CN117466939A - 一种控制体内药物释放的长效前药衍生物 - Google Patents
一种控制体内药物释放的长效前药衍生物 Download PDFInfo
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Abstract
本发明属于医药技术领域,涉及一种控制体内药物释放的长效前药衍生物,具体涉及一种控制体内药物释放的丙酚替诺福韦长效前药衍生物、其药物组合物及其在制备用于预防或治疗与慢性乙型肝炎(CHB)有关疾病的药物中的用途。丙酚替诺福韦前药衍生物,包括具有式(Ⅰ)所示结构的化合物:其中,R1选自C11‑C19的直链烯烃。本发明的丙酚替诺福韦前药衍生物进入体内经过代谢产生丙酚替诺福韦,使丙酚替诺福韦维持更长时间的有效血药浓度,从而降低给药次数,提高患者顺应性。
Description
技术领域
本发明属于医药技术领域,具体涉及一种控制体内药物释放的丙酚替诺福韦长效前药衍生物、其药物组合物及其用途。
背景技术
慢性乙型肝炎(chronic hepatitis B,CHB)是由乙型肝炎病毒(HBV)持续感染引起的慢性肝脏炎症性疾病。慢性HBV感染是一个世界性的公共健康问题,全球有约3.5亿感染者。15%-40%的慢性HBV感染者会发展为肝硬化、肝功能衰竭和肝细胞癌。由慢性HBV感染引起的肝硬化、肝功能衰竭和肝细胞癌每年可造成50-120万人死亡。
《慢性乙型肝炎防治指南(2019年版)》推荐符合治疗标准的CHB患者积极接受抗病毒药物治疗。其中,高效低毒的逆转录酶抑制剂丙酚替诺福韦(半富马酸盐形式)被推荐作为一线用药使用。丙酚替诺福韦是替诺福韦的前药,由于替诺福韦结构中有两个磷酸基团,极性大而不易通过生物膜,导致其生物利用度差,难以在被感染的肝脏部位有效聚集,入血后很快经肾脏排出体外。高浓度的替诺福韦排出时会在肾近端小管上皮细胞中累计造成肾损伤。前药丙酚替诺福韦具有良好的血浆稳定性,可经主动转运进入肝细胞,被肝细胞内的磷酸酯酶水解为替诺福韦发挥抗病毒作用。正是由于丙酚替诺福韦的血浆稳定性,使其在低剂量下(25mg/d)即可达到治疗效果。剂量的降低使经近端肾小管排泄的替诺福韦量大大减少,从而减少了其对肾的损伤。CHB的抗病毒药物治疗贯穿患者的整个生命周期,给药依从性是决定最终疗效结果的关键因素。开发丙酚替诺福韦的长效前药衍生物可以大幅度延长用药间隔,提高患者顺应性,提升CHB的抗病毒治疗效果。
Journal of Controlled Release 329(2021)257-269.报道了丙酚替诺福韦的聚合物碳酸酰胺前药衍生物在小鼠皮下可以实现50天的持续释药,但此种聚合物碳酸酰胺前药存在合成步骤长、载药量低、产品为油状物难以纯化和质量控制的不足。公告号为CN106565785B的中国发明专利报道了将丙酚替诺福韦中引入D-氨基酸酰胺结构,增加其在血液中的稳定性,从而提高在肝脏的药物浓度,得到具有更高化学稳定性、更高脂溶性和更好抑制病毒活性的新的非环核苷酸磷酰胺类化合物。
发明内容
针对上述现有技术存在的不足,本发明在丙酚替诺福韦结构中引入不饱和脂肪酸酰胺结构,合成了一系列丙酚替诺福韦不饱和脂肪酸酰胺前药衍生物,并对其进行了大鼠体内药代动力学筛选,发现了能够维持更长时间在体内稳定释放丙酚替诺福韦的化合物,达到了延长给药间隔、降低给药频次的目的。
本发明的第一个目的在于提供一种控制体内药物释放的丙酚替诺福韦前药衍生物,包括具有式(Ⅰ)所示结构的化合物:
其中,R1选自C11-C19的直链烯烃。
通过采用上述方案,本发明的丙酚替诺福韦前药衍生物在体内经缓慢代谢产生丙酚替诺福韦,使丙酚替诺福韦血药浓度波动小,有效血药浓度维持时间长,可以降低给药次数,提高患者顺应性。
进一步,R1选自C15-C17的直链烯烃。
更进一步,所述直链烯烃含有一个碳碳双键。
更进一步,R1选自如下官能团:
