CN102746314B - 含有稳定7元内酯环的喜树碱类化合物、制备方法和用途 - Google Patents
含有稳定7元内酯环的喜树碱类化合物、制备方法和用途 Download PDFInfo
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- CN102746314B CN102746314B CN201110097364.2A CN201110097364A CN102746314B CN 102746314 B CN102746314 B CN 102746314B CN 201110097364 A CN201110097364 A CN 201110097364A CN 102746314 B CN102746314 B CN 102746314B
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- Prior art keywords
- compound
- camptothecin
- pharmaceutically acceptable
- under
- reaction
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- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical class C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 title claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 68
- 150000003839 salts Chemical class 0.000 claims abstract description 19
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims abstract description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 10
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 claims description 20
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 claims description 19
- 229940127093 camptothecin Drugs 0.000 claims description 19
- 150000002596 lactones Chemical group 0.000 claims description 18
- 230000009471 action Effects 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- -1 camptothecin compound Chemical class 0.000 claims description 11
- 239000003513 alkali Substances 0.000 claims description 10
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 7
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 7
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 6
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- 229940125773 compound 10 Drugs 0.000 claims description 6
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 6
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims description 6
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 6
- 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 claims description 5
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims description 5
- 229940125797 compound 12 Drugs 0.000 claims description 5
- CSRZQMIRAZTJOY-UHFFFAOYSA-N trimethylsilyl iodide Chemical compound C[Si](C)(C)I CSRZQMIRAZTJOY-UHFFFAOYSA-N 0.000 claims description 5
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 4
- ILAHWRKJUDSMFH-UHFFFAOYSA-N boron tribromide Chemical compound BrB(Br)Br ILAHWRKJUDSMFH-UHFFFAOYSA-N 0.000 claims description 4
- 238000006266 etherification reaction Methods 0.000 claims description 4
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- 206010009944 Colon cancer Diseases 0.000 claims description 3
- 150000008065 acid anhydrides Chemical class 0.000 claims description 3
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- 238000005917 acylation reaction Methods 0.000 claims description 3
- 239000002246 antineoplastic agent Substances 0.000 claims description 3
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- 239000007800 oxidant agent Substances 0.000 claims description 3
- 229910052763 palladium Inorganic materials 0.000 claims description 3
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 claims description 3
