CN116143742A - 依前列醇一氧化氮供体药物 - Google Patents
依前列醇一氧化氮供体药物 Download PDFInfo
- Publication number
- CN116143742A CN116143742A CN202310167386.4A CN202310167386A CN116143742A CN 116143742 A CN116143742 A CN 116143742A CN 202310167386 A CN202310167386 A CN 202310167386A CN 116143742 A CN116143742 A CN 116143742A
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- CN
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- Prior art keywords
- alkylene
- epoprostenol
- nitric oxide
- oxide donor
- pharmaceutical composition
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- KAQKFAOMNZTLHT-VVUHWYTRSA-N epoprostenol Chemical compound O1C(=CCCCC(O)=O)C[C@@H]2[C@@H](/C=C/[C@@H](O)CCCCC)[C@H](O)C[C@@H]21 KAQKFAOMNZTLHT-VVUHWYTRSA-N 0.000 title claims abstract description 40
- 229960001123 epoprostenol Drugs 0.000 title claims abstract description 40
- 239000003814 drug Substances 0.000 title claims abstract description 36
- 239000002840 nitric oxide donor Substances 0.000 title claims abstract description 19
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- 150000001875 compounds Chemical class 0.000 claims description 22
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- 125000004093 cyano group Chemical group *C#N 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- BNRNXUUZRGQAQC-UHFFFAOYSA-N sildenafil Chemical compound CCCC1=NN(C)C(C(N2)=O)=C1N=C2C(C(=CC=1)OCC)=CC=1S(=O)(=O)N1CCN(C)CC1 BNRNXUUZRGQAQC-UHFFFAOYSA-N 0.000 claims description 6
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Abstract
本发明提供了一种如式I所示的依前列醇一氧化氮供体药物，
所述药物可以通过活化腺苷酸环化酶引起肺动脉平滑肌舒张并抑制平滑肌细胞增殖以及抗血小板聚集等作用达到治疗肺动脉高压的作用。本发明的依前列醇一氧化氮供体药物进一步提高了依前列醇的生物利用度，改善了其药代动力学，可以减少给药的剂量和服用频率，提高药物的有效性和安全性。
Description
技术领域
本发明属于医药技术领域，涉及一种治疗肺动脉高压的药物，具体涉及一种依前列醇一氧化氮供体药物及其应用。
背景技术
