CN110143934B - Fluorine-containing taxane compound and preparation method and application thereof - Google Patents
Fluorine-containing taxane compound and preparation method and application thereof Download PDFInfo
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- CN110143934B CN110143934B CN201810995609.5A CN201810995609A CN110143934B CN 110143934 B CN110143934 B CN 110143934B CN 201810995609 A CN201810995609 A CN 201810995609A CN 110143934 B CN110143934 B CN 110143934B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 60
- -1 taxane compound Chemical class 0.000 title abstract description 18
- 229940123237 Taxane Drugs 0.000 title abstract description 17
- 229910052731 fluorine Inorganic materials 0.000 title abstract description 17
- 239000011737 fluorine Substances 0.000 title abstract description 17
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 title abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 48
- 210000004027 cell Anatomy 0.000 claims abstract description 20
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 17
- 210000000130 stem cell Anatomy 0.000 claims abstract description 10
- 206010006187 Breast cancer Diseases 0.000 claims abstract description 5
- 208000026310 Breast neoplasm Diseases 0.000 claims abstract description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims abstract description 4
- 206010061535 Ovarian neoplasm Diseases 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims description 14
- 230000036457 multidrug resistance Effects 0.000 claims description 10
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000002018 overexpression Effects 0.000 claims description 6
- 208000015634 Rectal Neoplasms Diseases 0.000 claims description 5
- 206010038038 rectal cancer Diseases 0.000 claims description 5
- 201000001275 rectum cancer Diseases 0.000 claims description 5
- 150000003839 salts Chemical class 0.000 claims description 3
- 201000001441 melanoma Diseases 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 claims description 2
- 229930012538 Paclitaxel Natural products 0.000 abstract description 25
- 229960001592 paclitaxel Drugs 0.000 abstract description 25
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 abstract description 25
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 abstract description 13
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 5
- 230000003013 cytotoxicity Effects 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 3
- 206010009944 Colon cancer Diseases 0.000 abstract description 2
- 208000029742 colonic neoplasm Diseases 0.000 abstract description 2
- 230000000144 pharmacologic effect Effects 0.000 abstract description 2
- 150000002221 fluorine Chemical class 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 description 85
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 45
- 239000000243 solution Substances 0.000 description 42
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 21
- 239000000047 product Substances 0.000 description 18
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 16
- 239000012074 organic phase Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 16
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 description 14
- 238000001914 filtration Methods 0.000 description 14
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- 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 description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
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- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 11
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- 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 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 229940125797 compound 12 Drugs 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 5
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 229940125898 compound 5 Drugs 0.000 description 5
- 239000012467 final product Substances 0.000 description 5
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- 229910052710 silicon Inorganic materials 0.000 description 5
- 239000010703 silicon Substances 0.000 description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 4
- AEMRFAOFKBGASW-UHFFFAOYSA-N Glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 4
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229940041181 antineoplastic drug Drugs 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 3
- 229910004664 Cerium(III) chloride Inorganic materials 0.000 description 3
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 125000003460 beta-lactamyl group Chemical group 0.000 description 3
- VYLVYHXQOHJDJL-UHFFFAOYSA-K cerium trichloride Chemical compound Cl[Ce](Cl)Cl VYLVYHXQOHJDJL-UHFFFAOYSA-K 0.000 description 3
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 3
- 229940125904 compound 1 Drugs 0.000 description 3
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- 231100000263 cytotoxicity test Toxicity 0.000 description 3
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- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- AAIBYZBZXNWTPP-NWDGAFQWSA-N (1r,2s)-2-phenylcyclohexan-1-ol Chemical compound O[C@@H]1CCCC[C@H]1C1=CC=CC=C1 AAIBYZBZXNWTPP-NWDGAFQWSA-N 0.000 description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 2
- YWLXLRUDGLRYDR-ZHPRIASZSA-N 5beta,20-epoxy-1,7beta,10beta,13alpha-tetrahydroxy-9-oxotax-11-ene-2alpha,4alpha-diyl 4-acetate 2-benzoate Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](O)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-ZHPRIASZSA-N 0.000 description 2
- 102100033350 ATP-dependent translocase ABCB1 Human genes 0.000 description 2
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- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 230000008499 blood brain barrier function Effects 0.000 description 2
- 210000001218 blood-brain barrier Anatomy 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- 229940125773 compound 10 Drugs 0.000 description 2
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- 239000012043 crude product Substances 0.000 description 2
- ZOOSILUVXHVRJE-UHFFFAOYSA-N cyclopropanecarbonyl chloride Chemical compound ClC(=O)C1CC1 ZOOSILUVXHVRJE-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 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 description 2
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 description 2
- XMJHPCRAQCTCFT-UHFFFAOYSA-N methyl chloroformate Chemical compound COC(Cl)=O XMJHPCRAQCTCFT-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 2
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- DYHSDKLCOJIUFX-UHFFFAOYSA-N tert-butoxycarbonyl anhydride Chemical compound CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
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- YWLXLRUDGLRYDR-UHFFFAOYSA-N 10-deacetylbaccatin Chemical compound CC(=O)OC12COC1CC(O)C(C(C(O)C1=C(C)C(O)CC3(O)C1(C)C)=O)(C)C2C3OC(=O)C1=CC=CC=C1 YWLXLRUDGLRYDR-UHFFFAOYSA-N 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- YIIMEMSDCNDGTB-UHFFFAOYSA-N Dimethylcarbamoyl chloride Chemical compound CN(C)C(Cl)=O YIIMEMSDCNDGTB-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
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- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
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- JKEMAHLSSQQCDX-UHFFFAOYSA-N n,n-bis(methylamino)formamide Chemical compound CNN(NC)C=O JKEMAHLSSQQCDX-UHFFFAOYSA-N 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
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- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
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- QUANRIQJNFHVEU-UHFFFAOYSA-N oxirane;propane-1,2,3-triol Chemical compound C1CO1.OCC(O)CO QUANRIQJNFHVEU-UHFFFAOYSA-N 0.000 description 1
- BHAAPTBBJKJZER-UHFFFAOYSA-N p-anisidine Chemical compound COC1=CC=C(N)C=C1 BHAAPTBBJKJZER-UHFFFAOYSA-N 0.000 description 1
- 239000008389 polyethoxylated castor oil Substances 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
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- 229910052708 sodium Inorganic materials 0.000 description 1
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- 125000001424 substituent group Chemical group 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
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- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
The invention discloses a fluorine-containing taxane compound and a preparation method and application thereof. The structural general formula of the compound is shown as a formula I. Pharmacological experiments prove that compared with taxol, the series of fluorine-containing taxane derivatives synthesized by the invention have cytotoxicity superior to taxol for multidrug resistant human breast cancer cell lines MCF-7/Adr and ovarian cancer cell lines NCI/Adr, and are specific to colon cancer cell lines HCT-116 over-expressed by tumor stem cells ++ Exhibits cytotoxicity superior to that of paclitaxel.
