WO2010135918A1 - 去羟肌苷前体药物及其制备方法 - Google Patents

去羟肌苷前体药物及其制备方法 Download PDF

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WO2010135918A1
WO2010135918A1 PCT/CN2010/070253 CN2010070253W WO2010135918A1 WO 2010135918 A1 WO2010135918 A1 WO 2010135918A1 CN 2010070253 W CN2010070253 W CN 2010070253W WO 2010135918 A1 WO2010135918 A1 WO 2010135918A1
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didanosine
amino acid
prodrug
residue
protected
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PCT/CN2010/070253
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何仲贵
孙进
许佑君
闫中天
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沈阳药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

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  • the invention belongs to the technical field of medicine, relates to a didanosine prodrug and a preparation method thereof, and particularly relates to an anti-AIDS 2',3'-dideoxyinosine (ie "deoxyinosine") 5'-substituted- Amino acid ester prodrug and preparation method thereof.
  • Dehydroinosine has a chemical name of 2,, 3'-dideoxyinosine nucleoside.
  • Deoxyinosine is a synthetic nucleoside drug that has a 3'-hydroxyl group that is hydrogen compared to native adenosine.
  • Deoxyinosine is phosphorylated by cellular kinase to form an active metabolite 5'-trisede deoxyadenosine.
  • 5,-Tris-deoxyadenosine inhibits HIV reverse transcriptase, and its mechanism involves competition with the natural substrate deoxyadenosine triphosphate, and incorporation into viral DNA to terminate the elongation of the DNA strand. Deoxyinosine was released in 1991.
  • deoxyinosine is easily decomposed under acidic conditions, has a high polarity, and has poor membrane permeability in the small intestine, resulting in a transdermal bioavailability of only 20 to 40%. Therefore, it is necessary to find a way to improve the intestinal permeability and oral bioavailability of didanosine.
  • "natural" Z-amino acids can be actively transported in vivo, and they can be linked to pharmacodynamic molecules as pharmacophores, which can often promote the absorption and transport of pharmacophores, and even improve the targeting of drugs.
  • this patent intends to carry out the 5' free hydroxyl group of didanosine!
  • the amino acid is modified to overcome the shortcomings of poor oral absorption of the drug.
  • the object of the present invention is to provide a 5'-0-amino acid ester of 2',3 '-dideoxyinosine nucleoside, which is a 5 '- ⁇ --amino acid ester of didanosine and a preparation method thereof .
  • R is an L amino acid residue.
  • the didanosine 5'-0-amino acid ester includes the following compounds:
  • the didanosine prodrug of the present invention is prepared by the following method: dehydroxyinosine and N-protected amino acid are subjected to catalytic conditions under dicyclohexylcarbodiimide and N,N-dimethylformamide. The ester reaction, and then catalytic hydrogenation to remove the protecting group to form the didanosine L-amino acid ester prodrug, the reaction formula is as follows:
  • X is an N-protected amino acid
  • Y is an N-protected amino acid residue
  • R is an L-amino acid residue
  • X is an amino acid protected by N benzyloxycarbonyl group
  • Y is a residue of an amino acid protected by N benzyloxycarbonyl group
  • R is an amino acid residue.
  • X is N-benzyloxycarbonylproline, N-benzyloxycarbonyl isoleucine, N-hydroxycarbonyl-L-phenylalanine, N-hydroxycarbonylproline and hydrazine-benzyl Oxycarbonyl-L-tryptophan.
  • Y is the residue of the N-hydroxycarbonyl-amino acid.
  • the N-benzyloxycarbonyl-amino acid is preferably the following: N-benzyloxycarbonyl-proline, N-benzyloxycarbonyl--isoleucine, N-benzyloxycarbonyl-phenylalanine, N- Benzyloxycarbonylproline and N-benzyloxycarbonyl-tryptophan.
  • the second step adding 10 mmol of (III) to 250 ml of anhydrous ethyl acetate, adding an appropriate amount of 5% palladium carbon (W/W) as a catalyst under stirring, catalytic hydrogenation under hydrogen conditions, and 6 CTC reaction for 5 hours. After filtration, the filtrate was evaporated to dryness under reduced pressure to give compound (IV)-(VI).