肺动脉高压(pulmonary arterial hypertension,PAH)是以肺血管阻力进行性升高和右心功能进行性衰竭为主要特征的病理过程，是临床众多疾病常见的并发症，也可以原因不明，原因不明的肺动脉高压成为特发性肺动脉高压(idiopathic pulmonaryarterial hypertension,IPAH)。血管内皮细胞、平滑肌细胞、成纤维细胞以及血小板和单核巨噬细胞能够产生多种血管活性物质，正常情况下它们之间处于动态平衡，维持肺血管的正常生理结构和功能。在一些外来刺激下，这些介质发生分泌平衡失调，促进血管收缩、血管重构以及血栓形成，是肺动脉高压发生的重要机制。
依前列醇的临床应用给肺动脉高压的治疗带来了突破性进展，依前列醇通过活化腺苷酸环化酶引起肺动脉平滑肌舒张并抑制平滑肌细胞增殖，还具有强大的抗血小板聚集作用。1995年美国联邦食品和药品监督管理局(FDA)批准将依前列醇用于治疗重症IPAH患者，2000年批准其用于继发性肺动脉高压的治疗。持续输入依前列醇不仅能够改善临床症状和血流动力学状态，而且还能提高重度IPAH患者的生存率，并且能够改善硬皮病相关肺动脉高压患者的运动耐量和心肺循环血流动力学状态。依前列醇对于急性血管扩张试验没有反应的肺动脉高压患者也同样有效。对于口服钙通道拮抗剂无效的患者，若改为依前列醇静脉滴注仍可有效。
依前列醇半衰期较短(3～5min)，酸性条件下不稳定，因此需要持续静脉泵入，一般从小剂量(1～2ng·kg-1·min-1)开始，随后根据药物的不良反应和患者的耐受性，逐渐上调药物剂量，直到临床症状明显改善或出现明显的不良反应。依前列醇应用复杂，输注前需要低温保存，长期应用需中心静脉插管。其主要不良反应包括面部潮红、头痛、颌骨疼痛、下肢痛、腹泻、恶心以及静脉注射的相关感染和血栓形成。由于依前列醇给药不方便，治疗也较为昂贵，以及存在持续静脉治疗相关的不良反应，限制了其临床应用。
有鉴于此，通过改进依前列醇的结构，改善依前列醇的清除半衰期短、给药次数多、需要剂量大等缺陷具有重要的临床意义。
发明内容
本发明针对现有技术存在的问题，提供了一种依前列醇一氧化氮供体药物，可以用于治疗肺动脉高压，提高了依前列醇的生物利用度，改善了其药代动力学，解决了依前列醇半衰期短、给药次数多、需要剂量大等缺陷。
为实现上述目的，本发明采用的技术方案如下：
本发明第一个方面提供了一种依前列醇一氧化氮供体药物，其结构如式I所示：
其中，n为0，1，2，3或4；
R为-X-ONO2、-OC(O)-X-ONO2、-O-X-ONO2、或
其中X为直链或支链的C1-C10亚烷基、C3-7环亚烷基、C6-10芳基-C1-C10亚烷基或C1-C10亚烷基-C6-10芳基-C1-C10亚烷基；其中C1-C10亚烷基、C3-7环亚烷基或C6-10芳基可被以下一个或者多个取代基取代：卤原子、羟基、羧基、氰基或-(C1-C10亚烷基)-ONO2。
在一些实施方式中，X为直链或支链的C1-C6亚烷基、C4-6环亚烷基、苯基-C1-C6亚烷基或C1-C6亚烷基-苯基-C1-C6亚烷基；其中C1-C6亚烷基、C4-6环亚烷基或苯基可被以下一个或者多个取代基取代：卤原子、羟基、羧基、氰基或-(C1-C6亚烷基)-ONO2。
本发明第二个方面提供了一种药物组合物，包含本发明的依前列醇一氧化氮供体药物及药学上可接受的辅料。
在一些实施方案中，所述药物组合物还包含附加治疗剂，所述附加治疗剂选自波生坦、安贝生坦、西地那非等
本发明第三个方面提供了所述依前列醇一氧化氮供体药物或所述药物组合物在制备治疗肺动脉高压的药物中的应用。
本发明第四个方面提供了所述依前列醇一氧化氮供体药物在制备前列环素类似物中的应用。
相对于现有技术，本发明具有以下有益效果：
本发明提供的依前列醇一氧化氮供体药物，可以通过活化腺苷酸环化酶引起肺动脉平滑肌舒张并抑制平滑肌细胞增殖以及抗血小板聚集等作用达到治疗肺动脉高压的作用。本发明的依前列醇一氧化氮供体药物进一步提高了依前列醇的生物利用度，改善了其药代动力学，可以减少给药的剂量和服用频率，提高药物的有效性和安全性。
附图说明
图1为低氧性肺动脉高压大鼠体内试验结果。
具体实施方式
定义和一般术语
除非另有说明，本发明的术语采用以下定义：
术语“亚烷基”是指从直链或支链饱和碳氢化合物消去两个氢原子得到的饱和二价烃基。亚烷基基团的实例包括但并不限于，亚甲基(-CH2-)、亚乙基(-CH2CH2)、亚丙基(-CH2CH2CH2-)、次乙基(-CH(CH3)-)、次异丙基(-CH(CH3)CH2-)等等。
术语“环亚烷基”是指从3到7元饱和烃环上消去两个氢原子得到的饱和二价环烷烃基。环亚烷基的实例包括但不限于
等。