Description
Technical Field
The invention relates to a fluorine-containing taxane compound and a preparation method and application thereof.
Background
Malignant tumors are major diseases that severely threaten human life and quality of life. In recent decades, many highly cytotoxic chemotherapeutic drugs have been discovered in succession for clinical application as first-line drugs for the treatment of various cancers. Paclitaxel (Paclitaxel) was developed and marketed since 1992, its market sales rapidly dominate the first antitumor drugs, and Paclitaxel products have been kept increasing by 30% until now, and the worldwide trade volume of Paclitaxel has been kept above 50 billion dollars. Docetaxel (Docetaxel), another representative drug of taxus species, has stronger antitumor activity than paclitaxel and market share is increasing year by year.
Paclitaxel is currently used clinically by intravenous injection, and because of its extremely poor water solubility, it is dissolved in a mixed solvent of cremophor EL and ethanol (1 specific gravity) to make an injection of paclitaxel, which is marketed under the name of Taxol. The clinical application of Taxol is limited by a plurality of factors: (1) Firstly, the toxic and side effects of the medicine on normal tissue cells, the dose-limiting toxicity, bone marrow suppression (clinically needing to be matched with growth factors for treatment), incapability of passing through a blood brain barrier and the like are caused; (2) With the application of Chremophor EL, the following problems arise: severe allergic reactions, idiopathic hyperlipidemia, central neurotoxicity and changes in paclitaxel pharmacokinetics [ ten Tije AJ, et al, clin Pharmacokinet 42,655-685,2003; gelderblom, et al, eur.j. cancer 37 (13), 1590-1598,2001; van Zuylen L, et al, invest New Drugs 19,125-141,2001; R.B.Weiss, et al, J.Clin.Oncol.8 (7), 1263-1268,1990]. And (3) multidrug resistance caused by long-term administration. The paclitaxel is also the main reason of failure of paclitaxel chemotherapy, and the activity of paclitaxel itself on P-glycoprotein (P-gp) cell strains such as colon cancer and brain tumor is very low, thus greatly limiting the clinical application range. The clinical application of docetaxel is also accompanied with the problems of great toxic and side effects, multidrug resistance and the like.
The future development trend of the paclitaxel antitumor drugs is not to modify the structure to find taxane molecules with higher cytotoxicity any more, but to overcome the problem of multidrug resistance of the taxane drugs, so that the taxane antitumor drugs still maintain the anticancer curative effect on multidrug resistant tumors, can pass through the blood brain barrier more easily and have novel taxane molecules with better curative effect on digestive tract tumors, so as to expand the clinical application range of the taxane antitumor drugs and improve the therapeutic index on malignant tumors.In the invention Container
The invention aims to provide a fluorine-containing taxane compound and a preparation method and application thereof.
The fluorine-containing taxane compound provided by the invention has a structural general formula shown in formula I:
in the formula I, R is acyl group containing no more than six atoms or alkyl with 1-6 carbon atoms.
Specifically, R is acetyl, propionyl, methoxycarbonyl, N-dimethylformyl, cyclopropylformyl or methyl;
the compound shown in the formula I can be any one of the following JY-01 to JY-06 compounds:
JY-01
JY-02
JY-03
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JY-04
JY-05
JY-06
the invention provides a method for preparing a compound shown in the formula I, which comprises the following steps:
removing a silicon-based protecting group at the C2' position of the compound shown in the formula 002 to obtain the compound shown in the formula I;
in the method, in the step of removing the silicon-based protecting group at the C2' position, the reaction condition is an acidic condition;
the pH value of the acidic condition is 1-3;
the acidic condition is carried out in HF/Py solution; the volume ratio of HF/Py is 3-4:1.
in the step of removing the silicon-based protecting group at the C2' position, a reaction solvent is at least one of mixed solution consisting of acetonitrile and pyridine, tetrahydrofuran, dichloromethane, methanol and ethanol; in the mixed liquid composed of acetonitrile and pyridine, the volume ratio of acetonitrile to pyridine is specifically 1:1-2;
the reaction temperature is between room temperature and 0 ℃;
the reaction time is 12-24h.
