CN101033230B - 一类喜树碱衍生物及其应用 - Google Patents
一类喜树碱衍生物及其应用 Download PDFInfo
- Publication number
- CN101033230B CN101033230B CN2006100245907A CN200610024590A CN101033230B CN 101033230 B CN101033230 B CN 101033230B CN 2006100245907 A CN2006100245907 A CN 2006100245907A CN 200610024590 A CN200610024590 A CN 200610024590A CN 101033230 B CN101033230 B CN 101033230B
- Authority
- CN
- China
- Prior art keywords
- compound
- cpt
- oxygen base
- carbonyl oxygen
- camptothecine
- 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.)
- Active
Links
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 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 claims abstract description 14
- 229940127093 camptothecin Drugs 0.000 claims description 14
- 206010028980 Neoplasm Diseases 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 150000003839 salts Chemical class 0.000 claims description 11
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 230000000118 anti-neoplastic effect Effects 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims 1
- 239000007924 injection Substances 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 18
- 230000000259 anti-tumor effect Effects 0.000 abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 7
- 238000009509 drug development Methods 0.000 abstract description 3
- 239000000890 drug combination Substances 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 15
- 239000002585 base Substances 0.000 description 13
- -1 isobutyl- Chemical group 0.000 description 13
- 239000002207 metabolite Substances 0.000 description 10
- 238000011580 nude mouse model Methods 0.000 description 7
- DGHHQBMTXTWTJV-BQAIUKQQSA-N 119413-54-6 Chemical compound Cl.C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 DGHHQBMTXTWTJV-BQAIUKQQSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 229960000303 topotecan Drugs 0.000 description 6
- GURKHSYORGJETM-WAQYZQTGSA-N irinotecan hydrochloride (anhydrous) Chemical compound Cl.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 GURKHSYORGJETM-WAQYZQTGSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 238000002560 therapeutic procedure Methods 0.000 description 5
- 210000004881 tumor cell Anatomy 0.000 description 5
- 206010009944 Colon cancer Diseases 0.000 description 4
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 241000699660 Mus musculus Species 0.000 description 4
- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- QFDISQIDKZUABE-UHFFFAOYSA-N 1,1'-bipiperidine Chemical compound C1CCCCN1N1CCCCC1 QFDISQIDKZUABE-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- YGYAWVDWMABLBF-UHFFFAOYSA-N Phosgene Chemical compound ClC(Cl)=O YGYAWVDWMABLBF-UHFFFAOYSA-N 0.000 description 3