  • the present invention synthesizes a series of didanosine 5'-0-L-amino acid esters for the first time, and the preparation method is simple and easy.
  • the membrane permeability of Caco-2 is significantly improved in the compound of the present invention compared to didanosine.
  • the compounds of the invention have improved oral bioavailability compared to didanosine.
  • the didanosine prodrug (IV) of the present invention is an oral bioavailable anti-HIV prodrug, which is dehydroxylated after oral administration of the didanosine prodrug (W) of the present invention.
  • the absolute bioavailability of inosine in rats is comparable to tail vein injection.
  • Figure 1 is a graph showing the blood concentration of didanosine in rats in the form of a specific embodiment:
  • N-benzyloxycarbonylproline is reacted with didanosine, dicyclohexylcarbodiimide and W,N-4-dimethylaminopyridinium are added, and the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclohexane.
  • the reaction temperature is 0 ° C to the boiling point of the solvent, preferably 20 to 60 ° C, the reaction time is 8 hours; the reaction solution is cooled to room temperature, the solvent is evaporated under reduced pressure, and the residue is ethyl acetate or The methyl chloride is extracted, and washed with distilled water, saturated sodium hydrogen carbonate and saturated brine.
  • N-benzyloxycarbonyl-isoleucine is reacted with didanosine, dicyclohexylcarbodiimide and N dimethylaminopyridine are added, and the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclohexane or dimethyl
  • the reaction temperature is from 0 ° C to the boiling point of the solvent, preferably from 20 to 60 ° C, and the reaction time is 8 hours; the reaction solution is cooled to room temperature, the solvent is evaporated under reduced pressure, and the residue is extracted with ethyl acetate or dichloromethane.
  • N-benzyloxycarbonyl-phenylalanine is reacted with didanosine, dicyclohexylcarbodiimide and W,N-4-dimethylaminopyridine are added, and the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, and ring. Hexane or dimethylformamide, the reaction temperature is from 0 ° C to the boiling point of the solvent, preferably 20 to 60 ° C, and the reaction time is 8 hours; the reaction solution is cooled to room temperature, and the solvent is evaporated under reduced pressure. The mixture is extracted with dichloromethane, and washed with distilled water, saturated sodium hydrogencarbonate and brine, and the organic layer is collected.
  • the organic layer is dried over sodium sulfate and evaporated to dryness. Under the solvent of ethyl acetate or dichloromethane, Pd/C is added as a catalyst, and catalytic hydrogenation is carried out under hydrogen conditions. The reaction time is 5 hours, suction filtration, and the filtrate is evaporated under reduced pressure to obtain (VI.).
  • N-benzyloxycarbonyl-proline is reacted with didanosine, dicyclohexylcarbodiimide and N,W-4-dimethylaminopyridine are added, and the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclohexane Alkane or dimethylformamide, the reaction temperature is 0 ° C to the boiling point of the solvent, preferably 20 to 60 ° C, the reaction time is 8 hours; the reaction solution is cooled to room temperature, the solvent is evaporated under reduced pressure, and the residue is ethyl acetate or The mixture was extracted with methylene chloride, and washed successively with distilled water, saturated sodium bicarbonate and brine, and the organic layer was collected.
  • the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclohexane Alkane or dimethylformamide
  • the reaction temperature is 0 ° C to the boiling point of the solvent, preferably 20
  • Benzyloxycarbonyl tryptophan is reacted with didanosine, dicyclohexylcarbodiimide and N,W-4-dimethylaminopyridine are added, and the reaction solvent is anhydrous tetrahydrofuran, dichloromethane, cyclohexane or dimethyl Carboxamide, the reaction temperature is 0 ° C to the boiling point of the solvent, preferably 20 to 60 ° C, the reaction time is 8 hours; The reaction mixture was cooled to room temperature, and the solvent was evaporated evaporated evaporated. After drying, it is recrystallized from ethyl acetate or dichloromethane, and the product is recrystallized.