In addition, the application of the compound shown in the formula I or the pharmaceutically acceptable salt thereof provided by the invention in the preparation of a multi-drug resistance resistant product and/or a product for inhibiting the activity of a tumor stem cell overexpression cell line also belongs to the protection scope of the invention.
Specifically, in the cell strain for resisting multidrug resistance and inhibiting tumor stem cell overexpression, the targeted tumor is at least one of breast cancer, ovarian cancer, rectal cancer, non-small cell lung cancer and melanoma.
In addition, the invention also claims an intermediate compound used for preparing the compound shown in the formula I, the structural general formula of the intermediate compound is shown in a formula 002,
the invention provides a method for preparing a compound shown as a formula 002, which comprises the following steps:
the compound shown in the formula 001 and the compound shown in the formula 11 are subjected to Hilton docking reaction to obtain the compound;
in the Hilton docking reaction step of the above method, the equivalent ratio of the compound represented by formula 001 to the compound represented by formula 11 is 1 to 1;
the Hilton docking reaction is carried out under an alkaline condition;
the pH value of the alkaline condition is 7.5-9;
the alkaline condition is specifically the condition of existence of Lithium Hexamethyldisilazide (LHMDS);
the Hilton docking reaction is carried out in a solvent; the solvent is at least one selected from tetrahydrofuran, dichloromethane and dioxane;
the reaction temperature of the Hilton docking reaction is 0-40 ℃;
the reaction time is 2-12h.
In the above method, the compound represented by formula 11, that is, the β -lactam side chain precursor, can be synthesized as follows: glycolic acid is subjected to benzyl protection and tert-butylcarbonyl (Boc group) protection to generate Boc-protected benzyl glycolate; removing benzyl protection, reacting free carboxylic acid with N-hydroxysuccinimide to generate an active intermediate, esterifying and condensing the active intermediate with trans-2-phenyl-1-cyclohexanol to form a compound 5, forming a corresponding enamine compound 6 from methacrolein and p-anisidine, performing addition reaction on the compound 5 and the compound 6 to generate a chiral compound 7, oxidizing an isobutenyl side chain to form an aldehyde group, substituting difluoroethylene, removing a protecting group on a nitrogen atom, and finally protecting with tert-butyloxycarbonyl to generate a final beta-lactam side chain precursor.
The compound represented by formula 001, that is, the taxane core moiety, can be synthesized as follows: taking 10-deacetylbaccatin III as an initial raw material, firstly carrying out silicon alkylation protection on hydroxyl at the C7 position, then carrying out acylation protection on the hydroxyl at the C10 position, removing a silicon-based protecting group at the C7 position, generating sulfonate from free hydroxyl, carrying out elimination reaction with the adjacent C6 position under the action of high temperature and strong alkali to generate a C6 and C7 double bond structure, and carrying out addition reaction with HF to obtain a final mother nucleus structure.
Wherein, the acylation protection of the hydroxyl at the C10 position specifically comprises the following steps: when R is acetyl and propionyl is substituted, the reaction is carried out by taking tetrahydrofuran as a solvent and reacting with corresponding anhydride at room temperature under the action of cerous chloride. (anhydrides include acetic anhydride and propionic anhydride). When R is methoxy formyl, N, N-dimethyl formyl and cyclopropyl formyl for substitution, the related reaction is carried out with corresponding acyl chloride under alkaline condition, especially with hexamethyldisilazane lithium amide (LHMDS) as the best solvent, tetrahydrofuran, dichloromethane and dioxane as the best solvent, especially tetrahydrofuran as the best solvent, at room temperature to 0 ℃, especially 0 ℃. (the acid chlorides include methoxy formyl chloride, N, N-dimethyl formyl chloride, cyclopropyl formyl chloride.) when R is methyl substitution, the reaction involved is a reaction with methyl triflate under basic conditions, preferably Lithium Hexamethyldisilazide (LHMDS), most preferably tetrahydrofuran, dichloromethane, dioxane as solvent, most preferably tetrahydrofuran, at a temperature of 0 ℃ to-70 ℃, most preferably-40 ℃.
The invention obtains especially 6 novel fluorine-containing taxane compounds shown in formula I by simultaneously modifying substituent groups of a plurality of sites of C6, C7, C10 and C3' of paclitaxel, and the experimental results show that the multi-drug resistance activity of the 6 compounds is superior to that of paclitaxel by in vitro investigating the cell toxicity activity test of multi-drug resistance tumor cell strains and over-expressed cell strains of tumor stem cells. Therefore, the fluorine-containing taxane compound is a potential anti-multidrug-resistant tumor medicament.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples, but the present invention is not limited to the following examples. The method is a conventional method unless otherwise specified. The starting materials are commercially available from the open literature unless otherwise specified.