- LOUPRKONTZGTKE-WZBLMQSHSA-N Quinine Chemical compound C([C@H]([C@H](C1)C=C)C2)C[N@@]1[C@@H]2[C@H](O)C1=CC=NC2=CC=C(OC)C=C21 LOUPRKONTZGTKE-WZBLMQSHSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 229960004768 irinotecan Drugs 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- 229930002341 quinoline alkaloid Natural products 0.000 description 3
- 238000010898 silica gel chromatography Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000010025 steaming Methods 0.000 description 3
- HAWSQZCWOQZXHI-FQEVSTJZSA-N 10-Hydroxycamptothecin Chemical compound C1=C(O)C=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 HAWSQZCWOQZXHI-FQEVSTJZSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 208000005718 Stomach Neoplasms Diseases 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 230000004663 cell proliferation Effects 0.000 description 2
- 210000004671 cell-free system Anatomy 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 101150043789 cpt2 gene Proteins 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000011707 mineral Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000000452 restraining effect Effects 0.000 description 2
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 2
- 229950009213 rubitecan Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 201000000498 stomach carcinoma Diseases 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 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 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 239000004278 EU approved seasoning Substances 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 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 1
- 244000068988 Glycine max Species 0.000 description 1
- 235000010469 Glycine max Nutrition 0.000 description 1
- 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
- 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 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 240000002853 Nelumbo nucifera Species 0.000 description 1
- 235000006508 Nelumbo nucifera Nutrition 0.000 description 1
- 235000006510 Nelumbo pentapetala Nutrition 0.000 description 1
- 240000007817 Olea europaea Species 0.000 description 1
- 206010033128 Ovarian cancer Diseases 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- 208000015634 Rectal Neoplasms Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- 239000004902 Softening Agent Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003368 amide group Chemical group 0.000 description 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 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 1
- 230000037396 body weight Effects 0.000 description 1
- 201000008275 breast carcinoma Diseases 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001805 chlorine compounds Chemical class 0.000 description 1
