CN110590838A - Y27632前药、其制备方法及其在医药上的应用 - Google Patents
Y27632前药、其制备方法及其在医药上的应用 Download PDFInfo
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- CN110590838A CN110590838A CN201910508631.7A CN201910508631A CN110590838A CN 110590838 A CN110590838 A CN 110590838A CN 201910508631 A CN201910508631 A CN 201910508631A CN 110590838 A CN110590838 A CN 110590838A
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- Prior art keywords
- compound
- prodrug
- pharmaceutically acceptable
- liver
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Abstract
本发明涉及一种Y27632前药、其制备方法及其在医药上的应用,本发明所述的前药是如通式Ⅰ所示的化合物或其药学上可接受的盐,本发明所述的前药还包括,如通式Ⅰ所示的化合物或其药学上可接受的盐的溶剂化物、其光学异构体,本发明所述的前药可以治疗肝脏疾病,特别是肝纤维化疾病。经实验证明,本发明化合物具有肝靶向性,在肝纤维化模型动物中显著降低肝组织纤维化水平,降低细胞外基质蛋白(ECM)相关组分含量;显著抑制肝组织中肝星状细胞活化,促进胶原降解,作为活性成份用于制备抗肝纤维化药物,相比母药Y27632更高效低毒,为肝纤维化的治疗和预防提供了新的药物途径,从而扩大了临床用药的可选择范围,具有良好的应用开发前景。
Description
技术领域
本发明涉及一种新型Y27632前药或其异构体、可药用盐、水合物与溶剂化物及其制备方法与其在医药上的应用。
背景技术
肝纤维化(HF)是指肝脏内弥漫性细胞外基质(ECM)的过度沉积,是机体对慢性肝损伤的一种修复反应。肝纤维化是多种原因引起的慢性肝损害时共同的病理改变,也是慢性肝病发展到肝硬化必经环节。几乎各种慢性肝病的因素均可引起肝纤维化,肝纤维化的常见病因大致可分为感染性、先天性代谢缺陷、化学毒物性、自身免疫性肝病等。中国以病毒性肝炎,尤其是慢性乙型和丙型肝炎所致的肝纤维化最为常见。北美、西欧则以酒精性肝纤维化为最多。欧美国家酒精性肝纤维化占全部肝纤维化的50%~90%,我国近年来有上升趋势,其发病机制主要是酒精中间代谢产物乙醛对肝脏的直接损害。长期服用某些药物如双醋酚酊、甲基多巴、四环素等,或长期反复接触某些化学毒物如磷、砷、四氯化碳等,均可引起中毒性肝炎,而发生肝纤维化。其他如非酒精性脂肪性肝炎、自身免疫性肝病、遗传和代谢疾病、肝脏淤血等均可以引起肝纤维化。
虽然许多研究已经证明了在患者和实验动物模型的实验中肝纤维化的进展是可逆的,但是目前还没有有效的治疗办法。临床常用的干扰素(interferon,IFN)、水飞蓟素(Silybin)、扶正化瘀胶囊等效果仍不尽人意,并且副作用大、易出现耐药性。目前国际国内有少数小分子化学药物处于临床前或者已进入临床研究,但是尚无批准上市的治疗肝纤维化的小分子化学药物。
相关的药物研发主要是针对于肝星状细胞(HSCs)激活相关的环节,主要有减轻肝损伤,抑制HSCs激活,减少细胞外基质产生,调节细胞因子促进活化的 HScs凋亡,抑制肝脏成纤维细胞的增殖以及HSCs激活和大量分泌诱导肝脏成纤维细胞的增殖。HSCs的凋亡在肝纤维化逆转过程中起决定作用,Rock抑制剂Y27632 通过调控Rock介导的通路作用于HSCs靶点,通过减少HSCs收缩力、影响细胞迁移能力、促进HSCs凋亡而具有抗肝纤维化的作用。在肝纤维化模型动物实验中,经 Rock抑制剂Y27632治疗后的动物肝纤维化得到明显改善。但是由于ROCK在体内分布广泛,因此直接使用ROCK抑制剂Y27632会带来非靶系统上的副作用,如降低血管平滑肌张力,导致动脉血压急剧下降等;并且Y27632在动物体内代谢迅速,因而需要大剂量或多次给药从而在一定时间内保持药物治疗浓度,维持疗效,这进一步加大了药物的潜在毒性。
由于ROCK靶点在生物体内的广泛分布以及Y27632的代谢特点导致的潜在毒性可以通过局部给药或者靶向给药策略而降低或者消除,其中对化合物进行结构上的肝靶向前药修饰一直是本领域研究方向中肝脏靶向给药的重要研究方向。前药是一种本身无内在活性,但是在代谢的不同时期能够产生生物活性药物的分子。一般来讲,这种代谢转换是由特定的酶所催化的,主要是水解酶。前药的理想状态是它能在特定的靶点选择性地断裂而避免了副作用的发生,如肝靶向前药的理想状态是前药化合物在肝脏中快速代谢成活性母药,而在其他系统如胃肠道、血液中等保持稳定。这种前药修饰方法有时候需要满足几种生物学和物化参数,而这有时是矛盾的。比如:细胞的透过性、水溶性、化学与酶的稳定性、生物利用度、毒性以及血脑屏障的透过性,对于一个合适的前药来说既要有一定的亲脂性以通过细胞屏障,又要有一定的水溶性以满足溶解性、生物利用度和转运条件。因此,肝靶向片段取代基团的选择对于Y27632前药的开发非常重要,所选择的基团是否可以成功连接到Y27632结构上,连接上取代基之后是否可以达到肝靶向转运的目的,到达肝靶部位后是否可以顺利水解得到活性母药Y27632从而发挥药效,都是一个未知数。