- VXEGSRKPIUDPQT-UHFFFAOYSA-N 4-[4-(4-methoxyphenyl)piperazin-1-yl]aniline Chemical compound C1=CC(OC)=CC=C1N1CCN(C=2C=CC(N)=CC=2)CC1 VXEGSRKPIUDPQT-UHFFFAOYSA-N 0.000 claims description 2
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 2
- 238000007341 Heck reaction Methods 0.000 claims description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 2
- 238000007126 N-alkylation reaction Methods 0.000 claims description 2
- 206010028980 Neoplasm Diseases 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- 125000006278 bromobenzyl group Chemical group 0.000 claims description 2
- 201000011510 cancer Diseases 0.000 claims description 2
- 238000009903 catalytic hydrogenation reaction Methods 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 125000004803 chlorobenzyl group Chemical group 0.000 claims description 2
- 208000029742 colonic neoplasm Diseases 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 230000003301 hydrolyzing effect Effects 0.000 claims description 2
- 201000005202 lung cancer Diseases 0.000 claims description 2
- 208000020816 lung neoplasm Diseases 0.000 claims description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 239000005049 silicon tetrachloride Substances 0.000 claims description 2
- 210000001072 colon Anatomy 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 abstract description 4
- 238000010255 intramuscular injection Methods 0.000 abstract description 2
- 239000007927 intramuscular injection Substances 0.000 abstract description 2
- 238000010253 intravenous injection Methods 0.000 abstract description 2
- 125000005936 piperidyl group Chemical group 0.000 abstract description 2
- 125000000217 alkyl group Chemical group 0.000 abstract 4
- 125000000753 cycloalkyl group Chemical group 0.000 abstract 1
- 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 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 31
- 238000006243 chemical reaction Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 238000005160 1H NMR spectroscopy Methods 0.000 description 17
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 17
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 239000007787 solid Substances 0.000 description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000005406 washing Methods 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 7
- 238000002390 rotary evaporation Methods 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 7
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 6
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000007810 chemical reaction solvent Substances 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 238000001914 filtration Methods 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 5
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- 229940079593 drug Drugs 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical class [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 5
- 239000012312 sodium hydride Substances 0.000 description 5
- 229910000104 sodium hydride Inorganic materials 0.000 description 5