  • Pd/C is added as a catalyst under a solvent of ethyl acetate or dichloromethane, and catalytic hydrogenation is carried out under hydrogen for 5 hours. Filter by suction, distill off the filtrate under reduced pressure, that is, ( )
  • deoxyinosine and compound (IV.)- D small intestinal permeability, taken in Transwell® cultured Caco-2 cells for 21 days, at 37 °C, buffered with HBSS The Caco-2 cells were gently washed three times, the impurities on the surface of the cell monolayer were washed away, and the cells were cultured in a 37 ° C incubator for 30 min. They contained 0.5 mM of didanosine and the compound (IV.
  • the experimental group and the control group Sprague-Dawley rats were intragastrically administered (II), dehydroxyinosine and compound (IV.), ie 5'-0-L-prolyl didanosine (as didanosine) All were 30 mg/Kg), and the concentration of didanosine in rat plasma was measured. At the same time, Sprague-Dawley rats were injected with a solution of didanosine normal saline (5 mg/Kg) in the tail vein.

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Description

去羟肌苷前体药物及其制备方法 技术领域：
本发明属于医药技术领域， 涉及去羟肌苷前体药物及其制备方法， 具体 涉及一种抗艾滋药 2',3'-双脱氧肌苷 (即"去羟肌苷") 5'取代 -氨基酸酯前药 及其制备方法。
背景技术：
去羟肌苷其化学名称为 2，, 3' -二脱氧次黄嘌呤核苷。去羟肌苷是人工合 成的核苷类药物， 与天然的腺苷相比， 后者的 3'-羟基变为氢。 去羟肌苷被 细胞激酶磷酸化后形成有活性的代谢物 5'-三磷酸双脱氧腺苷。 5，-三磷酸双 脱氧腺苷抑制 HIV逆转录酶， 其机制包括与自然底物三磷酸脱氧腺苷竟争, 以及掺入至病毒 DNA, 终止 DNA链的延长。 去羟肌苷在 1991年上巿。 但 是去羟肌苷在酸性条件下容易分解， 极性大， 小肠的膜通透性差， 导致其口 服生物利用度只有 20~40%。 因此有必要寻找一种途径来提高去羟肌苷的小 肠渗透率和口服生物利用度。 根据大量文献报道 "天然的" Z-氨基酸在体内 能够实现主动转运， 将其作为药动团与药效分子相连， 往往能够促进药效团 的吸收和转运， 甚至还能提高药物的靶向性， 另根据已上市的伐昔洛韦和缬 更昔洛韦等抗病毒氨基酸酯前药,本专利拟对去羟肌苷 5'自由羟基进行！^氨 基酸修饰， 以克服药物口服吸收不好的缺点。
发明内容：
本发明的目的在于提供一种 2',3 '-二脱氧次黄嘌呤核苷的 5'-0- -氨基 酸酯， 也就是去羟肌苷的 5 '-ϋ- -氨基酸酯和其制备方法。
所述的去羟肌苷 5'-0- -氨基酸酯结构通式为：
Figure imgf000003_0001
其中 R是 L氨基酸残基。
所述的去羟肌苷 5'-0- -氨基酸酯包括如下化合物:
a. 5'-0- -缬氨酰去羟肌苷 （IV), 结构如下：
b.