发明内容
为了解决上述技术问题,本发明的目的在于提供一类新型Y27632前药化合物以提高药物的肝靶向性和在系统其它部位的代谢稳定性,从而减少药物用量,提高药物疗效,降低系统毒性。
本发明另一目的是提供Y27632前药化合物的其制备方法。
本发明还有一个目的是提供Y27632前药化合物在制备抗肝纤维化药物中的用途。
本发明具体通过下述技术方案实现:
本发明提供了一类Y27632前药化合物,通过连接掩蔽基团形成磷酯/磷酰胺前药来降低分子极性、增加透膜性、耐受消化道及血液的理化环境,当前药吸收进入体内后再在肝脏部位经特定酶水解释放出活性母药。本发明化合物在人肝S9 中有效代谢成活性母药Y27632,并且在人血浆、模拟胃肠液中稳定,从而降低了由于代谢快导致需要大剂量给药带来的和活性代谢产物出现在非靶器官带来的系统毒副作用。本发明化合物在肝纤维化模型动物中显著降低肝组织纤维化水平,降低细胞外基质蛋白(ECM)相关组分含量;显著抑制肝组织中肝星状细胞活化,促进胶原降解,作为活性成份用于制备抗肝纤维化药物,相比母药Y27632更高效低毒,为肝纤维化的治疗和预防提供了新的药物途径。
所述Y27632前药化合物如式Ⅰ所示的化合物、异构体及其溶剂化物、或它们药学上可接受的盐,
其中R1,R2分别独立地选自H、C1-C3直链烃基、C3-C10支链烃基、C3-C10环烃基、C6-C10芳香烃基或杂芳基,所述直链烃基、支链烃基、环烃基、芳香烃基中的碳原子有或者没有被一个到三个独立地选自O,S,N,Se的杂原子替代; R3独立地选自1-5个H、卤素、烷基、氨基、氰基、叠氮基、硝基、烷胺基、酰胺基、烷酰基、烷酰氧基、烷氧基、杂环基;Z独立地选自O,S,Se,-NH-或-CH2-。
优选的,根据上述Y27632前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐,其中R3独立地选自1-5个H、F、Cl、Br、甲基、乙基、环丙烷基、苯基、乙烯基、乙炔基、氯乙烯基、氟甲基、二氟甲基、三氟甲基、氨基、氰基、叠氮基、硝基、甲胺基、乙胺基、丙氨基、环丙胺基、乙酰氨基、乙酰基、乙酰氧基、乙氧基、异丙氧基、吡啶基。
优选的,Z为O或S。
更优选的,根据上述Y27632前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐,其中Z为O。
更优选的,根据上述任意一项所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其中,NH-C(R2)-COZR1为天然氨基酸或其手性异构体在羧基端形成的酯,其中R1为C1-C3直链烃基、C3-C5支链烃基、C6-C10芳香烃基。
更优选的,根据上述任意一项所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其中R1为异丙基(i-Pr)或苄基(Bn)。
更优选的,根据上述任意一项所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其中R2为氢原子或甲基(Me),所连接的碳原子构型为R或者S构型。
更优选的,根据上述任意一项所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其中R3独立地选自1-5个H、F、Cl、Br、甲基、乙基、环丙烷基、苯基、氟甲基、二氟甲基、三氟甲基、氨基、氰基、叠氮基、硝基、环丙胺基、乙酰基、乙酰氧基、乙氧基、异丙氧基、吡啶基。
更优选的,根据上述任意一项所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其中R3为1个H。
更优选的,根据上述任意一项所述的Y27632前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐,其中,R2为氢原子或甲基,所连接的碳原子构型为S构型;R1为异丙基或苄基;R3为1个H。结构式1-4:
本发明的前药,其中所述式(I)化合物药学上可接受的盐,包括与无机酸,如盐酸、硫酸形成的盐,与有机酸,如乙酸、三氟乙酸、柠檬酸、马来酸、草酸、琥珀酸、苯甲酸、酒石酸、富马酸、扁桃酸、抗坏血酸或苹果酸形成的盐,以及氨基酸,如丙氨酸、天冬氨酸、赖氨酸形成的盐或与磺酸,如甲磺酸、对甲苯磺酸形成的盐。根据需要和化合物的性质,也可按常规方法将它们制备成碱金属盐、碱土金属盐、银盐、钡盐等,如钾盐,钠盐,铵盐,钙盐,镁盐。