术语“卤原子”是指F、Cl、Br或I。
术语“取代”是指所给结构中的一个或多个氢原子被具体取代基所取代，当所给出的结构式中不只一个位置能被选自具体基团的一个或多个取代基所取代，那么取代基可以相同或不同地在各个位置取代。
术语“体内代谢物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。
术语“生物利用度”是指本文所公开的化合物被递送到所研究的动物或人的全身循环中的重量百分比。当静脉内施用时，药物的总暴露量(AUC(0-∞))通常被定义为100％生物利用度(F％)。“口服生物利用度”是指与静脉内注射相比，当口服药物组合物时，本文所公开的化合物被吸收到全身循环中的程度。
化合物
本发明涉及一种如式I所示的依前列醇一氧化氮供体药物：
其中，n为0，1，2，3或4；
R为-X-ONO2、-OC(O)-X-ONO2、-O-X-ONO2、或
其中X为直链或支链的C1-C10亚烷基、C3-7环亚烷基、C6-10芳基-C1-C10亚烷基或C1-C10亚烷基-C6-10芳基-C1-C10亚烷基；其中C1-C10亚烷基、C3-7环亚烷基或C6-10芳基可被以下一个或者多个取代基取代：卤原子、羟基、羧基、氰基或-(C1-C10亚烷基)-ONO2。
在一些实施方式中，X为直链或支链的C1-C6亚烷基、C4-6环亚烷基、苯基-C1-C6亚烷基或C1-C6亚烷基-苯基-C1-C6亚烷基；其中C1-C6亚烷基、C4-6环亚烷基或苯基可被以下一个或者多个取代基取代：卤原子、羟基、羧基、氰基或-(C1-C6亚烷基)-ONO2。
本发明所述的式I结构的化合物包括但不限于以下具体化合物：
组合物
本发明的药物组合物包括式I的化合物和药学上可接受的辅料。
所述的药用辅料可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
在一些实施方式中，本发明涉及的药物组合物，进一步包含附加治疗剂。所述附加治疗剂为适用于治疗肺动脉高压的药物，包括但不限于波生坦、安立生坦、西地那非等。
在一些实施方式中，本发明涉及的药物组合物为片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、颗粒剂或扁囊剂等剂型。
本发明的的内药物组合物可根据公开容使用本领域技术人员已知的任何方法来制备。例如，常规混合、溶解、造粒、乳化、磨细、包封、包埋或冻干工艺。
化合物和组合物的用途
本发明的化合物或药物组合物可用于制备治疗肺动脉高压的药物，或用于制备前列环素类似物。
肺动脉高压是以肺小动脉的血管痉挛、内膜增生和重构为主要特征的一种病理现象，发展到后期可引起右心功能衰竭，直至死亡。在静息状态下，通过右心导管测得平均肺动脉压(mPAP)≥25mmHg，肺动脉楔压(PAWP)≤15mmHg，即可诊断肺动脉高压。
前列环素类似物可增加前列环素的浓度，进而扩张肺动脉平滑肌，抑制平滑肌增生和抑制血小板聚集，改善右心功能和血流动力学。
本发明的化合物或组合物可作为前列环素类似物，发挥舒张血管平滑肌，治疗肺动脉高压的作用。
下面将对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。另外，值得说明的是，本发明所涉及的原料如无特殊说明均为普通市售产品。
实施例1
合成路线：
实施例1的合成
将依前列醇(55mg)，用2mL无水DMF溶解，将碘化钾(75mg)、碳酸钾(62mg)和2-溴乙基硝酸酯(80mg)的二氯甲烷溶液滴入，移至50℃条件下搅拌反应2h，TLC检测反应完全，旋干溶剂，HPLC纯化得实施例1，收率51％。
1H NMR(300MHz,Chloroform-d)δ5.89(dd,J＝15.6,5.7Hz,1H),5.73(dd,J＝15.6,7.0Hz,1H),4.90(q,J＝4.7Hz,2H),4.73–4.60(m,2H),4.41(td,J＝6.3,2.1Hz,2H),4.25–4.08(m,2H),4.05(qd,J＝5.5,4.7Hz,1H),3.45(d,J＝5.5Hz,1H),2.63–2.41(m,3H),2.43–2.28(m,3H),2.24–2.18(m,2H),2.17–1.96(m,2H),1.88–1.72(m,2H),1.69–1.48(m,2H),1.48–1.35(m,2H),1.35–1.20(m,4H),1.03–0.71(m,3H).
