CN106800573B - 一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用 - Google Patents
一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用 Download PDFInfo
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- 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
- C07F9/65616—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 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
技术领域
本发明涉及一种核苷酸膦酸酯一水合物及其制备方法和在医药上的应用,具体的说,本发明涉及一种化合物(I)的一水合物其制备方法、组合物和在制备用于治疗病毒感染性疾病的药物上的应用。
背景技术
乙肝是世界性的疾病之一,它由乙肝病毒引起。世界上有三分之一的人口均在某种程度上感染了乙肝病毒,其中包括3亿5千万慢性携带者。在一些亚洲和非洲国家,乙肝已经变成流行性疾病,尤其是在中国。乙肝病毒能引起急性和慢性感染,急性感染通常伴随着肝脏发炎,呕吐,黄疸,极个别的还会引起死亡,而慢性感染有可能诱发肝硬化及肝癌。目前虽然可以通过疫苗预防乙肝病毒感染,但仍无有效的方法治疗慢性乙肝疾病。
替诺福韦(tenofovir),化学名称为[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基-乙氧基]甲基磷酸(PMPA),是一种核苷酸类逆转录酶抑制剂,具有抗HBV和HIV;但是由于其含有磷酸基团,具有较大极性,生物膜穿透能力差,在生物体内生物利用度差等缺点。为了克服这一缺点,可制成膦酸酯或者膦酰胺前药形式。2002年由吉利德公司研发上市的药物Viread(富马酸替诺福韦二吡呋酯)为PMPA的一种前药方式,制备成膦酸酯的前药形式大大提高了生物利用度。Viread在治疗HIV和HBV方面发挥了重要的作用。同时,该公司的另一个PMPA的前药tenofoviralafenamide(TAF)与恩曲他滨/cobicistat/elvitegravir组成的复方(商品名Genvoya)已经被FDA批准,用于治疗HIV感染。tenofoviralafenamide单独服用,用于治疗HBV感染目前正处于临床3期。
本发明提供了一种新的PMPA前药的水合物,可用于治疗病毒感染性疾病,其中病毒感染性疾病包括HBV和HIV病毒引起的感染性疾病。
发明内容
本发明提供一种化合物(I)的一水合物:
本发明优选方案,一种化合物(I)的一水合物,该化合物通过单晶衍射结构分析确定属于单斜晶系,空间群为P21,晶胞参数为 α=γ=90°和β=95.086(5)°,晶轴比a/b=0.8391,b/c=0.4076和c/a=2.9237,Z=2,
本发明提供一种制备化合物(I)的一水合物的方法,该方法为将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物。
本发明优选方案,一种制备化合物(I)的一水合物的方法,该方法为将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物,所述适宜的温度优选10~30℃。
本发明优选方案,一种制备化合物(I)的一水合物的方法,该方法为将化合物(I)溶于乙腈和水的混合溶剂中,在适宜的温度下,溶剂挥发即可制备得到化合物(I)的一水合物,乙腈和水的体积比为10:1至2:1,优选10:1至1:1,更优选5:1至1:1,进一步优选4:1,适宜的温度优选10~30℃。
本发明提供一种药物组合物,所述药物组合物含有治疗有效剂量的上述任一项所述的化合物(I)的一水合物,以及药学上可接受的载体或者赋形剂。
本发明提供一种上述任一项所述的化合物(I)的一水合物或者其组合物在制备用于治疗病毒感染性疾病的药物上的应用,所述的病毒感染性疾病优选HBV和HIV引起的感染性疾病。
除非有相反的陈述,在说明书和权利要求书中使用的术语具有下述含义。
本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫、氮或卤素均包括它们的同位素情况,及本发明所述基团和化合物中所涉及的元素碳、氢、氧、硫或氮任选进一步被一个或多个它们对应的同位素所替代,其中碳的同位素包括12C、13C和14C,氢的同位素包括氕(H)、氘(D,又叫重氢)、氚(T,又叫超重氢),氧的同位素包括16O、17O和18O,硫的同位素包括32S、33S、34S和36S,氮的同位素包括14N和15N,氟的同位素19F,氯的同位素包括35Cl和37Cl,溴的同位素包括79Br和81Br。
“药物组合物”表示一种或多种文本所述化合物或其生理学/药学上可接受的盐与其他组成成分的混合物,其中其它组分包含生理学/药学上可接受的载体和赋形剂。
“载体”指的是不会对生物体产生明显刺激且不会消除所给予化合物的生物活性和特性的载体或稀释剂。
