CN101511816A - 具有改善的生物利用度的氨基异喹啉凝血酶抑制剂 - Google Patents
具有改善的生物利用度的氨基异喹啉凝血酶抑制剂 Download PDFInfo
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Abstract
本发明涉及化合物N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基-丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺或其可药用盐,涉及包括该化合物的药物组合物,以及涉及该化合物在制备用于治疗或预防由凝血酶介导的疾病的药物中的应用。
Description
本发明涉及包含氨基异喹啉基团的凝血酶抑制剂,包含该凝血酶抑制剂的药物组合物,以及所述抑制剂在制备用于治疗和预防由凝血酶介导的疾病的药物中的应用。
大部分的肽如凝血酶抑制剂在文献中据报道在所谓的P1位置包含碱性基团(R.Pfau,"Structure-based design of thrombininhibitors",Current Opinion in Drug Discovery & Development,6,437-450,2003)。这些碱性基团的实例包括碱性氨基酸精氨酸和赖氨酸,此外还有胍和苄脒。这些化合物中的碱性部分被认为是抗血栓形成活性所必不可少的。然而,这些高碱性基团在生理学pH下通常发生质子化,因此,这些化合物在口服剂量给药后被吸收穿过胃肠道的程度差并且具有低的口服生物利用度。
可经口给药的治疗剂因为其固有的容易使用性而通常被更加优选并且具有增强的商业潜力。
在国际专利申请WO 98/47876(Akzo Nobel N.V.)中公开了一类凝血酶抑制剂,其具有氨基异喹啉部分作为碱性基团并且这些化合物具有改善的跨上皮转运性质。特别地,该专利申请举例说明了以下化合物:N-(羧甲基)-D-苯基丙氨酰基-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺(WO98/47876:实施例77)和N-(羧甲基)-D-(4-甲氧基苯基)丙氨酰基-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺(WO98/47876:实施例111as),及其前体药物酯衍生物。
希望开发具有更高利用度的凝血酶抑制剂,特别是适于口服给药的那些。
本发明涉及新的化合物N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺,该化合物在口服给药时具有高的生物利用度。
在另一方面,本发明涉及包含N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺或其可药用盐以及载体或稀释剂的药物制剂。
本发明的其它方面涉及化合物N-(羧甲基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺,其是选择性凝血酶抑制剂,在口服给药后其从N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺原地产生,并且其在合成本发明的正丙基前体药物衍生物中用作中间体。
本发明的化合物N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺由以下的结构式1A表示:
式IA
本发明发现了,正丙基酯衍生物1A,与在结构上密切相关的氨基异喹啉类凝血酶抑制剂如在WO 98/4876中公开的N-(羧甲基)-D-苯基丙氨酰基-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺(2A)和N-(羧甲基)-D-(4-甲氧基苯基)丙氨酰基-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺(3A)的相应的正丙基酯衍生物的生物利用度相比,前者当口服给药时生物利用度高。
因此,本发明的化合物1A口服给药导致凝血酶抑制剂1B(其是1A的游离酸衍生物,一旦进入循环在体内迅速生成1B)的显著高的血浆浓度。
新的二苯基丙氨酸衍生物1A与相应的苯基丙氨酸衍生物2A相比或与甲氧基苯基丙氨酸衍生物3A相比具有意想不到的改善的口服活性,使得可以开发用于在较低剂量下口服给药的抗血栓形成剂。