其中,/>表示基团通过共价键连接的位点。
具体地,本发明所述的丙酚替诺福韦前药衍生物的结构如下所示:
通过采用上述方案,本发明的丙酚替诺福韦前药衍生物为不饱和脂肪酸酰胺前药衍生物,其在体内代谢产生丙酚替诺福韦的同时,还会产生一分子油酸。油酸是一种18个碳的单不饱和脂肪酸,具有抗氧化、调节血脂及降低血胆固醇的作用。人体不能自行合成油酸,需要从食用油中获取,如花生油中,油酸的含量为35.0%~69.0%。
进一步,所述的丙酚替诺福韦前药衍生物还包括式(Ⅰ)所示结构的化合物药学可接受的盐、溶剂合物及可药用赋形剂。
本发明的第二个目的在于提供一种药物组合物,包含如上所述的丙酚替诺福韦前药衍生物。
进一步,所述的药物组合物以胃肠外形式给药。
更进一步,所述的药物组合物为注射给药。
更进一步,所述的药物组合物为肌肉注射或皮下注射形式给药。
本发明的第三个目的在于提供一种如上所述的丙酚替诺福韦前药衍生物在制备用于预防或治疗与慢性乙型肝炎有关疾病的药物中的用途。
与现有技术相比,本发明的有益效果如下:
(1)本发明在丙酚替诺福韦结构中引入不饱和脂肪酸酰胺结构,合成了一系列丙酚替诺福韦不饱和脂肪酸酰胺前药衍生物,这类结构衍生物以固体形式存在,方便结晶纯化和质量控制。对这些衍生物进行了大鼠体内药代动力学筛选,发现了能够维持更长时间在体内稳定释放丙酚替诺福韦的化合物,达到了延长给药间隔、降低给药频次的目的;
(2)本发明的丙酚替诺福韦前药衍生物在体内经缓慢代谢产生丙酚替诺福韦,使丙酚替诺福韦血药浓度波动小,有效血药浓度维持时间长,可以降低给药次数,提高患者顺应性;
(3)本发明的丙酚替诺福韦不饱和脂肪酸酰胺前药衍生物代谢产生活性成分丙酚替诺福韦的同时,还会产生一分子不饱和脂肪酸,不饱和脂肪酸是人体不可缺少的脂肪酸,如亚油酸人体不能合成,必须从膳食中补充。
附图说明
图1为丙酚替诺福韦体内丙酚替诺福韦的浓度随时间变化的曲线;
图2为化合物2、3、4代谢产生丙酚替诺福韦的浓度随时间变化的曲线;
图3为化合物1代谢产生丙酚替诺福韦的浓度随时间变化曲线。
具体实施方式
以下结合实例对本发明的原理和特征进行描述,所举实例只用于解释本发明,并不以任何形式限制本发明的范围。对所公开的实施方案的各种改变和修改对本领域技术人员来说将是显而易见的,并且在不脱离本发明的精神和所附权利要求的范围的情况下,可以进行包括但不限于与本发明的化学结构、取代基、衍生物、制剂和/或方法有关的改变和修改。
实施例1:化合物1的制备
反应瓶中,依次加入1.80g的HOBt,2.52g的EDCI,50.0g二氯甲烷,3.75g油酸,2.85g三乙胺,室温下搅拌0.5h。加入2.50g的丙酚替诺福韦,N2保护,搅拌反应2天。反应结束后,体系加入25.0g饱和食盐水,分液。有机相用20.0g无水硫酸钠干燥后,经硅胶柱层析纯化(洗脱液的洗脱比例是二氯甲烷~二氯甲烷/甲醇91/9,V/V)。所得油状物在12.0g乙腈中搅拌打浆,有固体析出,过滤,干燥,得到白色固体0.8g。
HPLC纯度96.3%。ESI-MS(m/z):741.52[M+H]+.mp:63.2-64.7℃.1H NMR(400MHz,CDCl3)δ8.71(s,1H),8.68(s,1H),8.15(s,1H),7.26-7.17(m,2H),7.15-7.06(m,1H),7.03-6.94(m,2H),5.34(ddd,J=5.5,3.6,1.8Hz,2H),4.99(hept,J=6.3Hz,1H),4.40(dd,J=14.4,3.0Hz,1H),4.17(dd,J=14.5,7.8Hz,1H),4.09-3.83(m,3H),3.73-3.56(m,2H),2.83(t,J=7.5Hz,2H),2.24-1.92(m,6H),1.76(p,J=7.6Hz,2H),1.44-1.17(m,30H),0.93-0.79(m,3H).
