CN108586534A - 一种新的替诺福韦前药及其制备与应用 - Google Patents
一种新的替诺福韦前药及其制备与应用 Download PDFInfo
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- CN108586534A CN108586534A CN201810594117.5A CN201810594117A CN108586534A CN 108586534 A CN108586534 A CN 108586534A CN 201810594117 A CN201810594117 A CN 201810594117A CN 108586534 A CN108586534 A CN 108586534A
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- Prior art keywords
- methyl
- tenofovir
- bases
- fumaric acid
- propyl
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- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- VCMJCVGFSROFHV-WZGZYPNHSA-N tenofovir disoproxil fumarate Chemical compound OC(=O)\C=C\C(O)=O.N1=CN=C2N(C[C@@H](C)OCP(=O)(OCOC(=O)OC(C)C)OCOC(=O)OC(C)C)C=NC2=C1N VCMJCVGFSROFHV-WZGZYPNHSA-N 0.000 title abstract description 29
- 229960004556 tenofovir Drugs 0.000 title abstract description 22
- 229940002612 prodrug Drugs 0.000 title abstract description 10
- 239000000651 prodrug Substances 0.000 title abstract description 10
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims abstract description 27
- -1 Phosphonate ester Chemical class 0.000 claims abstract description 17
- 239000001530 fumaric acid Substances 0.000 claims abstract description 15
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 14
- 150000002148 esters Chemical class 0.000 claims abstract description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims abstract description 10
- 229920001577 copolymer Polymers 0.000 claims abstract description 7
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 claims description 11
- 229940079593 drug Drugs 0.000 claims description 9
- 229930024421 Adenine Natural products 0.000 claims description 7
- 229960000643 adenine Drugs 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Natural products OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 4
- NYYLZXREFNYPKB-UHFFFAOYSA-N 1-[ethoxy(methyl)phosphoryl]oxyethane Chemical compound CCOP(C)(=O)OCC NYYLZXREFNYPKB-UHFFFAOYSA-N 0.000 claims description 3
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- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 2