实验
总则:
在Applied Biosystems API 150EX质谱仪上获得LC-MS数据。在Bruker DPX 400或DRX 400分光计上记录1H NMR谱。
实施例1(反应路线I):
N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺(1A)
A:N-[2-(1,1-二甲基乙氧基)-2-氧代乙基]-β-苯基-D-苯基丙氨酸(a)
向搅拌的D-二苯基丙氨酸,H-D-Dpa-OH,(20.0g,82.9mmol)和碳酸钾(17.2g,125mmol)在二氧杂环己烷/水(1:1(v/v),100ml)中的混合物中加入溴乙酸叔丁酯(12.2ml,83.0mmol),搅拌过夜后加入水(100ml)并用0.5M柠檬酸液调节pH到5.5。所得沉淀物被滤出,用水洗涤,然后用二乙醚,并真空干燥,得到10.4克的标题化合物a。
反应路线I
B:(S)-2[[[(1-氨基-6-异喹啉基)甲基]氨基]羰基]-1-吡咯烷羧酸1,1-二甲基乙基酯盐酸盐(b)
向搅拌的N-叔丁氧羰基-L-脯氨酸,Boc-Pro-OH,(6.73g,31.25mmol)在无水N,N-二甲基甲酰胺(100ml)中的溶液中在氩气氛下加入磨细的1-氨基-6-氨基甲基异喹啉盐酸盐(10.0g,40.63mmol)和N,N-二异丙基乙胺(16.17g,125.00mmol)。在室温下搅拌浆料15分钟后,在5分钟内滴加2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(17.67g,46.88mmol),最后导致悬浮的1-氨基-6-氨基-甲基异喹啉盐酸盐完全溶解。在室温下在氩气氛下搅拌反应混合物达另外90分钟,之后形成了(S)-2-[[[(1-氨基-6-异喹啉基)甲基]氨基]羰基]-1-吡咯烷羧酸1,1-二甲基乙基酯盐酸盐(b)的黄色沉淀物。过滤收集该沉淀物,用二氯甲烷(300ml)洗涤直到滤液无色,然后真空干燥,得到7.8克(56%)的标题化合物(纯度94%,HPLC-LunaC18(2)46 x 30mm,梯度洗脱,流动相:乙腈:水5-100%/4分钟,恒量0.1%的三氟乙酸)。通过真空蒸发滤液以除去二甲基甲酰胺和过量的二异丙基乙胺并加入500ml的二氯甲烷分离出另外的产物。过滤除去所得的沉淀物,用二氯甲烷(300ml)洗涤并真空干燥,得到4.6克(33%)的标题化合物(纯度91%,HPLC-Luna C18(2)46 x 30mm,梯度洗脱,流动相:乙腈:水5-100%/4分钟,恒量0.1%的三氟乙酸)。
C:N-[2-(1,1-二甲基乙氧基)-2-氧代乙基]-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐(c)
向(S)-2-[[[(1-氨基-6-异喹啉基)甲基]氨基]羰基]-1-吡咯烷羧酸1,1-二甲基乙基酯盐酸盐b(4.14g,9.34mmol)在二氯甲烷(20ml)中的悬浮液中加入三氟乙酸(8ml)。搅拌该溶液2小时后,真空除去溶剂和过量的三氟乙酸。然后将残余物溶于N,N-二甲基甲酰胺(41ml)和2-(叔丁氧羰基甲基-氨基)-3,3-二苯基-丙酸(Boc-D-Dpa-OH)(3.30g,9.3mmol)中,加入2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓六氟磷酸盐(5.31g,13.9mmol)和N,N-二异丙基乙胺(9.75ml,56mmol)。在室温下搅拌混合物1小时,然后加入水,直到形成沉淀物。过滤收集湿的沉淀物,然后溶解在乙酸乙酯中,干燥(MgSO4),过滤并蒸干,得到粗产物(7.2克)。通过柱色谱纯化(二氧化硅,用二氯甲烷和甲醇(0-10%)的混合物梯度洗脱),得到4.6克的标题化合物c,为胶状物。
D:N-(羧甲基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐(1B)
向N-[2-(1,1-二甲基乙氧基)-2-氧代乙基]-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐c(4.6g,7.1mmol)在二氯甲烷(25ml)中的溶液中加入三氟乙酸(4.6ml)。放置过夜后,蒸干溶液,溶解在二氯甲烷中,加入包含过量盐酸的二乙醚。通过加入无水二乙醚使产物沉淀,然后过滤收集沉淀物并真空干燥,得到2.8克标题化合物。通过从母液中沉淀获得另外0.8克的标题化合物。