- 201000010989 colorectal carcinoma Diseases 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 235000011194 food seasoning agent Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 150000002596 lactones Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical group 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 229920001495 poly(sodium acrylate) polymer Polymers 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 description 1
- 206010038038 rectal cancer Diseases 0.000 description 1
- 201000001275 rectum cancer Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229940043267 rhodamine b Drugs 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- NNMHYFLPFNGQFZ-UHFFFAOYSA-M sodium polyacrylate Chemical compound [Na+].[O-]C(=O)C=C NNMHYFLPFNGQFZ-UHFFFAOYSA-M 0.000 description 1
- 238000007447 staining method Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/22—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains four or more hetero rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
本发明提供一类具有以下结构式所示结构的新的具有抗肿瘤活性的能溶于水的喜树碱衍生物及其应用、以及包括该化合物的药物组合物。本发明的化合物具有良好的抗肿瘤活性、以及水溶性，该化合物在药物开发中具有极好的前景。
Description
技术领域
本发明涉及药物化学领域，更具体地，涉及一类新的具有抗肿瘤活性的能溶于水的喜树碱衍生物及其应用、以及包括该化合物的药物组合物。
背景技术
喜树碱(camptothecin，以下简称CPT，J.Am.Chem.Soc.，1966，88，3888)由Wall等首次从喜树中提取分离得到，是一种吡咯[3，4-b]喹啉类生物碱，其结构式为 
其结构中含有五个环，E环的20位有一个S型手性中心，旁边有一个内酯结构。喜树碱对胃癌、直肠癌等有一定疗效，但其水溶性很差，毒副反应大，因而中止了临床研究。
人们为得到活性高、毒性小的CPT衍生物，进行了大量的结构改造，合成了众多的CPT类化合物，取得了很好的效果。研究发现在10-羟基喜树碱的9位上引入适当基团可以增加抗肿瘤活性，如目前已上市的拓扑替康。
CPT类化合物虽是一种生物碱，但该类化合物并不像常见的无机碱、有机碱成盐后具有水溶性。为解决水溶性问题，通常的方案有两种，一是在CPT类化合物中引入可以成盐而具有水溶性的基团，如一些氨基，拓扑替康就是这种情况；另外一种方法是向CPT类化合物中引入含有水溶性的临时性基团，这类化合物的水溶性基团在体内将离 解掉。水溶性的CPT类药物依立替康(化合物4，Irinotecan，CPT-11)就是第二种情况。
本发明的发明人在抗肿瘤药物筛选过程中惊奇地发现向10-羟基喜树碱的9位上引入简单的烷基得到的化合物(如以下结构式II所示，其中R1为H、C1～C4烷基、带有支链的C1～C4烷基、或被羟基和/或氨基取代的C1～C4烷基)具有很好的抗肿瘤活性，其中一些化合物对荷瘤裸小鼠的实体瘤具有很好的治疗效果，而且具有较高的治疗指数，显示出这类化合物在药物开发中的前景。
然而，具有结构式II所示结构的化合物也具有如上所述的水溶性较差的问题。
发明内容
因此，本发明的目的为基于以上通式II化合物进而提供一类具有高抗肿瘤活性、且溶于水的新的喜树碱衍生物。
本发明的另一目的为提供包括上述喜树碱衍生物的药物组合物。
本发明的再一目的为提供上述喜树碱衍生物在制备用于治疗肿瘤的药物中的应用。
本发明的再一目的为提供上述药物组合物在制备用于治疗肿瘤的药物中的应用。
本发明提供了一类具有以下结构式I所示结构的化合物、其异构体、对应体、或可药用的盐，
其中，R1为H、C1～C4烷基、乙烯基、羟基、氨基、带有支链的C1～C4烷基、或被羟基和/或氨基取代的C1～C4烷基。具体地，R1可以为氢原子；甲基、乙基、丙基、烯丙基、丁基、以及它们的可能异构体，例如异丙基、异丁基；以及羟甲基、羟乙基、羟丙基、氨甲基、氨乙基、氨丙基等。
所述可药用的盐的例子为在10位羟基上引入的哌啶基团上具有碱性的胺基与药用无机酸或有机酸形成的盐，这些盐可以使药物成水溶性。例如盐酸、硫酸、磷酸、乙酸、三氟乙酸、三氟甲磺酸形成的盐。
本发明的化合物优选为：
10-((4’-哌啶基哌啶)羰氧基)-9-甲基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-乙基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-丙基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-烯丙基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-异丙基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-正丁基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-异丁基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-羟甲基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-羟乙基喜树碱；或