本发明的式(I)化合物也可以溶剂化物(如水合物)的形式存在,因此,这些溶剂化物(如水合物)也包括在本发明的化合物之内。
本发明进一步包括所述的Y27632前药化合物制备方法,所述方法反应式如下:
具体包括如下步骤:
步骤(1)化合物A在碱的作用下与化合物B或者化合物C上的氨基反应后得到对应的氯磷酰胺中间体AB或AC;
步骤(2)氯磷酰胺中间体AB与化合物C或者氯磷酰胺中间体AC与化合物B 在碱的存在下反应生成如式Ⅰ所示的前药类化合物。
所述步骤中的碱是无机碱或有机碱,优选有机碱,进一步优选有机碱为胺类化合物,例如但不限于二异丙基乙基胺,三乙胺,叔丁基胺,二乙胺等。
本发明进一步包括含有本发明所述的前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐和药学上可接受的载体的药物组合物。所述的前药可以治疗治疗肝脏疾病,特别是肝纤维化疾病。
本发明的药物组合物,优选的是单位剂量的药物制剂形式,在制成药物制剂时可以制成任何可药用的剂型,这些剂型选自:片剂、糖衣片剂、薄膜衣片剂、肠溶衣片剂、胶囊剂、硬胶囊剂、软胶囊剂、口服液、口含剂、颗粒剂、混悬剂、溶液剂、注射剂、栓剂、软膏剂、硬膏剂、霜剂、喷雾剂、贴剂。优选的是口服制剂形式,最佳优选的是片剂,胶囊剂。
进一步的,本发明所述药物组合物还含有药学上可接受的载体。
可以采用制剂学常规技术制备该药物制剂,如将本发明的Y27632前药化合物、或其水合物、或其溶剂化物、或其药学上可接受的盐或其拆分的单一异构体与药学上可接受的载体混合。所述药学上可接受的载体包括但不限于:甘露醇、山梨醇、山梨酸或钾盐、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、盐酸半胱氨酸、巯基乙酸、蛋氨酸、维生素A、维生素C、维生素E、维生素D、EDTA二钠、EDTA 钙钠,一价碱金属的碳酸盐、醋酸盐、磷酸盐或其水溶液、盐酸、醋酸、硫酸、磷酸、氨基酸、氯化钠、氯化钾、乳酸钠、木糖醇、麦芽糖、葡萄糖、果糖、右旋糖苷、甘氨酸、淀粉、蔗糖、乳糖、甘露糖醇、硅衍生物、纤维素及其衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮、甘油、丙二醇、乙醇、吐温60-80、司盘-80、蜂蜡、羊毛脂、液体石蜡、十六醇、没食子酸酯类、琼脂、三乙醇胺、碱性氨基酸、尿素、尿囊素、碳酸钙、碳酸氢钙、聚乙二醇、环糊精、β-环糊精、磷脂类材料、高岭土、滑石粉、硬脂酸钙、硬脂酸镁等。
本发明的药物组合物,在制成药剂时,单位剂量的药剂可含有本发明的药物活性物质0.1-1000mg,其余为药学上可接受的载体。药学上可接受的载体以重量计可以是制剂总重量的0.1-99.9%。
本发明的药物组合物在使用时根据病人的情况确定用法用量。
有益效果
1.本发明提供的化合物在人肝S9中有效代谢成活性母药Y27632,因而具有抗肝纤维化作用,并且在人血浆、模拟胃肠液中稳定,从而降低了由于代谢过快的特征导致需要大剂量给药带来的和/或活性代谢产物出现在非靶器官带来的系统毒副作用。模型动物药效试验显示,本发明化合物显著降低四氯化碳(CCl4)诱导SD大鼠的肝纤维化程度和血清胶原指标,大幅改善肝组织炎症状态,效果显著优于母药Y27632,为肝纤维化的治疗和预防提供了新的药物途径。详见实施例。
2.本发明涉及的化合物,通过结构筛选,发现所设计和合成的化合物中包含两个磷酯基团和一个磷酰胺基团的化合物(如式IIa,IIb)在肝脏部位无代谢活性,包含三个磷酰胺基团的化合物(如式III,IIIa,IIIb,IIIc,IIId)在非肝脏部位稳定性较差,因而无法提高肝靶向性和抗肝纤维化活性。只有与母药Y27632形成一个磷酰胺结构并且在磷原子上另形成一个磷酯基团和一个磷酰胺基团保护后的化合物(如式I、式IV),在非肝脏系统中稳定,而在肝脏中在酶的作用下含磷基团与Y27632形成的磷酰胺键断裂释放出活性母药Y27632才具有提高肝靶向性,从而提高抗肝纤维化活性,式I的活性优于式IV;在式I结构上更换不同的R1和/或R2和/或R3基团,不影响含磷基团与Y27632形成的磷酰胺键断裂,因而都具有提高母药Y27632抗肝纤维化活性的作用。
附图说明
1.图1为本发明部分代表性化合物对CCl4诱导的肝纤维化SD大鼠肝组织纤维化程度的影响(相对胶原面积/%),与模型组比,*P<0.05;与Y27632组比,&P<0.05;与水飞蓟宾组比,#P<0.05;
2.图2为本发明部分代表性化合物对CCl4诱导的肝纤维化SD大鼠肝组织纤维化程度的影响(部分Masson染色图片;×40倍);
3.图3为本发明部分代表性化合物对CCl4诱导的肝纤维化SD大鼠肝组织α-平滑肌肌动蛋白(α-SMA)表达水平的影响(统计结果),与模型组比,*P<0.05;与 Y27632组比,&P<0.05;与水飞蓟宾组比,#P<0.05;