- KGDFHGMTFPQPSG-UHFFFAOYSA-N 2-bromo-3-(bromomethyl)quinoline Chemical compound C1=CC=C2N=C(Br)C(CBr)=CC2=C1 KGDFHGMTFPQPSG-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- PAEZRCINULFAGO-OAQYLSRUSA-N (R)-homocamptothecin Chemical compound CC[C@@]1(O)CC(=O)OCC(C2=O)=C1C=C1N2CC2=CC3=CC=CC=C3N=C21 PAEZRCINULFAGO-OAQYLSRUSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
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- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 3
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- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical group [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UKLNMMHNWFDKNT-UHFFFAOYSA-M sodium chlorite Chemical compound [Na+].[O-]Cl=O UKLNMMHNWFDKNT-UHFFFAOYSA-M 0.000 description 3
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- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
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- LFTLOKWAGJYHHR-UHFFFAOYSA-N N-methylmorpholine N-oxide Chemical compound CN1(=O)CCOCC1 LFTLOKWAGJYHHR-UHFFFAOYSA-N 0.000 description 2
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- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 2
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- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical compound CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 description 2
- FBDOJYYTMIHHDH-OZBJMMHXSA-N (19S)-19-ethyl-19-hydroxy-17-oxa-3,13-diazapentacyclo[11.8.0.02,11.04,9.015,20]henicosa-2,4,6,8,10,14,20-heptaen-18-one Chemical compound CC[C@@]1(O)C(=O)OCC2=CN3Cc4cc5ccccc5nc4C3C=C12 FBDOJYYTMIHHDH-OZBJMMHXSA-N 0.000 description 1
- CCDFCPCYBAITBD-BVAGGSTKSA-N (2r,3s)-3-[2-methoxy-3-(2-phenylethoxy)pyridin-4-yl]-3-phenylmethoxypentane-1,2-diol Chemical compound O([C@](CC)([C@H](O)CO)C=1C(=C(OC)N=CC=1)OCCC=1C=CC=CC=1)CC1=CC=CC=C1 CCDFCPCYBAITBD-BVAGGSTKSA-N 0.000 description 1
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Abstract
本发明提供了一种通式I所示的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐、其制备方法和用途。在通式I中,R1为H、C1~C3的烷基、乙酰基或丙酰基;R2为H、C1~C6的烷基、C3~C6环烷基、哌啶基、或由氨基取代的C1~C6的烷基;R3为H、C1~C3的烷基、或由氨基取代的C1~C6烷基;R4为H、羟基、或C1~C6的烷氧基;R5为H、或C1~C6的烷氧基;或者,R4和R5彼此连接形成-OCH2O-或-OCH2CH2O-。该化合物具有良好的抗肿瘤活性,在临床上可以进行口服、静脉注射、肌肉注射等方式应用。
Description
技术领域
本发明涉及提高抗肿瘤活性的新型喜树碱类化合物,以及制备这些化合物的方法和它们的用途。更具体地说,涉及具有以下结构的新型喜树碱类衍生物(I),以及它们的制备方法,和这些化合物在抗肿瘤领域中的应用。
背景技术
喜树碱(CPT)是一种生物碱,1966年有美国科学家Wall由中国特有的植物喜树中分离得到的,喜树碱对大鼠白血病L1210系统有显著的活性。喜树碱在结构上是一种含有吡啶酮结构的生物碱,具体的结构如下所示,化合物1:
在此结构中含有一个五环结构,在其结构中E环为一个六元环的内酯环,在内酯环上含有一个绝对构型为S的α羟基。在分离出喜树碱之后,由于其具有良好的抗白血病L1210活性,引起人们很大的兴趣。
随后,喜树碱的一系列衍生物由于其独特的生物活性机制和良好的药物特性,逐步成为已经上市或处于不同的研发阶段的抗癌新药,如10-羟基喜树碱(化合物2),在中国已广泛地应用于临床;10-羟基-9-二甲胺基甲基喜树碱(化合物3,托泊替康(Topotecan))于1996年上市,用作卵巢癌病人的二线治疗药物;化合物4(SN-38)具有极好的抗肿瘤活性,其水溶性前药伊立替康(Irinotecan,(化合物5)于1994年上市,用于结直肠癌的治疗;2005年贝洛替康(Belotecan,化合物6)在韩国获准上市,用于治疗前列腺癌。
另外,还有许多喜树碱类衍生物已经进入不同的临床测试阶段,但现有的结构表明这些化合物的疗效均不如托泊替康和伊立替康。因此需要发明疗效更好的喜树碱新型衍生物。
现有的喜树碱类药物具有内酯环不稳定的缺点,其在生理条件下内酯环将打开成为没有活性的结构形式,带来了疗效降低,毒性加强等严重问题,如下反应式所示:
为解决这个问题,有人提出了高喜树碱的解决方案,得到的化合物7(Diflomotecan)具有很好的抗肿瘤活性,进入了III期临床研究,然而其内酯环在生理条件下成开环形式后不能再转化回去,临床失败。如下反应式所示:
因此,还需开发内酯环稳定的喜树碱类新化合物。
发明内容
本发明的目的是寻找一类新型含有7元内酯环的喜树碱类化合物及其药学上可接受的盐,这种化合物具有内酯环稳定的特点,使其具有毒副作用小、活性强的优点。