10-((4’-哌啶基哌啶)羰氧基)-9-氨甲基喜树碱。
可以按与现有技术中报道的合成依立替康相同的方法合成本发明的化合物，这些方法在很多文献中都有报道(如Chem.Pharm.Bull，1991，39，2574)。
具体的合成方法可按以下两种路线进行，在方案1中，结构式为 
的吡咯[3，4-b]喹啉类生物碱首先和光气，或固体光气反应，得到酰氯化合物6，然后和哌啶基哌啶(化合物7)反应得到产物。
在方案2中，哌啶基哌啶首先与光气或固体光气反应，得到氯甲酸酰胺化合物8，然后和方案1中所述的吡咯[3，4-b]喹啉类生物碱反应，得到产物。
上述两种路线均采用常规的有机合成反应，参照有关的合成文献，一般的专业人士均可以进行操作，在此没有必要在进行详细的描述。
本发明的化合物的药用盐可按常规方法获得，在此不进行详细描述。本发明的化合物的化学特性，使其可以配成水溶性盐。
本发明还提供了包括治疗有效剂量的上述化合物和常规的药用辅料的药物组合物。“有效剂量”为化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效剂量根据治疗对象的年龄、体重、治疗适应症、给药途径、疗程及任何相关的治疗等具体情况来确定。所述药用辅料包括药学上可接受的载体，“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填充剂或赋形剂，它们适合于人使用，而且必须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和，而不明显降低化合物的药效。药学上可以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、微晶纤维素等)、丙烯酸树脂、聚丙烯酸钠、聚维酮、聚乙二醇、聚氧乙烯单硬脂酸酯、明胶、硅胶、滑石粉、硬脂酸、硬脂酸镁、硫酸钙，植物油(如豆油、芝麻油、花生油、橄榄油等)。还可以是乳化剂(如吐温 
)、润湿剂(如十二烷基硫酸钠)、增塑剂(如癸二酸二丁酯)、着色剂、调味剂、稳定剂、防腐剂、无热原水等。本发明的组合物对载体的选择取决于化合物的给药方式，而且，本领域普通技术人员可以依据现有技术选择适于特定给药方式的载体。
本发明还提供了上述药物组合物的剂型，所述剂型可以为适于口服、静脉、肌肉注射等的剂型，如粉针、片剂、胶囊等。
本发明的化合物具有抗肿瘤活性，因此，本发明的化合物、以及包括该化合物药物组合物可以用于制备用于治疗肿瘤的药物，进一步用于治疗肿瘤，也可以用于肿瘤的介入疗法。
本发明的化合物具有良好的抗肿瘤活性、以及水溶性，该化合物在药物开发中具有极好的前景。
附图说明
图1表示CPT-4活性代谢产物抑制Topo I对pBR322的解旋作用。
图2表示CPT-4活性代谢产物抗多药耐药作用。
图3表示CPT-4对人结肠癌裸小鼠移植瘤HCT-116的实验治疗作用。
图4表示CPT-4对人肺癌裸小鼠移植瘤SPC-A4的实验治疗作用。
具体实施方式
制备实施例
制备实施例1 10-((4’-哌啶基哌啶)羰氧基)-9-烯丙基喜树碱(CPT-4)的制备
哌啶基哌啶氯甲酸酰胺(化合物8)1g(1.25当量)溶于70mL的二氯甲烷中，将10-羟基-9-烯丙基喜树碱(1g，1当量)溶于70mL无水吡啶中，冷却条件下将上述二氯甲烷溶液加入，反应完后，减压蒸去溶剂，剩余物用硅胶柱层析，得1.25g CPT-4黄色固体。1HNMR(DMSO-d6) (ppm)：1.01(3H，t)，1.58～1.90(10H，m)，1.80～1.99(2H，m)，2.89(4H，b)，3.09(1H，b)，3.71(2H，d)，4.45(2H，dd)，4.94(1H，dd)，5.11(1H，dd)，5.14(2H，s)，5.15(1H，d)，5.66(1H，d)，6.00(1H，m)，7.47(1H，d)，7.65(1H，s)，8.11(1H，d)，8.51(1H，s)。
制备实施例2 10-((4’-哌啶基哌啶)羰氧基)-9-乙基喜树碱(CPT-2)的制备
哌啶基哌啶氯甲酸酰胺(化合物8)0.95g(1.25当量)溶于70mL的二氯甲烷中，将10-羟基-9-乙基喜树碱(1g，1当量)溶于70mL无水吡啶中，冷却条件下将上述二氯甲烷溶液加入，反应完后，减压蒸去溶剂，剩余物用硅胶柱层析，得1.24g CPT-2黄色固体。1HNMR(DMSO-d6)(ppm)：1.01(3H，t)，1.20(3H，t)，1.58～1.90(2H，m)，1.80～1.99(2H，m)，2.89(4H，b)，3.09(1H，b)，3.21(2H，q)，4.45(2H，dd)，5.14(2H，s)，5.15(1H，d)，5.66(1H，d)，6.00(1H，m)，7.47(1H，d)，7.65(1H，s)，8.11(1H，d)，8.67(1H，s)。
制备实施例3 10-((4’-哌啶基哌啶)羰氧基)-9-丙基喜树碱(CPT-3)的制备
哌啶基哌啶氯甲酸酰胺(化合物8)1g(1.25当量)溶于70mL的二氯甲烷中，将10-羟基-9-丙基喜树碱(1g，1当量)溶于70mL无水吡啶中，冷却条件下将上述二氯甲烷溶液加入，反应完后，减压蒸去溶剂，剩余物用硅胶柱层析，得1.17g CPT-3黄色固体。1HNMR(DMSO-d6)(ppm)：1.01(3H，t)，1.12(3H，t)，1.59(2H，m)，1.82～1.90(2H，m)，1.80～1.99(2H，m)，2.89(4H，b)，3.09，3.22(2H，t)，(1H，b)，4.45(2H，dd)， 5.14(2H，s)，5.15(1H，d)，5.66(1H，d)，6.00(1H，m)，7.47(1H，d)，7.65(1H，s)，8.11(1H，d)，8.51(1H，s)。
试验实施例
使用上述制备的本发明的化合物CPT-4进行以下药理试验。
试验实施例1无细胞体系对TOPO I的抑制作用