1H NMR δ(CD3OD)1.32(m,1H),1.83(m,3H),2.86(m,1H),3.53(m,1H),3.68(dd,2H;J=17.1Hz),3.80(d,2H;J=17.1Hz)(4.15(m,1H),4.52(d,1H;J=16.6Hz),4.59(d,1H;J=11.5Hz),4.69(d,1H;J=16.1Hz),5.3(d,1H;11.5Hz),7.2-7.6(m,10H),7.66(d,2H;J=7.5Hz),7.72(dd,1H;J=1.5,8.0Hz),7.89(s,1H),8.38(d,1H;J=9Hz);MS m/z 552.2(M+H)+。
E:N-(2-丙氧基-2-氧代乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺二盐酸盐(1A)
向N-(羧甲基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐(1B;300mg.0.5mmol)在正丙醇(5ml)中的悬浮液中滴加亚硫酰氯(0.4ml)。搅拌3天后,溶液用二氯甲烷稀释,用5%的碳酸氢钠水溶液洗涤并蒸干。粗产物通过反向HPLC纯化,然后通过溶于少量甲醇中并用经二乙醚中的1M盐酸沉淀将其被转化为盐酸盐。加入另外的无水二乙醚,过滤收集所得的沉淀物并真空干燥,得到185毫克的标题化合物,为白色粉末。
1H NMR δ(CD3OD)0.85(t,3H;J=7.5Hz),1.33(m,1H),1.57(六重峰,2H;J=7Hz),1.83(m,3H),2.88(m,1H),3.51(m,1H),3.73(d,1H;J=17.6Hz),3.84(d,1H;J=17.6Hz),4.07(m,2H),4.16(dd,1H;J=5.0,8.0Hz),4.53(d,1H;J=16.6Hz),4.56(d,1H,;J=13.6Hz),4.70(d,1H;J=16.6Hz),5.20(d,1H;J=11Hz),7.23-7.44(m,7H),7.50(t,2H;J=7.5Hz),7.56(d,1H;J=7.0Hz),7.65(d,2H;J=7.5Hz),7.72(dd,1H;J=1.5,8.0Hz),7.90(s,1H),8.39(d,1H;J=8.5Hz);MS m/z 594.4(M+H)+。
使用与上述方法和反应路线I中的所述方法类似的方法,从D-苯基丙氨酸或O-甲基-D-酪氨酸代替D-二苯基丙氨酸开始制备相应的衍生物。分离化合物2B和3B并使用其三氟乙酸盐的形式用于后面的试验。
实施例2
2B:N-(羧甲基)-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺三氟乙酸盐
1H NMR δ(CD3OD)1.41(m,1H),1.85(m,2H),1.99(m,1H),2.47(m,1H),3.35(dd,1H;J=5.0,13.1Hz),3.40(dd,1H;J=10.6,13.1Hz),3.45(m,1H),3.73(d,1H;J=16.6Hz),3.80(d,1H;J=16.6Hz),4.34(dd,1H;J=4.5,8.1Hz),4.5(dd,1H;J=5.0,10.6Hz),4.51(d,1H;J=16.1Hz),4.72(d,1H;J=16.6Hz),7.23(d,1H;J=7.1Hz),7.27-7.43(m,5H),7.52(d,1H;J=7.1Hz),7.71(dd,1H;J=1.5,8.6Hz),7.90(s,1H),8.34(d,1H;J=8.6Hz);MS m/z 476.0(M+H)+。
2A:N-(2-丙氧基-2-氧代乙基)-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐
1H NMR δ(CD3OD)0.89(t,3H;J=7.6Hz),1.41(m,1H),1.62(六重峰,2H:J=7.6Hz),1.83(m,2H),2.00(m,1H),2.44(m,1H),3.16(dd,1H;J=1.5,10.6Hz),3.37(dd,1H;J=5.5,13.1Hz),3.47(m,1H),3.93(d,1H;J=17.1Hz),4.06(d,1H;J=17.1Hz),4.14(m,2H),4.36(dd,1H;5.0,9.1Hz),4.54(m,2H),4.71(d,1H;J=17.1Hz),7.26(d,1H;7.1Hz),7.29-7.44(m,5H),7.56(d,1H;J=7.1Hz),7.73(d,1H;J=8.6Hz),7.92(s,1H),8.38(d,1H;J=8.6Hz);MS m/z 518.2(M+H)+。
实施例3
3B.N-(羧甲基)-O-甲基-D-酪氨酰基(tyrosinyl)-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺三氟乙酸盐
1H NMR δ(CD3OD)1.46(m,1H),1.87(m,2H),2.02(m,1H),2.56(m,1H),3.08(dd,1H;J=10.6,12.6Hz),3.27(dd,1H;J=5.5,13.6Hz),3.47(m,1H),3.71(d,1H;J=16.1Hz),3.79(d,1H;J=15.6Hz),3.79(s,3H),4.36(dd,1H;J=4.0,8.6Hz),4.46(dd,1H;J=4.0,8.66Hz),4.51(d,1H;J=16.6Hz),4.72(d,1H;J=16.6Hz),6.92(d,2H;J=8.6Hz),7.21(d,2H;J=8.6Hz),7.24(d,1H;7.1Hz),7.52(d,1H;J=7.1Hz),7.71(d,1H;J=8.1Hz),7.90(s,1H),8.35(d,1H;J=9.1Hz);MS m/z 506.3(M+H)+。
3A:N-(2-丙氧基-2-氧代乙基)-O-甲基-D-酪氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐
1H NMR δ(CD3OD)0.88(t,3H;J=7.1Hz),1.47(m,1H),1.61(六重峰,2H:J=7.1Hz),1.86(m,2H),2.04(m,1H),2.54(m,1H),3.10(dd,1H;J=10.6,15.1Hz),3.31(m,1H),3.49(m,1H),3.79(s,1H),3.91(d,1H;J=16.6Hz),4.04(d,1H;J=16.6Hz),4.13(m,2H),4.38(dd,1H;5.0,9.1Hz),4.48(dd,1H;J=5.0,10.6Hz),4.54(d,1H;J=16.1Hz),4.71(d,1H;J=16.1Hz),6.93(d,2H;J=8.6Hz),7.22(d,2H;J=8.6Hz),7.26(d,1H;7.1Hz),7.55(d,1H;J=7.1Hz),7.73(dd,1H;J=2.0,8.6Hz),7.92(s,1H),8.38(d,1H;J=8.6Hz);MS m/z 548.3(M+H)+。
实施例4:凝血酶活性测定
凝血酶抑制活性的测定如下进行:将各种浓度下的供试化合物与人α凝血酶在37℃下预温孵。10分钟后,向混合物中加入发光底物H-D-Phe-Pipecoliny1-Arg-对-硝基苯胺(S-2238)并在随后的8分钟内测量吸光度的改变。1A和1B都以浓度依赖性方式作为人α凝血酶的有效抑制剂,IC50值分别是13.0nM和12.6nM(都为n=5;图1)。在另一个实验中,还改变了S-2238的浓度,[S]/V对[S]的作图平行于所使用的S-2238的每一浓度,表明抑制的竞争性本质。这些数据的Hanes-Woolf分析提供了1B的Ki值为0.9nM(n=5),和1A的Ki值为1.0nM(n=3)。与化合物2和3的活性参数的比较如表1所示。
表1.凝血酶抑制活性参数
化合物 | IC 50 (nM) | Ki (nM) |
1A | 13.0 | 1.0 |
1B | 12.6 | 09 |
2A | 573 | 345 |
2B | 864 | 455 |
3A | 197 | 18 |
3B | 358 | 54 |
实施例5
在大鼠中测定化合物1A、2A和3A的生物利用度。
动物
雄性Wistar Ola大鼠(~250克),在整个研究期间随意获取食物和水。
手术准备
对于静脉内药代动力学研究,将导管(Portex polythene-ID 0.58mm,OD 0.96mm,具有用SF Medical硅树脂导管制成的末梢,SFM1-1350)插入处于异氟烷麻醉下的右颈静脉内。将导管从颈的背部取出,用肝素化盐水充满(100 IU/ml)并塞好。在剂量给药之前使动物恢复至少48小时。