本发明的另一目的是提供一种制备所述新型喜树碱类化合物及其药学上可接受的盐的方法。
本发明的另一目的是提供一种用于治疗癌症的组合物,该组合物包含治疗有效量的一种或多种所述新型喜树碱类化合物及其药学上可接受的盐以及药学上可接受的载体。所述药学上可接受的盐包括但不限于该化合物与盐酸、硫酸、磷酸、甲磺酸、琥珀酸、马来酸、富马酸、酒石酸、柠檬酸等的加成盐。
本发明的再一目的是提供一种所述喜树碱类化合物及其药学上可接受的盐在制备抗肿瘤药物中的应用。更具体地,提供了一种所述喜树碱类化合物及其药学上可接受的盐在制备治疗结肠癌或肺癌的药物中的应用。
按有机化合物知识,在羧基的a位引入吸电子基团可以增加羧基的酸性,本发明采用在高喜树碱的20a位引入羟基、烷氧基、或者酯基等基团,结果发现这类化合物可以提高内酯环稳定性,具有很好的抗肿瘤活性。
本发明是关于喜树碱新型衍生物,这些化合物是在高喜树碱类衍生物的20a位引入羟基、烷氧基、或者酯基基团。它们具有更好的抗肿瘤活性。
本发明所述的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐的具体结构如通式(I)所示:
其中,
R1为H、C1~C3的烷基、乙酰基或丙酰基;优选为H或乙酰基;
R2为H、C1~C6的烷基、C3~C6环烷基、哌啶基、或由氨基取代的C1~C6的烷基;优选为H或C1~C3的烷基;更优选为H或乙基;
R3为H、C1~C3的烷基、或由氨基取代的C1~C6烷基;优选为H或C1~C3的烷基;
R4为H、羟基、或C1~C6的烷氧基;优选为H、羟基、或C1~C3的烷氧基;更优选为H、羟基、或甲氧基;
R5为H、或C1~C6的烷氧基;优选为H或C1~C3的烷氧基;更优选为H;
或者,R4和R5彼此连接形成-OCH2O-或-OCH2CH2O-。
所述含有7元内酯环的喜树碱类化合物及其药学上可接受的盐优选为:
本发明提供了一种所述的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐的制备方法,该方法包括如下步骤:
其中,R1、R2、R3、R4和R5的定义如前所述,但R1不为H;
其中,通式IV的化合物可按照文献1)TheJournalofOrganicChemistry2000,65,5212;2)Tetrahedron1997,53,10953文献所报道的方法制备。
i)在碱作用条件下,化合物II与化合物IV发生N-烷基化反应得到化合物V;碱为叔丁醇钾、叔丁醇钠或氢化钠等,优选为叔丁醇钾,反应溶剂为四氢呋喃、二甲基甲酰胺或乙二醇二甲醚等,优选为乙二醇二甲醚。
ii)在钯催化条件下,化合物V进行Heck反应,制得通式I所示化合物;其中钯催化剂为醋酸钯或氯化钯,优选为醋酸钯;反应需要磷配体,可为三苯基磷、三(邻甲基苯基)磷、三叔丁基磷或三环己基磷;反应用碱为碳酸钾、醋酸钾或碳酸钠等,优选为醋酸钾;反应溶剂为乙腈、二甲基甲酰胺或甲苯,优选为乙腈。
iii)非必须地,当R1为乙酰基时,通式I所示化合物水解得到化合物I-1。
所述中间体化合物II通过如下方法制备:
其中,R1如前所述,但不为H;
起始原料化合物8可以按照我们已申请的专利制备(参见,中国专利申请200910054400.X);
1)在碱的条件下,化合物8和溴苄或氯苄发生醚化反应,生成化合物9;反应溶剂为四氢呋喃、甲苯、或N,N-二甲基甲酰胺等;反应中可采用无机碱或有机碱,例如,氢化钠、氢氧化钠、碳酸钾、三乙胺或二乙基异丙基胺;优选为氢化钠;反应温度为0-100℃,优选为室温;
2)化合物9在酸的作用下,水解制得化合物10;本步骤所采用的酸为稀盐酸(1N-12N)或者稀硫酸(10重量%-45重量%);本步骤使用溶剂为甲醇、乙醇、异丙醇或者四氢呋喃,优先选用甲醇为溶剂;本步骤反应温度为20-60℃;
3)化合物10在氧化剂的作用下,发生氧化反应制得化合物11;本步骤使用的氧化剂为:(i)次氯酸钠、亚氯酸钠及2,2,6,6-四甲基哌啶氧化物(TEMPO);或(ii)次氯酸钠、亚氯酸钠及N-甲基吗啉氧化物(NMO),优先选用(i)为氧化体系。本步骤使用的溶剂为饱和磷酸二氢钾的四氢呋喃溶液、饱和磷酸二氢钾的叔丁醇溶液、饱和磷酸二氢钾的乙腈溶液,优先选用饱和磷酸二氢钾的四氢呋喃溶液为反应溶剂;本步骤反应温度为20-55℃;
4)在催化加氢体系的作用下,化合物11脱去苄基保护基得到化合物12;本步骤所述催化体系为:采用Pd/C或者PtO2加氢反应脱除保护基,优先选用Pd/C为金属催化剂,溶剂为甲醇或者乙醇;反应温度为20-60℃;
5)化合物12在酸催化下成内酯环化合物13;本步骤所述的酸为三氟醋酸;本步骤所使用溶剂为无水四氢呋喃、无水二氯甲烷、无水甲醇、或无水乙醇,优选为甲醇;本步骤反应温度为0-40℃;
6)当R1为C1-C3烷基时,在碱的作用下,化合物13与溴代或氯代C1-C3烷烃进行醚化反应,得到化合物III;醚化反应采用的碱为氢化钠,反应溶剂为四氢呋喃或N,N-二甲基甲酰胺等;
当R1为乙酰基或丙酰基时,在碱的作用下,化合物13与相应的酸酐或酰氯进行酰化反应得到化合物III;其中,酰化反应采用相应的酸酐或酰氯为乙酸酐、丙酸酐、乙酰氯或丙酰氯,本步骤中使用的碱为有机碱或无机碱,其中有机碱为三乙胺、二异丙基乙胺、或吡啶,无机碱选自碱金属和碱土金属的氢氧化物中的一种或多种,例如,选自碳酸盐和碳酸氢盐中的一种或多种;其中,优先选用有机碱为反应试剂;
7)当R1为乙酰基、丙酰基时,在三甲基碘硅烷、三溴化硼、或四氯化硅(优先选用三甲基碘硅烷)的作用下,化合物III脱去甲基得到2-吡啶酮关键中间体化合物II;使用溶剂为乙腈、二氯甲烷,优先选用乙腈为反应溶剂;本步骤反应温度为20-50℃;
当R1为C1~C3的烷基时,在盐酸(1-12N)的作用下,化合物III脱去甲基得到制得中间体化合物II。
本发明所涉及的化合物具有良好的抗肿瘤活性,在临床上可以进行口服、静脉注射、肌肉注射等方式应用。
具体实施方式
本发明的新型喜树碱类衍生物和制备方法在如下实施例中更详细地叙述,但实施例不构成对本发明的限制。
实施例1:制备4-{[(1S)-1-苄氧基]-1-[(4R)-2,2-二甲基-[1,3]二氧戊环-4-基]-丙基}-3-苄氧基-2-甲氧基-吡啶(化合物9)
氮气保护下,60ml无水THF中,2.0g化合物8与0.5g氢化钠先室温下反应一段时间后,加入1.5ml苄溴,加热回流1h后,停止反应,冷却至室温,后加入饱和氯化铵水溶液淬灭反应,乙酸乙酯萃取,合并有机相,水洗,饱和食盐水洗涤,无水硫酸钠干燥,过滤,旋蒸得到粗产品,能后柱层析的2.8g无色液体。产率:87.5%.
1HNMR(CDCl3)(ppm)0.87(3H,t),1.35(6H,s),2.20(1H,m),2.31(1H,m),3.87(1H,t),3.96(3H,s),3.99(1H,t),4.45(2H,s),4.88(1H,d),4.68(2H,t),4.80(1H,t),4.88(1H,d),7.12(1H,d),7.12-7.34(10H,m),8.10(1H,d)。
实施例2:制备(2R,3S)-3-苄氧基-3-(3-苄基甲氧基-2-甲氧基-吡啶-4-基)-戊烷-1,2-二醇(化合物10)
室温下,把化合物9溶于50ml甲醇中,然后滴加入6ml的3N盐酸,室温下继续反应一段时间后,停止反应,旋蒸掉甲醇后,乙酸乙酯萃取,合并乙酸乙酯,水洗,饱和食盐水洗,无水硫酸钠干燥,过滤,旋蒸得粘稠状固体2.1g,产率92.1%。