Figure imgf000004_0001
本发明的去羟肌苷前体药物是通过如下方法制备的：去羟肌苷和 N保护 的氨基酸在二环己基碳二亚胺和 N,N-二甲基甲酰胺催化条件下， 进行成酯 反应， 然后再催化氢化脱去保护基形成去羟肌苷 L-氨基酸酯前药， 反应式 如下：
Figure imgf000005_0001
其中， X为 N保护的氨基酸， Y为 N保护的氨基酸残基， 以及 R为 L氨基 酸残基。
优选地， X为 N被苄氧羰基保护的氨基酸， Y为 N被苄氧羰基保护的 氨基酸的残基， R为 -氨基酸残基。更优选地， X为 N-苄氧羰基 缬氨酸、 N-苄氧羰基 异亮氨酸、 N-节氧羰基 -L-苯丙氨酸、 N-节氧羰基 脯氨 酸和 Λ -苄氧羰基 -L-色氨酸。
去羟肌苷的 5'-0- -氨基酸酯的具体合成方法按照以下通用路线进行： 第一步： 50 mmof N-苄氧羰基氨基酸和 50 mmol二环己基碳二亚胺以及 5 mmol NN-4-二甲氨基吡啶， 分别加到含有 11.8g(50mmol)去羟肌苷的 N,N-二甲基甲酰胺 (250ml)溶液中， 加完后继续反应 8 小时， 反应温度是室 温。 反应结束后， 抽滤， 减压蒸去滤液中的 N,N-二甲基甲酰胺， 残余物用 乙酸乙酯溶解， 然后依次用蒸馏水、 饱和碳酸氢纳， 饱和食盐水洗， 收集乙 酸乙酯层， 过硫酸钠干燥柱， 滤液减压蒸干， 固体用乙酸乙酯重结晶， 得到 化合物 (III), 结构如下：
Figure imgf000006_0001
(ΠΙ)
其中 Y是 N-节氧羰基 - -氨基酸的残基。 N-苄氧羰基 - -氨基酸优选以下几 种： N-苄氧羰基 - -缬氨酸、 N-苄氧羰基 - -异亮氨酸、 N-苄氧羰基 - -苯 丙氨酸、 N-苄氧羰基 脯氨酸和 N-苄氧羰基 - -色氨酸。
第二步： 将 lOmmol的 (III)加入到 250ml无水乙酸乙酯中， 搅拌条件下加入 加入适量 5%钯碳 (W/W)作催化剂， 在氢气条件下进行催化氢化， 6CTC反应 5 小时， 过滤， 滤液减压蒸干得到化合物 (IV)-(VI)。
本发明的优点： 本发明第一次合成了系列的去羟肌苷 5'-0-L-氨基酸 酯， 且制备方法简单， 易行。 本发明化合物与去羟肌苷相比， Caco-2的膜渗 透率有显著提高。 此外， 本发明化合物与去羟肌苷相比具有提高的口服生物 利用度。 优选地， 本发明的去羟肌苷前体药物 (IV)是口服生物利用度更好的 抗 HIV的前体药物， 在口服本发明的去羟肌苷前体药物 (W)后， 去羟肌苷在 大鼠体内的绝对生物利用度与尾静脉注射相当。
附图说明：
图 1为大鼠体内去羟肌苷经时血药浓度图 具体实施方式：
根据上述通用合成路线， 分别制得实施例 1-5的化合物 (见表 2)。
实施例 1 :
N-苄氧羰基 缬氨酸与去羟肌苷反应， 加入二环己基碳二亚胺和 W，N-4-二甲氨基吡咤， 反应溶剂是无水四氢呋喃、 二氯甲烷、 环己烷或二甲 基甲酰胺， 反应温度是 0°C至溶剂沸点， 优选 20〜60°C , 反应时间 8小时； 将反应液冷却至室温， 减压蒸去溶剂， 残余物用乙酸乙酯或二氯甲烷提取， 并依次用蒸馏水、 饱和碳酸氢钠和饱和食盐水洗， 收集有机层， 过硫酸钠干 燥柱， 滤液蒸干后， 用乙酸乙酯或二氯甲烷重结晶， 重结晶产物， 在乙酸乙 酯或二氯甲烷做溶剂下， 加入 Pd/C做催化剂， 在氢气条件下进行催化氢化， 反应时间 5小时， 抽滤， 减压蒸去滤液， 即得 (IV.) 实施例 2:
N-苄氧羰基 - -异亮氨酸与去羟肌苷反应，加入二环己基碳二亚胺和 N 二甲氨基吡啶， 反应溶剂是无水四氢呋喃、 二氯甲烷、 环己烷或二甲基 甲酰胺， 反应温度是 0°C至溶剂沸点， 优选 20~60°C , 反应时间 8小时； 将 反应液冷却至室温， 减压蒸去溶剂， 残余物用乙酸乙酯或二氯甲烷提取， 并 依次用蒸馏水、 饱和碳酸氢钠和饱和食盐水洗， 收集有机层， 过硫酸纳干燥 柱， 滤液蒸干后， 用乙酸乙酯或二氯甲烷重结晶， 重结晶产物， 在乙酸乙酯 或二氯甲烷做溶剂下， 加入 Pd/C做催化剂， 在氢气条件下进行催化氢化， 反应时间 5小时， 抽滤， 减压蒸去滤液， 即得 (V.)