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- 230000004060 metabolic process Effects 0.000 abstract description 2
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- ABADUMLIAZCWJD-UHFFFAOYSA-N 1,3-dioxole Chemical compound C1OC=CO1 ABADUMLIAZCWJD-UHFFFAOYSA-N 0.000 abstract 1
- 230000007812 deficiency Effects 0.000 abstract 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 abstract 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
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- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 2
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- 229920000881 Modified starch Polymers 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
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- 229960003205 adefovir dipivoxil Drugs 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- IYYIVELXUANFED-UHFFFAOYSA-N bromo(trimethyl)silane Chemical compound C[Si](C)(C)Br IYYIVELXUANFED-UHFFFAOYSA-N 0.000 description 2
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Classifications
-
- 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
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- 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
-
- 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
- A61P31/20—Antivirals for DNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
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Abstract
本发明公开了一种新的替诺福韦前药：（R）‑1‑（6‑氨基‑9H‑嘌呤‑9‑基）丙‑2‑基双（（5‑甲基‑2‑氧代‑1,3‑二氧杂环戊烯‑4‑基）甲基）膦酸酯（替诺福韦DM酯）与富马酸的共聚物及其制备方法与应用。本发明克服了替诺福韦二吡呋酯体内代谢生成有毒的甲醛这种不足，属于医药与化学领域。
Description
技术领域
本发明涉及替诺福韦前药及其制备方法与应用，属于医药及化学领域。
背景技术
替诺福韦（tenofovir），化学名为9-R-[(2-膦酸甲氧基)丙基]腺嘌呤 ( R-9-[2-(phosphonomethoxy)propyl]adenine, R-PMPA)是核苷类逆转录酶抑制剂，通过抑制HIV-1逆转录酶的活性有效抑制HIV病毒复制。HIV的复制需通过其膜蛋白gp120靶细胞的CD4受体及辅助受体结合，而后诱导gp41亚基启动病毒巨膜与靶细胞的融合，进入靶细胞，在靶细胞中通过逆转录酶合成病毒DNA,在整合酶的作用下，病毒DNA经环化整合至宿主染色体上，进一步合成病毒蛋白质，并在蛋白酶的作用下包装为成熟的病毒颗粒从宿主细胞中释放出来。几乎参与HIV复制整个周期的特异性酶及作用点均是抗HIV药物的作用靶点。大多数抗HIV药物通过直接抑制HIV复制过程中的３类关键酶，即逆转录酶，蛋白酶和整合酶来阻断病毒的复制。
结构中的磷酸铡链既是一个影响吸收的因素，又是一个活性基团，这种配体必须能够在生物体内最好在肝脏中顺利水解，且脱下的基团及中间代谢物要对身体无毒副作用。优选的药物分子应该在胃肠液中相对稳定，进入肝脏，之后被肝脏中特异的CYP3A4氧化分解，代谢特呈离子状态，不易扩散出肝细胞，此过程释放出的母体PMEA经磷酸激酶的两步磷酸化作用，最终转化为活性二磷酸盐(PMEApp)而起到抗HBV DNA的作用。