4.图4为本发明代表化合物1、3对CCl4诱导的肝纤维化SD大鼠血清中层粘连蛋白(Laminin,LN)水平的影响,与模型组比,*P<0.05;与Y27632组比,&P<0.05;
5.图5为本发明代表化合物1、3对CCl4诱导的肝纤维化SD大鼠血清中I型胶原(C-Ⅰ)水平的影响,与模型组比,*P<0.05;与Y27632组比,&P<0.05;
6.图6为本发明代表化合物1、3对CCl4诱导的肝纤维化SD大鼠血清中前III型胶原(PC-Ⅲ)水平的影响,与模型组比,*P<0.05;与Y27632组比,&P<0.05;与水飞蓟宾组比,#P<0.05;
7.图7为本发明代表化合物1、3对CCl4诱导的肝纤维化SD大鼠血清中Ⅳ型胶原(C-Ⅳ)水平的影响,与模型组比,*P<0.05;与Y27632组比,&P<0.05;
8.图8为本发明代表化合物1、3对CCl4诱导的肝纤维化SD大鼠肝组织病理切片炎症级别的影响(HE染色;×100倍)。
具体实施方式
以下结合具体实施例和试验例详细地解释本发明,使得本领域技术人员更全面地理解本专利。具体实施例仅用于说明本发明的技术方案,并不以任何方式限定本发明,本发明涉及的化合物不限于实施例中使用的代表性结构,更换不同的 R1和/或R2和/或R3基团,都具有提高母药Y27632抗肝纤维化活性的作用。
实施例1:化合物1的制备
往50mL两颈瓶中加入无水二氯甲烷20mL,二氯磷酸苯酯(254μL,1.7 mmol,)和L-丙氨酸异丙酯盐酸盐(285.6mg,1.7mmol),在-40℃(液氮乙醇控温)条件下缓慢滴加三乙胺(471.3μL,3.4mmol)的无水二氯甲烷溶液5mL,加毕保持-40℃搅拌1h,移至室温继续搅拌1h后加入Y27632.2HCl(320mg,1 mmol)和三乙胺(554.5μL,4mmol),室温搅拌12h。将反应液旋干,乙酸乙酯萃取,无水Na2SO4干燥,经硅胶柱层析(甲醇:二氯甲烷=1:20~1:10)纯化得白色固体,收率25.5%,mp:87~88℃。
ESI-MS(m/z):calcd.for C26H37N4O5P[M+H]+517.25,found 517.79.
1H NMR(400MHz,CDCl3)δ9.44(d,J=38.5Hz,1H),8.38(dd,J=5.3,4.0 Hz,2HH),7.56(dd,J=7.5,2.8Hz,2H),7.30(d,J=7.9Hz,1H),7.18(ddd,J= 33.3,20.4,12.0Hz,4H),5.01(m,1H),3.97(m,1H),3.67(m,2H),3.15(d,J=6.6 Hz,1H),2.81(ddd,J=21.0,18.3,10.5Hz,1H),2.30(m,1H),1.95(d,J=12.8Hz, 3H),1.77(t,J=13.4Hz,1H),1.52(m,2H),1.37(dt,J=12.2,7.3Hz,3H),1.23 (m,6H),1.14(m,3H),0.97(m,2H).31P NMR(162MHz,CDCl3)δ8.84,8.64,8.50, 8.29.
实施例2:化合物2的制备
制备方法同实施例1,其中化合物L-丙氨酸异丙酯盐酸盐用化合物甘氨酸苄酯替代。白色固体,收率27.6%。mp:91~93℃。ESI-MS(m/z):calcd.for C29H35N4O5P[M+H]+551.23,found 551.22.1H NMR(400MHz,CDCl3)δ9.72(d,J =22.6Hz,1H),8.37(s,2H),7.73(s,2H),7.32(m,6H),7.16(m,4H),5.15(m,2 H),3.78(m,2H),3.66(s,2H),2.30(s,1H),1.93(d,J=11.1Hz,3H),1.72(s,1H, 1.47(m,2H),1.35(dd,J=9.0,5.5Hz,2H),1.09(dd,J=10.3,6.5Hz,3H),0.91 (m,2H).31P NMR(162MHz,CDCl3)δ9.80,9.64.
实施例3:化合物3的制备
制备方法同实施例1,其中化合物L-丙氨酸异丙酯盐酸盐替换为甘氨酸异丙酯盐酸盐。白色固体,收率23.2%。mp:92~93℃。ESI-MS(m/z):calcd.for C25H35N4O5P[M+H]+503.23,found 503.14.1H NMR(400MHz,CDCl3)δ9.77(d,J =24.2Hz,1H),8.35(s,2H),7.61(d,J=3.7Hz,2H),7.20(ddd,J=29.6,14.5,7.5 Hz,5H),5.06(m,1H),3.78(s,1H),3.72(d,J=10.5Hz,2H),3.17(d,J=8.8Hz, 1H),2.28(s,1H),1.93(d,J=10.3Hz,3H),1.76(d,J=9.3Hz,1H),1.48(t,J= 19.0Hz,2H),1.23(d,J=6.2Hz,6H),1.13(d,J=10.8Hz,3H),0.94(ddd,J= 68.7,34.4,22.4Hz,2H).31P NMR(162MHz,CDCl3)δ10.07,9.91.