1HNMR(CDCl3)(ppm)0.90(3H,t),2.16(1H,m),2.30(1H,s,br),2.45(1H,m),3.31(1H,m),3.54(1H,m),3.93(3H,s),3.99(1H,s,br),4.11(1H,m),4.35(1H,d),4.44(1H,d),4.53(1H,d),4.67(1H,d),4.74(1H,d),4.96(1H,d),6.88(1H,d),7.26-7.42(10H,m),8.09(1H,d)。
实施例3:制备(2S,3S)-3-苄氧基-3-(3-苄氧基甲基-2-甲氧基-吡啶-4-基)-2-羟基-戊酸(化合物11)
化合物10(13.37g)溶于65ml的饱和磷酸二氢钾的乙腈溶液中,室温下向体系中加入5.6g亚氯酸钠,1.3g2,2,6,6-四甲基哌啶氧化物以及2.6ml次氯酸钠水溶液,反应3-4h后,倒入120ml水中,二氯甲烷萃取,合并有机相,水洗,饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸得12.1g粗产品,无需纯化,直接投入下步反应中,产率98.5%。
1HNMR(CDCl3)(ppm)0.88(3H,t),2.42(1H,m),2.63(1H,s),3.93(3H,s),4.20(2H,m),4.55(3H,m),4.77(1H,d),4.92(1H,d),6.88(1H,d),7.26-7.42(10H,m),8.09(1H,d)。
实施例4:制备(2S,3S)-2,3-二羟基-3-(3-羟甲基-2-甲氧基-吡啶-4-基)-戊酸(化合物12)
上步反应的产物(12.2g)溶于120ml无水甲醇中,加入1.3gPd/C(10%),室温常压下加氢反应12h,过滤,滤饼用甲醇洗涤2-3次,合并溶液,旋蒸得粗产品6.6g,产率:90%,无需纯化,直接投入下步反应中。
1HNMR(CDCl3)(ppm)0.88(3H,t),1.85(2H,m),2.32(1H,s),2.42(1H,s),2.63(1H,s),3.93(3H,s),4.66(1H,m),4.80(2H,s),6.72(1H,d),7.98(1H,d)。
实施例5:制备(5S,6R)-5-乙基-5,6-二羟基-1-甲氧基-5,9-二氢-6H-8-氧杂-2-氮杂-苯并环庚烯-7-酮(化合物13)
上步反应的产物(6.6g)溶于100ml甲醇中,向体系中加入4ml三氟乙酸,室温下反应24h,旋蒸,得粗产品6.5g,无需纯化,直接投入下步反应中。
实施例6:制备(5S,6R)-5-乙基-5-羟基-1-甲氧基-7-氧杂-5,6,7,9-四氢-8-氧杂-2-氮杂-苯并环庚烯-6-基乙酸酯(结构式III,R1=CH3CO-)
化合物13(8.5g)、对二甲氨基吡啶(0.82g)、三乙胺(8.4ml)溶于100ml无水二氯甲烷中,冰水下冷却至0℃后,向体系中慢慢滴入乙酰氯(4.4ml),滴完后移至室温下反应2h,然后向体系中加入50ml饱和氯化铵水溶液,分液,水层用二氯甲烷萃取2-3次,合并二氯甲烷,水洗,饱和食盐水洗涤,无水硫酸钠干燥,过滤,旋蒸,得粗产品10g,柱层析(石油醚∶乙酸乙酯=2∶1)得白色固体4.5g,产率53%。
1HNMR(CDCl3)(ppm)0.88(3H,t),2.08(1H,m),2.18(1H,m),2.29(3H,s),2.91(1H,s),3.98(3H,s),5.23(2H,d),5.74(2H,d),7.20(1H,d),8.20(1H,d)。
实施例7:制备(5S,6R)-5-乙基-5-羟基-1,7-二氧杂-1,2,5,6,7,9-六氢-8-氧杂-2-氮杂-苯并环庚烯-6-基乙酸酯(结构式II,R1=CH3CO-)
实施例6所得化合物(4.5g)溶于100ml无水乙腈中,加入4.6g碘化钠,室温下向体系中慢慢滴入3.9ml四甲基氯硅烷,现场形成三甲基碘硅烷。加完后继续反应4h,然后倒入100ml水中,二氯甲烷萃取4-5次,合并有机相,饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸得淡黄色固体,柱层析(二氯甲烷∶甲醇=50∶1)得白色固体2.1g,产率:52%。
1HNMR(DMSO-D6)(ppm)0.63(3H,t),1.81(1H,m),2.08(1H,m),2.19(3H,s),5.30(1H,d),5.50(1H,d),5.88(1H,s),6.01(1H,s),6.37(1H,d),7.39(1H,d),11.81(1H,s)。
实施例8:制备(20S,20aR)-20a-乙酰氧基高喜树碱(化合物ysb-1)
制备(5S,6R)-2-(2-溴-喹啉-3-基甲基)-5-乙基-5-羟基-1,7-二氧杂-1,2,5,6,7,9-六氢-8-氧杂-2-氮杂-苯并环庚烯-6-基乙酸酯:氮气氛围下,0.26g实施例7所得化合物分散于30ml无水乙二醇二甲醚中,室温下滴入1M叔丁醇钾的四氢呋喃溶于,滴完后继续反应30min,然后加入0.2992-溴-3-溴甲基喹啉,体系升温回流反应6h,冷却至室温,加入10ml水,1N稀盐酸调PH=2-3,二氯甲烷萃取3-4次,合并有机相,水洗,饱和食盐水洗涤,无水硫酸钠干燥,过滤旋蒸,粗产品柱层析(二氯甲烷∶甲醇=60∶1)得白色固体0.29g,产率:63%。
1HNMR(CDCl3)(ppm)0.75(3H,t),1.96(1H,m),2.09(1H,m),2.14(3H,s),2.78(1H,s),5.12(1H,d),5.30(1H,d),5.43(1H,d),5.92(1H,d),5.99(1H,d),6.53(1H,d),7.60(2H,m),7.75(1H,m),7.83(1H,d),8.17(2H,t)。
制备(20S,20aR)-20a-乙酰氧基高喜树碱(化合物ysb-1):氮气氛围下,原料15(50mg)、醋酸钯(5mg)、三(邻甲基苯基)磷(27mg)、醋酸钾(30mg)、四正丁基氯化铵(30mg)分散在20ml无水乙腈中,加入回流反应15h,冷却至室温,1N稀盐酸调PH=3-4,搅拌30min后旋干溶剂,柱层析(二氯甲烷∶甲醇=60∶1)得淡黄色固体20mg,产率:50%。
1HNMR(500MHz,DMSO-D6):0.68(t,J=7.5Hz,3H),2.01(m,1H),2.19(m,1H),2.23(s,3H),5.30(s,2H),5.53(d,J=15.2Hz,1H),5.68(d,J=15.4Hz,1H),6.03(s,1H),6.29(s,1H),7.42(s,1H),7.72(m,1H),7.88(m,1H),8.13(d,J=8.2Hz,1H),8.18(d,J=8.5Hz,1H),8.70(s,1H),ppm;13CNMR(300MHz,DMSO-D6):8.62,20.43,32.06,50.53,60.87,70.49,76.26,99.11,123.15,127.62,127.95,128.48,128.90,129.82,130.34,131.51,144.92,147.87,152.45,153.12,158.85,167.75,169.78,ppm;HRMS(ESI):m/zcalcdforC23H21N2O6[M+H]+421.1394,found421.1394.
