CN1198834C - 位阻醇或酚的水溶性前药 - Google Patents
位阻醇或酚的水溶性前药 Download PDFInfo
- Publication number
- CN1198834C CN1198834C CNB998114405A CN99811440A CN1198834C CN 1198834 C CN1198834 C CN 1198834C CN B998114405 A CNB998114405 A CN B998114405A CN 99811440 A CN99811440 A CN 99811440A CN 1198834 C CN1198834 C CN 1198834C
- Authority
- CN
- China
- Prior art keywords
- compound
- camptothecine
- methyl
- disoprofol
- solution
- 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.)
- Expired - Fee Related
Links
- 239000000651 prodrug Substances 0.000 title abstract description 51
- 229940002612 prodrug Drugs 0.000 title abstract description 51
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 title description 37
- 150000001298 alcohols Chemical class 0.000 title description 3
- 150000002989 phenols Chemical class 0.000 title 1
- 229960004134 propofol Drugs 0.000 claims description 80
- 150000001875 compounds Chemical class 0.000 claims description 79
- OLBCVFGFOZPWHH-UHFFFAOYSA-N propofol Chemical group CC(C)C1=CC=CC(C(C)C)=C1O OLBCVFGFOZPWHH-UHFFFAOYSA-N 0.000 claims description 77
- 239000000203 mixture Substances 0.000 claims description 51
- 239000001257 hydrogen Substances 0.000 claims description 16
- 229910052739 hydrogen Inorganic materials 0.000 claims description 16
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 239000011734 sodium Substances 0.000 claims description 11
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- 150000001412 amines Chemical class 0.000 claims description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 9
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 8
- 230000000903 blocking effect Effects 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 8
- 229940083542 sodium Drugs 0.000 claims description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 6
- 229910001413 alkali metal ion Inorganic materials 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 229910052700 potassium Inorganic materials 0.000 claims description 6
- 239000011591 potassium Substances 0.000 claims description 6
- 239000004475 Arginine Substances 0.000 claims description 5
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 5
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 claims description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 5
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 5
- 229930182817 methionine Natural products 0.000 claims description 5
- LDDMACCNBZAMSG-BDVNFPICSA-N (2r,3r,4s,5r)-3,4,5,6-tetrahydroxy-2-(methylamino)hexanal Chemical compound CN[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO LDDMACCNBZAMSG-BDVNFPICSA-N 0.000 claims description 4
- KGWDUNBJIMUFAP-KVVVOXFISA-N Ethanolamine Oleate Chemical compound NCCO.CCCCCCCC\C=C/CCCCCCCC(O)=O KGWDUNBJIMUFAP-KVVVOXFISA-N 0.000 claims description 4
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 4
- 150000001413 amino acids Chemical class 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- 229960004418 trolamine Drugs 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 3
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- 229960000281 trometamol Drugs 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 230000003533 narcotic effect Effects 0.000 claims description 2
- 229960003121 arginine Drugs 0.000 claims 1
- 229940086542 triethylamine Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 32
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 7
- 125000001931 aliphatic group Chemical group 0.000 abstract description 3
- 125000003118 aryl group Chemical group 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 96
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 63
- 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 description 58
- 239000000243 solution Substances 0.000 description 57
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 52
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 48
- -1 and wherein Chemical group 0.000 description 46
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 44
- 238000006243 chemical reaction Methods 0.000 description 32
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 31
- 238000005481 NMR spectroscopy Methods 0.000 description 29
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 25
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 22