但由于阿德福韦的膦酸基带负电荷，极性较强，导致生物膜透过性差，生物利用度低。为了提高口服吸收度，开发制成前药，酯类，可以通过血浆酯酶水解为替诺福韦，从而抑制病毒的复制。参见文献：Speit G, Schütz P, Merk O. Adefovir dipivoxil for thetreatment of hepatitis B antigen-positive chronic hepatitis B. [J]. The newEngland Journal of Medicine. 2003,348(9):808-816)。以及 DeChristoforo R ,Penzak SR . Tenofovir: a nucleotide analogue reverse-transcriptase inhibitorfor treatment of HIV infection [J]. American Journal of Health-systemPharmacy, 2004,61(1):86）。药效学试验显示其生物利用度均可得到不同程度提高。(朱玉平等替诺福韦前药研究概况，Journal of International Pharmaceutical Research(国际药学研究杂志) 2012,39(5):414-424)。
替诺福韦二吡酯作为一个HIV抑制剂，口服给药后，在肠内依靠D-糖蛋白载体的转运作用，在血液中迅速地转化为替诺福韦，半衰期长(15-50h)是其作为口服药的一个重要因素。替诺福韦的生物利用度（低于10%），替诺福韦酯的生物利用度有明显提高（27~40%）。Gilead开发的一个用于治疗HIV和其他逆转录病毒感染的核苷酸逆转录酶抑制剂的双酯前药其盐富马酸PMPA的二吡伏酯tenofovir disoproxil fumarate,分别于2001年和2008年被FDA批准用于治疗HIV和HBV感染。在体内很快被血浆中广泛存在的非特异性酯酶水解，尤其是在肠黏膜上皮细胞碳酸酯酶作用下迅速水解释放出PMPA.替诺福韦二吡酯含双甲基异丙基碳酸酯，脂溶性增加，生物利用度得到改善，在体内代谢为原型药PMPA而发挥作用，但是同时释放出毒性大的甲醛，这限制了其临床用途。Naesens, L.Bischofberger,N.Augustijns, P. etc. Antiretroviral efficacy and pharmacokinetics of oralbis(isopropyloxycarbonyloxymethyl)-9-(2-phosphonylmethoxypropyl)adenine inmice. Antimicrob. Agents Chemother.1998.42(7). 1568-73。
因此有必要通过结构改造，从PMPA出发合成新的替诺福韦衍生物，抗HIV/HBV活性高，高效低毒且能发展成一线治疗药物。
发明内容
本发明提供了一种新的替诺福韦前药( Tenofovir DM富马酸共聚物) ，结构式如下：
4，5-二甲基-1，3-二氧杂环戊烯-2-酮( 4，5-dimethyl-1，3-dioxolen-2-one，DMDO)载体前药已被应用于药物设计。以DMDO 为载体的二酯类前药经口服给药后，易被小肠吸收，在体内相应的羧酸酯酶和磷酸酯酶作用下，水解释放出母体药物和无毒性的二氧化碳及2，3-丁二酮进一步水解成2，3-丁二醇 ，从而达到改善药物吸收、提高药物口服生物利用度、降低毒性及不良反应、延长作用时间等目的。参考：蔡田成，张扬，孙博，孙铁民 “DMDO载体前药的研究进展” (沈阳药科大学学报)2013,30(7) :556-567。
还参考以下文献进行了替诺福韦DM酯富马酸共聚物的合成:
LM Schultze ， HH Chapman ， NJP Dubree ， RJ Jones ， KM Kent , el al.Practical synthesis of the anti-HIV drug, PMPA . Tetrahedron Lett, 1998, 39(14) : 1853-1856。
马帅等，富马酸替诺福韦酯的合成工艺改进，中国药物化学杂志2013(5)372-376。
具体实施方式
以下实施例用以说明本发明，但不作为对于本发明的限制。
合成路线：
替诺福韦DM酯富马酸共聚物合成路线
实施例１：
(R) -9- [2- (二乙氧膦酰甲氧基)丙基]腺嘌呤(5)的合成
(R)-9-(2-羟基丙基)腺嘌呤(2) (90.0 g, 0.47 mol)加至DMF(600 ml)中，0℃搅拌下加入叔丁醇锂(46.5 g, 0.58 mol) 。室温搅拌2 h 后冷却至0℃ ，加3(150.0 g , 0.47mol) ,同温搅拌10 h。加叔丁醇锂( 46 . 5 g , 0.58 mol),室温反应3 h 后冷却至0℃ ，再加入对甲苯磺酰氧基甲基膦酸二乙酯(3) (151.5 g ,0.47 mol)，同温搅拌6 h。加10mol/L 盐酸(约20 ml)调至pH7 ，所得4 粗品直接用于下步反应。