实施例4:化合物4的制备
制备方法同实施例1,其中化合物L-丙氨酸异丙酯盐酸盐用化合物L-丙氨酸苄酯替代。白色固体,收率49.6%。mp:102~103℃。ESI-MS(m/z):calcd.for C30H37N4O5P[M+H]+564.25,found 565.21.1H NMR(400MHz,CDCl3)δ9.89(d,J =13.4Hz,1H),8.35(s,2H),7.62(s,2H),7.25(m,10H),5.12(m,2H),4.06(m,1 H),3.76(m,2H),3.06(m,1H),2.98(m,1H),2.26(s,1H),1.89(s,3H),1.71(s,1 H,),1.48(d,J=10.8Hz,2H),1.38(m,3H),1.07(m,3H),0.91(m,2H).31P NMR (162MHz,CDCl3)δ8.82,8.62,8.49,8.32.
试验例
对前药化合物而言,最关键的是前药在非靶器官系统中的稳定性和在靶器官部分的代谢活性。在系统(如胃肠道,血液等)中稳定,在靶器官(如本发明中的肝脏等)中代谢成活性化合物,则化合物具有靶向性,可以避免脱靶带来的系统毒副作用。为了验证所设计的前药化合物是否可以在肝细胞内释放出有效药物分子,而在其他细胞中代谢较低。通过以下试验例,对体外系列代谢活性与代谢稳定性进行了评估,具体如下:
试验例1:肝靶部位代谢活性研究
1.1实验方法
1.1.1酶溶液及相关溶液的配制
磷酸缓冲液(PBS,pH=7.4)溶液的配制:称取一定量K2HPO4和KH2PO4,分别用超纯水配制成0.100M,调节pH至约7.40。
氯化镁水溶液:称取一定量的MgCl2·6H2O,用PBS溶解,使浓度为10.0mM,备用。
NADPH储备液的配制:称取一定量NADPHNa4,用氯化镁水溶液溶解,使浓度为10.0mM,备用。
UDPGA储备液的配制:称取一定量UDPGA,用PBS溶解,使浓度为20.0mM,备用。
人肝S9酶溶液:将人肝S9于-80℃冰箱取出后,迅速在湿冰上解冻,然后用 PBS稀释成1.43mg/mL(初始浓度为20.0mg/mL),备用。
化合物1-4储备液的配制:分别称取一定量化合物1-4,用甲醇和DMSO溶解,浓度为11.5mM。
化合物1-4工作溶液1的配制:用R01(甲醇:H2O=1:1)将储备液稀释成5.75 mM,备用。
化合物1-4工作溶液2的配制:用磷酸缓冲液将工作溶液1稀释成115μM。 1.1.2孵育试验
化合物1-4样品孵育
取700μL 1.43mg/mL人肝S9酶溶液分别于5.00mL离心管中,分别加入 100μL化合物1-4工作溶液2于37℃水浴中孵育10min,然后加入100μL 10.0 mM NADPH和100μL 20.0mM UDPGA启动反应。孵育60min后,在反应体系中加入到200μL 10%三氯乙酸终止反应,涡旋混匀,然后以17000×g、4℃离心5min。离心后取1.00mL上清液过SPE柱,甲醇洗脱部分在氮气下挥干,残渣用200μL R01复溶后再进行样品分析。
化合物1-4对照样品孵育
不添加人肝S9的对照样品:取700μLPBS分别于5.00mL离心管中,加入100μL 化合物1-4工作溶液2于37℃水浴中孵育10min,然后加入100μL 10.0mM NADPH 和100μL 20.0mMUDPGA启动反应。孵育60min后,在反应体系中加入到200μL10%三氯乙酸终止反应,涡旋混匀,然后以17000×g、4℃离心5min。离心后取 1.00mL上清液过SPE柱,甲醇洗脱部分在氮气下挥干,残渣用200μL R01复溶后再进行样品分析。
不添加NADHP的对照样品:取700μL 1.43mg/mL人肝S9酶溶液分别于5.00mL 离心管中,加入100μL化合物1-4工作溶液2于37℃水浴中孵育10min,然后加入 100μL PBS和100μL 20.0mM UDPGA启动反应。孵育60min后,在反应体系中加入到200μL10%三氯乙酸终止反应,涡旋混匀,然后以17000×g、4℃离心5min。离心后取1.00mL上清液过SPE柱,甲醇洗脱部分在氮气下挥干,残渣用200μL R01 复溶后再进行样品分析。
1.1.3样品测定方法
应用本发明建立的HPLC-QTRAP(MRM-IDA-EPI及MIM-IDA-EPI)分析方法,对采集的以上样品进行检测。
1.2实验结果
按以上实验方法对化合物1-4进行人肝S9中代谢活性研究,结果显示化合物1-4在肝脏中迅速代谢成活性母药Y27632,半衰期为分别为15.6min、28.8min、 17.3min、34.5min;内在清除率分别为44.4μL/min/mg、24.1μL/min/mg、 40.1μL/min/mg、20.1μL/min/mg。
化合物 | 半衰期min | 清除率μL/min/mg |
化合物1 | 15.6 | 44.4 |
化合物2 | 28.8 | 24.1 |
化合物3 | 17.3 | 40.1 |