实施例2
参考实施例1的合成方法，可制得化合物2。
1H NMR(300MHz,Chloroform-d)δ5.89(dd,J＝15.6,5.7Hz,1H),5.73(dd,J＝15.6,7.0Hz,1H),4.90(td,J＝5.0,4.0Hz,2H),4.42(t,J＝6.1Hz,2H),4.25(t,J＝6.1Hz,2H),4.21–4.09(m,2H),4.05(qd,J＝5.5,4.7Hz,1H),3.45(d,J＝5.5Hz,1H),2.62–2.41(m,3H),2.40–2.29(m,3H),2.28–1.98(m,6H),1.82–1.70(m,2H),1.70–1.48(m,2H),1.48–1.35(m,2H),1.35–1.20(m,4H),0.96–0.76(m,3H).
实施例3
参考实施例1的合成方法，可制得化合物3。
1H NMR(300MHz,Chloroform-d)δ5.90(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.6,7.0Hz,1H),4.90(td,J＝5.0,4.0Hz,2H),4.47–4.25(m,2H),4.22–4.08(m,4H),4.05(qd,J＝5.7,4.8Hz,1H),3.33(d,J＝5.3Hz,1H),2.64–2.39(m,3H),2.39–2.29(m,3H),2.27–2.17(m,2H),2.17–1.98(m,2H),1.94–1.72(m,6H),1.69–1.51(m,2H),1.51–1.36(m,2H),1.36–1.14(m,4H),1.04–0.63(m,3H).
实施例4
参考实施例1的合成方法，可制得化合物4。
1H NMR(300MHz,Chloroform-d)δ5.90(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.6,7.0Hz,1H),4.90(td,J＝5.0,4.0Hz,2H),4.30(t,J＝6.1Hz,2H),4.20–3.93(m,5H),3.33(d,J＝5.3Hz,1H),2.68–2.40(m,3H),2.40–2.28(m,3H),2.28–2.17(m,2H),2.17–1.99(m,2H),1.88–1.68(m,6H),1.68–1.48(m,4H),1.48–1.36(m,2H),1.36–1.19(m,4H),0.94–0.76(m,3H).
实施例5
参考实施例1的合成方法，可制得化合物5。
1H NMR(300MHz,Chloroform-d)δ7.52–7.42(m,2H),7.42–7.29(m,2H),5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),5.41(dt,J＝2.9,1.0Hz,2H),5.10(dt,J＝1.8,1.1Hz,2H),4.90(td,J＝4.9,3.8Hz,2H),4.15(dqd,J＝6.7,5.7,1.0Hz,1H),4.08–3.93(m,2H),3.52(d,J＝5.5Hz,1H),2.64–2.41(m,3H),2.43–2.28(m,3H),2.27–2.17(m,2H),2.17–1.99(m,2H),1.79(p,J＝6.8Hz,2H),1.70–1.50(m,2H),1.50–1.36(m,2H),1.36–1.20(m,4H),0.99–0.76(m,3H).
实施例6
参考实施例1的合成方法，可制得化合物6。
1H NMR(300MHz,Chloroform-d)δ7.51–7.33(m,2H),7.16–7.02(m,2H),5.90(dd,J＝15.6,5.7Hz,1H),5.73(dd,J＝15.7,7.0Hz,1H),5.52–5.33(m,2H),4.90(td,J＝4.9,3.8Hz,2H),4.41–4.08(m,3H),4.08–3.92(m,2H),3.52(d,J＝5.5Hz,1H),2.88(tt,J＝6.4,1.1Hz,2H),2.64–2.40(m,3H),2.40–2.28(m,3H),2.22(tdq,J＝6.2,5.1,1.1Hz,2H),2.18–1.96(m,2H),1.79(p,J＝6.8Hz,2H),1.68–1.51(m,2H),1.48–1.37(m,2H),1.37–1.20(m,4H),0.99–0.73(m,3H).
实施例7
参考实施例1的合成方法，可制得化合物7。
1H NMR(300MHz,Chloroform-d)δ5.90(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.6,7.0Hz,1H),4.99–4.76(m,3H),4.51–4.29(m,2H),4.21–4.09(m,2H),4.05(qd,J＝5.7,4.8Hz,1H),3.33(d,J＝5.3Hz,1H),2.64–2.41(m,3H),2.41–2.27(m,3H),2.26–2.18(m,2H),2.18–1.99(m,2H),1.85–1.71(m,4H),1.69–1.48(m,2H),1.48–1.36(m,2H),1.36–1.22(m,4H),1.02(t,J＝7.4Hz,3H),0.93–0.77(m,3H).