Example 1, preparation of JY-01
1) Preparation of Compound 11
a. Preparation of Compound 1
Glycolic acid (7.60g, 0.10 mol) was dissolved in 10mL of acetonitrile, and benzyl bromide (13.60g, 0.08mol) was added to the solution, and after stirring to be uniform, DBU (12.16g, 0.08mol) was slowly added dropwise to the reaction solution at 0 ℃, and after completion of the dropwise addition, the reaction solution was stirred at room temperature overnight. The reacted solution was poured into ice water, extracted with ethyl acetate, the organic phases were combined, washed with 1M hydrochloric acid solution, saturated brine, dried over anhydrous magnesium sulfate, and concentrated by rotary evaporation to give compound 1 as a yellow oil.
b. Preparation of Compound 2
Compound 1 (12.5g, 75.3mmol) was dissolved in 100mL of dichloromethane, 4-dimethylaminopyridine (1.04g, 8.42mmol) and triethylamine (14.1mL, 101mmol) were added to the solution, and after stirring, 1M triisopropylchlorosilane (22.3mL, 101mmol) was added dropwise to the reaction solution at 0 ℃. Stirring the mixture at room temperature overnight, monitoring the reaction by TLC, adding 25mL of saturated ammonium chloride solution into the reaction solution after the reaction is finished, filtering to remove the generated white solid, repeatedly washing the filtrate by ethyl acetate, combining organic phases, washing by saturated saline, drying by anhydrous magnesium sulfate, filtering, and concentrating by rotary evaporation to obtain a yellow oily compound.
c. Preparation of Compound 3
Compound 2 (5 g, 15.53mmol) was dissolved in 50mL of ethyl acetate, and 10% palladium on carbon (82.5 mg, 0.775mmol) was added to the reaction mixture. And (3) evacuating the air in the reaction bottle, continuously supplementing hydrogen into the reaction bottle, reacting for 4 hours, monitoring the reaction by TLC, and filtering and concentrating after the reaction is finished to obtain a yellow oily compound 3.
d. Preparation of Compound 4
Compound 3 (3.6g, 15.5 mmol) was dissolved in 50mL of dichloromethane, 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) (3.03g, 15.5 mmol) and N-hydroxysuccinimide (NHS) (2.18g, 18.6 mmol) were added to the reaction mixture, the reaction was allowed to proceed overnight at room temperature, the reaction was monitored by TLC, after completion of the reaction, dichloromethane was extracted a plurality of times, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give Compound 4.
e. Preparation of Compound 5
Trans 2-phenylcyclohexanol (1.95g, 11.08mmol) and 4-Dimethylaminopyridine (DMAP) (1.37g, 11.08mmol) were dissolved in 25mL of toluene, and compound 4 (4.38g, 13.3mmol) was slowly added to the reaction solution. The reaction is carried out at room temperature, TLC monitors the reaction, after the reaction is finished, 20mL of saturated saline solution is added into the reaction solution, ethyl acetate is extracted for multiple times, organic phases are combined, anhydrous magnesium sulfate is dried, filtration and concentration are carried out, and the compound 5 is obtained through column separation and purification.
f. Preparation of Compound 6
P-anisidine (0.31g, 2.51mmol) was dissolved in 10mL of methylene chloride, and a small amount of anhydrous magnesium sulfate was added to the reaction solution. Then, 3-methyl-2-butylaldehyde was added dropwise to the reaction solution. And (4) reacting for 4 hours in a dark place, monitoring the reaction by TLC, and filtering and concentrating to obtain a compound 6 after the reaction is finished.
g. Preparation of Compound 7
Compound 5 (0.65g, 1.67mmol) was dissolved in 4mL of tetrahydrofuran, 1M lithium diisopropylamide (2.5 mL, 2.50mmol) was added dropwise to the reaction mixture at-78 ℃ to react for 0.5 hour, then Compound 6 (2.50 mmol) was added dropwise to the reaction mixture and dissolved in 3mL of tetrahydrofuran to react for 2.5 hours, then the reaction was terminated, 5mL of a saturated ammonium chloride solution was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate several times, the organic phases were combined, washed with saturated brine, dried over magnesium sulfate, filtered and concentrated, and separated and purified by column chromatography to give Compound 7.
h. Preparation of Compound 8
Compound 7 (485mg, 1.20mmol) was dissolved in 10mL of methylene chloride, and O was continuously introduced into the reaction mixture 3 And reacting at-78 ℃ for 0.5 hour until the solution shows light blue, adding 2mL of dimethyl sulfide into the reaction solution, reacting for 3 hours, concentrating the reaction solution, and separating and purifying by a column to obtain the compound 8.
i. Preparation of Compound 9
Compound 8 (230mg, 0.61mmol), sodium 2-chloro-2-difluoroacetate (285mg, 1.83mmol) and triphenylphosphine (485mg, 1.83mmol) were dissolved in 10mL of N, N-dimethylformamide. After reacting for 2 hours at 90-100 ℃, slightly cooling the reaction solution, adding 20mL of water into the reaction solution, extracting with ethyl acetate for multiple times, combining organic phases, washing with saturated saline solution, drying with anhydrous magnesium sulfate, filtering, concentrating, and separating and purifying through a column to obtain the compound 9.
j. Preparation of Compound 10
Compound 9 (124mg, 0.30mmol) was dissolved in 10mL of acetonitrile/water (4.
k. Preparation of Compound 11
Compound 10 (270mg, 0.89mmol), triethylamine (0.75mL, 5.38mmol) and 4-dimethylaminopyridine (43mg, 0.35mmol) were dissolved in 10mL of dichloromethane, di-tert-butyl dicarbonate (398mg, 1.77mmol) was added to the reaction mixture at room temperature to react overnight, after the reaction was completed, the reaction mixture was extracted with ethyl acetate several times, the organic phases were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated, and separated and purified by column to give Compound 11.