- 238000000034 method Methods 0.000 description 22
- 238000002360 preparation method Methods 0.000 description 22
- 241000700159 Rattus Species 0.000 description 21
- MHDVGSVTJDSBDK-UHFFFAOYSA-N dibenzyl ether Chemical compound C=1C=CC=CC=1COCC1=CC=CC=C1 MHDVGSVTJDSBDK-UHFFFAOYSA-N 0.000 description 21
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 20
- 210000004369 blood Anatomy 0.000 description 20
- 239000008280 blood Substances 0.000 description 20
- 238000004128 high performance liquid chromatography Methods 0.000 description 20
- 239000007787 solid Substances 0.000 description 20
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 19
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 19
- 238000003756 stirring Methods 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 17
- 239000003921 oil Substances 0.000 description 17
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 16
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 229930105110 Cyclosporin A Natural products 0.000 description 15
- 108010036949 Cyclosporine Proteins 0.000 description 15
- 229960001265 ciclosporin Drugs 0.000 description 15
- 238000001914 filtration Methods 0.000 description 14
- 239000007924 injection Substances 0.000 description 14
- 238000002347 injection Methods 0.000 description 14
- 239000000741 silica gel Substances 0.000 description 14
- 229910002027 silica gel Inorganic materials 0.000 description 14
- 239000000725 suspension Substances 0.000 description 14
- 229960005420 etoposide Drugs 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 13
- 238000003818 flash chromatography Methods 0.000 description 13
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- 239000002904 solvent Substances 0.000 description 13
- 238000005406 washing Methods 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000006837 decompression Effects 0.000 description 12
- 230000008569 process Effects 0.000 description 12
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 description 11
- PMATZTZNYRCHOR-CGLBZJNRSA-N Cyclosporin A Chemical compound CC[C@@H]1NC(=O)[C@H]([C@H](O)[C@H](C)C\C=C\C)N(C)C(=O)[C@H](C(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](CC(C)C)N(C)C(=O)[C@@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CC(C)C)N(C)C(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)N(C)C(=O)CN(C)C1=O PMATZTZNYRCHOR-CGLBZJNRSA-N 0.000 description 11
- XLYOFNOQVPJJNP-ZSJDYOACSA-N Heavy water Chemical compound [2H]O[2H] XLYOFNOQVPJJNP-ZSJDYOACSA-N 0.000 description 11
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 11
- 229910052786 argon Inorganic materials 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000007864 aqueous solution Substances 0.000 description 10
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 10
- 238000000605 extraction Methods 0.000 description 10
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000002253 acid Substances 0.000 description 9
- 229940087168 alpha tocopherol Drugs 0.000 description 9
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- 239000002076 α-tocopherol Substances 0.000 description 9
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 8
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 206010002091 Anaesthesia Diseases 0.000 description 7
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- 238000011160 research Methods 0.000 description 7
- GGCZERPQGJTIQP-UHFFFAOYSA-N sodium;9,10-dioxoanthracene-2-sulfonic acid Chemical compound [Na+].C1=CC=C2C(=O)C3=CC(S(=O)(=O)O)=CC=C3C(=O)C2=C1 GGCZERPQGJTIQP-UHFFFAOYSA-N 0.000 description 7
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- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 7
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- 150000002148 esters Chemical class 0.000 description 6
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical compound COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 description 6
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 6
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- SEGLCEQVOFDUPX-UHFFFAOYSA-N di-(2-ethylhexyl)phosphoric acid Chemical compound CCCCC(CC)COP(O)(=O)OCC(CC)CCCC SEGLCEQVOFDUPX-UHFFFAOYSA-N 0.000 description 5
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Abstract
本发明涉及脂族或芳族含位阻羟基药物的水溶性前药。
Description
本发明涉及新的含脂族或芳族位阻羟基药物的水溶性前药。更具体地说,本发明涉及新的含位阻醇和酚药物的水溶性膦酰氧基甲基醚,如喜树碱、丙泊酚、依托泊苷、维生素E和环孢菌素A。本发明也涉及用于生产最终药物的中间体及包含新化合物的药物组合物。