化合物的给药
化合物1A、2A和3A经口给药(PO)。化合物1B、2B和3B静脉内给药(IV)。根据矩阵设计方案(每个时间点三个样品)从第3分钟到第24小时的时间点从外侧静脉(终点样品通过心脏穿刺取得)取得连续的血样(用于血浆)。将血浆保存在-20℃下直到分析之前。
血浆样品分析
使用LC-MS方法分析血浆样品的相关的游离酸凝血酶衍生物1B、2B和3B。Cmax(最大血浆浓度)和AUC值从平均血浆浓度-时间曲线测定。
实验
进行以下一组实验:
-以5毫克/千克基准(5毫克/毫升溶液,以1毫升/千克剂量给药)对5只大鼠静脉内给药(IV)含有化合物1B的盐水。
-以10毫克/千克基准(2毫克/毫升溶液,以5毫升/千克剂量给药)对4只大鼠经口给药(PO)含有化合物1B的盐水。
-以10毫克/千克基准(2毫克/毫升溶液,以5毫升/千克剂量给药)对5只大鼠经口给药含有化合物1A的5% mulgofen/95%盐水。
-以2毫克/千克基准(2毫克/千克,以1毫升/千克剂量给药)对4只大鼠静脉内给药含有化合物2B的盐水。
-以10毫克/千克基准(2毫克/毫升溶液,以5毫升/千克剂量给药)对4只大鼠经口给药含有化合物2A的盐水。
-以2毫克/千克基准(2毫克/毫升溶液,以1毫升/千克剂量给药)对4只大鼠静脉内给药含有化合物3B的盐水。
-以10毫克/千克基准(2毫克/毫升溶液,以5毫升/千克剂量给药)对4只大鼠经口给药含有化合物3A的盐水。
结论
使用WinNonlin Professional 3.1和4.1进行非房室药代动力学分析。所得药代动力学参数如表2所示。
发现二苯基丙氨酸衍生物N-(羧甲基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺盐酸盐(1B)的正丙基酯衍生物(1A),与相应的苯基丙氨酸(2A)和对甲氧基苯基丙氨酸(3A)凝血酶抑制剂相比,前者的生物利用度(以AUC(IV)/AUC(PO)×100%表示)非常高(58%)。
表2.药代动力学参数
化合物 | 1Ba | 1Bb | 1Bb在1A给药后 | 2B | 2B在2A给药后 | 3B | 3B在3A给药后 |
剂量(mg/kg) | 5 | 10 | 10 | 2 | 10 | 2 | 10 |
给药途径 | IV | PO | PO | IV | PO | IV | PO |
媒介物 | 盐水 | mul/盐水 | 盐水 | 盐水 | 盐水 | 盐水 | |
AUC(IV)(ng/ml.h) | 4864 | 659 | 1008 | ||||
T1/2(h) | 0.32 | 0.61 | 0.16 | ||||
清除(ml/min/kg) | 17 | 54 | 34 | ||||
Vss(L/kg) | 0.48 | 2.4 | 0.46 | ||||
Cmax(ng/ml) | 35 | 2130 | 4 | 62 | |||
Tmax(h) | 1.2 | 1 | 0.067 | 1.6 | |||
AUC(PO)(ng/ml.h) | 119 | 5647 | ND | 97 | |||
生物利用度(%) | 1.3 | 58b | 可以忽略 | 1.9 |
ND=未测得
a=数据是两次研究的平均值
b=在1A给药后1B的生物利用度为30到60%,在01a Wistar大鼠中,对于化合物1A使用不同类型的媒介物(在明胶/甘露醇中的悬浮液,或在甘露醇/磷酸盐缓冲盐水中的溶液,或在5% mulgofen/95%盐水中的溶液)进行多次实验测得的。
Claims (6)
1.化合物N-(2-氧代-2-丙氧基乙基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺或其可药用盐。
2.权利要求1的化合物,其为二盐酸盐。
3.药物组合物,其包含权利要求1的化合物和其可药用的助剂。
4.权利要求1的化合物,其用于治疗。
5.权利要求1的化合物在制备用于治疗或预防由凝血酶介导的疾病的药物中的应用。
6.化合物N-(羧甲基)-β-苯基-D-苯基丙氨酰基-N-[(1-氨基-6-异喹啉基)甲基]-L-脯氨酰胺或其可药用盐。
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