“赋形剂”指的是加入到药物组合物中以进一步依赖于化合物给药的惰性物质。赋形剂的实例包括但不限于碳酸钙、磷酸钙、各种糖和不同类型的淀粉、纤维素衍生物(包括微晶纤维素)、明胶、植物油、聚乙二醇类、稀释剂、成粒剂、润滑剂、粘合剂、崩解剂等。
附图说明
图1为化合物(I)的一水合物单晶衍射谱图。
具体实施方式
以下通过具体实施例详细说明本发明的实施过程和产生的有益效果,旨在帮助阅读者更好地理解本发明的实质和特点,不作为对本案可实施范围的限定。
化合物的结构是通过核磁共振(NMR)或(和)质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用(Bruker Avance III 400和BrukerAvance 300)核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),内标为四甲基硅烷(TMS)。
MS的测定用(Agilent 6120B(ESI)和Agilent 6120B(APCI))。
HPLC的测定使用安捷伦1260DAD高压液相色谱仪(Zorbax SB-C18 100×4.6mm)。
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板,薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm~0.20mm,薄层层析分离纯化产品采用的规格是0.4mm~0.5mm。
柱层析一般使用烟台黄海硅胶200~300目硅胶为载体。
本发明的己知的起始原料可以采用或按照本领域已知的方法来合成,或可购买于泰坦科技、安耐吉化学、上海德默、成都科龙化工、韶远化学科技、百灵威科技等公司。
氮气氛是指反应瓶连接一个约1L容积的氮气气球。
氢气氛是指反应瓶连接一个约1L容积的氢气气球。
氢化反应通常抽真空,充入氢气,反复操作3次。
实施例中无特殊说明,反应在氮气氛下进行。
实施例中无特殊说明,溶液是指水溶液。
实施例中无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,为20℃~30℃。
实施例1
(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基-苯氧基-磷酰基]氨基]丙酸硫代异丙酯一水合物(化合物1,光学纯Rp-1)
S-isopropyl
(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino ]propanethioatehydrate
第一步:(S)-2-(叔丁氧基羰基)氨基丙酸硫代异丙酯(1B)
(S)-S-isopropyl 2-((tert-butoxycarbonyl)amino)propanethioate
将N-叔丁氧基羰基-L-丙氨酸(1A)(5g,26.4mmol)溶解于四氢呋喃(40mL)中,加入N,N'-羰基二咪唑(CDI)(4.7g,29.1mmol),室温搅拌2小时。加入硫代异丙醇(6.2g,79.3mmol),室温反应过夜。加入4mol/L的氢氧化钠溶液(30mL),用二氯甲烷(50mL×4)萃取,合并有机层,无水硫酸钠干燥,浓缩,残留物用硅胶柱分离纯化(石油醚:乙酸乙酯(v/v)=1:0~9:1),得标题化合物(S)-2-(叔丁氧基羰基)氨基丙酸硫代异丙酯(1B),浅黄色液体(4g,产率61%)。
1H NMR(400MHz,CDCl3)δ3.61(m,1H),2.37–2.16(m,1H),1.46(s,9H),1.36(d,3H),1.30(d,6H)。
第二步:(S)-2-氨基丙酸硫代异丙酯三氟乙酸盐(1C)
(S)-S-isopropyl 2-aminopropanethioate triflouroacetate
将(S)-2-(叔丁氧基羰基)氨基丙酸硫代异丙酯(1B)(4g,16.2mmol)溶于二氯甲烷(10mL)中,加入三氟乙酸(10mL),室温搅拌4小时。减压浓缩至干得粗品(S)-2-氨基丙酸硫代异丙酯三氟乙酸盐(1C)(4g),直接用于下一步。
第三步:[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基次磷酸(1E)
[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphinicacid
氮气保护下将[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]磷酸(即PMPA)(1D)(5g,17.4mmol)加到三颈瓶中,加入乙腈(40mL),三乙胺(3.5g,34.8mmol),4-二甲氨基吡啶(即DMAP)(2.1g,17.4mmol)和亚磷酸三苯酯(8.1g,26.1mmol)加完后,加热至内温80℃反应两天。将反应液减压浓缩除去乙腈,向残留物中加入乙酸乙酯(10mL)和水(15mL),分液,水层用乙酸乙酯(10mL×2)萃取,合并水层,水层用浓盐酸调节pH至3,室温搅拌10分钟,用浓盐酸调节pH至2,冰水冷却至10℃搅拌两小时后静置过夜,过滤,滤饼用水(10mL)洗涤,收集滤饼,烘干标题化合物[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基次磷酸(1E),(3.5g,产率56%)。