成功地向患者传送药物是治疗疾病中起着关键作用。但是,许多具有公知性质的临床药物应用却受到其水溶性非常低的限制。低水溶性的结果是,这些药物必须配制成助溶剂药物赋形剂中,包括表面活性剂。已表明,这些表面活性剂会导致对人体严重的副作用,这限制了这些药物的临床安全性,从而也限制了对严重的疾病的治疗。
例如,喜树碱是一种从中国喜树(camptotheca)(Camptothecaaccuminata)的树皮中分离出的天然产物。业已表明,在几种体内动物模型中其具有很强的抗肿瘤活性,包括主要的肿瘤类型,如肺癌、乳腺癌、卵巢癌、胰腺,结肠癌和胃癌和恶性黑素瘤。喜树碱可以抑制细胞酶DNA拓扑异构酶I并会引起导致编程性细胞死亡的级联事件。拓扑异构酶I是一种基本核酶,其负责组织和调节DNA的拓扑学特性,从而使细胞可以复制、转录和恢复遗传信息。
图1--喜树碱
喜树碱的主要缺点是其在水中的溶解度非常低。对于生物学研究来说,必须将化合物溶解于强有机溶剂(DMSO)或配制成作为在吐温80∶盐水中的悬浮液的药物,对于人体治疗来说,这种药物制剂是不理想的。近年来,美国已批准了两类具有适中水溶性的喜树碱用于治疗晚期卵巢癌(Hycamtin)和结肠直肠癌(Camptosar)。
其它类似于喜树碱存在类似问题的药物为环孢菌素A(CsA)、丙泊酚、依托泊苷和维生素E(α-生育酚)。与喜树碱类似,CsA的结构内也具有空间位阻的醇,在此情形下的仲醇。CsA配制成Cremophor EL/乙醇混合物。
环孢菌素A
丙泊酚作为一种麻醉剂是另一种空间位阻的水溶性很差的酚的实例。
丙泊酚(2,6-二异丙基苯酚)
丙泊酚配制成o/w乳液用于体内临床使用。丙泊酚不仅水溶性差,而且也会引起注射部件的疼痛。这种疼痛必需使用利多卡因来改善。由于其配制为乳液这一事实,因而很难且不可能向制剂中加入其它药物,并且对制备的物理改变如增加油滴尺寸可能会导致肺栓塞等。丙泊酚的水溶性和化学稳定的前药将可提供如下的优点。这种制剂可为一种简单的水溶液,其可与其它药物混合。如果前药本身无痛,则前药可对患者更为友好,最后,不会存在由于赋形剂造成的毒性问题。其它水溶性差的空间位阻酚为抗癌药依托泊苷和维生素E(α-生育酚)。
本发明提供了一种水溶性形式的含醇和酚的药物如喜树碱和丙泊酚。就喜树碱来说,本发明的化合物为游离酸和其可药用盐形式的喜树碱的膦酰氧基甲基醚。酸和盐的水溶性可方便制备药物制剂。与其各个母药相比,本发明所有的前药显示出优异的水溶性。用于开发本发明的化合物的方法可用于将许多的其它具有脂族或芳族位阻羟基的水不溶性药物转化成水溶性衍生物。
本发明包含新的组合物主题。本发明涉及包含由通式I表示的含醇和酚药物的水溶性膦酰氧基甲基衍生物:
上式I为ROH的衍生物,其中,ROH代表一种含醇或酚的药物,如喜树碱、丙泊酚、依托泊苷、维生素E和环孢菌素A。在上式I中,n表示1或2的整数。当n为2时,ROH优选为含酚的药物,如丙泊酚。同样还包括某些因其水溶性相对较差不可以注射形式使用的药物。这些药物包括:达那唑、甲基睾酮、双碘喹啉和阿托喹酮。R1为氢或碱金属离子,包括钠、钾或锂,或者质子化的胺或质子化的氨基酸或任何其它可药用的阳离子。R2为氢或碱金属离子,包括钠,钾或锂或质子化的胺或质子化的氨基酸或任何其它可药用的阳离子。在静脉内给药或口服给药后,式I的衍生物可通过水解和/或磷酸酶作用而转化成其母药。
因而,本发明的目的是提供一种显示出优良活性和水溶性的水不溶性药物的衍生物。
本发明的另一个目的是提供这些水溶性化合物的药物组合物,其包含一定量的式I的化合物和可药用载体。
本发明的另一个目的是提供在适用于制备药物制剂的pH值条件下具有优良稳定性,但在生理条件下很快体内分解成有效用作药物的药物衍生物。
附图简述
以下解释本申请的附图:
图1说明体外酶转化丙泊酚前药成丙泊酚。
图2说明在狗研究中从丙泊酚前药或Diprivan给药起丙泊酚的血浓度随时间的变化。
图3说明体外酶转化喜树碱前药成喜树碱。
图4说明在大鼠研究中喜树碱的血浆浓度与喜树碱前药和与在有机助溶剂中的喜树碱间的关系。
在本发明中,除非另有说明,采用下述定义:
“膦酰基-”是指基团-P(O)(OH)2,
“膦酰氧基甲氧基”或“膦酰氧基甲基醚”一般是指基团-OCH2OP(O)(OH)2。“甲基硫甲基”是指基团-CH2SCH3。本发明也包括其中n=2的化合物,从而“膦酰基二(氧甲基)醚”一般是指基团-OCH2OCH2OP(O)(OH)2。
“喜树碱部分”是指包含20个碳的喜树碱核心结构,其包含2个氮原子和4个氧原子,通过具有绝对构型的如下显示的结构式表示。
如上所示的该计数体系为在常规喜树碱衍生物中采用的体系,并在本申请中采用。例如,标号C20是指标记为“20”的碳原子。
“喜树碱类似物”是指具有基本喜树碱核心结构的化合物。可以理解,喜树碱类似物包括但不限于下述化合物:Topotecan,商购自SmithKline Beecham,Irinotecan(CPT-11),商购自Pharmacia &Upjohn,9-氨基喜树碱(9AC),9-硝基喜树碱(9NC),GI 147211C,商购自Glaxo Wellcome,和DX-8951f(最早的六种喜树碱类似物目前正在进行临床研究,它们在Claire McDonald由西太平洋癌症基金指导的综述中有述(1997年12月)。
此外,其它几种引入本文中作为参考的非限定性喜树碱类似物公开于下述文献中:Sawada等,当前药物设计(CurrentPharmaceutical Design),Vol.1,No.11 PP 113-132,以及US专利5,646,159、5,559,235、5,401,747、5,364,858、5,342,947、5,244,903、5,180,722、5,122,606、5,122,526、5,106,742、5,053,512、5,049,668、4,981,968和4,894,456。
几种包含其各自的喜树碱衍生物的药物化合物包含多于一个的羟基,例如,10-羟基喜树碱,topotecan以及列于上述文献中的几种。可以理解,本发明可应用于多于一个羟基的情形。这一点可通过在进行衍生之前保护其它的羟基来实现。
“膦酰基保护基”是指可用于阻断或保护膦酰基官能团的基团。优选这种保护基团为那些可通过不会对分子的其它部分有明显影响的方法除去的保护基。适宜的膦酰氧基保护基例如包括苄基(用“Bn”表示)、叔丁基和烯丙基。
“可药用盐”是指酸性膦酰基团的金属或胺盐,其中,阳离子不会显著影响活性化合物的毒性或生物活性。适宜的金属盐包括:锂、钾、钠、钙、钡、镁、锌和铝盐。优选的盐为钠和钾盐。适宜的胺盐例如为:氨、氨丁三醇、三乙醇胺、乙二胺、葡糖胺、N-甲基葡糖胺、甘氨酸、赖氨酸、鸟氨酸、精氨酸、乙醇胺,可列出这些但还有其它盐。优选的胺盐为:赖氨酸、精氨酸、N-甲基葡糖胺和氨丁三醇盐。
在说明书和权利要求书中,除非对游离酸有具体说明,否则术语-OCH2OP(O)(OH)2包括游离酸和其可药用盐。
一方面,本发明提供了如下所示式I的含醇和酚药物的衍生物:
式I的衍生物可按照反应路线1所示的反应顺序制备:
反应路线1
其中,ROH代表含醇或酚的药物,如喜树碱、丙泊酚、依托泊苷、维生素E、环孢菌素A。可以理解,上述路线仅仅是几种不同路线之一。这些不同路线在阅读了下述详细公开和实施例后将会非常明显。
上述反应路线1的一个实例可采用化合物喜树碱进行说明。可以理解,这些反应路线均适用于本发明式I所包括的其它化合物,例如如上列出的化合物。因此,本发明的另一个方面是提供式II的喜树碱衍生物:
其包括游离酸,其中,Z为氢,以及其可药用盐,其中,Z为金属或胺。
或者,式II包括二酸,其中,在两种情形下Z为金属或胺。
式II化合物的优选可药用盐为碱性盐,包括锂、钠和钾盐;胺盐,包括三乙胺、三乙醇胺、乙醇胺、精氨酸、赖氨酸、和N-甲基葡糖胺盐。
式II的喜树碱衍生物的最优选的实施方案包括下述化合物:(20)-O-膦酰氧基甲基喜树碱,(20)-O-膦酰氧基甲基喜树碱单或二钠盐,(20)-O-膦酰氧基甲基喜树碱单或二钾盐,(20)-O-膦酰氧基甲基喜树碱单或二精氨酸盐,(20)-O-膦酰氧基甲基喜树碱单或二赖氨酸盐,(20)-O-膦酰氧基甲基喜树碱单或二N-甲基葡糖胺盐和(20)-O-膦酰氧基甲基喜树碱单或二-三乙醇胺盐。
式II的化合物可直接由喜树碱(显示为c-OH)按照反应路线2所示的反应顺序制备:
式III的化合物(甲基硫甲基醚,MTM醚)可通过用二甲基亚砜/乙酸酐/乙酸处理喜树碱制备。
在反应路线2所示的第二步中,甲基硫甲基醚被转化成相应的保护的膦酰氧基甲基醚(式IV的化合物)。这可以通过用N-碘代琥珀酰亚胺和保护的磷酸酯HOP(O)(OR)2处理MTM醚完成。在第三步中,可除去膦酰基保护基团以得到式II的化合物。例如,一种适宜的膦酰基保护基为苄基,其可通过催化氢解除去。
用于制备式I化合物的反应路线2的一般方法可更具体地由反应路线3举例说明:
方案3
在第一步中,喜树碱的游离羟基被转化成甲基硫甲基醚(-OCH2SCH3)基团。该转化过程是通过与二甲亚砜在乙酸酐和乙酸存在下反应完成的。该方法通常被称为Pummer反应,由Bristol-Myers Squibb成功地用于紫杉醇的甲基硫甲基化反应(EP专利0604910A1,Bioorg.Med.Chem.Lett.,6,1837,1996,还可参见EP0639577A)。该反应通常在室温下进行24-72小时以生产甲基硫甲基醚。
在反应顺序的第二步中,甲基硫甲基醚被转化成相应的保护的膦酰氧基甲基醚。这种公知的转化方法由Bristol-Myers Squibb成功地用于紫杉醇的膦酰氧基甲基化反应(EP专利0604910A1,Bioorg.Med.Chem.Lett.,6,1837,1996)。因此,式III的化合物可用N-碘代琥珀酰亚胺和保护的磷酸如磷酸二苄酯处理。反应在分子筛存在下,在惰性有机溶剂如四氢呋喃和卤代烃如二氯甲烷中进行。反应在室温下进行。相对于甲基硫甲基醚,N-碘代琥珀酰亚胺和保护的磷酸过量使用(3-5当量)。
