CN108794532A - 脑磷脂类似物、制备方法及用途 - Google Patents
脑磷脂类似物、制备方法及用途 Download PDFInfo
- Publication number
- CN108794532A CN108794532A CN201810479191.2A CN201810479191A CN108794532A CN 108794532 A CN108794532 A CN 108794532A CN 201810479191 A CN201810479191 A CN 201810479191A CN 108794532 A CN108794532 A CN 108794532A
- Authority
- CN
- China
- Prior art keywords
- cephalin
- analog
- ococh
- carries out
- chloride
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical class CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 239000002246 antineoplastic agent Substances 0.000 claims abstract description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims abstract description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 claims description 22
- 150000001875 compounds Chemical class 0.000 claims description 10
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 9
- 230000003285 pharmacodynamic effect Effects 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 150000008065 acid anhydrides Chemical class 0.000 claims description 6
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 230000032050 esterification Effects 0.000 claims description 6
- 238000005886 esterification reaction Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 125000002347 octyl 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])[H] 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims description 4
- VUQPJRPDRDVQMN-UHFFFAOYSA-N 1-chlorooctadecane Chemical compound CCCCCCCCCCCCCCCCCCCl VUQPJRPDRDVQMN-UHFFFAOYSA-N 0.000 claims description 4
- CTKINSOISVBQLD-UHFFFAOYSA-N Glycidol Chemical compound OCC1CO1 CTKINSOISVBQLD-UHFFFAOYSA-N 0.000 claims description 4
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims description 4
- MLQBTMWHIOYKKC-KTKRTIGZSA-N (z)-octadec-9-enoyl chloride Chemical compound CCCCCCCC\C=C/CCCCCCCC(Cl)=O MLQBTMWHIOYKKC-KTKRTIGZSA-N 0.000 claims description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- 230000010933 acylation Effects 0.000 claims description 3
- 238000005917 acylation reaction Methods 0.000 claims description 3
- 238000006482 condensation reaction Methods 0.000 claims description 3
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 3
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- 239000008194 pharmaceutical composition Substances 0.000 claims 3
- 239000002775 capsule Substances 0.000 claims 1
- 239000003795 chemical substances by application Substances 0.000 claims 1
- 239000003405 delayed action preparation Substances 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 238000002347 injection Methods 0.000 claims 1