实施例2:化合物2的制备
反应瓶中,依次加入0.99g的HOBt,1.45g的EDCI,50.0g二氯甲烷,2.27g反油酸与1.48g三乙胺,室温下搅拌1h。加入1.40g的丙酚替诺福韦,N2保护,搅拌反应2天。反应结束后,加入20.0g饱和食盐水,分液。有机相用10.0g无水硫酸钠干燥后,经硅胶柱层析纯化(洗脱液的洗脱比例是二氯甲烷~二氯甲烷/甲醇94/6,V/V)。所得油状物在8.0g乙腈中搅拌打浆,有固体析出。过滤,干燥,得白色固体0.6g。
HPLC纯度95.7%。ESI-MS(m/z):741.44[M+H]+.mp:74.5-75.4℃.1H NMR(400MHz,CDCl3)δ8.69(s,1H),8.64(s,1H),8.12(s,1H),7.22-7.13(m,2H),7.10-7.00(m,1H),6.92-6.81(m,2H),5.30(ddd,J=5.5,3.6,1.8Hz,2H),4.89(hept,J=6.3Hz,1H),4.31(dd,J=14.4,3.0Hz,1H),4.12(dd,J=14.5,7.8Hz,1H),4.00-3.79(m,3H),3.70-3.50(m,2H),2.83(t,J=7.5Hz,2H),2.24-1.92(m,6H),1.76(p,J=7.6Hz,2H),1.44-1.17(m,30H),0.90-0.76(m,3H).
实施例3:化合物3的制备
反应瓶中,依次加入0.99g的HOBt,1.29g的EDCI,50.0g二氯甲烷,1.40g棕榈油酸与1.40g三乙胺,室温下搅拌1h。加入1.40g的丙酚替诺福韦,N2保护,搅拌反应2天。反应结束后,加入20.0g饱和食盐水,分液。有机相用20.0g无水硫酸钠干燥后,经硅胶柱层析纯化(洗脱液的洗脱比例是二氯甲烷~二氯甲烷/甲醇95/5,V/V)。所得油状物在10g正庚烷中搅拌打浆,有固体析出。过滤,干燥,得白色蜡状固体0.55g。
HPLC纯度95.6%。ESI-MS(m/z):713.48[M+H]+.1H NMR(400MHz,CDCl3)δ8.67(s,1H),8.16(s,1H),7.25-7.18(m,2H),7.14-7.06(m,1H),7.02-6.94(m,2H),5.37-5.32(m,2H),4.99(hept,J=6.2Hz,1H),4.40(dd,J=14.4,3.0Hz,1H),4.18(dd,J=14.4,7.9Hz,1H),4.07-3.95(m,2H),3.91(dd,J=13.3,7.5Hz,1H),3.67(dd,J=13.3,10.5Hz,1H),3.60(t,J=10.3Hz,1H),2.84(t,J=7.5Hz,2H),2.64(d,J=9.3Hz,1H),2.01(d,J=6.3Hz,4H),1.78(dt,J=14.9,7.8Hz,5H),1.42-1.20(m,25H),0.92-0.83(m,3H).
实施例4:化合物4的制备
反应瓶中,依次加入0.74g的HOBt,1.04g的EDCI,30.0g二氯甲烷,1.40g十六酸与1.30g三乙胺,室温下搅拌1h。加入1.00g的丙酚替诺福韦,N2保护,搅拌反应1天。反应结束后,加入25.0g饱和食盐水,分液。有机相用20.0g无水硫酸钠干燥后,经硅胶柱层析纯化(洗脱液的洗脱比例是二氯甲烷~二氯甲烷/甲醇94/6,V/V)。所得油状物在5g正庚烷中搅拌打浆,有固体析出。过滤,干燥,得白色固体0.35g。
HPLC纯度95.0%。ESI-MS(m/z):715.45[M+H]+.mp:73.5-76.2℃.1H NMR(400MHz,CDCl3)δ8.68(s,1H),8.14(s,1H),7.25-7.18(m,2H),7.14-7.06(m,1H),7.02-6.94(m,2H),5.00(p,J=6.3Hz,1H),4.41(dd,J=14.4,2.9Hz,1H),4.18(dd,J=14.5,7.8Hz,1H),4.07-3.95(m,2H),3.91(dd,J=13.3,7.5Hz,1H),3.67(dd,J=13.3,10.5Hz,1H),3.59(t,J=10.3Hz,1H),2.83(t,J=7.5Hz,2H),1.76(p,J=7.5Hz,2H),1.46-1.18(m,36H),0.92-0.80(m,3H).