在反应顺序的第三步中,除去膦酰基保护基。解封采用现有技术中公知的常规方法完成,例如,酸或碱催化的水解、氢解、还原等。例如,可采用催化氢解以除去苄基膦酰基保护基。脱保护方法可在标准教科书中有述,例如T.W.Green和P.G.M.Wutz,有机合成中的保护基团,J.Wiley publishers,New York,NY,1991,pp.47-67。
式II化合物的碱性盐可通过常规技术形成,包括使式II的游离酸化合物与金属碱或胺接触。适宜的金属碱包括:钠、钾、锂、钙、钡、镁、锌和铝的氢氧化物、碳酸盐和碳酸氢盐;适宜的胺包括三乙胺、氨、赖氨酸、精氨酸、N-甲基葡糖胺、乙醇胺、普鲁卡因、苯乍生、二苄胺、氨丁三醇(TRIS)、氯普鲁卡因、胆碱、二乙醇胺、三乙醇胺等。碱盐可进一步通过色谱法,再经冷冻干燥或结晶法纯化。
本发明的化合物为膦酰氧基甲基醚药物如:喜树碱、丙泊酚、依托泊苷、生育酚等。与母化合物相比,可药用盐形式显示出改善的水溶性,因而成为更方便的药物制剂。不受任何理论的限制,据信,本发明的膦酰氧基甲基醚为母药物的前药;膦酰氧基乙基部分会在体内会与磷酸酯酶接触而分解,结果产生母化合物。如上所示,本发明的化合物为有效的药物或治疗剂。
例如,本发明的式II的化合物可以与喜树碱类似的方式使用。喜树碱前药的结构如上所示。因此,在癌症治疗领域中的肿瘤学家将能够不进行过度的实验确定一种适宜的治疗方案以给药本发明的化合物。本发明化合物的给药剂量、方式和安排并无特殊限制,将根据所采用的具体化合物改变。因此,式II的化合物可通过任一种适宜的给药路径给药,优选非肠道给药;剂量例如可以为约0.1-约100mg/kg体重,或者约5-500mg/m2。式II的化合物也可口服给药;口服剂量可为约5-约500mg/kg体重。实际上采用的剂量将根据特定制剂的配方、给药路径以具体位置、宿主和所治疗肿瘤的类型改变。须考虑改变药物作用的许多因素来确定剂量,这些因素包括年龄、性别、饮食和患者的身体状态。
本发明式I前药的另一个实例是丙泊酚。丙泊酚前药的结构如下所示:
丙泊酚前药
在上式中,对于丙泊酚前药来说,Z与对式II中的定义相同。因而,在麻醉领域的麻醉学家将能够不进行过度的实验确定一种适宜的治疗方案以给药本发明的化合物。本发明化合物的给药剂量、方式和安排并无特殊限制,将根据所采用的具体化合物改变。因此,式I的化合物如丙泊酚可通过任一种适宜的给药路径给药,优选非肠道给药;给药剂量例如可以为约0.5-约10mg/kg,按照通常的麻醉诱导或保持通常的麻醉过程进行。或者,式I的化合物可通过非肠道输注法给药,剂量可以为2μg/kg/分钟-800μg/kg/分钟,按照用于保持通常麻醉的过程给药,开始并保持MAC镇静或开始并保持ICU镇静。
本发明也提供了药物组合物,其含有药物有效量的式I的化合物和一种或多种可药用载体、赋形剂、稀释剂或辅剂。例如,本发明的化合物可配制成片剂、丸剂、粉末混合物、胶囊、可注射剂、溶液、栓剂、乳液、分散剂、食品预混物和其它适宜的形式。它们也可以无菌固体组合物的形式生产,例如,经过冷冻干燥,并且,如果需要的话,还可结合有其它的可药用赋形剂。这种固体组合物可用无菌水、生理盐水或水与有机溶剂如丙二醇、乙醇等或某些其它的无菌可注射介质在非肠道给药前复配。
典型的可药用载体例如为:甘露糖醇、脲、葡聚糖、乳糖、非还原糖、马铃薯和玉米淀粉、硬脂酸镁、滑石、植物油、聚亚烷基二醇、乙基纤维素、聚(乙烯基吡咯烷酮)、碳酸钙、油酸乙酯、肉豆蔻酸异丙酯、苯甲酸苄酯、碳酸钠、明胶、碳酸钾、硅酸。药物制剂也可包含无毒的辅助性物质,如乳化剂、防腐剂、润湿剂等,例如,单月桂酸脱水山梨醇酯、三乙醇胺油酸酯、聚氧亚乙基单硬脂酸酯、甘油基三棕榈酸酯、磺基琥珀酸钠二辛酯等。
在下述实验过程中,除非另有说明,所有的温度均指摄氏温度(C)。核磁共振(NMR)光谱特性是指化学位移(δ),以ppm表示,用四甲基硅烷(TMS)作为参考标准。对在质子NMR光谱数据中各种位移所报告的相对面积相应于在分子中特定功能类型的氢原子数。位移的多重性以下述报告:宽单峰(bs),宽双峰(bd),宽叁峰(bt),宽四峰(bq),单峰(s),多重峰(m),双峰(d),四重峰(q),三重峰(t),双峰的双峰(dd),三峰的双峰(dt)和四重峰的双峰(dq)。用于取得NMR光谱的溶剂为丙酮-d6(氘化丙酮)、DMSO-d6(全氘二甲基亚砜),D2O(氘化水),CDCl3(氘化氯仿)和其它常规氘化溶剂。
本文中采用的简写为本领域中广泛采用的常规简写。其中的一些是:MS(质谱);HBMS(高分辨质谱);Ac(乙酰基);Ph(苯基);FAB(快速原子轰击);min(分钟);h或hrs(小时);NIS(N-碘代琥珀酰亚胺);DMSO(二甲基亚砜);THF(四氢呋喃)。
由下述实施例说明本发明代表性化合物的合成,无论如何,它们并非对本发明保护范围的限定。本领域的技术人员能够采用这些方法,不进行过度的实验合成出在本发明范围内的但未具体描述的化合物。例如,在下述实施例中,采用了特定的盐,但这些盐并非是限定性的。这种情形的一个实例就是报导使用磷酸二苄基酯的银盐。四烷基铵盐,如四甲基铵盐或其它碱金属盐可用来代替银盐。
实施例
I.合成O-磺酰氧基甲基丙泊酚
Ia.合成O-甲基硫甲基丙泊酚:
在15分钟内,向保持在氩气氛下,搅拌中的氢化钠(150mg,6.2mmol)在无水HMPA(10mL)中的悬浮液中滴加丙泊酚(1.1mL,97%,5.7mmol)。然后,将反应混合物在室温下再搅拌30分钟。向混合物中滴加氯甲基甲基硫化物(550μl,95%,6.2mmol),再在室温下搅拌。20小时后,使反应混合物在搅拌下于水(10mL)与苯(20mL)间分配。分离出水层,用苯(10mL)萃取。合并苯馏分,用水(2×3mL)洗涤,用硫酸钠干燥,减压蒸发。将形成的油状残余物进行柱色谱处理(硅胶,己烷,然后4∶1己烷/氯仿),得到1.15g(85%收率)的标题化合物,为无色油。
EIMS:[M+],m/z 238。
1H NMR(300MHz,CDCl3,δ):1.24(d,J=6.9Hz,12H),2.37(s,3H),3.37(hept,J=6.9Hz,2H),4.86(s,2H),7.12(s,203H)。13C NMR(75MHz,CDCl3,δ):15.40,23.98,26.68,78.12,124.04,125.05,141.74,152.20。
Ib-合成O-氯甲基丙泊酚。
在5℃及5分钟内,向保持在氩气氛下,搅拌中的O-甲基硫甲基丙泊酚(3.00g,12.5mmol)的无水二氯甲烷(30mL)溶液中加入1M的SO2Cl2的无水二氯甲烷(12.2mL,12.2mmol)溶液。将反应混合物在相同的温度下搅拌10分钟,然后在室温下搅拌3小时。减压蒸出溶剂。将褐色的残余物油用快速柱色谱纯化(硅胶,1∶20己烷/乙酸乙酯),得到2.36g(83%收率)的标题化合物,为一种黄色油。
CIMS(NH3):[M+],m/z 226,[MH+NH3]+,m/z 244。
1H NMR(300MHz,CDCl3,δ):1.22(d,J=6.9Hz,12H),3.35(hept,J=6.9Hz,2H),5.76(s,2H),7.15(m,3H)。13C NMR(75MHz,CDCl3,δ)23.93,26.84,83.34,124.34,125.95,141.34,150.93。
Ic.合成O-膦酰氧基甲基丙泊酚二苄基酯(反应路线-1):
将O-氯甲基丙泊酚(2.20g,9.7mmol)、磷酸二苄基酯银盐(3.85g,10.0mmol)和无水甲苯(50mL)的混合物在氩氛气下回流45分钟。将混合物冷却至室温,过滤。在真空蒸出溶剂后,将油状残余物通过硅胶快速柱色谱纯化(9∶1己烷/乙酸乙酯,然后1∶1己烷/乙酸乙酯),得到4.43g(98%收率)的标题化合物,为一种黄色油。
CIMS(NH3):[MH]+,m/z 469,[MH+NH3]+,m/z 486。
1H NMR(300MHz,CDCl3,δ:1.17(d,J=6.8Hz,12H),3.33(hept,J=6.9Hz,2H),5.00(d,J=7.8Hz,2H),5.01(d,J=7.8Hz,2H),5.42(d,J=.9.9Hz,2H),7.12(m,3H),7.32 10(m,10H)。13C NMR(75MHz,CDCl3,δ):23.79,26.57,69.15,69.23,94.14,94.20,124.07,125.62,127.70,128.44,135.42,135.51,141.50,151.07。
Ic.合成O-膦酰氧基甲基丙泊酚二苄基酯(另一种反应路线-1):
在0-5℃及5分钟内,向氩气氛下,搅拌中的O-甲基硫甲基丙泊酚(1.45g,6.08mmol)的无水二氯甲烷(15mL)溶液中加入1M的SO2Cl2的无水二氯甲烷(6.5mL,6.5mmol)溶液。将反应混合物在5℃下搅拌10分钟,然后在室温下搅拌3小时。减压蒸出溶剂。将残余物油溶解于甲苯(ACS-级,20mL);加入磷酸二苄基酯银盐(3.50g,9.1mmol),将形成的混合物回流45分钟。将棕色的反应混合物冷却至室温,过滤。在真空蒸出溶剂后,将油状残余物用硅胶快速柱色谱纯化(9∶1己烷/乙酸乙酯,然后1∶1-己烷/乙酸乙酯),得到2.41g(85%收率)的标题化合物,为一种黄色油。该产物与确认的实例具有相同的Rf(TLC)和1H NMR光谱(300MHz,CDCl3)。
Ic.合成O-膦酰氧基甲基丙泊酚二苄基酯(另一种反应路线-2):
在5分钟内,在氩气氛下,向搅拌中的氢化钠(41mg,60%矿物油中的分散液,1.02mmol)在无水二甲氧基乙烷(1.5mL)中滴加丙泊酚(200μl,97%,1.04mmol),将形成的混合物再搅拌15分钟。在15分钟内,向形成的均匀溶液滴加搅拌中的氯碘代甲烷(4.0mL,53mmol)的无水二甲氧基乙烷(4mL)溶液。将反应混合物搅拌2小时,过滤,蒸出溶剂和过量的氯碘代甲烷。将残余物油溶解于溶解于甲苯(HPLC-级,10mL)中。向该溶液中中入磷酸二苄基酯银盐(400mg,1.04mmol),将形成的混合物回流10分钟。在将反应混合物冷却至室温后,过滤,真空蒸出溶剂。将油状残余物用硅胶快速柱色谱纯化(9∶1己烷/乙酸乙酯和然后1∶1己烷/乙酸乙酯),得到205mg(42%收率)的标题化合物,为一种黄色油。该产物与确认的实例具有相同的Rf(TLC)和1H NMR光谱(300MHz,CDCl3)。