实施例9:制备(20S,20aR)-20a-羟基高喜树碱(化合物ysb-2)
(20S,20aR)-20a-乙酰氧基高喜树碱(ysb-1,0.11g)分散于20ml甲醇中,加入0.1g氢氧化钠,室温下搅拌反应3h,然后加入5ml三氟乙酸,继续室温下反应5h后,过滤,滤饼用甲醇和水各洗涤两次后,烘干后得白色固体65mg,产率60%。
1HNMR(500MHz,DMSO-D6):0.71(t,J=7.5Hz,3H),1.85(m,1H),2.30(m,1H),5.25(m,4H),5.39(d,J=14.5Hz,1H),5.68(d,J=15.0Hz,1H),5.82(s,1H),7.42(s,1H),7.72(m,1H),7.87(m,1H),8.13(d,J=8.0Hz,1H),8.18(d,J=8.0Hz,1H),8.69(s,1H),ppm;13CNMR(300MHz,DMSO-D6):8.65,31.96,50.42,60.52,68.75,77.32,99.66,123.32,127.55,127.90,128.46,128.90,129.81,130.30,131.47,144.51,147.87,152.56,153.93,158.92,173.15,ppm;HRMS(ESI):m/zcalcdforC21H19N2O5[M+H]+379.1288,found379.1266.
实施例10:制备(20S,20aR)-10-甲氧基-20a-乙酰氧基高喜树碱(化合物ysb-3)
操作同实施例8,以2-溴-3-溴甲基-6-甲氧基喹啉代替2-溴-3-溴甲基喹啉为原料,得化合物ysb-3,淡黄色固体,产率55%。
1HNMR(500MHz,DMSO-D6):0.68(t,J=7.5Hz,3H),2.01(m,1H),2.19(m,1H),2.23(s,3H),3.95(s,3H),5.30(s,2H),5.53(d,J=15.2Hz,1H),5.68(d,J=15.4Hz,1H),6.03(s,1H),6.29(s,1H),7.42(s,1H),7.88(m,1H),8.13(d,J=8.2Hz,1H),8.18(d,J=8.5Hz,1H),8.70(s,1H),ppm;13CNMR(300MHz,DMSO-D6):8.61,20.42,32.07,50.53,55.54,60.87,70.49,76.26,79.12,98.43,106.26,122.50,122.98,129.44,129.98,130.25,130.36,143.97,145.18,153.16,158.16,158.86,167.76,169.78,ppm;HRMS(ESI):m/zcalcdforC24H23N2O7[M+H]+451.1500,found451.1502.
实施例11:制备(20S,20aR)-10-甲氧基-20a-羟基高喜树碱(化合物ysb-4)
操作同实施例9,以化合物ysb-3代替化合物ysb-1为原料,得到化合物ysb-4,淡黄色固体,产率58%。
1HNMR(500MHz,DMSO-D6):0.72(t,J=7.5Hz,3H),1.88(m,1H),2.30(m,1H),3.95(s,3H),5.26(m,4H),5.39(d,J=14.5Hz,1H),5.68(d,J=15.0Hz,1H),5.82(s,1H),7.42(s,1H),7.87(m,1H),8.13(d,J=8.0Hz,1H),8.18(d,J=8.0Hz,1H),8.69(s,1H),ppm;13CNMR(300MHz,DMSO-D6):8.29,31.90,50.10,55.49,60.43,68.98,76.99,98.76,106.24,122.43,122.53,129.15,129.65,129.89,130.15,143.85,144.54,149.97,153.72,157.98,158.73,172.70,ppm;HRMS(ESI):m/zcalcdforC22H20N2NaO6[M+Na]+431.1214,found431.1286.