- RDRCCJPEJDWSRJ-UHFFFAOYSA-N pyridine;1h-pyrrole Chemical group C=1C=CNC=1.C1=CC=NC=C1 RDRCCJPEJDWSRJ-UHFFFAOYSA-N 0.000 claims 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 6
- 235000011187 glycerol Nutrition 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 210000004556 brain Anatomy 0.000 description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 4
- 239000000969 carrier Substances 0.000 description 4
- 239000001913 cellulose Substances 0.000 description 4
- 229920002678 cellulose Polymers 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000314 lubricant Substances 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- -1 oily beans Chemical compound 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 229940127093 camptothecin Drugs 0.000 description 3
- 238000001338 self-assembly Methods 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- RCEAADKTGXTDOA-UHFFFAOYSA-N OS(O)(=O)=O.CCCCCCCCCCCC[Na] Chemical compound OS(O)(=O)=O.CCCCCCCCCCCC[Na] RCEAADKTGXTDOA-UHFFFAOYSA-N 0.000 description 2
- 235000019483 Peanut oil Nutrition 0.000 description 2
- 244000046052 Phaseolus vulgaris Species 0.000 description 2
- 235000010627 Phaseolus vulgaris Nutrition 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 239000000470 constituent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229940099112 cornstarch Drugs 0.000 description 2
- 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 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000857 drug effect Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000000945 filler Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000013402 health food Nutrition 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000004006 olive oil Substances 0.000 description 2
- 235000008390 olive oil Nutrition 0.000 description 2
- 239000000312 peanut oil Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 229920001592 potato starch Polymers 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 230000002335 preservative effect Effects 0.000 description 2
- 235000013772 propylene glycol Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000008159 sesame oil Substances 0.000 description 2
- 235000011803 sesame oil Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 150000005846 sugar alcohols Polymers 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- JZNWSCPGTDBMEW-UHFFFAOYSA-N Glycerophosphorylethanolamin Natural products NCCOP(O)(=O)OCC(O)CO JZNWSCPGTDBMEW-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 208000007443 Neurasthenia Diseases 0.000 description 1
- 206010067482 No adverse event Diseases 0.000 description 1
- 244000131316 Panax pseudoginseng Species 0.000 description 1