对于上述反应Ic(另一种反应路线-2)来说,可以理解,可使用其它的试剂,这取决于所需的化合物。例如,当需要其中n=2的式I化合物时,可用诸如X-CH2-O-CH2-Cl(其中X为优良的离去基团)代替氯碘代甲烷。
Ic.合成O-膦酰氧基甲基丙泊酚二苄基酯(另一种反应路线-3):
在氩气氛下,向搅拌中的O-甲基硫甲基丙泊酚(91mg,0.38mmol)的无水二氯甲烷(2mL)溶液中滴加粉末状的、活化的4A分子筛(100mg),然后加入磷酸二苄基酯盐(127mg,0.45mmol)和N-碘代琥珀酰亚胺(102mg,95%,0.43mmol)在四氢呋喃(2mL)中的溶液。将反应混合物在室温下搅拌1小时,过滤,用二氯甲烷(30mL)稀释。将形成的溶液用硫代硫酸钠(2mL,1M溶液)、饱和碳酸氢钠溶液(3mL)、盐水(5mL)洗涤,用硫酸钠与硫酸镁的混合物干燥,过滤,真空浓缩。将油状残余物用硅胶快速柱色谱纯化(1∶1己烷/乙酸乙酯),得到120mg(67%收率)的标题化合物,为一种黄色油。该产物与确认的实例具有相同的Rf(TLC)和1H NMR光谱(300 MHz,CDCl3)。
Ic.合成O-膦酰氧基甲基丙泊酚二苄基酯(另一种反应路线-4):
向丙泊酚(38mg,97%,0.21mmol)的二氯甲烷(1mL)溶液中加入四丁基溴化铵(10mg,0.03mmol)和氢氧化钠(40mg,1mmol)的水(0.2mL)溶液。将非均相混合物搅拌15分钟。然后,加入磷酸二苄基氯代甲基酯(104mg,0.32mmol)的二氯甲烷(1mL)溶液,将反应混合物剧烈搅拌8小时。再将混合物用二氯甲烷(10mL)稀释,用水(2mL)洗涤,用硫酸钠干燥,过滤,真空蒸发。将油状残余物用硅胶快速柱色谱纯化(己烷,20∶1己烷/乙酸乙酯,和10∶1己烷/乙酸乙酯),得到44mg(45%收率)的标题化合物,为一种黄色油。该产物与确认的实例具有相同的Rf(TLC)和1H NMR光谱(300MHz,CDCl3)。
对于上述反应Ic(另一种反应路线-4)来说,可以理解,下述试剂:
一般可用下式表示:
其中,X代表离去基团,R3和R4分别为氢原子、有机基团或无机基团,Y为磷酸酯保护基。离去基团的实例包括:氯、溴、碘、甲苯磺酸根,或者任一种其它适宜的离去基团。磷酸酯保护基的实例包括暂时阻断磷酸酯基团的反应性并允许用亲核置换反应进行选择性置换。这种阻断基团的实例包括但不限于:苄基、烯丙基、叔丁基和异丙基、乙基和β-氰基乙基。
Ic.合成O-磺酰氧基甲基丙泊酚二苄基酯(另一种反应路线-5):
在5分钟内,在氩气氛下,向搅拌中的氢化钠(36mg,60%矿物油分散液,0.91mmol)的无水二甲氧基乙烷(2mL)悬浮液中滴加丙泊酚(172μl,97%,0.90mmol)。将形成的混合物在室温下搅拌20分钟。然后,向混合物中加入甲醛双(二苄基膦酰基)缩乙醛(500mg,0.88mmol)的无水二甲氧基乙烷(3mL)溶液。将反应混合物在室温下搅拌20小时,然后在70℃下搅拌2.5小时。然后,将混合物过滤,真空蒸出溶剂。将油状残余物用硅胶快速柱色谱纯化(己烷,10∶1己烷/乙酸乙酯,然后1∶1己烷/乙酸乙酯),得到29mg(7%收率)的标题化合物,为一种黄色油。该产物与确认的实例具有相同的Rf(TLC)和1HNMR光谱(300MHz,CDCl3)。
Id.合成O-膦酰氧基甲基丙泊酚:
向O-膦酰氧基甲基丙泊酚二苄基酯(115mg,0.245mmol)的甲醇(10mL)溶液中加入钯/炭(10%,20mg)。将该混合物在氢气氛(1atm)下搅拌1.5小时。通过硅藻土过滤除去催化剂,将滤液经减压蒸发,得到70.5mg(100%收率)的标题化合物,为一种无色油,在室温下放置不稳定。
FABMS-(GLY):[M-H]-,m/z 287。
1H NMR(300MHz,丙酮-d6,δ):1.19(d,J=6.8Hz,12H),3.46(sext,J=6.8Hz,2H),5.45(d,J=9.7Hz,2H),7.15(m,3H)。13CNMR(75MHz,丙酮-d6,δ):24.2178,27.1496,94.63,94.65,124.08,126.30,142.46,152.32。
Ie.合成O-膦酰氧基甲基丙泊酚二钠盐:
向O-膦酰氧基甲基丙泊酚二苄基酯(1.05g,2.24mmol)的四氢呋喃(100mL)溶液中加入水和钯/炭(10%,300mg)。将此混合物在氢气(1atm)下搅拌1小时。经硅藻土过滤除去催化剂,将滤液用碳酸钠的水合物(263mg,3mL水中,2.12mmol)处理。减压蒸出THF,将残余的水溶液用乙醚(3×3mL)萃取。将水层蒸发至干(氩气流或旋转蒸发器),将形成的固体在真空下过夜干燥,用乙醚(4×4mL)、己烷(2×4mL)洗涤,再在真空中干燥,得到655mg(93%收率)的标题化合物,为一种白色粉末。
FABMS-(GLY):(M-2Na+H]-,m/z 287。
1H NMR(300MHz,D2O,δ):1.22(d,J=7.0Hz,12H),3.46(hept,J=6.9Hz,2H),5.27(d,J=7.5Hz,2H),7.28(m,3H)。
II.合成O-膦酰氧基甲基-α-生育酚
IIa.合成O-膦酰氧基甲基-α-生育酚二苄基酯:
向磷酸二苄基氯代甲基酯(323mg,0.98mmol)、α-生育酚(409mg,97%,0.92mmol)和四丁基溴化铵(301mg,0.92mmol)的苯(5mL)溶液中加入氢氧化钠的水溶液(150mg,在0.2mL水中,3.7mmol)。在氩气氛下,将形成的反应混合物在室温下剧烈搅拌2小时。然后将混合物用苯(10mL)稀释,再用水(3×3mL)洗涤,用硫酸镁干燥,过滤,减压蒸发。将褐色的油状残余物用硅胶快速柱色谱纯化(10∶1己烷/乙酸乙酯),得到336mg(51%收率)的标题化合物,为一种黄色油。
FABMS+(NBA):[M]+,m/z 720。
1H NMR(500MHz,CDCl3,δ):0.85(m,12H),1.21(s,3H),1.27(m,24H),1.75(m,2H),2.06(s,3H),2.11(s,3H),2.14(s,3H),2.54(t,J=6.8Hz,2H),4.97(m,4H),5.20(d,J=9.3Hz,2H),7.31(m,10H)。
IIb.合成O-磺酰氧基甲基-α-生育酚:
向O-膦酰氧基甲基-α-生育酚二苄基酯(88mg,0.12mmol)的四氢呋喃(10mL)溶液中加入加入钯/炭(10%,15mg)。将混合物在氢气(1atm)下搅拌10分钟(反应在5分钟后完成,根据TLC判断)。经硅藻土过滤除去催化剂,将滤液在减压下蒸发,然后在真空下干燥。获得标题化合物70mg(100%收率),为一种褐色油,其在室温下不稳定。
FABMS+(NBA):[M]+,m/z 540,[M+Na]+,m/z 563;(NBA+Li):[M+Li]+,m/z 547。
IIc.合成O-膦酰氧基甲基-α-生育酚
向O-膦酰氧基甲基-α-生育酚二苄基酯(100mg,0.14mmol)的四氢呋喃(10mL)溶液中加入钯/炭(10%,18mg)。将混合物在氢气(1atm)下搅拌5分钟。经硅藻土过滤除去催化剂,将滤液在室温及减压下蒸发,将形成的残余物溶解于乙醚(2mL)中。然后,醚溶液用氢氧化钠的水溶液(11.2mg,在100mL水中,0.28mmol)处理,将形成的混合物在室温下搅拌10分钟。除去醚相,将水相用乙醚(3×3mL)洗涤,然后在真空下干燥20小时,得到73mg(89%收率)的标题化合物,为一种灰色的固体。
FABMS+(TG/G):[MH]+,m/z 585,[M+Na]+,m/z 607。
喜树碱的水溶性衍生物的合成过程也如以下详细描述:
III.合成20-O-膦酰氧基甲基喜树碱
IIIa.合成20-O-甲基硫甲基喜树碱:
向喜树碱(5.0g,14.3mmol)在二甲亚砜(250mL)中的悬浮液中加入乙酸酐(125mL)和乙酸(35mL)。将多相混合物在室温下剧烈搅拌24小时,再倒入冰(800mL)中,再搅拌30分钟,然后用二氯甲烷(4×100ml)萃取。将合并后的二氯甲烷萃取液用水(2×100mL)洗涤,再用硫酸镁干燥。减压除去二氯甲烷,得到一种褐色的固体。将该固体溶解于少量的二氯甲烷中。将溶解过滤,并用10倍过量的己烷稀释,然后在冰箱中过夜。滤除沉淀出的固体,用己烷洗涤几次,干燥,得到5.38g(92%收率)的标题化合物,为一种浅褐色粉末。αD 20-123.6°(c0.55,CHCl3)。
FABMS+(NBA):[MH]+,m/z 409。
1H NMR(400MHZ,CDCl3,δ):0.93(t,J=7.2Hz,3H),2.11(sext,J=7.6Hz,1H),2.29(sext,J=7.6Hz,1H),2.30(s,3H),4.58(s,2H),5.33(s,2H),5.40(d,J=17.2Hz,1H),5.62(d,J=17.3Hz,1H),7.48-(s,1H),7.69(t,J=7.1Hz,1H),7.86(t,J=7.1Hz,1H),7.96(d,J=8.1Hz,1H),8.25(d,J=8.5Hz;1H),8.42(s,1H)。
13C NMR(75MHz,CDCl3,δ):7.76,14.89,33.90,49.92,66.68,71.02,76.57,97.51,122.63,128.02,128.09,128.30,129.71,130.64,131.11,145.14,146.10,148.88,152.27,157.43,169.34,169.73。
IIIb.合成20-O-膦酰氧基甲基喜树碱二苄基酯:
向搅拌良好的20-O-甲基硫甲基喜树碱(1.00g,2.44mmol)和粉末状的活化的4分子筛(5g)在四氢呋喃(20mL)中的悬浮液中加入N-碘代琥珀酰亚胺(2.00g,95%,8.44mmol)和磷酸二苄基酯(2.20g,7.83mmol)在二氯甲烷(12mL)中的悬浮液。将形成的混合物在室温下剧烈搅拌30分钟,过滤,用乙酸乙酯(300mL)稀释。将溶液用硫代硫酸钠水溶液(10%,2×15mL)、水(2×20mL)、盐水(50mL)洗涤,用硫酸镁干燥。将混合物过滤,减压蒸出溶剂。将褐色的油状残余物用硅胶快速柱色谱纯化(98∶2乙酸乙酯/甲醇),并在真空下过夜干燥,得到1.19g(76%收率)的标题化合物,为一种黄色泡沫物。αD 20-43.1 °(c0.55,CHCl3)。
FABMS+(NBA):[MH]+,m/z 639。
1H NMR(400MHz,CDCl3,δ):0.91(t,J=7.4Hz,3H),2.09(sext,J=7.4Hz,1H),2.26(sext,J=7.4-Hz,1H),5.06(m,4H),5.28(m,3H),5.35(d,J=17.0Hz,1H),5.48(2xd,J=10.5Hz,1H),5.64(d,J=17.3Hz,1H),7.59(s,1H),7.67(t,J=7.0Hz,1H),7.80(t,J=7.1Hz,1H),7.94(d,J=8.0Hz,1H),8.13(d,=8.5Hz,1H),8.35(S,1H)。
13C NMR(100MHz,CDCl3,δ):7.73,29.53,32.49,49.86,66.74,69.37,69.44,78.48,88.99,89.04,98.09,121.55,127.65,127.70,127.90,128.01,128.25,128.35,128.36,129.62,130.48,130.97,135.45,135.55,145.47,145.82,148.76,152.15,157.18,168.67。
IIIc.合成20-O-膦酰氧基甲基喜树碱:
向20-O-膦酰氧基甲基喜树碱二苄基酯(500mg,0.78mmol)在四氢呋喃(100mL)和水(5mL)中的溶液中加入钯/炭(10%,500mg)。将混合物在氢气(1atm)下搅拌35分钟。经硅藻土过滤除去催化剂。然后,硅藻土用四氢呋喃(300mL)洗涤,合并后的滤液在减压下蒸发。将形成的绿色固体用乙醚(2×20mL)、己烷(50mL)洗涤,真空干燥,然后溶解于热甲醇(60mL)中。将溶液过滤,减压浓缩至约10mL体积。在室温下放置1小时后,将溶液放置在冰箱中过夜。滤出过夜形成的结晶沉淀,真空干燥,得到155mg的标题化合物,为一种黄色固体。将滤液浓缩至约1mL体积,并在冰箱中保持1小时,得到另一部分28mg的产物。总收率:183mg(51%)。
FABMS+(NBA):[MH]+,m/z 459,[M+Na]+,m/z 481。
1H NMR(400MEz,D2O,δ):0.95(t,J=7.5Hz,3H),2.25(m,2H),4.98(d,J=5.0Hz,2H),5.14(2xd,J=9.3Hz,1H),5.22(2xd,J=8.9Hz,1H),5.48(d,J=17.0Hz,1H), 5.60(d,J=16.9Hz,1H),7.54(s,1H),7.56(t,J=7.7Hz,1H),7.77(t,J=7.2Hz,1H),7.86(d,J=8.2Hz,1H),8.01(d,=8.5Hz,1H),8.44(s,1H)。
产物的化学结构与纯度也通过其二钠盐的1H NMR光谱确认,所述二钠盐是由酸与D2O中的两摩尔当量的碳酸氢钠形成的。
IIIc.合成20-O-膦酰氧基甲基喜树碱(另一种方式):
向20-O-膦酰氧基甲基喜树碱二苄基酯(500mg,0.78mmol)在四氢呋喃(100mL)和水(5mL)中的溶液中加入钯/炭(10%,500mg)。将混合物在氢气(1atm)下搅拌30分钟。经硅藻土过滤除去催化剂。然后,硅藻土用四氢呋喃(2×100mL)洗涤,合并后的滤液用碳酸钠水合物(97mg,2mL水中,0.78mmol)的水溶液处理。减压蒸出THF,将多相的含水残余物用水(10mL)稀释,再用乙酸乙酯(2×3mL)萃取。将形成的黄色均匀溶液用盐酸(10%)酸化至pH值为1。将形成的沉淀过滤,在真空下干燥过夜,得到145mg(41%收率)的标题化合物,为一种黄色固体。
IIId.合成20-O-膦酰氧基甲基喜树碱二钠盐:
向20-O-膦酰氧基甲基喜树碱(5mg,10.9μmol)在氧化氘(0.5mL)中的悬浮液中加入碳酸氢钠(50μl,0.44M溶液,22μmol)的氧化氘溶液。将多相混合物进行超声处理几分钟,得到标题产物的黄色均匀溶液。
1H NMR(400MHz,D2O,10mm后,96%内酯,4%羧酸盐,δ):1.05(t,J=7.2Hz,3H),2.27(m,2H),4.57(d,J=18.8Hz,1H),4.70(d,J=18.9Hz,1H),5.06(dd,J=8.3,J=5.4Hz,1H),5.18(dd,J=7.6,J=5.5Hz,1H),5.45(d,J=16.7Hz,1H),5.59(d,J=16.8Hz,1H),7.34(t,J=7.1Hz,1H),7.41(s,1H),7.60(m,2H),7.81(d,J=8.3Hz,1H),8.17(s,1H)。
IIId.合成20-O-膦酰氧基甲基喜树碱二钠盐(另一种方式):
向20-O-膦酰氧基甲基喜树碱二苄基酯(78mg,0.122mmol)在四氢呋喃(10mL)和水(3mL)中的溶液中加入钯/炭(10%,80mg)。将混合物在氢气(1atm)下搅拌30分钟。经硅藻土过滤除去催化剂。然后,滤液用碳酸钠水合物(20mg,0.5mL水中,0.238mmol)的水溶液处理。滤出黄色的沉淀,用二氯甲烷洗涤,真空干燥,得到35mg(57%收率)的标题化合物(浅褐色固体),为其内酯形式(82%)和其羧酸盐形式(18%)的混合物(通过1H NMR)。
IIId.合成20-O-膦酰氧基甲基喜树碱二钠盐(另一种方式):
向20-O-膦酰氧基甲基喜树碱二苄基酯(500mg,0.78mmol)在四氢呋喃(10mL)和水(5mL)的溶液中加入钯/炭(10%,500mg)。将混合物在氢气(1atm)下搅拌30分钟。经硅藻土过滤除去催化剂。然后,硅藻土用四氢呋喃(50mL)洗涤,合并后的滤液用碳酸钠水合物(90mg,2mL水中,0.72mmol)的水溶液处理。减压蒸出四氢呋喃,将残余物溶解于水(15mL)中。多相混合物用乙酸乙酯(2×15mL)和乙醚(20mL)萃取,将形成的均匀水溶液在氩气氛及室温下蒸发至干。将残余物在真空下过夜干燥,得到290mg(80%收率)的标题化合物(橙色固体),为其内酯形式(60%)和其羧酸盐形式(40%)的混合物,并有少量的副产物(通过1H NMR)。
IIIe.合成20-O-膦酰氧基甲基喜树碱一钠盐:
向连续进行超声处理的20-O-膦酰氧基甲基喜树碱(5mg,10mmol)在氧化氘(0.5mL)中的悬浮液中滴加碳酸氢钠(21μl,0.44M溶液,9.2mmol)的氧化氘溶液直至完全均匀。获得标题化合物的黄色均匀溶液。
1H NMR(400MHz,D2O,δ):1.00(t,J=7.2Hz,3H),2.23(m,2H),4.40(d,J=18.8Hz,1H),4.50(d,J=18.8Hz,1H),5.10(dd,J=9.7,J=5.9Hz,1H),5.26(dd,J=9.0,J=6.1Hz,1H),5.39(d,J=16.7Hz,1H),5.50(d,J=16.7Hz,1H),7.20(t,J=7.3Hz,1H),7.28(s,1H),7.46(m,2H),7.66(d,J=8.4Hz,1H),8.02(s,1H)。
IIIf.合成20-O-膦酰氧基甲基喜树碱赖氨酸盐:
向连续进行超声处理的20-O-膦酰氧基甲基喜树碱(5mg,10mmol)在氧化氘(0.5mL)中的悬浮液中滴加L-赖氨酸(25μl,0.43M溶液,10.7mmol)的氧化氘溶液直至完全均匀。获得标题化合物的黄色均匀溶液。
1HNMR(400MHz,D2O,94%内酯,6%羧酸盐,δ):1.02(t,J=7.2Hz,1H),1.49(m,2H),1.73(m,2H),1.88(m,2H),2.25(m,2H),3.03(t,J=7.5Hz,2H),3-76(t,J=6.0Hz,1H),4.43(d,J=19.0Hz,1H),4.52(d,J=18.9Hz,1H),5.11(dd,J=9.7,J=5.8Hz,1H),5.27(dd,J=9.2,J=5.8Hz,1H),5.41(d,J=16.7Hz,1H),5.53(d,J=16.7Hz,1H),7.23(t,J=7.4Hz,1H),7.30(s,1H),7.49(m,2H),7.68(d,J=8.4Hz,1H),7.04(s,1H)。
IIIg.合成20-O-膦酰氧基甲基喜树碱精氨酸盐:
向连续进行超声处理的20-O-膦酰氧基甲基喜树碱(5mg,10mmol)在氧化氘(0.5mL)中的悬浮液中滴加L-精氨酸(27μl,0.40M溶液,10.8mmol)的氧化氘溶液直至完全均匀。获得标题化合物的黄色均匀溶液。
1H NMR(400MHz,D2O,δ):1.02(t,J=7.1Hz,1H),1.66(m,2),1.89(m,2H),2.25(m,2H),3.20(t,J=6.8Hz,2H),3.77(t,J=6.0Hz,1H),4.40(d,J=19.0Hz,1H),4.49(d,J=1018.8Hz,.1H),5.12(dd,J=9.7,J=6.0Hz,1H),5.29(dd,J=8.8,J=6.1Hz,1H),5.40(d,J=16.7Hz,1H),5.51(d,J=16,7Hz,1H),7.20(t,J=7.3Hz,1H),7.29(s,1H),7.47(m,2H),7.66(d,J=8.3Hz,1H),8.03(s,1H)。
IIIh.合成20-O-膦酰氧基甲基喜树碱N-葡糖胺盐:
向连续进行超声处理的20-O-膦酰氧基甲基喜树碱(5mg,10.9mmol)在氧化氘(0.5mL)中的悬浮液中滴加(D)-N-甲基葡糖胺(21μl,0.51M溶液,10.7mmol)的氧化氘溶液直至完全均匀。获得标题化合物的黄色均匀溶液。