1H NMR(400MHz,DMSO)δ8.16(s,1H),8.14(s,1H),7.55(s,2H),7.32–7.25(m,2H),7.09(m,3H),4.30(dd,1H),4.19(dd,1H),3.97(m,1H),3.87–3.69(m,2H),1.05(d,3H)。
31P NMR(400MHz,DMSO)δ16.66。
第四步:[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氯(1F)
9-[(2R)-2-[[chloro(phenoxy)phosphoryl]methoxy]propyl]purin-6-amine
将[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基次磷酸(1E)(2g,5.5mmol)悬浮于乙腈(20mL)中,加入氯化亚砜(2.6g,22.0mmol)加热至内温85℃反应4小时,将反应液减压浓缩,得粗品直接用于下一步。
第五步:(2S)-2-[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氨基丙酸硫代异丙酯(1G)(光学纯Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioate
将(S)-2-氨基丙酸硫代异丙酯三氟乙酸盐(1C)(4g,16.2mmol)溶于干燥的二氯甲烷(20mL)中,氮气保护下,干冰-乙醇冷却至-50℃,滴加三乙胺(5mL,35.8mmol)搅拌10分钟,滴加[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氯(1F)(2.1g,5.5mmol)的二氯甲烷(20mL)悬浊液,完成后,自然升温至室温反应1小时。向反应液中加入水(20mL),分液,有机层用水(10mL)洗涤一次,无水硫酸钠干燥,减压浓缩,将残留物溶于乙酸乙酯(50mL)中,冰浴冷却下用4mol/L的盐酸调节pH至2,分液,水层用乙酸乙酯(20mL)萃取,取水层,加入二氯甲烷(50mL),冰浴冷却下滴加饱和碳酸氢钠水溶液调节pH至8,分液,水层用二氯甲烷(20mL)萃取,合并有机层,饱和氯化钠(10mL)洗涤,无水硫酸钠干燥,减压浓缩,得(2S)-2-[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氨基丙酸硫代异丙酯(1G)的两种非对映异构体混合物(300mg,产率11%),将该混合物采用HPLC拆分得到1G(光学纯Rp-1)),化合物1G为HPLC拆分后的峰1。
分离分析方法:仪器,Thar analytical SFC;柱,ChiralPak AS-H,250×4.6mm;流动相,A为CO2以及B为Methanol(0.05%DEA);梯度,B 40%;流量,2.4mL/min;背压,100bar;柱温,35℃;波长,220nm。
制备分离方法:仪器,MGⅡpreparative SFC;柱,ChiralPak AS-H,250×30mmI.D.;流动相,A为CO2以及B为Methanol;梯度,B 40%;流量,40mL/min;背压,100bar;柱温38℃;波长,220nm;周期,5.5min。
样品制备:1G的两种非对映异构体混合物(300mg)溶解于甲醇中,制得样品浓度10mg/mL的溶液,进样3mL/每针,分离后得到两个光学异构体化合物,其中峰1为化合物1G(保留时间:2.21min,106mg,白色固体,ee%=100%),峰2为化合物1G的非对映异构体1G’(保留时间:3.82min,109mg,白色固体,ee%=100%)。
化合物1G
1H NMR(400MHz,CDCl3)δ8.31(s,1H),8.01(s,1H),7.32(t,2H),7.21–7.11(m,3H),6.04(s,2H),4.47(dd,1H),4.21–4.13(m,1H),4.13–4.06(m,1H),4.06–3.96(m,2H),3.69(dd,1H),3.54–3.39(m,2H),1.28–1.17(m,12H)。
31P NMR(162MHz,CDCl3)δ23.15。
LC-MS M/Z(ESI):493.1[M+1]。
化合物1G的非对映异构体1G’
1H NMR(400MHz,CDCl3)δ8.35(s,1H),7.97(s,1H),7.25–7.17(m,2H),7.13–7.05(m,1H),7.03–6.95(m,2H),5.90(s,2H),4.34(dd,1H),4.16–4.03(m,2H),3.99–3.89(m,2H),3.84(t,1H),3.76–3.52(m,2H),1.33–1.20(m,12H)。
31P NMR(162MHz,CDCl3)δ22.12。
LC-MS M/Z(ESI):493.1[M+1]。
第六步:(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基-苯氧基-磷酰基]氨基]丙酸硫代异丙酯一水合物(化合物1,光学纯Rp-1)