- 235000005035 Panax pseudoginseng ssp. pseudoginseng Nutrition 0.000 description 1
- 235000003140 Panax quinquefolius Nutrition 0.000 description 1
- 208000034189 Sclerosis Diseases 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 206010000210 abortion Diseases 0.000 description 1
- 231100000176 abortion Toxicity 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 206010003549 asthenia Diseases 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 210000001772 blood platelet Anatomy 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 229940031098 ethanolamine Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 150000004665 fatty acids Chemical group 0.000 description 1
- 150000002190 fatty acyls Chemical group 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 235000008434 ginseng Nutrition 0.000 description 1
- 230000023597 hemostasis Effects 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 210000004126 nerve fiber Anatomy 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- CCVKPWUMYBYHCD-UHFFFAOYSA-N oxolane;pyridine Chemical compound C1CCOC1.C1=CC=NC=C1 CCVKPWUMYBYHCD-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000003208 petroleum Substances 0.000 description 1
- 150000008104 phosphatidylethanolamines Chemical class 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- RINCXYDBBGOEEQ-UHFFFAOYSA-N succinic anhydride Chemical class O=C1CCC(=O)O1 RINCXYDBBGOEEQ-UHFFFAOYSA-N 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明提供了式(1)所示的脑磷脂类似物,本发明还提供了该类脑磷脂类似物的制备方法及在制备抗肿瘤药物上的用途。
Description
技术领域
本发明涉及药物化学和治疗学领域,具体涉及脑磷脂类似物、制备方法及其作为抗肿瘤药物的用途。
背景技术
脑磷脂(即磷脂酰乙醇胺)是由甘油二酯、磷酸和乙醇胺缩合而成的一种磷脂。脑磷脂在动物体内广泛分布,尤富集于脑和脊髓中。脑磷脂是神经细胞膜的重要组成部分,参与调节神经细胞的代谢活动,影响着神经组织的一系列重要功能,如细胞渗透性、髓鞘形成、线粒体转移、氧化加磷氧基作用等。口服脑磷脂能直接为人脑利用,令神经细胞膜修复,恢复神经元的正常代谢。脑磷脂与血液凝固有关,凝血激酶是由脑磷脂与蛋白质组成的,存在于血小板内,能促使血液凝固,可应用于局部止血。此外,脑磷脂还对神经衰弱、动脉粥样硬化、肝硬化和脂肪性病变等疾病具有一定的疗效。早在20世纪70年代,美国就将脑磷脂用于保健食品,长期临床应用结果表明脑磷脂除了健脑、美容、防衰老、保护心血管等营养保健作用外无不良反应,深受广大消费者青睐,成为市场上重要的保健食品。
喜树碱(Camptothecin,CPT)是从我国特有植物喜树中提取得到的生物碱,喜树碱具有较强的抗肿瘤活性,对多种实体肿瘤和白血病具有明显的抑制作用,但喜树碱水溶性差、毒性强,因此限制了它在肿瘤治疗上的应用。目前,对喜树碱及其衍生物的研究多集中于化学结构修饰,主要致力于改善其在人体内的吸收状况和增强治疗效果。
喜树碱衍生物的制备方法研究较多,以下给出部分文献作为参考。
美国专利104894,1990-3-1号
PCT专利申请2001009139,2001-2-8号
PCT专利申请9602546,1996-7-12号
J Biol Chem,1985,260,14873-14878
J Med Chem,1991,34(1),98-107
J Med Chem,1998,41(1),31-37
Bioorg Med Chem Lett,2002,12(9),1241-1244
Bioorg Med Chem Lett,2003,13(21),3739-3741
Bioorg Med Chem,2004,12(15),4003-4008
Bioorg Med Chem,2004,12(13),3657-3662
Chem Pharm Bull,1991,39,3183-3188
Cancer Res,1993,53,1577-1582
Cancer Res,1995,55,753-760
N Y Acada Sci,1996,803,231-246
Arch Pharm Res,1998,21,581-590
J Med Chem,1995,38(3),395-401