应用TOPO I介导的负超螺旋PBR322解旋实验检测CPT-4活性代谢产物对TOPO I酶活性的影响。在无细胞体系实验中(图1，其中，RLX：解旋DNA；SC：超螺旋DNA)，CPT-4活性代谢产物能抑制Topo I对超螺旋DNA的解旋作用，相同浓度下，CPT-4活性代谢产物的抑制作用强于CPT、TPT(拓扑替康)和SN38(依立替康的原药)。
试验实施例2体外抗肿瘤活性
1、用磺酰罗丹明B蛋白染色法(SRB法)法检测了化合物抑制肿瘤细胞增殖作用。结果表明，CPT-4活性代谢产物能在较低浓度有效的抑制肿瘤细胞的增殖(表1)，它对十三株肿瘤细胞IC50的平均值(115.2nM)低于对照化合物TPT(378.6nM)，SN38(218.5nM)和9-硝基喜树碱(9-NC)(167.0nM)。同时，该化合物对不同组织来源的肿瘤细胞株具有选择性。其中肺癌、结肠癌和乳腺癌细胞株对CPT-4活性代谢产物较敏感，而其对肝癌、胃癌和卵巢癌的作用相对较弱(结果见表1)。
表1CPT-4活性代谢产物抑制肿瘤细胞增殖
2、选用多药耐药细胞株K562/A02和其亲本K562细胞评价了CPT-4活性代谢产物的抗多药耐药作用。阿霉素对K562和K562/A02细胞的IC50分别为0.493和69.141μM，耐药因子(Resistance Factor，RF)为140.24。结果表明，CPT-4活性代谢产物对两株细胞的细胞毒性相当，呈现出明显的抗多药耐药作用，且该作用强于TPT和SN38(结果参见图2，其中，(A)对MDR K562/A02和其亲本K562细胞的IC50；(B)耐药因子)。
试验实施例3体内抗肿瘤活性研究
将人结肠癌HCT-116移植瘤或人肺癌SPC-A4移植瘤接种于裸小鼠腋下，待肿瘤体积至100～200mm3时，随机分笼给药，静脉给以不同 浓度CPT-4或生理盐水，每周三次。结果显示该化合物可以显著抑制移植瘤的生长，且作用强度与CPT-11(水溶性的CPT类药物依立替康)相当，结果见表2，表3。
表2CPT-4对人结肠癌裸小鼠移植瘤HCT-116的实验治疗作用
表3CPT-4对人肺癌裸小鼠移植瘤SPC-A4的实验治疗作用
注：CPT-4 15mg/kg组有一只裸小鼠肿瘤完全消退。
Claims (6)
1.一类具有以下结构式I所示结构的化合物或其可药用的盐，
其中，R1为C1～C4烷基、乙烯基或被羟基和/或氨基取代的C1～C4烷基。
2.如权利要求1所述的化合物或其可药用的盐，其特征在于，所述化合物选自以下化合物之中：
10-((4’-哌啶基哌啶)羰氧基)-9-乙基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-丙基喜树碱；
10-((4’-哌啶基哌啶)羰氧基)-9-烯丙基喜树碱。
3.一种抗肿瘤药物组合物，其特征在于，该组合物包括治疗有效剂量的权利要求1-2中任一项所述的化合物或其可药用的盐和常规的药用辅料。
4.如权利要求3所述的抗肿瘤药物组合物，其特征在于，所述药物组合物被制备为口服或注射剂型。
5.权利要求1-2中任一项所述的化合物或其可药用的盐在制备用于治疗肿瘤疾病的药物中的应用。
6.权利要求3所述的药物组合物在制备用于治疗肿瘤疾病的药物中的应用。
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100245907A CN101033230B (zh) | 2006-03-10 | 2006-03-10 | 一类喜树碱衍生物及其应用 |
| PCT/CN2007/000177 WO2007104214A1 (fr) | 2006-03-10 | 2007-01-17 | Dérivés de la camptothécine et leurs utilisations |
| EP07702109A EP1995249B1 (en) | 2006-03-10 | 2007-01-17 | Camptothecin derivatives and their use |
| BRPI0707089-6A BRPI0707089A2 (pt) | 2006-03-10 | 2007-01-17 | derivados de camptotecina e seus usos |
| US12/282,397 US8685997B2 (en) | 2006-03-10 | 2007-01-17 | Camptothecin derivatives and their use |
| MX2008011262A MX2008011262A (es) | 2006-03-10 | 2007-01-17 | Derivados de la camptotecina y sus usos. |
| KR1020087022692A KR20080096832A (ko) | 2006-03-10 | 2007-01-17 | 캄토테신 유도체 및 그의 용도 |
| RU2008138749/04A RU2411244C2 (ru) | 2006-03-10 | 2007-01-17 | Производные камптотецина и их применение |
| AT07702109T ATE487724T1 (de) | 2006-03-10 | 2007-01-17 | Camptothecinderivate und ihre verwendung |
| DE602007010430T DE602007010430D1 (de) | 2006-03-10 | 2007-01-17 | Camptothecinderivate und ihre verwendung |
| CA2643400A CA2643400C (en) | 2006-03-10 | 2007-01-17 | Camptothecin derivatives and their uses |
| AU2007224896A AU2007224896B2 (en) | 2006-03-10 | 2007-01-17 | Camptothecin derivatives and their use |
| JP2008558616A JP4923067B2 (ja) | 2006-03-10 | 2007-01-17 | カンプトテシン誘導体及びその応用 |