实施例8
参考实施例1的合成方法，可制得化合物8。
1H NMR(300MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),5.07–4.79(m,2H),4.35–4.08(m,6H),4.05(qd,J＝5.7,4.8Hz,1H),3.44(d,J＝5.3Hz,1H),2.65–2.43(m,3H),2.43–2.29(m,3H),2.27–2.18(m,2H),2.18–1.99(m,2H),1.96–1.86(m,3H),1.80(p,J＝6.9Hz,2H),1.69–1.47(m,4H),1.47–1.36(m,2H),1.36–1.20(m,4H),1.00–0.79(m,6H).
实施例9
参考实施例1的合成方法，可制得化合物9。
1H NMR(300MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),4.90(td,J＝4.9,3.8Hz,2H),4.66(p,J＝5.5Hz,1H),4.15(dqd,J＝6.6,5.7,1.0Hz,1H),4.09–3.91(m,4H),3.52(d,J＝5.5Hz,1H),2.68–2.41(m,3H),2.40–2.27(m,3H),2.22(dtt,J＝6.4,5.0,1.0Hz,2H),2.17–1.98(m,2H),1.98–1.73(m,7H),1.73–1.50(m,6H),1.50–1.37(m,2H),1.37–1.17(m,4H),0.92–0.79(m,3H).
实施例10
参考实施例1的合成方法，可制得化合物10。
1H NMR(300MHz,Chloroform-d)δ5.90(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.6,7.0Hz,1H),5.02–4.77(m,3H),4.26–4.09(m,2H),4.09–3.96(m,3H),3.33(d,J＝5.3Hz,1H),2.61–2.41(m,3H),2.41–2.27(m,3H),2.27–1.97(m,7H),1.97–1.87(m,2H),1.79(p,J＝6.8Hz,2H),1.69–1.51(m,2H),1.51–1.36(m,2H),1.36–1.18(m,4H),1.02–0.68(m,3H).
实施例11
参考实施例1的合成方法，可制得化合物11。
1H NMR(300MHz,Chloroform-d)δ5.90(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.6,7.0Hz,1H),5.09(s,2H),4.99–4.85(m,2H),4.71–4.56(m,2H),4.20–4.09(m,2H),4.05(qd,J＝5.7,4.8Hz,1H),3.87(t,J＝6.1Hz,2H),3.33(d,J＝5.3Hz,1H),2.63–2.44(m,3H),2.44–2.29(m,3H),2.21(tdt,J＝6.2,5.1,1.0Hz,2H),2.17–2.01(m,2H),1.79(p,J＝6.9Hz,2H),1.70–1.51(m,2H),1.51–1.36(m,2H),1.36–1.21(m,4H),1.05–0.44(m,3H).
实施例12
参考实施例1的合成方法，可制得化合物12。
1H NMR(300MHz,Chloroform-d)δ5.90(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.6,7.0Hz,1H),4.90(td,J＝5.0,4.0Hz,2H),4.57(t,J＝6.2Hz,2H),4.38–4.16(m,2H),4.18–4.10(m,2H),4.05(qd,J＝5.7,4.8Hz,1H),3.81(t,J＝6.2Hz,2H),3.71(t,J＝6.2Hz,2H),3.33(d,J＝5.3Hz,1H),2.63–2.40(m,3H),2.40–2.28(m,3H),2.24–2.17(m,2H),2.17–1.97(m,2H),1.79(p,J＝6.9Hz,2H),1.68–1.51(m,2H),1.51–1.35(m,2H),1.35–1.19(m,4H),0.95–0.79(m,3H).