脑磷脂是一种两性分子,具有与磷酸相连的氨醇构成的亲水头和由脂肪酸链构成的疏水尾组成,可自组装成类似于生物膜的结构,即脂质体。通过化学键合作用使单脂肪酰甘油脑磷脂与喜树碱或喜树碱衍生物分子结合,可以形成喜树碱(喜树碱衍生物)-脑磷脂复合物。该复合物能通过自组装制成相应的脂质体药物传递系统,进而提高了其生物利用度。
发明内容
本发明的一个目的是提供一类与抗癌药物结合的脑磷脂类似物,有利于提高药物的抗癌活性和生物利用度。
本发明的另一个目的是提供该类脑磷脂类似物的制备方法。
本发明的再一个目的是提供该类脑磷脂类似物作为抗肿瘤药物的应用。
为了实现上述目的,本发明提供的是具有式(1)所示的脑磷脂类似物。
R1选自:-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH(CH2)7CH3、-OCOCH2(CH2)13CH3;R2选自:-H或-OCH3;R3选自:-H或-NO2、;n=2或3。
本发明提供制备具有(1)所示的脑磷脂类似物的方法,包括如下步骤:
(1)在干燥的有机溶剂中,喜树碱或其衍生物与相应的酸酐进行酯化反应,得到具有式(2)结构的中间体a;
其中,R2选自:-H或-OCH3;R3选自:-H或-NO2、;n=2或3;
(2)中间体a与缩水甘油进行酯化反应后,再与相应的脂肪酰氯进行氧酰化反应得到具有式(3)结构的中间体b;
其中,R1选自:-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH(CH2)7CH3、-OCOCH2(CH2)13CH3;R2选自:-H或-OCH3;R3选自:-H或-NO2、;n=2或3;
(3)中间体b与2-邻苯二甲酰亚胺乙基-二氯磷酰进行缩合反应后,用水合肼脱保护得到权利要求1所述的脑磷脂类似物。
其中,制备脑磷脂类似物的方法中所述的有机溶剂是吡啶、四氢呋喃、二氯甲烷;所述的酸酐是丁二酸酐或戊二酸酐;所述的脂肪酰氯是硬脂酰氯、油酰氯、棕榈酰氯。
本发明还涉及含有作为活性成分的本发明化合物及药效学上可接受载体的各种制剂。
“药效学上可接受载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,他们适合于人使用,而且有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺合,而不明显降低化合物的药效。药效学上可接受的载体部分例子有糖(如葡萄糖、蔗糖、乳糖等),淀粉(如玉米淀粉、马铃薯淀粉等),纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等),明胶,滑石,固体润滑剂(如硬脂酸、硬脂酸镁),硫酸钙,植物油(如油豆、芝麻油、花生油、橄榄油等),多元醇(如丙二醇、甘油、甘露醇、山梨醇等),乳化剂(如吐温)、润滑剂(如十二烷基硫酸钠),着色剂,调味剂,稳定剂,抗氧化剂,防腐剂,无热原水等。
本发明还涉及本发明所述的化合物在制备抗肿瘤药物中的应用。
体外活性筛选实验表明所述的脑磷脂类似物具有明显的抗肿瘤作用及良好的剂量依赖关系。以人卵巢癌细胞系HXB1309H为受试细胞株,测定了脑磷脂类似物的半数抑制浓度(IC50),其中部分样品的实验结果见表1:
表1:脑磷脂类似物对XB1309的半数抑制浓度
具体实施方式
下面结合实施例对本发明作进一步详细描阐述:
具有式(1)所示的脑磷脂类似物。
R1选自:-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH(CH2)7CH3、-OCOCH2(CH2)13CH3;R2选自:-H或-OCH3;R3选自:-H或-NO2、;n=2或3。
本发明提供制备具有(1)所示的脑磷脂类似物的方法,包括如下步骤:
(1)在干燥的有机溶剂中,喜树碱或其衍生物与相应的酸酐进行酯化反应,得到具有式(2)结构的中间体a;
其中,R2选自:-H或-OCH3;R3选自:-H或-NO2、;n=2或3;
(2)中间体a与缩水甘油进行酯化反应后,再与相应的脂肪酰氯进行氧酰化反应得到具有式(3)结构的中间体b;
其中,R1选自:-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH(CH2)7CH3、-OCOCH2(CH2)13CH3;R2选自:-H或-OCH3;R3选自:-H或-NO2、;n=2或3;
(3)中间体b与2-邻苯二甲酰亚胺乙基-二氯磷酰进行缩合反应后,用水合肼脱保护得到权利要求1所述的脑磷脂类似物。
其中,制备脑磷脂类似物的方法中所述的有机溶剂是吡啶、四氢呋喃、二氯甲烷;所述的酸酐是丁二酸酐或戊二酸酐;所述的脂肪酰氯是硬脂酰氯、油酰氯、棕榈酰氯。
本发明还涉及含有作为活性成分的本发明化合物及药效学上可接受载体的各种制剂。
“药效学上可接受载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,他们适合于人使用,而且有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺合,而不明显降低化合物的药效。药效学上可接受的载体部分例子有糖(如葡萄糖、蔗糖、乳糖等),淀粉(如玉米淀粉、马铃薯淀粉等),纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等),明胶,滑石,固体润滑剂(如硬脂酸、硬脂酸镁),硫酸钙,植物油(如油豆、芝麻油、花生油、橄榄油等),多元醇(如丙二醇、甘油、甘露醇、山梨醇等),乳化剂(如吐温)、润滑剂(如十二烷基硫酸钠),着色剂,调味剂,稳定剂,抗氧化剂,防腐剂,无热原水等。
本发明还涉及本发明所述的化合物制备抗肿瘤药物中的应用。
本发明的脑磷脂类似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制备喜树碱-20-O-丁二酰单酯(中间体a)
将1.0克(0.01摩尔)丁二酸酐溶于100毫升吡啶中,加入3.5克(0.01摩尔)喜树碱,回流反应24小时,冷却至室温后,将反应液倒入500毫升石油醚中,过滤、收集沉淀,将沉淀用硅胶柱层析(二氯甲烷:甲醇=100:1),得浅黄色喜树碱-20-O-丁二酰单酯3.9克,收率87%。