实施例 3:
N-苄氧羰基 - -苯丙氨酸与去羟肌苷反应， 加入二环己基碳二亚胺和 W，N-4-二甲氨基吡啶， 反应溶剂是无水四氢呋喃、 二氯甲烷、 环己烷或二甲 基甲酰胺， 反应温度是 0°C至溶剂沸点， 优选 20〜60°C , 反应时间 8小时； 将反应液冷却至室温， 减压蒸去溶剂， 残余物用乙酸乙酯或二氯甲烷提取， 并依次用蒸馏水、 饱和碳酸氢纳和饱和食盐水洗， 收集有机层， 过硫酸钠干 燥柱， 滤液蒸干后， 用乙酸乙酯或二氯甲烷重结晶， 重结晶产物， 在乙酸乙 酯或二氯甲烷做溶剂下， 加入 Pd/C做催化剂， 在氢气条件下进行催化氢化， 反应时间 5小时， 抽滤， 减压蒸去滤液， 即得 (VI.)
实施例 4:
N-苄氧羰基- -脯氨酸与去羟肌苷反应， 加入二环己基碳二亚胺和 N, W-4-二甲氨基吡啶， 反应溶剂是无水四氢呋喃、 二氯甲烷、 环己烷或二甲基 甲酰胺， 反应温度是 0°C至溶剂沸点， 优选 20~60°C , 反应时间 8小时； 将 反应液冷却至室温， 减压蒸去溶剂， 残余物用乙酸乙酯或二氯甲烷提取， 并 依次用蒸馏水、 饱和碳酸氢钠和饱和食盐水洗， 收集有机层， 过硫酸钠干燥 柱， 滤液蒸干后， 用乙酸乙酯或二氯甲烷重结晶， 重结晶产物， 在乙酸乙酯 或二氯甲垸做溶剂下， 加入 Pd/C做催化剂， 在氢气条件下进行催化氢化， 反应时间 5小时， 抽滤， 减压蒸去滤液， 即得
实施例 5:
苄氧羰基 色氨酸与去羟肌苷反应， 加入二环己基碳二亚胺和 N, W-4-二甲氨基吡啶， 反应溶剂是无水四氢呋喃、 二氯甲烷、 环己焼或二甲基 甲酰胺， 反应温度是 0°C至溶剂沸点， 优选 20~60°C , 反应时间 8小时； 将 反应液冷却至室温， 减压蒸去溶剂， 残余物用乙酸乙酯或二氯甲烷提取， 并 依次用蒸馏水、 饱和碳酸氢钠和饱和食盐水洗， 收集有机层， 过硫酸钠干燥 柱， 滤液蒸干后， 用乙酸乙酯或二氯甲烷重结晶， 重结晶产物， 在乙酸乙酯 或二氯甲烷做溶剂下， 加入 Pd/C做催化剂， 在氢气条件下进行催化氢化， 反应时间 5小时， 抽滤， 减压蒸去滤液， 即得 ( ）
实施例 6: Caco-2细胞转运实验
利用 Caco-2细胞模型， 考察了去羟肌苷和化合物 (IV.) - ( D小肠膜渗透 率， 取在 Transwell®培养 21天的 Caco-2细胞进行实验， 在 37 °C , 用 HBSS 缓冲液轻柔地清洗 Caco-2细胞 3次， 洗去细胞单分子层表面的杂质， 最后 一次置于 37 °C培养箱中培养 30 min。将分别含有 0.5mM的去羟肌苷和化合 物 (IV.) - ( )的 HBSS缓冲液 0.4mL加入到 Caco-2细胞的 Apical侧 ,在 Basal 测加入 0.6 mL HBSS缓冲液作为接收液， 分别在不同时间点吸取 200 接 收液， 测定得到去羟肌苷和化合物 (IV.) - (賈)的膜渗透率。 表 1 去羟肌苷和化合物（IV) - (VID)的膜渗透率
化合物 膜渗透率 (xl 06 cm/s)
去羟肌苷 0.61
(IV.) 8.74
(V) 4.37
(VI.) 2.91
(VII) 1.84
( ） 2.00 实施例 7: Sprague-Dawley 大鼠体内药物动力学研究
给实验组和对照组 Sprague-Dawley大鼠分别灌胃（ II )即去羟肌苷和化合 物 (IV.)即 5'-0 -L-缬氨酰去羟肌苷 (以去羟肌苷计均为 30mg/Kg), 测定大鼠 血浆中去羟肌苷的浓度。同时给 Sprague-Dawley大鼠尾静脉注射去羟肌苷生 理盐水水溶液 (5mg/Kg)。 由表 2和图 1可得出， 化合物 IV与口服去羟肌苷相 比生物利用度有明显提高，相对生物利用度达 266% ,且与静脉给药去羟肌苷 生物利用度相当， 达到了预期设计目的。 表 2 分别口服 ov)和去羟肌苷后， 大鼠体内去羟肌苷的药动学参数