实施例13
参考实施例1的合成方法，可制得化合物13。
1H NMR(300MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),4.95–4.85(m,2H),4.58(t,J＝6.2Hz,2H),4.20–4.08(m,4H),4.05(qd,J＝5.7,4.8Hz,1H),3.76(t,J＝6.2Hz,2H),3.57–3.42(m,3H),2.64–2.39(m,3H),2.40–2.28(m,3H),2.23–2.18(m,2H),2.18–2.04(m,2H),2.04–1.92(m,2H),1.78(p,J＝6.9Hz,2H),1.65–1.48(m,2H),1.48–1.36(m,2H),1.36–1.22(m,4H),1.02–0.63(m,3H).
实施例14
参考实施例1的合成方法，可制得化合物14。
1H NMR(300MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),4.90(td,J＝4.9,3.8Hz,2H),4.71–4.48(m,2H),4.45–4.22(m,4H),4.22–3.98(m,3H),3.44(d,J＝5.3Hz,1H),2.79(t,J＝7.1Hz,2H),2.68–2.41(m,3H),2.41–2.30(m,3H),2.21(tdq,J＝6.3,4.9,1.0Hz,2H),2.17–2.02(m,2H),1.78(p,J＝6.8Hz,2H),1.72–1.50(m,2H),1.50–1.39(m,2H),1.39–1.10(m,4H),1.04–0.69(m,3H).
实施例15
参考实施例1的合成方法，可制得化合物15。
1H NMR(300MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.86–5.69(m,3H),4.99–4.80(m,2H),4.63(t,J＝7.1Hz,2H),4.24–4.08(m,2H),4.05(qd,J＝5.7,4.8Hz,1H),3.44(d,J＝5.3Hz,1H),2.82(t,J＝7.1Hz,2H),2.62–2.43(m,3H),2.43–2.28(m,3H),2.24–2.18(m,2H),2.18–1.99(m,2H),1.79(p,J＝6.9Hz,2H),1.69–1.48(m,2H),1.48–1.36(m,2H),1.36–1.21(m,4H),1.11–0.68(m,3H).
实施例16
参考实施例1的合成方法，可制得化合物16。
1H NMR(500MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),4.90(td,J＝4.9,3.8Hz,2H),4.62(td,J＝7.1,2.4Hz,2H),4.23–4.09(m,5H),4.09–3.93(m,2H),3.52(d,J＝5.5Hz,1H),2.78(t,J＝7.1Hz,2H),2.62–2.40(m,3H),2.40–2.28(m,3H),2.22(dtt,J＝6.5,5.1,1.1Hz,2H),2.19–1.96(m,4H),1.79(p,J＝6.8Hz,2H),1.70–1.48(m,2H),1.48–1.37(m,2H),1.37–1.22(m,4H),1.04–0.77(m,3H).
实施例17
参考实施例1的合成方法，可制得化合物17。
1H NMR(300MHz,Chloroform-d)δ5.91(dd,J＝15.7,5.6Hz,1H),5.75(dd,J＝15.7,7.1Hz,1H),4.90(td,J＝4.9,3.8Hz,2H),4.72–4.55(m,2H),4.45–4.21(m,4H),4.21–4.08(m,2H),4.05(qd,J＝5.7,4.8Hz,1H),3.44(d,J＝5.3Hz,1H),2.79(t,J＝7.1Hz,2H),2.61–2.43(m,3H),2.43–2.28(m,3H),2.21(tdq,J＝6.3,4.9,1.0Hz,2H),2.18–1.99(m,2H),1.78(p,J＝6.8Hz,2H),1.70–1.50(m,2H),1.50–1.37(m,2H),1.37–1.22(m,4H),1.00–0.66(m,3H).
实施例18
参考实施例1的合成方法，可制得化合物18。
1H NMR(300MHz,Chloroform-d)δ7.57–7.35(m,2H),7.33–7.08(m,2H),5.97–5.79(m,3H),5.71(dd,J＝15.6,7.0Hz,1H),5.50–5.33(m,2H),5.05–4.70(m,2H),4.21–3.82(m,3H),3.62(q,J＝0.8Hz,2H),3.52(d,J＝5.5Hz,1H),2.63–2.43(m,3H),2.43–2.28(m,3H),2.22(tdq,J＝6.5,5.1,1.2Hz,2H),2.18–1.98(m,2H),1.79(p,J＝6.9Hz,2H),1.68–1.51(m,2H),1.51–1.35(m,2H),1.35–1.19(m,4H),1.02–0.69(m,3H).