化合物4 | 34.5 | 20.1 |
试验例2:非肝靶部位代谢稳定性研究
2.1实验方法
2.1.1相关溶液的配制
化合物1-4分析物工作溶液配制:用R01(乙腈:水=1:1,v:v)将化合物1-4储备液分别稀释成一系列工作溶液40.0、36.0、20.0、10.0、4.00、2.00、 0.800及0.400μM用于配制校正标样。并将化合物1-4储备液稀释成一系列工作溶液30.0、6.00及1.20μM用于配制质控样品。
母药Y27632分析物工作溶液配制:用R01(乙腈:水=1:1,v:v)将母药Y27632 储备液稀释成一系列工作溶液10.0、9.00、4.00、2.00、1.00、0.800、0.400 及0.200μM分别用于配制校正标样。并将母药Y27632储备液稀释成一系列工作溶液7.50、2.00及0.600μM用于配制质控样品。
2.1.2孵育实验
人血浆孵育实验:分别取990μL人混合血浆于5.0mL的EP管中,于37℃水浴中预孵育10.0min。然后加入10.0μL 100μM WHM-III-01工作溶液2启动反应。于0、0.5、1、2、4、8h后,取出100μL反应液加入到500μL含内标(双氯芬酸浓度为100ng/ml和拉贝洛尔的浓度为2.00ng/ml)的冰乙腈中终止反应。
涡旋混匀,17000×g,4℃条件下离心5min,取上清50.0μL,加入350μL R01(乙腈:H2O=1:1)复溶,进行LC-MS/MS分析。
人工胃液孵育实验:分别取990μL人工胃液于5.0mL的EP管中,于37℃水浴中预孵育10.0min。然后加入10.0μL 100μM WHM-III-01工作溶液2启动反应。于0、0.5、1、2、4、8h后,取出100μL反应液加入到400μL含内标(双氯芬酸浓度为100ng/ml和拉贝洛尔的浓度为2.00ng/ml)的冰乙腈中终止反应。
涡旋混匀,17000×g,4℃条件下离心5min,取上清50.0μL,加入450μL R01(乙腈:H2O=1:1)复溶,进行LC-MS/MS分析。
人工小肠液孵育实验:分别取7920μL人工小肠液于10.0mL的EP管中,于37℃水浴中预孵育10.0min。然后加入80.0μL 100μM WHM-III-01工作溶液2启动反应。向每个时间点的每个平行样中分装1.2mL反应液,于0、0.5、1、2、4、8h后,取出100μL反应液加入到400μL含内标(双氯芬酸浓度为 100ng/ml和拉贝洛尔的浓度为2.00ng/ml)的冰乙腈中终止反应。
涡旋混匀,17000×g,4℃条件下离心5min,取上清50.0μL,加入450μL R01(乙腈:H2O=1:1)复溶,进行LC-MS/MS分析。
2.1.3样品测定与计算方法
通过液质联用(LC-MS/MS)方法考察原形化合物1-4在人血浆、人工胃液和人工小肠液中的代谢速度和程度,以及代谢物Y27632的生成速率。分别求算化合物1-4的浓度,与t0时间的浓度对比求得不同孵育时间的原形化合物的相对含量(R),然后对此比值求对数Ln R,最后以时间为横坐标、Ln R为纵坐标作图。根据斜率ke(消除速率常数)求得原形化合物(化合物1-4)分别在人血浆、人工胃液和人工小肠液中的半衰期(t1/2=0.693/ke)。同时对代谢产物 (Y27632)进行绝对定量,求算Y27632随孵育时间的生成速率。
2.2实验结果
按照以上实验方法对化合物1-4进行系列体外稳定性研究,考察前药化合物 1-4在人血浆、人工胃液和人工小肠液中的代谢速度和程度,以及代谢产物 Y27632的生成速率。
结果显示化合物1、3在人血浆中基本不代谢,孵育8h后均未检测到活性母药Y27632,化合物2、4在人血浆中缓慢代谢,代谢半衰期分别为5.3h、22.6 h。化合物1-4在人工胃液中属于慢代谢,在人工胃液中孵育8h后,化合物1-4 分别有12%、26%、15%、22%被代谢成活性母药Y27632。在人工肠液中孵育8h,化合物1约有20%的原形被代谢,化合物3基本不代谢,化合物2和化合物4的半衰期分别为1.7h、2.5h。
结论:通过试验例1和2考察本发明前药化合物在人肝S9细胞、人血浆、人工胃液或人工小肠液中的代谢活性与速度,以及活性母药Y27632的生成速率,证实了本发明化合物在肝脏中生成活化母药、在其他系统中稳定或缓慢代谢,因而具有体外肝靶向性,预示此类前药化合物可以在体内胃肠道和血液中稳定、在肝中快速代谢成活性母药,因而具有肝脏靶向活化而在其他系统中稳定的特点,从而具有在同剂量药效更高或达到相同药效时使用更低剂量并进一步降低系统毒性的特征。
试验例3:本发明化合物显著降低四氯化碳(CCl4)诱导SD大鼠的肝纤维化程度
在动物药效试验中,本发明化合物显著降低四氯化碳(CCl4)诱导SD大鼠的肝纤维化程度和血清胶原指标,大幅改善肝组织炎症状态,效果显著优于母药 Y27632。以下试验例通过肝纤维化模型动物药效实验验证了本发明化合物的这些优势特征。