S-isopropyl(2S)-2-[[[(1R)-2-(6-aminopurin-9-yl)-1-methyl-ethoxy]methyl-phenoxy-phosphoryl]amino]propanethioate hydrate
取约5mg(2S)-2-[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基]苯氧基磷酰氨基丙酸硫代异丙酯(1G)(光学纯Rp-1))放于玻璃小瓶中,用乙腈(1.6mL)及水(0.4mL)超声溶清,室温下小孔挥发,得到块状晶体,即为(2S)-2-[[[(1R)-2-(6-氨基嘌呤-9-基)-1-甲基乙氧基]甲基-苯氧基-磷酰基]氨基]丙酸硫代异丙酯一水合物(化合物1,光学纯Rp-1)。
实施例2:化合物1(光学纯Rp-1)单晶X-射线结晶学测量(图1所示)
1.仪器信息和检测方法参数
2单晶结构数据
U(eq)定义为正交化Uij张量轨迹的三分之一(U(eq)is defined as one thirdof the trace of the orthogonalizedUijtensor)
各项异性位移因子指数采取如下形式:-2π2[h2a*2U11+...+2h k a*b*U12]。
生物测试例
抗乙型肝炎病毒活性筛选
用HepG2.2.15细胞测定化合物的抗乙肝病毒活性。使用的材料与仪器如下:HepG2.2.15细胞,RPMI 1640培养液,胎牛血清,96孔板,DMSO,QIAamp 96DNABlood Kit,Cell-titer blue,酶标仪,Applied Biosystems 7900real-time PCR system。
用DMSO将化合物1(光学纯Rp-1)溶解至20mM,-20℃贮存,将化合物1(光学纯Rp-1)的20mM贮存液用DMSO 3倍梯度稀释,共9个浓度。再用含2.0%FBS的RPMI 1640培养液稀释200倍。化合物的最高测试终浓度为100M。实验步骤参照QIAamp 96DNA Blood Kit(QIAGEN51161)说明书,qPCR法测定化合物抗乙肝病毒活性并计算EC50(半数有效抑制浓度)。分析数据和计算抑制百分比:应用如下公式计算抑制百分比:抑制率(%)=(DMSO对照组的HBV总量-受试样品组的HBV总量)/DMSO对照组的HBV总量×100。最后使用GraphPad Prism软件计算化合物的EC50值。
Cell-titer blue法测定化合物的细胞毒性并计算CC50(致50%细胞毒性浓度)。分析数据和计算相对细胞活力:应用如下公式计算细胞活性百分比:细胞生存率(%)=(受试样品的荧光数值-背景荧光数值)/(DMSO对照组的荧光数值-背景荧光数值)×100。最后使用GraphPad Prism软件计算化合物的CC50值。结果如下表所示:
化合物编号 | EC<sub>50</sub>(nM) | CC<sub>50</sub>(μM) |
化合物1(光学纯Rp-1) | 8 | >100 |
Claims (8)
3.制备权利要求1所述的化合物(I)的一水合物的方法,其特征在于将化合物(I)溶于乙腈和水的混合溶剂中,在10~30℃下,溶剂挥发即可制备得到化合物(I)的一水合物。
4.根据权利要求3所述的方法,其特征在于乙腈和水的体积比为10:1至2:1。
5.根据权利要求4所述的方法,其特征在于乙腈和水的体积比为4:1。
6.一种药物组合物,所述药物组合物含有治疗有效剂量的权利要求1~2中任一项所述的化合物(I)的一水合物,以及药学上可接受的载体或者赋形剂。
7.权利要求1或2所述的一水合物或6所述的药物组合物在制备用于治疗病毒感染性疾病的药物上的应用。
8.根据权利要求7所述的应用,所述的病毒感染性疾病包括HBV和HIV引起的感染性疾病。
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CN103665043A (zh) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | 一种替诺福韦前药及其在医药上的应用 |
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EP0481214A1 (en) * | 1990-09-14 | 1992-04-22 | Institute Of Organic Chemistry And Biochemistry Of The Academy Of Sciences Of The Czech Republic | Prodrugs of phosphonates |
CN103224530A (zh) * | 2012-08-13 | 2013-07-31 | 洛阳聚慧投资股份有限公司 | 一组替诺福韦酯化合物、制备方法及其在抗病毒方面的应用 |
CN103665043A (zh) * | 2012-08-30 | 2014-03-26 | 上海源力生物技术有限公司 | 一种替诺福韦前药及其在医药上的应用 |
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