(；以去羟肌苷计 30 mg/Kg)
AUC0-t(ng Cmax( g
ti/2( ) T (h) F(%) 给药途径 h/mL) /mL) 化合物 (IV) (口服） 4441.6 0.61 0.33 6.6 266% 去羟肌苷 (口服） 1739.5 0.64 0.25 1.6
去羟肌苷 (尾静脉注 Π 7 2
1 JO. J O.J I .J
射， 5mg/kg)
OAV
Figure imgf000010_0001
/s/u/ O csososld 816S2S0iAV
Figure imgf000011_0001

Claims

权利要求
1. 去羟肌苷前体药物， 其特征在于： 去羟肌苷的 5'位羟基被 -氨基酸酯化, 其结构通式如下：
Figure imgf000012_0001
其中 R是 L氨基酸残基。
2. 按照权利要求 1所述的去羟肌苷前体药物， 其特征在于所述的前体药物是去 羟肌苷和氨基酸通过酯键链接而成的， 其中 R为 -缬氨酸、 -异亮氨酸、 L- 苯丙氨酸、 -脯氨酸或 L-色氨酸残基。
3. 一种如权利要求 1或 2所述的去羟肌苷前体药物的制备方法， 其特征在于： 去羟肌苷和 N保护的氨基酸在二环己基碳二亚胺和 ¥ -二甲基甲酰胺催化条件 下，进行成酯反应， 然后再催化氢化脱去保护基形成去羟肌苷 L-氨基酸酯前药， 反应式如下：
Figure imgf000012_0002
其中， X为 N保护的氨基酸， Y为 N保护的氨基酸残基， 以及 R为 L氨基酸残 基。
4. 按照权利要求 3所述的制备方法， 其特征在于： 其中 X为 N被苄氧羰基保护 的氨基酸， Y为 N被苄氧羰基保护的氨基酸的残基， R为 L-氨基酸残基。
5. 按照权利要求 4所述的制备方法， 其特征在于： X优选 N-苄氧羰基 缬氨 酸、 N-节氧羰基 - -异亮氨酸、 N-节氧羰基 苯丙氨酸、 N-节氧羰基 - -脯氨 酸和 N-苄氧羰基 -L-色氨酸。
6. 权利要求 1所述的去羟肌苷前体药物在制备抗 HIV药物中的用途。
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JPS4935394A (zh) * 1972-07-31 1974-04-01
US20060241017A1 (en) * 2003-07-29 2006-10-26 Chandran V R Novel compounds with high therapeutic index
CN101580529A (zh) * 2009-05-27 2009-11-18 沈阳药科大学 去羟肌苷前体药物及其制备方法

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Publication number Priority date Publication date Assignee Title
JPS4935394A (zh) * 1972-07-31 1974-04-01
US20060241017A1 (en) * 2003-07-29 2006-10-26 Chandran V R Novel compounds with high therapeutic index
CN101580529A (zh) * 2009-05-27 2009-11-18 沈阳药科大学 去羟肌苷前体药物及其制备方法

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