2) Preparation of 6-fluoro-7-deoxy-10-acetylbaccatin III
Preparation of 7-triethylsilyl-10-deacetylbaccatin III
10-DAB (0.55g, 1.01mmol) and imidazole (0.21g, 3.03mmol) are dissolved in 10mL of N, N-dimethylaminocarboxamide DMF, triethylchlorosilane TESCl (0.52mL, 3.03mmol) is dropwise added into a reaction solution at 0 ℃, reaction is carried out for 1 hour, after the reaction is finished, 25mL of water is added into the reaction solution, extraction is carried out for multiple times by ethyl acetate, organic phases are combined, washing is carried out by saturated saline, drying is carried out by anhydrous magnesium sulfate, filtering and concentrating are carried out, and the product is obtained by column separation and purification.
b.preparation of 10-acetyl-7-triethylsilyl-baccatin III
Dissolving a compound 12 (658mg, 1.0mmol) and cerous chloride (4.9mg, 0.02mmol) in 10mL of tetrahydrofuran solution, dropwise adding acetic anhydride (1.88mL, 20.0 mmol) into the reaction solution at room temperature, monitoring the reaction by TLC, after the reaction is finished, adding 20mL of water into the reaction solution, extracting by ethyl acetate for multiple times, combining organic phases, washing by saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating, and separating and purifying by a column to obtain the product.
Preparation of 10-acetyl-baccatin III
Dissolving 10-acetyl-7-triethylsilyl-baccatin III (586 mg,1.0 mmol) in 10mL of acetonitrile/pyridine (1.
Preparation of 10-acetyl-7-trifluoromethanesulfonate baccatin III
Dissolving 1 equivalent of 10-acetyl-baccatin III in dry dichloromethane, adding 5 equivalents of pyridine, stirring at 0 ℃, dropwise adding 2 equivalents of methyl trifluoromethanesulfonate into the reaction solution, reacting for 3 hours, pouring the reaction solution into water, extracting with dichloromethane, combining organic phases, sequentially washing with 0.1M hydrochloric acid solution, saturated sodium bicarbonate and saturated saline solution, drying, filtering, rotary steaming, and separating by a column to obtain the product.
Preparation of 10-acetyl-6, 7-double bond baccatin III
Dissolving 1 equivalent of 10-acetyl-7-trifluoromethanesulfonate baccatin III in a dioxane/tetrahydrofuran (10.
Preparation of 10-acetyl-6-fluoro-7-deoxybaccatin III
Dissolving 1 equivalent of 10-acetyl-6, 7-double bond baccatin III in tetrahydrofuran, adding into hydrogen kettle, and charging 2atm of CH into reactor at 40 deg.C 3 OCH 3 5HF gas, reacting for 4 hours, ending the reaction, concentrating, and separating by a column to obtain the product.
3) Preparation of JY-01
Dissolving 1 equivalent of mother nucleus and 2 equivalents of beta-lactam side chain precursor in a proper amount of tetrahydrofuran, dropwise adding 1.5 equivalents of Lithium Hexamethyldisilazide (LHMDS) into reaction liquid at-40 ℃, monitoring the reaction by TLC, adding a proper amount of saturated ammonium chloride solution after the reaction is finished, extracting with ethyl acetate for multiple times, combining organic phases, drying and concentrating to obtain a crude product. Dissolving the crude product obtained in the last step in a proper amount of acetonitrile/pyridine (1).
m.p.＝163–164℃； 1 H NMR(500MHz,CDCl 3 )δ1.03(m,2H),1.17(m,2H),1.19(s,3H),1.29(s,3H),1.38(s,9H),1.70(s,3H),1.77(s,3H),1.81(s,3H),1.83(m,1H),1.90(m,1H),1.93(s,3H),2.37(s,3H),2.38-2.43(m,2H),2.59(m,1H),2.63(s,br,1H),3.84(d,J＝7.0Hz,1H),3.90(s,3H),4.22(m,2H),4.38(d,J＝8.5Hz,1H),4.76(m,1H),4.80(m,1H),5.00(d,J＝8.0,1H),5.35(m,1H),5.69(d,J＝7.0Hz,1H),6.21(t,J＝8.0Hz,1H),6.33(s,1H),7.18(dd,J＝8.0,2.0Hz,1H),7.41(t,J＝8.0Hz,1H),7.67(s,1H),7.73(d,J＝7.5Hz,1H)； 13 C NMR(125MHz,CDCl 3 )δ9.24,9.49,9.53,13.06,15.02,18.56,21.98,22.44,23.74,26.72,28.23,35.56,35.58,43.21,45.63,51.52,55.34,58.58,72.24,72.40,73.71,75.14,75.47,76.47,79.14,80.05,81.12,84.44,114.61,120.16,120.64,122.56,129.67,130.49,132.90,137.93,142.70,155.42,159.65,166.83,170.05,173.18,175.18,203.96.
From the above, the product has a correct structure and is the target compound.
Example 2, JY-02 preparation
1) Preparation of Compound 11
The preparation of compound 11 is exactly the same as shown in step 1) in example 1, see the reaction of step 1) in example 1.
2) Preparation of 6-fluoro-7-deoxy-10-propionyl baccatin III
The 6-fluoro-7-deoxy-10-propionyl baccatin III was prepared in substantially the same manner as in step 2) of example 1, except that the reaction in step 2) of example 1 was followed except for the difference in step b.
b.preparation of 10-propionyl-7-triethylsilylbaccatin III
Dissolving a compound 12 (658mg, 1.0mmol) and cerous chloride (4.9mg, 0.02mmol) in 10mL of tetrahydrofuran solution, dropwise adding propionic anhydride (1.92mL, 20.0 mmol) into the reaction solution at room temperature, monitoring the reaction by TLC, after the reaction is finished, adding 20mL of water into the reaction solution, extracting by ethyl acetate for multiple times, combining organic phases, washing by saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating, and separating and purifying by a column to obtain the product.