实施例19
合成方法
将依前列醇(55mg)，氯甲基呋咱氮氧化物和DMAP，TEA用2mL无水二氯甲烷溶解，室温搅拌四小时后，反应液中加入3mL二氯甲烷稀释，依次用10％的盐酸洗两次，饱和食盐水洗一次，过滤，滤液浓缩，HPLC纯化得化合物19，收率52％。
1H NMR(300MHz,Chloroform-d)δ8.09–7.76(m,2H),7.76–7.49(m,3H),6.02(q,J＝2.7Hz,2H),5.90(dd,J＝15.6,5.5Hz,1H),5.71(dd,J＝15.6,7.0Hz,1H),5.02–4.73(m,2H),4.24–4.09(m,1H),4.09–3.96(m,2H),3.52(d,J＝5.5Hz,1H),2.64–2.42(m,3H),2.41–2.31(m,3H),2.22(tdq,J＝6.1,5.0,1.0Hz,2H),2.16–2.02(m,2H),1.79(p,J＝6.8Hz,2H),1.67–1.49(m,2H),1.47–1.37(m,2H),1.35–1.22(m,4H),0.92–0.81(m,3H).
实施例20
参考实施例19的合成方法，可制得化合物20。
1H NMR(300MHz,Chloroform-d)δ7.80–7.64(m,2H),7.64–7.50(m,3H),5.90(dd,J＝15.6,5.5Hz,1H),5.71(dd,J＝15.6,7.0Hz,1H),4.90(td,J＝4.9,3.8Hz,2H),4.62(td,J＝6.2,1.4Hz,2H),4.55–4.37(m,2H),4.23–3.98(m,3H),3.69(d,J＝5.5Hz,1H),2.63–2.43(m,3H),2.41–2.28(m,3H),2.22(dtt,J＝6.5,5.4,1.1Hz,2H),2.18–1.98(m,2H),1.82–1.68(m,2H),1.68–1.47(m,2H),1.47–1.36(m,2H),1.36–1.20(m,4H),1.03–0.74(m,3H).
实施例21
参考实施例19的合成方法，可制得化合物21。
1H NMR(300MHz,Chloroform-d)δ7.99–7.80(m,2H),7.73–7.50(m,3H),5.90(dd,J＝15.6,5.5Hz,1H),5.71(dd,J＝15.6,7.0Hz,1H),4.90(td,J＝4.9,3.8Hz,2H),4.38(t,J＝6.1Hz,2H),4.26–4.08(m,4H),4.05(qd,J＝5.7,4.8Hz,1H),3.69(d,J＝5.5Hz,1H),2.63–2.41(m,3H),2.41–2.30(m,3H),2.27–1.98(m,6H),1.75(pd,J＝6.8,1.7Hz,2H),1.65–1.47(m,2H),1.41(dq,J＝7.1,6.2Hz,2H),1.36–1.22(m,4H),0.96–0.70(m,3H).