| HK07113787.3A HK1105419A1 (en) | 2006-03-10 | 2007-12-18 | Camptothecin derivatives and their uses |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2006100245907A CN101033230B (zh) | 2006-03-10 | 2006-03-10 | 一类喜树碱衍生物及其应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101033230A CN101033230A (zh) | 2007-09-12 |
| CN101033230B true CN101033230B (zh) | 2010-12-08 |
Family
ID=38509032
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2006100245907A Active CN101033230B (zh) | 2006-03-10 | 2006-03-10 | 一类喜树碱衍生物及其应用 |
Country Status (14)
| Country | Link |
|---|---|
| US (1) | US8685997B2 (zh) |
| EP (1) | EP1995249B1 (zh) |
| JP (1) | JP4923067B2 (zh) |
| KR (1) | KR20080096832A (zh) |
| CN (1) | CN101033230B (zh) |
| AT (1) | ATE487724T1 (zh) |
| AU (1) | AU2007224896B2 (zh) |
| BR (1) | BRPI0707089A2 (zh) |
| CA (1) | CA2643400C (zh) |
| DE (1) | DE602007010430D1 (zh) |
| HK (1) | HK1105419A1 (zh) |
| MX (1) | MX2008011262A (zh) |
| RU (1) | RU2411244C2 (zh) |
| WO (1) | WO2007104214A1 (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103313992A (zh) * | 2011-01-12 | 2013-09-18 | 克莱斯托生物药业有限公司 | 具有hdac抑制作用的喜树碱衍生物 |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102477042A (zh) * | 2010-11-26 | 2012-05-30 | 复旦大学 | 10-羟基喜树碱衍生物及其制备方法和用途 |
| CN102731516B (zh) * | 2011-04-07 | 2014-07-02 | 宁波天衡药业股份有限公司 | 一类具有抗肿瘤活性的喜树碱衍生物 |
| US8952033B2 (en) * | 2011-12-30 | 2015-02-10 | Kaohsiung Medical University | 4-anilinofuro[2,3-b]quinoline derivatives, their preparation processes, and pharmaceutical compositions comprising the same |
| CN103289015B (zh) * | 2012-02-26 | 2015-07-29 | 河南工业大学 | 季鏻盐型阳离子淀粉的制备方法 |
| CN104774209B (zh) | 2014-01-15 | 2018-06-19 | 上海海和药物研究开发有限公司 | 一种9-烯丙基喜树碱衍生物的合成方法 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1673225A (zh) * | 2004-03-23 | 2005-09-28 | 中国科学院上海药物研究所 | 羟基喜树碱及其衍生物的碳酸酯前药、制备方法与应用 |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS6019790A (ja) * | 1983-07-14 | 1985-01-31 | Yakult Honsha Co Ltd | 新規なカンプトテシン誘導体 |
| US5004758A (en) | 1987-12-01 | 1991-04-02 | Smithkline Beecham Corporation | Water soluble camptothecin analogs useful for inhibiting the growth of animal tumor cells |
| US5674872A (en) * | 1993-08-20 | 1997-10-07 | Smithkline Beecham Corporation | Treatment of ovarian cancer |
| AU7732996A (en) * | 1995-11-22 | 1997-06-11 | Research Triangle Institute | Camptothecin compounds with combined topoisomerase i inhibition and dna alkylation properties |
| IT1282673B1 (it) | 1996-02-23 | 1998-03-31 | Ist Naz Stud Cura Dei Tumori | Derivati della camptotecina e loro uso come agenti antitumorali |
| CN100406460C (zh) | 2003-11-10 | 2008-07-30 | 中国科学院上海药物研究所 | 喜树碱的新衍生物、制备方法和用途 |
| CN100354279C (zh) * | 2004-06-04 | 2007-12-12 | 中国科学院上海药物研究所 | 喜树碱的新型结构衍生物、制备方法和用途 |
-