3) Preparation of JY-02
The process in step 3) of JY-02 is the same as the reaction process of 3) in specific example 1, see step 3) in specific example 1). The purity of the final product reaches more than 95 percent.
m.p.＝168–169℃； 1 H NMR(500MHz,CDCl 3 )δ1.16(s,3H),1.22(t,J＝7.5Hz,3H),1.26(s,3H),1.35(s,9H),1.68(s,3H),1.74(s,3H),1.77(s,3H),1.88(m,1H),1.90(s,3H),2.34-2.41(m,2H),2.36(s,3H),2.46-2.60(m,4H),3.49(s,br,1H),3.83(d,J＝7.0Hz,1H),3.88(s,3H),4.20(m,2H),4.35(d,J＝8.5Hz,1H),4.44(m,1H),4.74(m,1H),4.78(m,1H),4.98(d,J＝8.5Hz,1H),5.33(m,1H),5.67(d,J＝7.0Hz,1H),6.18(t,J＝9.0Hz,1H),6.32(s,1H),7.15(dd,J＝8.0,2.0Hz,1H),7.38(t,J＝8.0HZ,1H),7.65(s,1H),7.71(d,J＝7.5Hz,1H)； 13 C NMR(125MHz,CDCl 3 )δ9.06,9.56,14.97,18.55,21.88,22.43,25.73,26.64,27.60,28.22,29.72,35.54,43.20,45.66,51.53,55.38,58.56,72.19,72.38,73.71,73.13,75.46,76.47,79.08,79.99,81.12,84.45,114.62,120.14,120.64,122.55,129.67,130.45,132.93,137.90,142.50,155.44,159.63,166.81,170.09,173.19,174.67,203.86.
From the above, the product was found to be the target compound with a correct structure.
Example 3, preparation of JY-03
1) Preparation of Compound 11
The preparation of compound 11 is exactly the same as shown in step 1) in example 1, see the reaction of step 1) in example 1.
2) Preparation of 6-fluoro-7-deoxy-10-methoxyformyl baccatin III
The preparation of 6-fluoro-7-deoxy-10-methoxycarbonylbaccatin III is essentially the same as that shown in step 2) of example 1, except that the b step is different, as described in step 2) of example 1.
b.preparation of 10-Methoxybenzoyl-7-triethylsilylbaccatin III
Dissolving a compound 12 (658mg, 1.0mmol) in 10mL of tetrahydrofuran solution, dropwise adding 1M LHMDS (1.5mL, 1.5mmol) into a reaction solution at 0 ℃, reacting for 0.5 hour, dropwise adding methoxycarbonyl chloride (1.5 mmol) into the reaction solution, monitoring the reaction by TLC, after the reaction is finished, adding 20mL of water into the reaction solution, extracting by ethyl acetate for multiple times, combining organic phases, washing by saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating, and separating and purifying by a column to obtain a product.
3) Preparation of JY-03
The process in step 3) of JY-03 is the same as the reaction process of 3) in specific example 1, see step 3) in specific example 1). The purity of the final product reaches more than 95 percent.
m.p.＝165-167℃； 1 H NMR(500MHz,CDCl 3 )δ0.82–0.98(m,2H),1.14(s,3H),1.23(t,J＝7.8Hz,3H),1.25(s,3H),1.34(s,9H),1.65(s,1H),1.67(s,3H),1.73(s,1H),1.75(s,3H),1.76(s,3H),1.87(m,1H),1.89(s,3H),2.36(s,3H),2.40(m,1H),2.42(s,3H),2.48–2.62(m,4H),3.38(d,J＝6.9Hz,1H),3.81(d,J＝7.2Hz,1H),4.13–4.22(m,2H),4.31(d,J＝7.8Hz,1H),4.42(m,1H),4.73–4.80(m,2H),4.97(d,J＝9.6Hz,1H),5.33(d,J＝8.1Hz,1H),5.65(d,J＝6.6Hz,1H),6.16(t,J＝8.7Hz),6.31(s,1H),7.30–7.42(m,2H),7.90(d,J＝7.5Hz,1H),7.93(s,1H)； 13 C NMR(125MHz,CDCl 3 )δ9.06,9.56,14.99,18.59,21.38,21.88,22.38,25.74,26.64,27.60,28.23,35.58,43.20,45.68,51.57,58.57,72.25,72.45,73.75,74.92,75.47,76.49,79.16,79.97,91.10,84.43,120.65,127.32,128.54,129.12,130.83,132.93,134.48,137.89,138.36,142.51,153.43,167.08,170.04,173.17,174.68,203.86.
From the above, the product has a correct structure and is the target compound.
Example 4, preparation of JY-04
1) Preparation of Compound 11
The preparation of compound 11 is exactly the same as shown in step 1) in example 1, see the reaction of step 1) in example 1.