实验:丙酚替诺福韦及其前药衍生物注射给药在大鼠体内的药代动力学行为
试验动物:雄性SD大鼠,购自济南朋悦实验动物繁育有限公司,体重180~220g,每组3只。
化合物3以油性溶液给药。油性溶液配制方法:取油状或蜡状丙酚替诺福韦前药衍生物溶于注射用大豆油中,配制成40mg/ml(以丙酚替诺福韦计)的油溶液。
丙酚替诺福韦以及化合物1、2、4以水性混悬液给药。水性混悬液配制方法:取CMC-Na和吐温20溶于超纯水中,配制成含CMC-Na浓度为1%,吐温20浓度为0.4%的水溶液,将固体丙酚替诺福韦前药衍生物过200目筛后,取适量加入上述水溶液中,配成40mg/ml(以丙酚替诺福韦计)的混悬液。
每组大鼠按20mg/kg剂量分别肌肉注射上述药物,于给药前及给药后15min、1h、6h、1d、2d、3d、5d、7d、9d、11d、14d、18d、21d、25d、28d眼眶取血,每次采血0.25m1,置于预先用肝素处理过的EP管中。12000rpm离心5min,取血浆置于-80℃冷冻保存,待检测。
生物样品前处理:50μL含药血浆加入200μL甲醇,涡流1min沉降蛋白,12000rpm离心5min,取上清液100μL,加入超纯水100μL,混合均匀,进样分析。
检测仪器:高效液相色谱-四极杆线性离子阱质谱联用仪,SCIEX,QTRAP 5500。
质谱条件:离子源为电喷雾电离源(ESI),正离子检测模式;电离电压3500V,温度为350℃,鞘气为40Arb;辅助气为15Arb。
不同时间点大鼠体内丙酚替诺福韦的血药浓度平均值如表1所示。
表1各化合物对应的不同时间点大鼠体内丙酚替诺福韦的血药浓度
备注:表中每个化合物药物浓度为三只大鼠血中药物浓度的平均值;“ND”代表未检出。
由表1可见,作为对照药物的化合物丙酚替诺福韦,经肌肉注射1h(0.04d)后即达到峰浓度(Tmax),7d时血药浓度即低于1ng/mL。
图1为丙酚替诺福韦体内丙酚替诺福韦的浓度随时间变化的曲线。由图1可直观的看出化合物丙酚替诺福韦血药浓度快速达峰,快速降低,不能维持长时间的释放药物。
相比化合物丙酚替诺福韦,表1中的化合物2、3可以在长达14d时保持>1ng/mL的药物浓度,达峰时间可延迟至1d。化合物4可以在9d时保持>1ng/mL的药物浓度,达峰时间为6h(0.25d)。
图2为化合物2、3、4代谢产生丙酚替诺福韦的浓度随时间变化的曲线,相比图1,化合物2、3、4维持有效血药浓度的时间更长、达峰时间也更晚,但药物浓度仍然有较大的波动。
表1中的化合物1血药浓度达峰时间进一步延长至7d,并且可以在28d时仍保持>1ng/mL的药物浓度。
图3为化合物1代谢产生丙酚替诺福韦的浓度随时间变化曲线,相比图2中的化合物2、3、4,化合物1经注射给药后,药物浓度达峰时间明显延长、保持有效血药浓度的时间明显延长,且释放药物更加平稳。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种控制体内药物释放的丙酚替诺福韦前药衍生物,其特征在于,包括具有式(Ⅰ)所示结构的化合物:
其中,R1选自C11-C19的直链烯烃。
2.根据权利要求1所述的丙酚替诺福韦前药衍生物,其特征在于,R1选自C15-C17的直链烯烃。
3.根据权利要求2所述的丙酚替诺福韦前药衍生物,其特征在于,所述直链烯烃含有一个碳碳双键。
4.根据权利要求3所述的丙酚替诺福韦前药衍生物,其特征在于,R1选自如下官能团:
5.根据权利要求1所述的丙酚替诺福韦前药衍生物,其特征在于,还包括式(Ⅰ)所示结构的化合物药学可接受的盐、溶剂合物及可药用赋形剂。
6.一种药物组合物,其特征在于,包含如权利要求1~5任一项所述的丙酚替诺福韦前药衍生物。
7.根据权利要求6所述的药物组合物,其特征在于,以胃肠外形式给药。
8.一种如权利要求1~5任一项所述的丙酚替诺福韦前药衍生物在制备用于预防或治疗与慢性乙型肝炎有关疾病的药物中的用途。
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