实施例12:制备(20S,20aR)-9,10-(1,3-二氧戊环)-20a-乙酰氧基高喜树碱(化合物ysb-5).
操作同例8,以2-溴-3-溴甲基-6,7-(1,3-二氧戊环)-喹啉代替2-溴-3-溴甲基喹啉为原料,得到化合物ysb-5,淡黄色固体,产率61%。
1HNMR(500MHz,DMSO-D6):0.68(t,J=7.5Hz,3H),1.99(m,1H),2.17(m,1H),2.22(s,3H),5.22(s,2H),5.50(d,J=15.1Hz,1H),5.68(d,J=15.4Hz,1H),6.01(s,1H),6.26(s,1H),6.28(s,2H),7.30(s,1H),7.51(d,J=6.6Hz,1H),8.46(s,1H),ppm;13CNMR(300MHz,DMSO-D6):8.61,20.42,32.07,50.47,60.88,70.49,76.42,98.28,101.53,103.06,104.68,122.24,125.60,128.40,130.10,145.32,146.50,148.61,149.81,151.30,153.15,158.85,167.77,169.78,ppm;HRMS(ESI):m/zcalcdforC24H21N2O8[M+H]+465.1292,found465.1280.
实施例13:制备(20S,20aR)-9,10-(1.3-二氧戊环)-20a-羟基高喜树碱(化合物ysb-6)
操作同例9,以化合物ysb-5代替ysb-1为原料,得到化合物ysb-6,淡黄色固体,产率56%。
1HNMR(500MHz,DMSO-D6):0.70(t,J=7.5Hz,3H),1.83(m,1H),2.30(m,1H),5.23(m,4H),5.36(d,J=15.2Hz,1H),5.58(d,J=15.0Hz,1H),5.78(s,1H),6.28(s,2H),7.30(s,1H),7.50(d,J=6.6Hz,2H),8.46(s,1H),ppm;HRMS(ESI):m/zcalcdforC22H18N2NaO7[M+Na]+445.1006,found445.1017.
实施例14:制备(20S,20aR)-9,10-(1.4-二氧六环)-20a-乙酰氧基高喜树碱(化合物ysb-7)
操作同例8,以2-溴-3-溴甲基-6,7-(1,4-二氧六环)-喹啉代替2-溴-3-溴甲基喹啉为原料,得到化合物ysb-7,淡黄色固体,产率58%。
1HNMR(500MHz,DMSO-D6):0.68(t,J=7.5Hz,3H),1.99(m,1H),2.18(m,1H),2.22(s,3H),4.43(s,4H),5.21(s,2H),5.50(d,J=15.1Hz,1H),5.68(d,J=15.4Hz,1H),6.01(s,1H),6.25(s,1H),7.32(s,1H),7.54(d,J=2.1Hz,2H),8.45(s,1H),ppm;13CNMR(300MHz,DMSO-D6):8.75,20.55,32.20,50.53,54.94,61.02,64.35,70.63,76.40,98.77,112.16,113.04,122.61,113.04,122.61,124.24,128.03,129.72,144.50,145.38,147.61,150.59,153.34,159.03,168.00,170.02,ppm;HRMS(ESI):m/zcalcdforC25H23N2O8[M+H]+479.1449,found479.1469.
实施例15:制备(20S,20aR)-9,10-(1,4-二氧六环)-20a-羟基高喜树碱(化合物ysb-8)
操作同例9,以化合物ysb-7代替ysb-1为原料,得到化合物ysb-8,淡黄色固体,产率57%。
1HNMR(500MHz,DMSO-D6):0.70(t,J=7.5Hz,3H),1.83(m,1H),2.30(m,1H),4.43(s,4H),5.24(m,4H),5.37(d,J=15.2Hz,1H),5.58(d,J=15.0Hz,1H),5.79(s,1H),7.32(s,1H),7.50(d,J=3.3Hz,2H),8.45(s,1H),ppm;HRMS(ESI):m/zcalcdforC23H21N2O7[M+H]+437.1343,found437.1344.
