙酸钠或2-溴乙酸钠或2-碘乙酸钠或2-氯乙酸钾或2-溴乙酸钾或2-碘乙酸钾或2-氯乙酸铵或2-溴乙酸铵或2-碘乙酸铵或2-氯丙酸钠或2-溴丙酸钠或2-碘丙酸钠或2-氯丙酸钾或2-溴丙酸钾或2-碘丙酸钾或2-氯丙酸铵或2-溴丙酸铵或2-碘丙酸铵或2-氯丁酸钠或2-溴丁酸钠或2-碘丁酸钠或2-氯丁酸钾或2-溴丁酸钾或2-碘丁酸钾或2-氯丁酸铵或2-溴丁酸铵或2-碘丁酸铵或2-氯戊酸钠或2-溴戊酸钠或2-碘戊酸钠或2-氯戊酸钾或2-溴戊酸钾或2-碘戊酸钾或2-氯戊酸铵或2-溴戊酸铵或2-碘戊酸铵或2-氯己酸钠或2-溴己酸钠或2-碘己酸钠或2-氯己酸钾或2-溴己酸钾或2-碘己酸钾或2-氯己酸铵或2-溴己酸铵或2-碘己酸铵或2-氯庚酸钠或2-溴庚酸钠或2-碘庚酸钠或2-氯庚酸钾或2-溴庚酸钾或2-碘庚酸钾或2-氯辛酸钠或2-溴辛酸钠或2-碘辛酸钠或2-氯辛酸钾或2-溴辛酸钾或2-碘辛酸钾或2-氯壬酸钠或2-溴壬酸钠或2-碘壬酸钠或2-氯壬酸钾或2-溴壬酸钾或2-碘壬酸钾或2-氯癸酸钠或2-溴癸酸钠或2-碘癸酸钠或2-氯癸酸钾或2-溴癸酸钾或2-碘癸酸钾或2-氯十二酸钠或2-溴十二酸钠或2-碘十二酸钠或2-氯十二酸钾或2-溴十二酸钾或2-碘十二酸钾或2-氯十四酸钠或2-溴十四酸钠或2-碘十四酸钠或2-氯十四酸钾或2-溴十四酸钾或2-碘十四酸钾或2-氯十六酸钠或2-溴十六酸钠或2-碘十六酸钠或2-氯十六酸钾或2-溴十六酸钾或2-碘十六酸钾或2-氯十八酸钠或2-溴十八酸钠或2-碘十八酸钠或2-氯十八酸钾或2-溴十八酸钾或2-碘十八酸钾或2-氯油酸钠或2-溴油酸钠或2-碘油酸钠或2-氯油酸钾或2-溴油酸钾或2-碘油酸钾;
所用的溶剂为水或甲醇或乙醇或丙醇或丁醇或戊醇或二氯甲烷或三氯甲烷或四氯化碳或苯或甲苯或二甲苯或1,4-二氧六环或1,2-二氯乙烷或四氢呋喃或N,N-二甲基甲酰胺或二甲基亚砜,每摩尔结构通式(Ⅱ)的化合物溶于10~100L溶剂;
所用的中和用盐酸或氢溴酸或氢碘酸或硫酸或硝酸或甲酸或乙酸或苯甲酸或草酸或富马酸。
5.权利要求1-3任一项所述的双苄基异喹啉甜菜碱在制备抗肿瘤药物中的应用。
6.权利要求1-3任一项所述的双苄基异喹啉甜菜碱在制备抗肝癌、结肠癌药物中的应用。
7.含有权利要求1-3任一项所述的双苄基异喹啉甜菜碱的药物。
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