1H NMR(400MHz,D2O,δ):1.02(t,J=7.3Hz,3H),2.25(m,2H),2.78(s,3H),3.20(m,2H),3.65(m,2H),3.80(m,3H),4.11(m,1H),4.44(d,J=18.9Hz,1H),4.53(d,J=19.0Hz,1H),5.12(dd,J=9.8,J=5.9Hz,1H),5.27(dd, J=9,2,J=5.9Hz,1H),5.41(d,J=16.7Hz,1H),5.53(d,J=16.7Hz,1H),7.23(t,J=7.4Hz,1H),7.49(m,2H),7.69(d,J=8.4Hz,1H),8.05(s,1H)。
Iv.合成4′-O-膦酰氧基甲基依托泊苷:
Iva.合成4′-O-膦酰氧基甲基依托泊苷二苄基酯:
向磷酸二苄基氯代甲基酯(670mg,2.0mmol)、依托泊苷(300mg,0.51mmol)和四丁基溴化铵(164.4mg,0.51mmol)的四氢呋喃(0.5mL)溶液中加入粉末碳酸钾(352.4mg,2.55mmol)。将形成的混合物在室温下剧烈搅拌35分钟。然后,将混合物直接用硅胶快速柱色谱进行纯化(30∶1二氯甲烷/甲醇),得到272mg(61%收率)的标题化合物,为一种白色固体(超过95%保留反式立体化学)。
FABMS+(NBA):[MH]+,m/z 879。
1H NMR(400MHz,CDCl3,δ):1.41(d,J=5.0Hz,3H),2.79(brs,1H),2.86(m,1H),2.97(br s,1H),3.30(dd,J=14.2,J=5.3Hz,1H),3.35(m,2H),3.45(t,J=8.5,J=8.0Hz,1H),3.59(m,1H),3.66(s,6H),3.74(m,1H),4.19(m,1H),4.20(t,J=8.5,J=8.0Hz,1H),4.42(dd,J=10.3,J=9.1Hz,1H),4.60(d,J=5.2Hz,1H),4.64(d,J=7.6Hz,1H),4.76(q,J=5.0Hz,1H),4.92(d,J=3.4Hz,1H),5.03(dd,J=7.3,J=4.3Hz,4H),5.54(dd,J=11.7,J=5.1Hz,1H),5.59(dd,J=11.3,J=5.1Hz,1H),5.99(d,J=3.5Hz,2H),6.26(s,2H),6.51(s,1H),6.84(s,1H),7.33(m,10H)。
13C NMR(75MHz,CDCl3,δ):20.21,37.49,41.00,43.78,56.07,66.32,67.87,67.97,69.06,69.14,73.01,73.29,74.47,79.70,92.55,92.62,99.70,101.57,101.72,107.89,109.13,110.55,127.82,127.97,128.15,128.35,128.43,132.40,133.08,135.68,135.78,136.49,147.14,148.73,152.18,174.90。
IVb.合成4′-O-膦酰氧基甲基依托泊苷
向4’-O-膦酰氧基甲基依托泊苷二苄基酯(20.5mg,0.023mmol)的四氢呋喃(2mL)溶液中加入钯/炭(10%,5mg)。将混合物在氢气(1atm)下搅拌10分钟。经硅藻土过滤除去催化剂,减压蒸出四氢呋喃。将形成的残余物在真空下干燥,得到16mg(100%收率)的标题化合物,为一种白色固体。
FABMS+(NBA)[MH]+,m/z 699。
1H NMR(400MHz,CDCl3/DMSO-d6,δ):1.29(d,J=5.0Hz,3H),2.78(m,1H),3.21(m,2H),3.29(t,J=8.6,J=7.8Hz,1H),3.37(dd,J=14.0,J=5.3Hz,1H),3.52(m,2H),3.62(s,6H),4.09(m,1H),4.17(t,J=8.1Hz,1H),4.38(dd,J=8.8,J=8.7Hz,1H),4.44(d,J=7.6Hz,1H),4.48(d,J=5.3Hz,1H),4.66(q,J=5.0Hz,1H),4.88(d,J=3.3Hz,1H),5.05(brs,7H),5.40(dd,J=10.7,J=7.8Hz,1H),5.43(dd,J=10.4,J=7.5Hz,1H),5.89(dd,J=8.8Hz,1H),6.18(s,2H),6.41(s,1H),6.78(s,1H)。
IVc.合成4′-O-膦酰氧基甲基依托泊苷二钠盐:
向4′-O-膦酰氧基甲基依托泊苷二苄基酯(200mg,0.227mmol)的四氢呋喃(10mL)溶液中加入钯/炭(10%,45mg)。将混合物在氢气(1atm)下搅拌25分钟。经硅藻土过滤除去催化剂,将滤液进行减压蒸发,将残余物进行真空干燥。将形成的白色固体溶解于碳酸氢钠的水溶液中(2.9mL,0.136M,0.394mmol)。将形成的多相混合物与活性炭混合,搅拌几分钟,然后通过40μm的过滤单元过滤。将均匀的无色滤液进行冷冻干燥,得到140mg(96%收率)的标题化合物,为一种白色固体(超过95%保留反式立体化学)。
FABMS+(NBA):[MH]+,m/z 743,[M-Na+2H]+,m/z 721,[M-2Na+3H]+,m/z 699。
1H NMR(400MHz,D2O,δ):1.37(d,J=5.1Hz,3H),3.10(m,1H),3.37(dd,J=8.9,J=8.0Hz,1H),3.48(m,2H),3.65(m,3H),3.75(s,6H),4.29(dd,J=10.4,J=4.5Hz,1H),4.41(t,J=8.3,J=8.0Hz,1H),4.49(dd,J=10.5,J=8.9Hz,1H),4.68(d,J=5.7Hz,1H),4.74(d,J=7.8Hz,1H),4.91(q,J=5.0Hz,1H),5.13(d,J=3.0Hz,1H),5.26(2xd,J=5.3,J=3.3Hz,1H),5.28(2xd,J=5.3,J=3.3Hz,1H),5.98(d,J=10.5Hz,2H),6.40(s,2H),6.58(s,1H),7.00(s,1H)。
13C NMR(125MHz,D2O,δ):22.13,40.74,43.56,46.11,59.12,68.70,70.41,72.40,75.46,75.95,76.95,82.46,94.87,102.88,103.66,104.62,111.14,112.82,113.23,130.73,135.45,135.74,140.22,149.56,151.43,154.94,166.36,181.61。
31P NMR(200MHz,D2O,δ):s(2.19)。
V.合成膦酰氧基甲基化试剂
Va.合成磷酸二苄基氯代甲基酯
在20分钟内,分几次向回流中的氯碘代甲烷(25g,97%,0.14mol)的甲苯(HPLC-级,30mL)溶液中加入磷酸二苄基酯银盐(7.0g,0.018mol)。继续回流1小时。在将反应混合物冷却至室温后,过滤,减压蒸出溶剂。将油状残余物进行硅胶快速柱色谱纯化(7∶3己烷/乙酸乙酯),得到3.63g(62%收率)的标题化合物,为一种黄色油。
FABMS+(NBA):[MH]+,m/z 327。
1H NMR(300MHZ,CDCl3,δ):5.10(d,J=8.0Hz,4H),5.63(d,J=15.7Hz,2H),7.36(s,10H)。
13C NMR(75MHz,CDCl3,δ):69.68,69.75,73.33,73.42,127.93,128.51,128.63,135.07。
Vb.合成磷酸二苄基(对甲苯砜甲基)酯:
在氩气氛下,向搅拌中的对甲苯磺酸银(600mg,2.15mmol)的无水乙腈(3mL)溶液中加入磷酸二苄基氯代甲基酯(150mg,0.46mmol)。在将反应混合物于室温下搅拌21小时后,除去溶剂,将残余物用乙醚(3×3mL)萃取。合并后的萃取液过滤,蒸发,真空下干燥,得到210mg(99%收率)的标题化合物,为一种白色固体。
EIMS:[MHJ+,m/z 463.
1H NMR(300MHz,CDCl3,δ):2.37(s,3H),4.91(2xd,J=7.9Hz,4H),5.61(d,J=14.2Hz,2H),7.29(m,12H),7.78(d,J=8.4Hz,2H)。
对于上述反应Vb来说,也可以上述Ic解释,试剂
可通常由下式表示:
其中,所有的符号均与以上的定义相同。
Vc.合成甲醛双(二苄氧基膦酰基)缩乙醛:
向二碘代甲烷(4mL,50mmol)的无水甲苯(15mL)溶液中加入磷酸二苄基酯银盐(3.0g,7.8mmol)。将形成的混合物在氩气氛下回流15分钟。然后,将混合物冷却至室温,过滤。再在真空下蒸出溶剂。将油状残余物进行硅胶快速柱色谱纯化(1∶1己烷/乙酸乙酯和然后乙酸乙酯),得到一种淡黄色油,将其再结晶,得到1.97g(90%收率)的标题化合物,为一种白色固体,mp39~42℃。
CIMS(NH3):[MH]+,m/z 569。
1H NMR(300MHz,CDCl3,δ):5.03(d,J=7.9Hz,8H),5.49(t,J=14.3Hz,2H),7.30(m,20H)。
13C NMR(75MHz,CDCl3,δ):69.54,69.61,86.48,127.88,128.48,128.55,135.10,135.20。
VI-合成O-膦酰氧基甲基环孢菌素A:
VIa.合成O-甲基硫甲基环孢菌素A:
向环孢菌素A的二甲亚砜(250mL)悬浮液中加入乙酸酐(125mL)和乙酸(35mL)。将多相混合物在室温下剧烈搅拌24小时,倒入冰(800mL)中,再搅拌30分钟,再用二氯甲烷萃取(4×100mL)。合并后的二氯甲烷萃取液用水(2×100mL)洗涤,用硫酸镁干燥。减压除去二氯甲烷,得到一种产物。将该产物进一步经硅胶色谱纯化。
VIb.合成O-膦酰氧基甲基环孢菌素A二苄基酯:
向搅拌良好的O-甲基硫甲基环孢菌素A和粉末状的活化4分子筛(5g)在四氢呋喃(20mL)中的悬浮液中加入N-碘代琥珀酰亚胺(2.00g,95%,8.44mmol)和磷酸二苄基酯(2.20g,7.83mmol)在二氯甲烷(12mL)中的悬浮液。将形成的混合物在室温下剧烈搅拌30分钟,过滤,用乙酸乙酯(300mL)稀释。将溶液用硫代硫酸钠水溶液(10%,2×15mL)、水(2×20mL)、盐水(50mL)洗涤,用硫酸镁干燥。将混合物过滤,减压蒸出溶剂。将残余物用硅胶快速柱色谱纯化。