实施例16:制备(20S,20aR)-10-羟基-7-乙基-20a-乙酰氧基高喜树碱(化合物ysb-9)
操作同例8,以2-溴-3-溴甲基-4-乙基-6-羟基-喹啉代替2-溴-3-溴甲基喹啉为原料,得到化合物ysb-9,淡黄色固体,产率40%。
1HNMR(500MHz,DMSO-D6):0.68(t,J=7.5Hz,3H),1.30(t,J=10.0Hz,3H),1.88(m,2H),2.22(s,3H),3.09(q,J=10.0Hz,2H),5.21(s,2H),5.50(d,J=15.1Hz,1H),5.68(d,J=15.4Hz,1H),6.01(s,1H),6.25(s,1H),7.32(s,1H),7.43(m,1H),7.54(d,J=2.1Hz,2H),8.45(s,1H),10.3(s,1H),ppm;
实施例17:制备(20S,20aR)-10羟基-7-乙基-20a-羟基高喜树碱(化合物ysb-10)
操作同例9,以化合物ysb-9代替ysb-1为原料,得到化合物ysb-10,淡黄色固体,产率56%。
1HNMR(500MHz,DMSO-D6):0.68(t,J=7.5Hz,3H),1.30(t,J=10.0Hz,3H),1.88(m,2H),3.09(q,J=10.0Hz,2H),5.21(s,2H),5.50(d,J=15.1Hz,1H),5.68(d,J=15.4Hz,1H),5.78(s,1H),6.01(s,1H),6.25(s,1H),7.32(s,1H),7.43(m,1H),7.54(d,J=2.1Hz,2H),8.45(s,1H),10.1(s,1H),ppm;
实验实施例18.抗肿瘤活性测试:
所有化合物的细胞毒活性测试都在相应的肿瘤细胞株上进行,每100μL的培养液中有6000~10000个肿瘤细胞,置于96孔板中(Falcon,CA)。肿瘤细胞分成三份,用梯度浓度的药物处理,在37℃下培养72h,采用SRB法测试。50%的肿瘤细胞生长抑制时药物的浓度即IC50使用量效曲线来计算的。
表1.对HCT-116和A549细胞的生长抑制活性
上表显示了本发明所述的化合物对HCT-116和A549等肿瘤细胞抑制率非常高,表现出了很好的抗肿瘤活性。
Claims (9)
1.一种通式I所示的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐:
其中,
R1为H、乙酰基或丙酰基;
R2为H或C1~C6的烷基;
R3为H;
R4为H、羟基、或C1~C6的烷氧基;
R5为H;
或者,R4和R5彼此连接形成-OCH2O-或-OCH2CH2O-。
2.根据权利要求1所述的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐,其中,
R1为H或乙酰基;
R2为H或C1~C3的烷基;
R3为H;
R4为H、羟基、或C1~C3的烷氧基;
R5为H;
或者,R4和R5彼此连接形成-OCH2O-或-OCH2CH2O-。
3.根据权利要求1所述的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐,其中,
R1为H或乙酰基;
R2为H或乙基;
R3为H;
R4为H、羟基、或甲氧基;
R5为H;
或者,R4和R5彼此连接形成-OCH2O-或-OCH2CH2O-。
4.根据权利要求1所述的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐,其中,所述喜树碱类化合物及其药学上可接受的盐为以下化合物:
5.根据权利要求1所述的通式I所示的含有7元内酯环的喜树碱类化合物及其药学上可接受的盐的制备方法,该方法包括如下步骤:
其中,R1、R2、R3、R4和R5的定义如权利要求1所述,但R1不为H;
i)在碱作用条件下,化合物II与化合物IV发生N-烷基化反应得到化合物V;
ii)在钯催化条件下,化合物V进行Heck反应,制得通式I所示化合物;
iii)非必须地,当R1为乙酰基时,通式I所示化合物水解得到化合物I-1。
6.根据权利要求5所述的制备方法,其中,所述化合物II通过如下方法制备:
其中,R1的定义如权利要求1所述,但不为H;
1)在碱的条件下,化合物8和溴苄或氯苄发生醚化反应,生成化合物9;
2)化合物9在酸的作用下,水解制得化合物10;
3)化合物10在氧化剂的作用下,发生氧化反应制得化合物11;
4)在催化加氢体系的作用下,化合物11脱去苄基保护基得到化合物12;
5)化合物12在酸催化下成内酯环化合物13;
6)当R1为乙酰基或丙酰基时,在碱的作用下,化合物13与相应的酸酐或酰氯进行酰化反应得到化合物III;
7)当R1为乙酰基、丙酰基时,在三甲基碘硅烷、三溴化硼、或四氯化硅的作用下,化合物III脱去甲基得到2-吡啶酮关键中间体化合物II。
7.一种用于治疗癌症的组合物,该组合物包含治疗有效量的一种或多种权利要求1至4中任一项所述的喜树碱类化合物及其药学上可接受的盐以及药学上可接受的载体。
8.一种权利要求1至4中任一项所述的喜树碱类化合物及其药学上可接受的盐在制备抗肿瘤药物中的应用。
9.一种权利要求1至4中任一项所述的喜树碱类化合物及其药学上可接受的盐在制备治疗结肠癌或肺癌的药物中的应用。
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CN1192740A (zh) * | 1995-06-21 | 1998-09-09 | 科学研究与运用咨询公司 | 新的喜树碱类似物、其制备方法和药物应用及其药物组合物 |
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CN1192740A (zh) * | 1995-06-21 | 1998-09-09 | 科学研究与运用咨询公司 | 新的喜树碱类似物、其制备方法和药物应用及其药物组合物 |
CN1241192A (zh) * | 1996-12-20 | 2000-01-12 | 科学研究与运用咨询公司 | 喜树碱的前药形式和类似物,及其药物用途 |
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