2) Preparation of 6-fluoro-7-deoxy-10-N, N-dimethylcarbamoylbaccatin III
The 6-fluoro-7-deoxy-10-N, N-dimethylcarbamoylbaccatin III was prepared in substantially the same manner as shown in step 2) of practical example 1, except that the reaction in step 2) of practical example 1 was carried out except for the difference in step b.
b.preparation of 10-N, N-dimethylcarbamoyl-7-triethylsilylbaccatin III
Dissolving a compound 12 (658mg, 1.0mmol) in 10mL of tetrahydrofuran solution, dropwise adding 1M LHMDS (1.5mL, 1.5mmol) into the reaction solution at 0 ℃, after reacting for 0.5 hour, dropwise adding N, N-dimethylcarbamoyl chloride (1.5 mmol) into the reaction solution, monitoring the reaction by TLC, after the reaction is finished, adding 20mL of water into the reaction solution, extracting by ethyl acetate for multiple times, combining organic phases, washing by saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating, and separating and purifying by a column to obtain a product.
3) Preparation of JY-04
The process in step 3) of JY-04 is the same as the reaction process of 3) in specific example 1, see step 3) in specific example 1. The purity of the final product reaches more than 95 percent.
m.p.＝161–162℃； 1 H NMR(400MHz,CDCl 3 )δ1.23(s,3H),1.30(s,3H),1.36(m,1H),1.42(s,9H),1.74(s,3H),1.79(m,1H),1.81(s,6H),1.96(m,1H),2.11(s,3H),2.43(s,3H),2.46(m,1H),2.60(m,1H),3.03(s,3H),3.11(s,3H),3.28(d,J＝3.6Hz,1H),3.43(m,1H),2.88(d,J＝6.9Hz,1H),4.20(m,2H),4.27(d,J＝8.4Hz,1H),4.38(d,J＝8.4Hz,1H),4.53(m,1H),4.81(m,1H),5.05(d,J＝7.8Hz,1H),5.73(d,J＝6.9Hz,1H),5.25(t,1H),6.33(s,1H),7.54(t,J＝7.2Hz,2H),7.68(t,J＝7.2,1H),8.18(d,J＝7.2Hz,2H). 13 C NMR(125MHz,CDCl 3 )δ9.33,10.14,14.28,18.64,21.31,22.40,25.78,26.92,28.30,35.46,35.75,36.01,36.68,43.27,45.68,58.50,59.31,72.46,72.52,73.85,75.28,76.51,79.34,80.02,81.21,84.73,120.76,128.59,129.36,130.22,133.70,133.59,156.21,166.93,130.02,205.76.
From the above, the product has a correct structure and is the target compound.
Example 5, preparation of JY-05
1) Preparation of Compound 11
The preparation of compound 11 is exactly the same as shown in step 1) in example 1, see the reaction of step 1) in example 1.
2) Preparation of 6-fluoro-7-deoxy-10-cyclopropylformyl baccatin III
The 6-fluoro-7-deoxy-10-cyclopropylformylbaccatin III was prepared in substantially the same manner as in step 2) of example 1 except that the reaction was carried out in step 2) of example 1.
b.preparation of 10-Cyclopropylformyl-7-triethylsilylbaccatin III
Dissolving a compound 12 (658mg, 1.0mmol) in 10mL of tetrahydrofuran solution, dropwise adding 1M LHMDS (1.5mL, 1.5mmol) into reaction liquid at 0 ℃, reacting for 0.5 hour, dropwise adding cyclopropyl formyl chloride (1.5 mmol) into the reaction liquid, monitoring the reaction by TLC, after the reaction is finished, adding 20mL of water into the reaction liquid, extracting by ethyl acetate for multiple times, combining organic phases, washing by saturated saline water, drying by anhydrous magnesium sulfate, filtering, concentrating, and performing column separation and purification to obtain the product.
3) Preparation of JY-05
The process in step 3) of JY-05 is the same as the reaction process of 3) in specific example 1, see step 3) in specific example 1). The purity of the final product reaches more than 95 percent.
mp 155-156℃； 1 H NMR(300MHz,CDCl 3 )δ1.08(m,2H),1.20(m,1H),1.23(s,3H),1.33(s,3H),1.42(s,9H),1.74(s,3H),1.79(s,1H),1.83(s,6H),1.90(m,1H),1.97(s,3H),2.11(s,1H),2.42(s,3H),2.45(m,1H),2.60(m,1H),2.65(m,1H),3.45(d,J＝6.6Hz,1H),3.88(d,J＝6.9Hz,1H),4.24(m,2H),4.38(d,8.4Hz,1H)4.48(m,1H),4.83(m,2H),5.03(d,7.8H),5.38(m,1H),5.74(d,7.2Hz,1H),6.24(t,1H),6.37(s,1H),7.54(t,7.2,2H),7.68(t,7.5Hz,1H),8.17(d,7.2Hz,2H). 13 C NMR(125MHz,CDCl 3 )δ9.19,9.43,9.51,13.04,14.98,18.56,21.35,21.45,22.35,25.71,26.69,28.2 2,35.54,43.19,45.66,51.56,58.56,72.24,72.41,73.73,74.95,75.44,79.17,79.95,81.11,84.44,120.67,127.31,128.57,129.14,139.81,132.94,134.45,137.56,138.34,142.64,155.41,167.07,170.01,173.14,175.14,203.56.。
From the above, the product has a correct structure and is the target compound.
Example 6, JY-06 preparation
1) Preparation of Compound 11
The preparation of compound 11 is exactly the same as shown in step 1) in example 1, see the reaction of step 1) in example 1.