如上所得溶液中加入三甲基溴硅烷（TMSBr） (270 g, 1.76 mol),加热至100 ℃反应8 h。减压蒸除溶剂，剩余物中加水(300 ml) ，用乙酸乙酯(120 ml x 2) 洗涤，分除上层有机层后，向水层加40% 氢氧化钠溶液(约20 ml)调至pH 2.5 ~ 3 。室温搅拌15 h，抽滤， 滤饼用水重结晶，得白色晶体5(65 .2 g ，以2 计收率48 . 7 % )。
实施例２
（R）-1-（6-氨基-9H-嘌呤-9-基）丙-2-基双（（5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基）甲基）膦酸酯(7)的合成
将实施例1中的5(45.0g, 0.16mol)和三乙胺(63.8 g, 0.63 mol)加至DMF (200 ml)中，室温搅拌0.5 h 后加6(98.0 g , 0.66 mol)和KI(25.0g ，0.15mol) 60℃反应12 h ，冷却至室温，加乙酸乙酯(200 ml) ，搅拌1 h ，抽滤，滤液用饱和氯化钠溶液(100mlx2)洗涤，无水硫酸镁干燥后过滤。滤液减压浓缩，剩余物中加入石油醚(150 ml), 4℃ 搅拌12 h，抽滤，干燥得白色固体7 (48.4 g , 60.4 % )。
实施例３：
富马酸（R）-1-（6-氨基-9H-嘌呤-9-基）丙-2-基双（（5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基）甲基）膦酸酯 (1)的制备
富马酸(11.7 g , 0.096 mol)溶于异丙醇(450 ml)中，搅拌下加入例２中的7(44.5 g, 0.087mol), 55ºC 反应3 h 。冷却至0ºC ，搅拌5 h ，抽滤，滤饼用异丙醇(60 ml)洗涤，干燥得白色晶体1 ( 44.8g ,82.1%) 。纯度99.5% ( HPLC 面积归一化法，色谱柱Diamonsil C18( 250 mm ×4. 6 mm，5μm) ; 流动相: 0. 01 mol /L 磷酸二氢钾∶乙腈=40∶ 60; 检测波长: 255 nm; 流速: 1 mL /min)。
实施例４
(R)-9-[2-(二乙氧膦酰甲氧基)丙基]腺嘌呤(5)的制备
向2(90.0 g, 0.47 mol)的N-甲基-2-吡咯烷酮（450mL）溶液中加入叔丁醇镁（160.3g，0.94mol），然后加热至70℃℃。 将化合物3（195.2g，0.61mol）滴加到搅拌的混合物中。 通过TLC检测反应。 搅拌约7小时后，反应完成。 将该混合物冷却至环境温度，用乙酸将pH调节至6，然后用乙酸乙酯（2000mL）稀释。 搅拌混合物并加热至50℃以沉淀镁盐。搅拌约30分钟后，冷却混合物，过滤沉淀物。 滤饼用乙酸乙酯洗涤，合并所有滤液并集中。 最终得到淡黄色液体。 粗品(4)直接用于下一步而无需进一步纯化。
实施例５
将实施例４中的（4）的粗溶液冷却至0℃。 加入溴化钠（191.7g，1.86mol）并搅拌。 滴加三甲基氯硅烷（202.4g，1.86mol），然后将反应混合物加热至75℃。 反应在约20小时完成。然后将反应混合物冷却至环境温度，用1L水淬灭并用乙酸乙酯萃取。 将水层冷却至约0℃，用40％氢氧化钠溶液将pH调节至3。 将剩余的混合物搅拌约12小时以结晶，然后过滤。 将固体用冷水洗涤并干燥，得到白色固体(5)77.9g，产率为58.2％，纯度为98.3％。
实施例６
（R）-1-（6-氨基-9H-嘌呤-9-基）丙-2-基双（（5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基）甲基）膦酸酯(7)的制备
将实施例６中的化合物5（74g，0.258mol）和三乙胺（101.0g，1.0mol）加入到N-甲基-2-吡咯烷酮（400mL）中并搅拌。四丁基溴化铵（83.2g，0.258mol），并将所得混合物加热至50℃。 逐滴加入6（148.5g，1.0mol），然后搅拌约6小时。 通过HPLC监测反应完成。 将混合物冷却至环境温度并加入1L水，然后用乙酸乙酯萃取。 将合并的有机萃取物用饱和盐水洗涤两次。所得有机相用无水硫酸钠干燥并浓缩减压得到淡黄色固体112g。粗产物(7)直接用于下一步而无需进一步纯化。
实施例７
富马酸（R）-1-（6-氨基-9H-嘌呤-9-基）丙-2-基双（（5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基）甲基）膦酸酯 (1)的制备
向实施例６中的粗品(7)（59g，0.114mol）的异丙醇（200mL）溶液中加入富马酸（15.8g，0.136mol），将混合物加热至50℃并搅拌 约2小时。 在0℃冷却后，将反应混合物搅拌结晶。将晶体过滤并0℃的异丙醇洗涤。真空干燥固体，得到白色粉末52.5g。 收率72.5％，纯度为99.4％。( HPLC 面积归一化法，色谱柱Diamonsil C18( 250 mm ×4. 6 mm，5μm) ; 流动相: 0. 01 mol /L 磷酸二氢钾∶乙腈= 40:60; 检测波长: 255 nm; 流速: 1 mL /min)。
实施例8