1HNMR(300MHz,DMSO-d6,ppm):δ0.90(3H,t,H-19),1.96(2H,m,H-18),2.52-2.75(4H,m,-OOCCH2 CH2 COO-),5.20(2H,s,H-5),5.50(2H,s,H-17),6.89(1H,d,N-H),7.14(H,s,H-14),7.72(1H,q,H-10),7.87(H,t,H-11),8.00(1H,d,H-12),8.14(1H,d,H-9),8.42(1H,t,N-H),8.65(1H,s,H-7)。
ESIMS m/z:539.3(M-1)-
实施例2制备1-O-硬脂酰-3-O-(喜树碱-20-O-丁二酰)甘油(中间体b)
将4.5克(0.01摩尔)喜树碱-20-O-丁二酰单酯溶于500毫升二氯甲烷中,冷却至0℃,搅拌下缓慢滴加0.74克(0.01摩尔)缩水甘油,在0℃下,搅拌24小时后,依次加入3.1克(0.01摩尔)硬脂酰氯、2.0克碳酸钠,升温至室温,搅拌24小时,过滤,减压浓缩滤液,将浓缩液用硅胶柱层析(二氯甲烷:甲醇=25:1),得黄色1-O-硬脂酰-3-O-(喜树碱-20-O-丁二酰)甘油1.5克,收率18%。
1HNMR(300MHz,DMSO-d6,ppm):1.96(2H,m,H-18),2.29(2H,m,-OOC CH2 -),2.52-2.75(4H,m,-OOCCH2 CH2 COO-),4.19-4.26(4H,dd,-OCH2 -CHOH-CH2 O-),4.56(1H,m,-OCH2-CHOH-CH2O-),5.20(2H,s,H-5),5.50(2H,s,H-17),6.89(1H,d,N-H),7.14(H,s,H-14),7.72(1H,q,H-10),7.87(H,t,H-11),8.00(1H,d,H-12),8.14(1H,d,H-9),8.42(1H,t,N-H),8.65(1H,s,H-7)。
实例3制备1-O-硬脂酰-3-O-(喜树碱-20-O-丁二酰)-2-O-甘油磷酰乙醇胺(脑磷脂类似物)
将0.8克(0.001摩尔)1-O-硬脂酰-3-O-(喜树碱-20-O-丁二酰)甘油溶于50毫升体积比为4:1的四氢呋喃-吡啶混合液中,冷却至0℃,搅拌下加入0.3克(0.001摩尔)2-邻苯二甲酰亚胺乙基-二氯磷酰在0℃下,搅拌10小时后,依次加入40毫升体积比为1:3的四氢呋喃-无水乙醇混合液、0.2克水合肼(12g),加热至50℃,搅拌反应2小时,应完毕后滴加2N盐酸调节pH值为5,冷却至室温,冷冻离心,弃去上清液,将离心剩余物水洗3次后,冷冻干燥得1.1克橙黄色固体,将其用硅胶柱层析(二氯甲烷:甲醇:水=65:25:2),得黄色1-O-硬脂酰-3-O-(喜树碱-20-O-丁二酰)-2-O-甘油磷酰乙醇胺(即脑磷脂类似物)0.3克,收率32%。
1HNMR(300MHz,DMSO-d6,ppm):1.96(2H,m,H-18),2.29(2H,m,-OOC CH2 -),2.52-2.75(4H,m,-OOCCH2 CH2 COO-),2.90(2H,m,NH2CH2 CH2O-),3.82(2H,m,NH2CH2CH2 O-),4.19-4.26(4H,dd,-OCH2 -CHOH-CH2 O-),4.56(1H,m,-OCH2-CHOH-CH2O-),5.20(2H,s,H-5),5.50(2H,s,H-17),6.89(1H,d,N-H),7.14(H,s,H-14),7.72(1H,q,H-10),7.87(H,t,H-11),8.00(1H,d,H-12),8.14(1H,d,H-9),8.42(1H,t,N-H),8.65(1H,s,H-7)。
实例4制备脑磷脂类似物自组装脂质体
将0.05克1-O-硬脂酰-3-O-(喜树碱-20-O-丁二酰)-2-O-甘油磷酰乙醇胺溶于20毫升二氯甲烷中,并加入50毫升蒸馏水,超声20分钟后,室温下搅拌,挥发除去二氯甲烷后,剩余物经冷冻干燥制得纳米级别微粒(粒径≤200nm),即为含脑磷脂类似物自组装脂质体。
Claims (6)
1.式(1)所示的脑磷脂类似物
其中,选自:-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH(CH2)7CH3、-OCOCH2(CH2)13CH3;选自:-H或-OCH3;选自:-H或-NO2、;n=2或3。
2.制备权利要求1所述的脑磷脂类似物的方法,包括如下步骤:
(1)在干燥的有机溶剂中,喜树碱或其衍生物与相应的酸酐进行酯化反应,得到具有式(2)结构的中间体a;
其中,选自:-H或-OCH3;选自:-H或-NO2、;n=2或3;
(2)中间体a与缩水甘油进行酯化反应后,再与相应的脂肪酰氯进行氧酰化反应得到具有式(3)结构的中间体b;
其中,选自:-OCOCH2(CH2)15CH3、-OCOCH2(CH2)6CH=CH(CH2)7CH3、-OCOCH2(CH2)13CH3;选自:-H或-OCH3;选自:-H或-NO2、;n=2或3;
(3)中间体b与2-邻苯二甲酰亚胺乙基-二氯磷酰进行缩合反应后,用水合肼脱保护得到权利要求1所述的脑磷脂类似物。
3.按照权利要求2所述的制备脑磷脂类似物的方法,其特征在于:所述的有机溶剂是吡啶、四氢呋喃、二氯甲烷;所述的酸酐是丁二酸酐或戊二酸酐;所述的脂肪酰氯是硬脂酰氯、油酰氯、棕榈酰氯。
4.一种药物组合物,含有权利要求1所述的任一化合物,以及药效学上可接受的载体。
5.根据权利要求4的药物组合物,其特征在于所述的药物组合物可以是片剂、胶囊、丸剂、注射剂、缓释制剂。
6.权利要求1所述的脑磷脂类似物在制备抗肿瘤药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810479191.2A CN108794532A (zh) | 2018-05-18 | 2018-05-18 | 脑磷脂类似物、制备方法及用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201810479191.2A CN108794532A (zh) | 2018-05-18 | 2018-05-18 | 脑磷脂类似物、制备方法及用途 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN108794532A true CN108794532A (zh) | 2018-11-13 |