2) Preparation of 6-fluoro-7-deoxy-10-methylcarbutin III
The preparation method of 6-fluoro-7-deoxy-10-methylcarbutin III is substantially the same as that shown in step 2) of the specific example 1, except that the b step is different, and the rest steps are referred to the reaction of step 2) of the specific example 1.
b.preparation of 10-methyl-7-triethylsilylbaccatin III
Dissolving a compound 12 (658mg, 1.0mmol) in 10mL of tetrahydrofuran solution, dropwise adding 1M LHMDS (1.5mL, 1.5mmol) into reaction liquid at the temperature of minus 40 ℃, after reacting for 0.5 hour, dropwise adding methyl trifluoromethanesulfonate (2 mmol) into the reaction liquid, monitoring the reaction by TLC, after the reaction is finished, adding 20mL of water into the reaction liquid, extracting by ethyl acetate for multiple times, combining organic phases, washing by saturated saline solution, drying by anhydrous magnesium sulfate, filtering, concentrating, and purifying by column separation to obtain the product.
3) Preparation of JY-06
The process in step 3) of JY-06 is the same as the reaction process of 3) in specific example 1, see step 3) in specific example 1). The purity of the final product reaches more than 95 percent.
m.p.＝172-174℃； 1 H NMR(400MHz,CDCl 3 )δ1.02(m,2H),1.61(m,2H),1.18(s,3H),1.28(s,3H),1.38s,9H),1.67(s,3H),1.77(s,3H),1.81(s,3H),1.85(m,1H),1.89(m,1H),1.92(s,3H),2.37(s,3H),2.42(m,1H),2.45(s,3H),2.52-2.61(m,2H),3.82(d,J＝6.8Hz,1H),3.90(s,br,1H),4.22(d,J＝8.4Hz,1H),4.24(m,1H),4.33(d,J＝8.4Hz,1H),4.75-4.83(m,2H),4.78(m,1H),4.99(d,J＝8.0Hz,1H),5.34(d,J＝8.0Hz,1H),5.66(d,J＝6.8Hz,1H),6.19(t,J＝8.4Hz,1H),6.32(s,1H),7.37(t,J＝7.6Hz,1H),7.43(d,J＝7.6Hz,1H),7.92(d,J＝7.6Hz,1H),7.95(s,1H)； 13 C NMR(125MHz,CDCl 3 )δ9.19,9.43,9.51,13.04,14.98,18.56,21.35,21.45,22.35,25.71,26.69,28.2 2,35.54,43.19,45.66,51.56,58.56,72.24,72.41,73.73,74.95,75.44,79.17,79.95,81.11,84.44,120.67,127.31,128.57,129.14,139.81,132.94,134.45,137.56,138.34,142.64,155.41,167.07,170.01,173.14,175.14,203.93.
From the above, the product was found to be the target compound with a correct structure.
Example 7 application of Fluorotaxane Compounds to resistance to multidrug resistance
Pharmacological experiment of the fluorine-containing taxane compound
1) Cytotoxicity test on human tumor cell lines
Paclitaxel is taken as a positive control drug, the cytotoxicity of the fluorine-containing taxane compound on 3 tumor cell lines (including sensitive human breast cancer cell lines MCF-7, multidrug-resistant human breast cancer cell lines MCF-7/Adr and multidrug-resistant human ovarian cancer cell lines NCI/Adr) is inspected by adopting an MTT method, and the experimental results are shown in table 1.
TABLE 1 in vitro cytotoxicity test (IC) of fluorine-containing taxane compounds 50 nM)
a Resistance factor＝(IC 50 for drug resistant cell line,R)/(IC 50 for drug-sensitive cell line,S).
Preliminary activity evaluation shows that the fluorine-containing taxane derivative not only has better activity than paclitaxel for sensitive tumor cell strains, but also has better activity than positive control paclitaxel for multidrug resistant tumor cell strains, and the drug resistance factor (R/S value) is 4.5-45 times better than paclitaxel. The experimental result shows that the fluorine-containing taxane derivative has good activity of inhibiting sensitive and multidrug-resistant tumor cell strains.
2) Cytotoxicity test for tumor cell line over-expressed by tumor stem cells
The method uses paclitaxel as positive control drug, and adopts MTT method to examine the dry tumor of fluorine-containing taxane compoundHuman rectal cancer cell line HCT-116 with over-expression of cells (cancer stem cells, CSCs) ++ The results of the experiments are shown in Table 2.
TABLE 2 fluorine-containing taxane compounds aiming at CSC over-expressed human rectal cancer cell line HCT-116 ++ Inhibition of proliferation (IC) 50 nM)
The experimental result shows that the fluorine-containing taxane compound aims at the human rectal cancer cell line HCT-116 over-expressed by the tumor stem cells ++ The cytotoxicity of the compound is 40-120 times better than that of positive control drug taxol, and the compound has good function of inhibiting the activity of over-expression cell strains of tumor stem cells.
Claims (3)
1. A compound represented by formula JY-03 or JY-06 or a pharmaceutically acceptable salt thereof;
JY-03
JY-06
2. use of a compound represented by formula JY-03 or JY-06 or a pharmaceutically acceptable salt thereof according to claim 1 in the preparation of a multi-drug resistance product and/or a product for inhibiting the activity of a tumor stem cell over-expression cell line.
3. Use according to claim 2, characterized in that: the multi-drug resistance resisting and tumor stem cell overexpression inhibiting cell strain aims at least one of breast cancer, ovarian cancer, rectal cancer, non-small cell lung cancer and melanoma.
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