CCl4诱导肝纤维化模型是一种传统的经典动物模型,因其在形态学、病理生理学等诸多方面,都与人体肝纤维化有极大的相似性,不仅具有毒物诱导的肝纤维化特征,而且还与乙肝病毒感染后的病理特征相似,能很好地模拟人类肝纤维化的病理变化。低剂量CCl4长期刺激后,不但动物表现出的肝功异常与人肝硬化体征十分相似,而且纤维化发生分子机制、损伤后血清标志物、肝组织病理改变与人也非常相似。因此,CCl4诱导肝纤维化模型现被广泛应用于研究肝纤维化发病机制、抗肝纤维化药物筛选、抗肝纤维化药物的作用机制等。
1.材料与方法
1)试验动物
种属及等级:SD大鼠,SPF级;
动物数量和性别:购入88只,雄性。80只建模,成模后选取60只入组试验;8只留做正常对照动物,选取6只入组试验;
年龄:购入时约5~8周龄,建模时约6~9周龄;
体重:购入时体重160~220g,建模时体重220~280g;
来源:北京维通利华实验动物技术有限公司提供,生产许可证号:SCXK(京)
2)药品、试剂及其配制
水飞蓟宾(江苏天士力帝益药业有限公司,批号20180101),Y27632.2HCl (苏州凯瑞医药科技有限公司,批号20180820),纯度均大于99%;本发明化合物由本发明人所在实验室合成,纯度大于99%;药用低聚羧甲基纤维素钠 (CMC-Na)购于安徽山河药用辅料有限公司,橄榄油和CCl4购于成都市科隆化学品有限公司,均为分析纯,其它试剂均为市售分析纯。
3)试验方法
SD大鼠适应性喂养一周,按体重随机分组,造模组大鼠四肢内侧皮下注射 40%CCl4/橄榄油(4:6,V/V),每周2次,注射剂量为3mL/kg;正常对照组大鼠四肢内侧按3mL/kg皮下注射同等体积的橄榄油,每周2次。造模4周后,进行超声及血生化检查,根据二维成像模式扫查肝脏,观察肝实质回声、肝包膜、肝静脉壁形态、肝边缘并进行评分,同时参考血生化指标,选择回声增强、ALT、 AST升高大鼠进行分组,8只/组。给药过程中,模型和各给药动物组大鼠仍按建模操作继续给予40%CCl4橄榄油(4:6,V/V),正常对照组给予等体积的橄榄油。水飞蓟宾剂量为50mg/kg,Y27632.2HCl剂量为30mg/kg,本发明化合物高剂量均为Y27632.2HCl相同的摩尔物质量,中剂量为高剂量摩尔物质量的1/3,低剂量为高剂量摩尔物质量的1/9;模型组和正常组动物给予等量的0.5% CMC-Na。大鼠在末次灌胃前8h更换垫料,严格禁食不禁水。
给药后1h腹腔注射3%的戊巴比妥钠(2mL/kg)麻醉剂,采血后迅速完整地剖离肝脏。采集的血液在37℃孵育箱中静置45min后,4℃下3500rpm离心15 min,取上层血清,分装备用。取大鼠左叶下半部分肝脏于10倍体积4%多聚甲醛固定液中固定,24h后更新固定液。固定充分后进行病理切片,经Masson三色染观察肝脏纤维化程度,Image-Pro Plus软件对Masson染色切片的拍照结果进行纤维化组织学半定量分析。计算相对胶原面积:(给药组平均面积-正常组平均面积)/(模型组平均面积-正常组平均面积)×100%,利用免疫组织化学法评价肝组织α-SMA(HSC活化程度的标志物)表达情况,使用Image-Pro Plus对阳性表达进行量化分析。数据利用SPSS 17.0统计学软件进行处理和分析。数据均采用平均值±标准差来表示;P﹤0.05组间差异有显著性意义。
2.实验结果
结合图1、2、3,结果表明:本发明化合物能显著降低动物肝组织的纤维化程度。分别与模型组、水飞蓟宾组、母药Y27632组相比,本发明化合物治疗组大鼠肝组织的胶原面积、肝组织中α-SMA表达水平均显著降低。说明本发明化合物具明显的抗肝纤维化作用,其抗肝纤维化作用与抑制肝星状细胞HSC活化有关,且抗肝纤维化效果显著优于母药Y27632。
试验例4:本发明化合物对四氯化碳(CCl4)诱导SD大鼠肝纤维化动物血清胶原指标的影响
正常肝组织中,胶原物质是窦间隙基质膜的重要组成成分,以C-Ⅰ和C-Ⅳ为主。当肝脏受到损伤后,大量胶原物质和糖蛋白被转录、翻译和组装,以LN、 C-Ⅰ和C-Ⅲ为主。临床上,血清LN、C-Ⅰ、PC-Ⅲ和C-Ⅳ水平是纤维化患者诊断的重要指标。
1.材料与方法
同试验例3。
以本发明化合物H为代表,采用ELISA方法测定动物血清中LN、C-Ⅰ、PC- Ⅲ和C-Ⅳ水平。血清中胶原指标变化见附图4-7。数据利用SPSS 17.0统计学软件进行处理和分析。数据均采用平均值±标准差来表示;P﹤0.05组间差异有显著性意义。
2.实验结果
结果显示,与正常组相比,模型组中血清LN、C-Ⅰ、PC-Ⅲ和C-Ⅳ水平均大幅提高;与模型组相比,本发明化合物1的等摩尔剂量组、化合物3的1/3摩尔剂量组显著降低肝组织中LN和C-I含量,母药Y27632降低了LN和C-I含量,但不显著;与母药Y27632相比,本发明化合物1的等摩尔剂量组降低LN有显著性差异,本发明化合物1的等摩尔剂量组、化合物3的1/3摩尔剂量组、化合物 3的1/9摩尔剂量组降低肝组织中C-I含量有显著性差异;与母药Y27632相比,本发明化合物1的等摩尔剂量组、有显著性差异;与模型组相比,本发明化合物显著降低肝组织中PC-Ⅲ水平,与Y27632相比,化合物1的等摩尔剂量组、化合物3的1/3摩尔剂量组降低PC-Ⅲ水平有显著性差异;与模型组相比,本发明化合物显著降低肝组织中C-IV水平,与Y27632相比,本发明化合物1的等摩尔剂量组、化合物3的1/3摩尔剂量组降低血清C-Ⅳ水平有显著性差异。