将实施例１里的中间体(5)10g，4-羟基甲基-5-甲基 - 1,3-间二氧杂环戊烯-2-酮（6’）（30mL;可按照Synthetic Communications（1984），22（9）,p1277- 1282合成）和PyBOP（9.05g）加入到无水DMF（70mL）中，搅拌溶解，然后加入DIPEA（47.3mL），并将溶液在45℃下在氮气下搅拌18小时，混合物用二氯甲烷稀释，用10％柠檬酸溶液，饱和NaHCO3和盐水洗涤，分层后，下层有机层用无水Na2SO4干燥，并减压蒸去溶剂。 通过柱分离，条件如下：
（１）正相：
溶剂A:乙酸乙酯EA，
溶剂B:乙酸乙酯:甲醇(v/v)（8:2）
梯度：10至100％B / 15CV，100％B / 2CV
（２）然后反相：
溶剂A:水，溶剂B：乙腈，
梯度：5至95％B / 15CV，95％B / 2CV）
在冷冻干燥后得到(7)，为白色粉末（3.2g）。
纯度为99.7％。( HPLC 面积归一化法，色谱柱Diamonsil C18( 250 mm ×4. 6mm，5μm) ; 流动相: 0. 01 mol /L 磷酸二氢钾∶乙腈= 40:60; 检测波长: 255 nm; 流速: 1 mL /min)。
IR(KBr), νmax (cm-1):
3225,2974,2938, 2902,2875,1832,1757,1740,1682,1474,1435,1390,1376,1266 ,1235 ,1192
1H-NMR ( 300 MHz，DMSO-d6)
δ:13.12(bs,2H) ,8.23 (s,1H, CH), 8.14 (s,1H, CH), 7.09 (s,2H, NH2),6.76(s,2H,CH),4.70 (d,4H CH2,),3.85 (m,2H, CH2),3.84(d,2H),3.4 (m,1H, CH),2.26(s,6H, CH3),1.22 (d, 3H, CH3)
13CNMR(100Mhz,DMSO-d6)
δ:162.4,157.3,152.2,149.7,147.4,140.5,132.9,121.6,119.3,116.2,76.0,72.3,69.0,54.6,20.1,16.3
ESI-MS (m/z) : 512 [M+H]
实施例９
富马酸替诺福韦DM酯片剂工艺
富马酸替诺福韦DM酯 45.5%
乳糖 27%
微晶纤维素 12.5%
预胶化淀粉 10%
羧甲基纤维素钠 4%
硬脂酸镁 1%
50%乙醇 25%
包衣粉
富马酸替诺福韦DM酯片每片含300mg（相当于替诺福韦DM酯244.5mg）
素片组成：交联羧甲基纤维素钠、乳糖、硬脂酸镁、微晶纤维素、预胶化淀粉
包衣：欧巴代 II
湿法制粒：加入50%乙醇
干燥整粒：60ºC干燥１.５小时，整粒过筛
压片后包衣，包液浓度为5%
实施例10
体外细胞抗HBV活性实验
化合物对HepG2.2.15细胞外HBV DNA的抑制作用
将HepG2.2.15细胞接种至24孔板上，使每孔细胞数达2X104个；连续培养24小时，分别用含有浓度为5 μM的测试化合物和含有浓度为0.1 μ的阳性对照物恩替卡韦的培养液对各孔进行处理；用PRMI 1640培养基处理组作为空白对照组。
提取细胞上清液中的HBV DNA，利用实时荧光PCR分析仪测定细胞内外HBV DNA的拷贝数。
化合物对HepG2.2.15体外细胞HBV DNA复制的抑制作用。
样品：浓度5μM
３天拷贝数6.81±0.33X106/ml,抑制率48.7%;
6天拷贝数5.19±0.58X106/ml,抑制率61.3%;
9天拷贝数2.92±0.09X106/ml,抑制率69.2.%*
恩替卡韦：浓度0.1μM
３天拷贝数8.70±0.69X106/ml,抑制率36.2%;
6天拷贝数8.11±0.74X106/ml,抑制率47.1%;
9天拷贝数3.01±0.12X106/ml,抑制率68.6.%*
* P<0.01:在同一时间与空白组对照。
结果：化合物对HepG2.2.15细胞外HBV DNA复制有明显抑制作用。
Claims (4)
1.（R）-1-（6-氨基-9H-嘌呤-9-基）丙-2-基双（（5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基）甲基）膦酸酯与富马酸的共聚物。
2.权利要求1的共聚物，与富马酸摩尔比为1：1或２：1。
3.权利要求1的化合物的制备方法，其特征是：以(R)-9-[2-(二乙氧膦酰甲氧基)丙基]腺嘌呤为起始物料，与对甲苯磺酰氧基甲基膦酸二乙酯成酯，经酯水解后，与4-卤甲基-5-甲基-1,3-二氧杂环戊烯-2-酮或4-羟甲基-5-甲基-1,3-二氧杂环戊烯-2-酮缩合，生成（R）-1-（6-氨基-9H-嘌呤-9-基）丙-2-基双（（5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基）甲基）膦酸酯，再与富马酸形成共聚物。
4.权利要求1的化合物在制备抗HIV和HBV药物中的应用。
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