2006
- 2006-03-10 CN CN2006100245907A patent/CN101033230B/zh active Active
-
2007
- 2007-01-17 EP EP07702109A patent/EP1995249B1/en not_active Not-in-force
- 2007-01-17 WO PCT/CN2007/000177 patent/WO2007104214A1/zh active Application Filing
- 2007-01-17 JP JP2008558616A patent/JP4923067B2/ja not_active Expired - Fee Related
- 2007-01-17 RU RU2008138749/04A patent/RU2411244C2/ru active
- 2007-01-17 MX MX2008011262A patent/MX2008011262A/es active IP Right Grant
- 2007-01-17 BR BRPI0707089-6A patent/BRPI0707089A2/pt not_active Application Discontinuation
- 2007-01-17 AT AT07702109T patent/ATE487724T1/de not_active IP Right Cessation
- 2007-01-17 US US12/282,397 patent/US8685997B2/en active Active
- 2007-01-17 KR KR1020087022692A patent/KR20080096832A/ko not_active Application Discontinuation
- 2007-01-17 DE DE602007010430T patent/DE602007010430D1/de active Active
- 2007-01-17 CA CA2643400A patent/CA2643400C/en active Active
- 2007-01-17 AU AU2007224896A patent/AU2007224896B2/en not_active Ceased
- 2007-12-18 HK HK07113787.3A patent/HK1105419A1/xx not_active IP Right Cessation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1673225A (zh) * | 2004-03-23 | 2005-09-28 | 中国科学院上海药物研究所 | 羟基喜树碱及其衍生物的碳酸酯前药、制备方法与应用 |
Non-Patent Citations (2)
| Title |
|---|
| 杨眉 等.喜树碱及其衍生物的研究进展.现代医药卫生19 8.2003,19(8),977-978. |
| 杨眉等.喜树碱及其衍生物的研究进展.现代医药卫生19 8.2003,19(8),977-978. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103313992A (zh) * | 2011-01-12 | 2013-09-18 | 克莱斯托生物药业有限公司 | 具有hdac抑制作用的喜树碱衍生物 |
| CN103313992B (zh) * | 2011-01-12 | 2016-04-27 | 天堃医药科技（杭州）有限公司 | 具有hdac抑制作用的喜树碱衍生物 |
Also Published As
| Publication number | Publication date |
|---|---|
| EP1995249A4 (en) | 2009-05-27 |
| BRPI0707089A2 (pt) | 2011-04-19 |
| DE602007010430D1 (de) | 2010-12-23 |
| ATE487724T1 (de) | 2010-11-15 |
| MX2008011262A (es) | 2009-02-18 |
| CA2643400C (en) | 2012-11-27 |
| RU2411244C2 (ru) | 2011-02-10 |
| AU2007224896A1 (en) | 2007-09-20 |
| CN101033230A (zh) | 2007-09-12 |
| JP2009529546A (ja) | 2009-08-20 |
| JP4923067B2 (ja) | 2012-04-25 |
| HK1105419A1 (en) | 2008-02-15 |
| EP1995249B1 (en) | 2010-11-10 |
| EP1995249A1 (en) | 2008-11-26 |
| AU2007224896B2 (en) | 2010-10-28 |
| KR20080096832A (ko) | 2008-11-03 |
| US20090325996A1 (en) | 2009-12-31 |
| US8685997B2 (en) | 2014-04-01 |
| WO2007104214A1 (fr) | 2007-09-20 |
| RU2008138749A (ru) | 2010-04-20 |
| CA2643400A1 (en) | 2007-09-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Khaiwa et al. | Camptothecin's journey from discovery to WHO Essential Medicine: Fifty years of promise | |
| WO2021129820A1 (zh) | 含螺环的喹唑啉化合物 | |
| JP6921101B2 (ja) | プロテインキナーゼ阻害剤及びその調製方法と医薬用途 | |
| JP6404717B2 (ja) | アミドスピロ環状アミド及びスルホンアミド誘導体 | |
| CN101033230B (zh) | 一类喜树碱衍生物及其应用 | |