试验例1
低氧性肺动脉高压大鼠体内试验
(一)实验仪器和材料
HX-200动物呼吸机，实验所用SD雄性大鼠均购自扬州大学，生理盐水。所有对照组在正常环境下饲养，干预组和模型组在低压低氧舱内饲养(气压50kPa，氧浓度10％)。
(二)实验步骤
化合物2使用DMSO/solutol/water(10/10/80)溶解制成澄清溶液，干预组从低氧第二天开始，灌胃给药化合物化合物2剂量5mg/kg，所有大鼠每周称重，记录生存情况，四周后测定肺动脉压力。用水合氯醛(100g/L)麻醉大鼠(3mL/kg)，仰卧位固定，行气管切开，用小动物呼吸机辅助呼吸(频率60次/min，潮气量5mL，吸呼比4:5)。游离左侧第3肋骨，将一端连接张力换能器的导管送至肺动脉，通过BL-420E生物机能实验系统记录平均肺动脉压力(mPAP)。检查并收集胸水、腹水，最后从腹主动脉抽血将大鼠处死。
(三)实验结果
见附图1，与对照组相比，模型组大鼠的mPAP明显升高，给药化合物2的干预组mPAP较模型组降低。
试验例2
化合物的药代动力学实验
(一)实验仪器和材料
高速冷冻离心机，涡旋振荡器(Vortex Genius3)，高速离心机(Eppendorf5415D)，一次性使用注射器，移液枪(Eppendorf)，实验所用SD雄性大鼠均购自扬州大学，EDTA-K2真空采血管，生理盐水。所有口服组大鼠在给药前禁食12h，自由饮水，给药期间自由进水和进食。
(二)实验步骤
本发明的实施例化合物使用DMSO/solutol/water(10/10/80)溶解制成澄清溶液，灌胃给药化合物剂量25mg/kg，尾静脉给药化合物的剂量为5mg/kg。于尾静脉给药后的2min,10min,30min,1h,2h,3h,5h,8h,12h,16h,24h，从眼底静脉丛连续取血0.5mL至肝素管中，灌胃给药后的5min,15min,30min,1h,2h,3h,5h,8h,12h,16h,24h，从眼底静脉丛连续取血0.5mL肝素管中。将样品在8000r，4℃条件下离心10min后，取上层血浆0.15mL，-20℃条件下保存，之后进行LC-MS/MS分析。数据通过WinNolin非房室模型分析，得到关键药代动力学参数。
(三)实验结果
表1化合物的药代动力学参数
由上述试验结果可以发现，相对于依前列醇的达峰时间(0.1h)和半衰期(0.4h)，本发明的化合物明显延长了达峰时间和半衰期，具有优异的长效给药的潜力及良好的口服给药潜力。
最后应当说明的是，以上内容仅用以说明本发明的技术方案，而非对本发明保护范围的限制，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。
Claims (8)
1.一种如式I所示的依前列醇一氧化氮供体药物：
其中，n为0，1，2，3或4；
R为-X-ONO2、-OC(O)-X-ONO2、-O-X-ONO2、或
其中X为直链或支链的C1-C10亚烷基、C3-7环亚烷基、C6-10芳基-C1-C10亚烷基或C1-C10亚烷基-C6-10芳基-C1-C10亚烷基；其中C1-C10亚烷基、C3-7环亚烷基或C6-10芳基可被以下一个或者多个取代基取代：卤原子、羟基、羧基、氰基或-(C1-C10亚烷基)-ONO2。
2.根据权利要求1所述的依前列醇一氧化氮供体药物，其特征在于：X为直链或支链的C1-C6亚烷基、C4-6环亚烷基、苯基-C1-C6亚烷基或C1-C6亚烷基-苯基-C1-C6亚烷基；其中C1-C6亚烷基、C4-6环亚烷基或苯基可被以下一个或者多个取代基取代：卤原子、羟基、羧基、氰基或-(C1-C6亚烷基)-ONO2。
3.根据权利要求1所述的依前列醇一氧化氮供体药物，其特征在于，式I化合物选自如下结构：
4.一种药物组合物，包含权利要求1-3任一项所述的依前列醇一氧化氮供体药物和药学上可接受的辅料。
5.根据权利要求4所述的药物组合物，其特征在于，所述组合物还包含附加治疗剂，所述附加治疗剂为波生坦、安贝生坦和/或西地那非。
6.根据权利要求4或5所述的药物组合物，其特征在于，所述药物组合物为片剂、胶囊剂、囊片剂、丸剂、含片剂、粉剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、颗粒剂或扁囊剂。
7.权利要求1-3任一项所述的依前列醇一氧化氮供体药物或权利要求4-6任一项所述的药物组合物在制备治疗肺动脉高压的药物中的应用。
8.权利要求1-3任一项所述的依前列醇一氧化氮供体药物或权利要求4-6任一项所述的药物组合物在制备前列环素类似物中的应用。
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|---|---|---|---|---|
| GB1554044A (en) * | 1976-02-04 | 1979-10-17 | Upjohn Co | Prostaglandins |
| CN113943266A (zh) * | 2021-11-18 | 2022-01-18 | 广州楷石医药有限公司 | 一种氧化氮供体型贝前列素类衍生物及其药物组合物和用途 |
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