结合图4、5、6、7,结果表明:本发明化合物与母药Y27632相比,大幅降低LN、C-Ⅰ、PC-III和C-Ⅳ等肝纤维化特异性指标水平。本发明化合物在1/3 和1/9摩尔当量剂量时对肝纤维化指标的抑制作用优于或者相当于1摩尔当量剂量的Y27632的作用。
试验例5:本发明化合物大幅改善四氯化碳(CCl4)诱导SD大鼠肝纤维化动物肝组织炎症状态
1材料与方法
同试验例3。
以本发明化合物1、3为代表,通过HE染色观察分析本发明化合物对肝组织免疫炎症状态的改善和纤维组织生成的抑制情况,结果见附图8。数据利用SPSS 17.0统计学软件进行处理和分析。数据均采用平均值±标准差来表示;P﹤0.05 组间差异有显著性意义。
2实验结果
结合图8和病理切片炎症分级数据分析,结果表明:正常组大鼠的肝小叶结构完整、肝细胞围绕中央静脉向四周放射、排列整齐,没有异变;未见脂肪变性、坏死,无炎细胞浸润、无纤维结缔产生。模型组大鼠肝小叶排列混乱,表现为点状、片状或灶状坏死,肝细胞肿胀变性,炎细胞浸润严重,肝小叶结构被破坏,形成假小叶。与模型组相比,给药组动物肝损伤均得到不同程度的改善,尤其是本发明化合物1的等摩尔当量剂量治疗组、本发明化合物3的1/3摩尔当量剂量治疗组最为显著,肝细胞仅有轻微肿大,肝细胞索的结构正常,明显优于模型组和母药Y27632治疗组。
综合分析上述试验例3、4、5中所述HE、Masson染色结果与血清胶原指标,发现Y27632、化合物1、化合物3治疗组大鼠肝脏纤维化程度均比模型对照组有所减轻,减轻肝纤维化的程度对比结果为:化合物3>化合物1>Y27632,证实了本发明化合物具有治疗肝纤维化的效果,且优于母药Y27632。
Claims (10)
1.一种Y27632前药如式Ⅰ所示的化合物、异构体及其溶剂化物、或它们药学上可接受的盐,
其中R1,R2分别独立地选自H、C1-C3直链烃基、C3-C10支链烃基、C3-C10环烃基、C6-C10芳香烃基或杂芳基,所述直链烃基、支链烃基、环烃基、芳香烃基中的碳原子有或者没有被一个到三个独立地选自O,S,N,Se的杂原子替代;R3独立地选自1-5个H、卤素、烷基、氨基、氰基、叠氮基、硝基、烷胺基、酰胺基、烷酰基、烷酰氧基、烷氧基、杂环基;Z独立地选自O,S,Se,-NH-或-CH2-。
2.根据权利要求1所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其特征在于:NH-C(R2)-COZR1为天然氨基酸或其手性异构体在羧基端形成的酯,R1为C1-C3直链烃基、C3-C5支链烃基、C6-C10芳香烃基。
3.根据权利要求1所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其特征在于:所述R1为异丙基或苄基。
4.根据权利要求2或3所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其特征在于:所述R2为氢原子或甲基,所连接的碳原子构型为R或者S构型。
5.根据权利要求1-4任意一项所述的Y27632前药化合物、异构体及其溶剂化物、或它们药学上可接受的盐,其特征在于:R3独立地选自1-5个H、F、Cl、Br、甲基、乙基、环丙烷基、苯基、乙烯基、乙炔基、氯乙烯基、氟甲基、二氟甲基、三氟甲基、氨基、氰基、叠氮基、硝基、甲胺基、乙胺基、丙氨基、环丙胺基、乙酰氨基、乙酰基、乙酰氧基、乙氧基、异丙氧基、吡啶基;优选R3独立地选自1-5个H、F、Cl、Br、甲基、乙基、环丙烷基、苯基、氟甲基、二氟甲基、三氟甲基、氨基、氰基、叠氮基、硝基、环丙胺基、乙酰基、乙酰氧基、乙氧基、异丙氧基、吡啶基;优选R3为1个H。
6.根据权利要求1-5任意一项所述的Y27632前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐,其特征在于,其中Z为O或S。
7.根据权利要求6所述的Y27632前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐,其特征在于,
8.一种Y27632前药的制备方法,所述方法反应式如下:
9.一种药物组合物,其特征在于,该药物组合物含有权利要求1-7任一项所述的化合物、异构体及其溶剂化物、或它们药学上可接受的盐和药学上可接受的载体。
10.一种Y27632前药化合物、异构体及其溶剂合物、或它们药学上可接受的盐在制备治疗肝纤维化疾病的药物中的应用。
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