VIc.合成O-膦酰氧基甲基环孢菌素A:
向O-膦酰氧基甲基环孢菌素A二苄基酯在四氢呋喃(100mL)和水(5mL)中的溶液中加入钯/炭(10%,500mg)。将混合物在氢气(1atm)下搅拌35分钟。经硅藻土过滤除去催化剂。然后,硅藻土用四氢呋喃(300mL)洗涤,合并后的滤液进行减压蒸发。将形成的固体用乙醚(2×20mL)、己烷(50mL)洗涤,真空干燥,然后溶解于热甲醇(60mL)中。将溶液过渡,减压浓缩至约10mL体积。在室温下放置1小时后,将溶液放置于冰箱中过夜。滤出过夜形成的结晶沉淀,真空干燥,得到标题化合物,为一种固体。将滤液浓缩至约1mL体积,并在冰箱中保持1小时,得到另一部分产物。
生物学评价
本发明的化合物为新的药剂;对式I的代表性化合物在体外和体内转化研究结果进行了评价。在所有这些研究中,前药均被转化成药物活性的母化合物。
(1)
丙泊酚前药在水中的溶解性评价
丙泊酚前药的水溶性大约为500mg/mL,基于饱和水溶液的HPLC分析。
(2)
丙泊酚前药向丙泊酚的体外转化
丙泊酚前药向丙泊酚的体外转化采用在pH值为10.4的培养基的甘氨酸缓冲液中的碱性磷酸酶进行。制备25mL的100μg/mL丙泊酚前药在甘氨酸缓冲液中的溶液。将1mL用作0时间点保存,其余的24mL放置在37℃的水浴中。向24mL的丙泊酚前药溶液中加入960μL的0.1mg/mL碱性磷酸酶的甘氨酸缓冲溶液,混合,再返回水浴中。在下述时间取出1.5mL的样品:5、10、20、30、40、60、90、120、180、240、300和360分钟。立即向每一样品中加入10μL的冰醋酸停止酶反应。通过HPLC对样品进行分析,以确定丙泊酚前药与丙泊酚的浓度。体外转化的结果示于图1中。这些结果表明,丙泊酚前药是一种碱性磷酸酶的酶作用物。
(3)
在大鼠中进行的总毒性评价
制备一种用于体内注射的丙泊酚前药,其在0.9%氯化钠注射液,USP中的浓度为68mg/mL。该浓度相当于36mg/mL的丙泊酚。在给药前用0.22μm的尼龙膜对丙泊酚前药溶液进行过滤。用两支体重为820和650g的雄性Harlen Sprague-Dawley大鼠进行丙泊酚前药的评价。使820g的大鼠经尾静脉接受200μL的丙泊酚前药体内制剂(相当于9mg/kg丙泊酚)。在大约12分钟后,从尾静脉取血样(采用肝素化的注射器)。而650g的大鼠在接受丙泊酚前药制剂前先接受一定剂量的温和镇静剂Metaphane。给650g的大鼠在尾静脉处注射125μL的丙泊酚前药制剂,并在大约6分钟后从尾静脉取血样(采用肝素化的注射器)。将来自两支大鼠的血样用HPLC进行丙泊酚分析。
结果,在两支大鼠的丙泊酚前药注射结果是类似的。两支大鼠均在几分钟后不稳定,但,并未失去其正常的反射。基于目视观察,大鼠完全从丙泊酚前药注射中恢复。经HPLC分析证实来自两支大鼠取得的血样均存在丙泊酚。由于丙泊酚前药的作用,大鼠并未显示出不适的迹象。
(4)
狗的药物动力学评价
对涉及Diprivan或丙泊酚前药的药动学研究在狗体中进行,并在两次研究之间具有充分的洗出时间。通过荧光检测由HPLC测量血浓度,并同时用两个铅脑电图描记术(EEG)来检测大脑的活性。在给狗服药前,将狗遮眼,将棉花放置在狗耳内,将狗腿捆绑住以减少活动和其它外部刺激,从而使丙泊酚对狗的脑波活性的作用最有效地检测出来。
采用重13kg的长耳短腿小猎犬进行丙泊酚血浓度随时间变化的评价。在注射之前取得大约8mL的血用作标准曲线制备和0时血液水平。经头侧静脉注射,使狗接受一定量的Diprivan或丙泊酚前药制剂,相当于7mg/kg的丙泊酚。
在注射后1、3、5、10、15、20和30分钟后,经头侧(与制剂注射位置不同的静脉)、颈静脉或隐静脉(肝素化注射器)取得2mL血样。还在60、90、120、180、240、300、360、480和1440分钟后取血样。在从狗身上取得血样后立即对血样提取以除去丙泊酚。在接受Diprivan或丙泊酚前药制剂前使狗禁食大约20小时。在取样120分钟后,允许狗饮水。在获得血样480分钟后,给狗进食。狗的常规饮食为Hills’Science Diet Maintenance。使狗每天以亮/暗12小时的循环接受光线。
通过荧光检测由HPLC测量丙泊酚在血样中的浓度。结果如表2所示。所采用的血液提取法和HPLC法均基于Plummer的工作报告(1987),只有很少的修改。样品制备和实验过程如下:
向1mL的血样中加入10μL的百里酚内标物(20μg/mL)和1mL的磷酸盐缓冲液(0.1M,pH7.2),在每次加入后进行涡流混合。然后加入5mL的环己烷,使样品在75rpm下混合20-30分钟。通过在约2000rpm下进行1分钟的离心,分离出有机层。将大约4.5mL的有机层转移至包含50μL稀四甲基氢氧化铵(TMAH)溶液(大约为1.8%(v/v))的试管中。在氮气流下将溶剂蒸发至干,并用200μL的流动相A进行复配。将样品在15,000rmp下再离心30秒以除去任何颗粒,将上清液注入HPLC中。标准曲线样品制备:将1mL的初始血液的等分试样中掺加含量为5、1、0.5、0.1和0.01mg/mL的丙泊酚。这些标准均与样品一样进行相同的处理。
HPLC系统由下述Shimadzu部件组成:LC-10AT泵、SCL-10A系统控制器、RF353荧光检测器和SIL-10A自动进样器。HPLC的参数如下:275nm下激发和在320nm下发射;流速为1mL/分钟;注射体积为3-30μL,取决于丙泊酚浓度。HPLC柱为Zorbax RX-C18,15cm×4.6mm内径,5μm粒径。流动相A为60∶40(v/v)乙腈:25mM磷酸盐、15mM TAAP缓冲液pH7.1。流动相B为80∶10∶10(v/v/v)乙腈∶水∶THF。流动相B用于在采用流动相A洗脱百里酚和丙泊酚后对柱子进行清洗(分别为4.2和7.4分钟)。
根据目视观察和EEG图形,狗显示出对注射的两种制剂有麻醉迹象。狗从两种制剂的麻醉中恢复时间为20-30分钟。注射丙泊酚前药导致的丙泊酚血浓度值与注射Diprivan所产生的血浓度值近似。
(5)
喜树碱前药在水中溶解性的评价
根据目视观察和HPLC分析,喜树碱前药的水溶性大于50mg/mL。
(6)
喜树碱前药(p-cpt)酶性研究
将16μg/mLp-cpt用酸性磷酸酶(0.02单位/mL p-cpt溶液)进行分裂。介质为0.09M的柠檬酸盐缓冲液,pH4.8,温度为37℃。p-cpt至喜树碱的转化通过HPLC进行检测。
HPLC参数:
MP:24%磷酸钾缓冲液,pH4,76%乙腈
柱:Zorbax RX-C18,15cm×4.6mm内径,粒径5μm
检测:370nm UV
流速:1mL/分钟
酸性磷酸酶来自牛前列腺(sigma)。结果如图3所示。结果表明,喜树碱前药是一种磷酸酶的酶作用物。
(7)
采用大鼠进行的喜树碱前药的药物动力学研究
采用喜树碱前药和喜树碱制剂对雄性Sprague-Dawley大鼠给药以进行药物动力学研究。被研究的喜树碱前药的两种制剂分别由将前药溶解于15mM磷酸盐(pH4.0)得到和将喜树碱溶解于有机助溶剂中得到。以下是药物动力学实验的概述:
制备一定体积的喜树碱前药制剂或喜树碱制剂,其浓度应使剂量相当于1mg喜树碱/kg给药于大鼠。在大鼠的左颈静脉中采用留置套管给药于大鼠。经位于大鼠右颈静脉中的留置套管取得血样。两个套管在使用前均用肝素化盐水冲洗,并在肝素化盐水存在下进行研究。
在向颈静脉插入套管之前,用戊巴比妥钠将大鼠麻醉,并在研究过程中保持用戊巴比妥麻醉。在研究过程中,将大鼠放置在37℃的加热垫上并切开气管。在给药前取大约150μL的血样,在向大鼠给药制剂后的1、3、5、10、15、20、45、60和90分钟后取血样。
将血样放置在微量离心管中,并在大约15000rpm下离心20秒。将来自每种血样的50μL血浆等分液转移至第二个微量离心管中。向血浆中加入150μL冰冷的乙腈并涡旋振动5秒。然后加入450μL冰冷的磷酸钠(0.1M,pH7.2),将微量离心管的内容物涡旋振动5秒钟,然后在约15000rpm下离心20秒,将上清液转移至设置在4℃的HPLC自动进样器中进行分析(50μL注射量)。
HPLC系统由下述Shimadzu部件组成:LC-10AT泵、SCL-10A系统控制器、RF353荧光检测器和SIL-10A自动进样器(设置在4℃)和CTO-10A柱烘箱(温度设置在30℃)。HPLC的参数如下:370nm下激发和在435nm下发射;流速为2mL/分钟。HPLC柱为Hypersil ODS,15cm×4.5mm内径,5μm粒径。流动相为75%25nM的磷酸钠,pH6.5/25%乙腈(v/v),还含有25mM的四丁基磷酸二氢铵作为离子-减少剂。
从附图(图4)可以看出,前药提供的喜树碱血浆浓度与直接注射喜树碱在有机助溶剂中的溶液所获得的血浆浓度相当。该附图提供了接受了前药的五只大鼠和接受了喜树碱的六只大鼠的平均值和标准偏差。
Claims (9)
2.权利要求1的化合物,其中所述的碱金属离子R1和R2各自独立选自钠、钾和锂。
4.权利要求3的化合物,其中的Z选自钠、氨丁三醇、三乙醇胺、三乙胺、精氨酸、赖氨酸、乙醇胺以及N-甲基葡糖胺。
6.化合物
其中Y是膦酰基保护基团,n是1或2的整数。
7.权利要求6的化合物,所述的膦酰基保护基团选自苄基,叔丁基和烯丙基。
8.含有有效量权利要求1所述化合物和药学上可接受载体的药物组合物。
9.权利要求8所述的组合物用于制备麻醉剂的用途。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN109456360A (zh) * | 2018-12-17 | 2019-03-12 | 河南中医药大学 | 一种磷丙泊酚钠的制备方法 |
CN109456360B (zh) * | 2018-12-17 | 2021-05-14 | 河南中医药大学 | 一种磷丙泊酚钠的制备方法 |
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