Family
ID=64092686
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201810479191.2A Pending CN108794532A (zh) | 2018-05-18 | 2018-05-18 | 脑磷脂类似物、制备方法及用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN108794532A (zh) |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104306332A (zh) * | 2014-09-24 | 2015-01-28 | 东南大学 | 一种喜树碱类磷脂化合物、其药物组合物及应用 |
CN105873569A (zh) * | 2013-11-06 | 2016-08-17 | 芝加哥大学 | 用于化疗剂、核酸和光敏剂的递送或共递送的纳米级载体 |
WO2017201528A1 (en) * | 2016-05-20 | 2017-11-23 | The University Of Chicago | Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof |
-
2018
- 2018-05-18 CN CN201810479191.2A patent/CN108794532A/zh active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105873569A (zh) * | 2013-11-06 | 2016-08-17 | 芝加哥大学 | 用于化疗剂、核酸和光敏剂的递送或共递送的纳米级载体 |
CN104306332A (zh) * | 2014-09-24 | 2015-01-28 | 东南大学 | 一种喜树碱类磷脂化合物、其药物组合物及应用 |
WO2017201528A1 (en) * | 2016-05-20 | 2017-11-23 | The University Of Chicago | Nanoparticles for chemotherapy, targeted therapy, photodynamic therapy, immunotherapy, and any combination thereof |
Non-Patent Citations (1)
Title |
---|
刘祥 等: "透明质酸-喜树碱复合体的合成及表征", 《信阳师范学院学报:自然科学版》 * |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN104497084B (zh) | 用于治疗用途的7-脱氮嘌呤核苷 | |
CN106916177B (zh) | 一种氘代的二肽硼酸或其酯类化合物及其合成方法与用途 | |
CN103880910B (zh) | 一种环黄芪醇的制备方法及其用途 | |
CN105732381B (zh) | 牛樟芝提取物及其制备方法和应用 | |
CN108341829B (zh) | 一种具有心脑血管疾病防治活性的青蒿素酯类化合物、其制备方法及其应用 | |
CN101511843A (zh) | 制备盐酸1(10)β-环氧-13-二甲基氨基-5,7α,6,11β(H)-愈创木-3(4)-烯-6,12-内酯,一种冻干的抗肿瘤制品“阿格拉滨”的方法 | |
CN101259124A (zh) | 蟛蜞菊内酯及其衍生物的药物用途 | |
CN1308000C (zh) | 用于治疗实体瘤的含有白头翁根浸膏作为活性成分的药物 | |
CN104666247A (zh) | 肝素修饰的可断键阿霉素脂质体制剂及其制备方法 | |
CN104327097B (zh) | 雷帕霉素的三氮唑衍生物和用途 | |
WO2017092230A1 (zh) | 双黄酮化合物及其治疗癌症和制备药物的用途 | |
CN111662250A (zh) | 季铵化修饰紫杉烷衍生物、其药物组合物、其合成途径和用途 | |
CN109675053A (zh) | 鬼臼毒素及其衍生物的靶向制剂及其制备方法 | |
CN104415029A (zh) | 一种穿心莲内酯聚合物胶束及其制备方法与医药用途 | |
CN104557909B (zh) | 3-酰氧基取代右旋去氧娃儿藤宁衍生物、其制法和药物组合物与用途 | |
CN102898433A (zh) | 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 | |
CN102344475A (zh) | 一种灯盏花乙素衍生物及其制备方法和应用 | |
CN108794532A (zh) | 脑磷脂类似物、制备方法及用途 | |
CN108774264A (zh) | 卵磷脂类似物、制备方法及用途 | |
CN108434457B (zh) | 一种阿霉素聚乙二醇埃博霉素b偶联物及其制备方法 | |
CN101402667A (zh) | 糖基化修饰的一氧化氮供体型齐墩果酸类化合物、其制备方法及用途 | |
CN108017656A (zh) | 喜树碱衍生物及其在制备抗肿瘤药物中的应用 | |
CN102115483B (zh) | 卤代双去氧糖衍生物及其制备方法与应用 | |
CN105503988A (zh) | 天然抗癫痫活性化合物及其在药物制剂中的用途 | |
CN115025088A (zh) | 十氢萘吡啶酮生物碱及其药物组合物的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
WD01 | Invention patent application deemed withdrawn after publication | ||
WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181113 |