| CZ20013077A3 (cs) | Kamptothecinové deriváty mající protinádorové účinky | |
| RU2300535C2 (ru) | Полиморфная форма кристаллического гидрохлорида иринотекана, способ ее получения и фармацевтическая композиция на ее основе | |
| CN114736214B (zh) | 一种倍半萜衍生物、其药物组合物及其制备方法和用途 | |
| CN105985323A (zh) | 新型表皮生长因子受体抑制剂及其应用 | |
| CN104230952A (zh) | 含有嘧啶骨架的化合物及其制备方法和用途 | |
| IL175369A (en) | Topotecan monohydrochloride pentahydrate products, processes for making them, pharmaceutical compositions comprising them and use thereof in the preparation of medicaments for therapy | |
| US6759416B2 (en) | Anticancer conjugates of camptothecin and unsaturated fatty acids | |
| CN102731516B (zh) | 一类具有抗肿瘤活性的喜树碱衍生物 | |
| CN109153639B (zh) | 葫芦巴碱类化合物 | |
| CN102603630A (zh) | 邻氨基苯甲酸磺酰化衍生物及其制备方法和应用 | |
| CN103288842B (zh) | 氟取代e环喜树碱类似物及其作为药物的用途 | |
| CN102911197B (zh) | 喜树碱硅杂衍生物、含该衍生物的组合物及其用途 | |
| JP2024515338A (ja) | ポリ（ａｄｐ－リボース）ポリメラーゼの阻害剤 | |
| CN105175411A (zh) | 一种脲类化合物及其盐类化合物的合成方法和应用 | |
| WO2005070936A1 (fr) | Derives de camptothecine 20-esterifies, preparation, compositions pharmaceutiques et utilisation | |
| CN102086207A (zh) | 一类具有抗肿瘤活性的喜树碱衍生物 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1105419 Country of ref document: HK |
|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1105419 Country of ref document: HK |
|
| ASS | Succession or assignment of patent right |
Owner name: SHANGHAI HAIHE MEDICINE RESEARCH DEVELOPMENT CO., Free format text: FORMER OWNER: SHANGHAI INST. OF MEDICINE, CHINESE ACADEMY OF SCIENCES Effective date: 20140605 |
|
| C41 | Transfer of patent application or patent right or utility model | ||
| COR | Change of bibliographic data |
Free format text: CORRECT: ADDRESS; FROM: 200031 XUHUI, SHANGHAI TO: 201203 PUDONG NEW AREA, SHANGHAI |
|
| TR01 | Transfer of patent right |
Effective date of registration: 20140605 Address after: 201203 Shanghai Guo Shou Jing Road, Zhangjiang High Tech Park of Pudong New Area No. 498 Building 1 room 503/07-503/11 Patentee after: Shanghai Haihe Medicine Research Development Co., Ltd. Address before: 200031 No. 294, Taiyuan Road, Shanghai Patentee before: Shanghai Institute of Materia Medica, Chinese Academy of Sciences |
|
| CP03 | Change of name, title or address |
Address after: Room 102, building 6, No. 421, Newton Road, Pudong New Area pilot Free Trade Zone, Shanghai, 201203 Patentee after: Shanghai Haihe pharmaceutical research and Development Co., Ltd Address before: Room 503 / 07-503 / 11, building 1, 498 GuoShouJing Road, Zhangjiang High Tech Park, Pudong New Area, Shanghai 201203 Patentee before: Shanghai Haihe Pharmaceutical Research and Development Co.,Ltd. |
|
| CP03 | Change of name, title or address |