CN115894240A - 曲前列尼尔的前体药物及其应用 - Google Patents
曲前列尼尔的前体药物及其应用 Download PDFInfo
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- CN115894240A CN115894240A CN202211256979.XA CN202211256979A CN115894240A CN 115894240 A CN115894240 A CN 115894240A CN 202211256979 A CN202211256979 A CN 202211256979A CN 115894240 A CN115894240 A CN 115894240A
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- Prior art keywords
- treprostinil
- prodrug
- pharmaceutically acceptable
- pharmaceutical composition
- stereoisomer
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- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical compound C1=CC=C(OCC(O)=O)C2=C1C[C@@H]1[C@@H](CC[C@@H](O)CCCCC)[C@H](O)C[C@@H]1C2 PAJMKGZZBBTTOY-ZFORQUDYSA-N 0.000 title claims abstract description 43
- 229960005032 treprostinil Drugs 0.000 title claims abstract description 39
- 239000000651 prodrug Substances 0.000 title claims abstract description 29
- 229940002612 prodrug Drugs 0.000 title claims abstract description 29
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 19
- 208000002815 pulmonary hypertension Diseases 0.000 claims abstract description 17
- 239000003814 drug Substances 0.000 claims abstract description 16
- 208000031104 Arterial Occlusive disease Diseases 0.000 claims abstract description 5
- 201000009794 Idiopathic Pulmonary Fibrosis Diseases 0.000 claims abstract description 5
- 230000001684 chronic effect Effects 0.000 claims abstract description 5
- 208000036971 interstitial lung disease 2 Diseases 0.000 claims abstract description 5
- -1 Alkyl radical Chemical class 0.000 claims description 32
- 150000003839 salts Chemical class 0.000 claims description 24
- 125000000217 alkyl group Chemical group 0.000 claims description 14
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 9
- 239000000243 solution Substances 0.000 claims description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 239000001257 hydrogen Substances 0.000 claims description 8
- 125000003118 aryl group Chemical group 0.000 claims description 7
- 239000002552 dosage form Substances 0.000 claims description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 4
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- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 3
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- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims description 2
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Abstract
本发明提供了一种如式I所示的曲前列尼尔的前体药物及其药物组合物，
Description
技术领域
本发明属于生物医药领域，具体涉及曲前列尼尔的前体药物，其药物组合物 及用途。
背景技术
肺高压(Pulmonary Hypertension，包括肺动脉高压Pulmonary ArterialHypertension，PAH)是一类以肺血管阻力升高、右心室衰竭为特征的疾病。患 者被确证后存活期短死亡率高，是一种恶性疾病。机体内的前列素通过与血小板 或血管平滑肌上的前列素受体作用，激活腺苷酸环化酶，进而提高细胞内cAMP 的浓度，可以起到扩张血管的作用。前列环素可对抗血栓烷A2(TXA2)，PAH 患者前列环素合成减少，TXA2的浓度升高，导致血管收缩，内皮细胞增生和血 小板激活(Tuder RM等人,Am J respir Crit Care Med,1999)。
曲前列尼尔(treprostinil)作为一种前列素类似物，可以与前列素受体特异性结合，发挥舒张血管平滑肌、降低肺动脉压力并抑制肺动脉血管重构和原位血栓形 成的作用。该药能产生类似前列环素(PGI2)的效果，包括肺血管和循环血管扩张， 抑制血小板聚集和抑制平滑肌细胞增生(ClappLH,等人,Am J Respir Cell Mol Biol,2002)。目前也有认为曲前列尼尔的血管舒张和抗细胞增生作用由过氧化 物酶体增殖物活化受体介导(LiY,等人,Am J Respir Cell Mol Biol,2012)。美国 联合治疗公司开发该药物注射制剂于2002年被FDA批准用于肺动脉高压PAH 的治疗在美国上市。2021年4月该药又进一步被批准为用于间质性肺病相关肺 动脉高压(PH-ILD)的治疗。相比依前列醇和依诺前列醇较短的半衰期，曲前 列尼尔消除半衰期约4h，有明显的优势，主要排泄途径为尿液(79％)；肝功能不 全患者消除减少80％，而肾功能不全患者口服该药后暴露量并未增加，透析可减 少该药50％的暴露量(Jenkins A,等人,Am J respir Crit Care Med,2011)。
曲前列尼尔是目前临床上用于治疗PAH唯一可以皮下/静脉、口服、吸入多 个途径给药的前列环素类药物，其结构稳定、作用时间比前列环素更长，通过皮 下/静脉途径给药起效快，可以在数分钟起生物作用。PAH的临床研究中，皮下、 静脉和吸入给药均表现出良好的有效性和安全性。其中，皮下和静脉制剂(注射 用曲前列尼尔，商品名:Remodulin)和吸入溶液(商品名:Tyvaso)缓释片(商 品名:Orenitram)和注射液(商品名:Remodulin)分别于2002年、2009年、2013、 2018年被FDA批准上市。
由于需要长期给药，因此注射和吸入给药非常不方便，口服是最佳的给药途 径，然而口服形式药效不佳，有全身性毒副作用且需要一日多次给药，因此已有 缓释片开发上市用于临床，但由于化合物本身的缺陷，目前口服制剂的临床使用 一直不好，主要是吸入制剂为主，如最新吸入曲前列尼尔治疗肺高压的国际多中 心临床试验总结报告发表在2021年新英格兰医学杂志上。为改善患者依从性， 降低全身给药的毒副作用，INSMED公司修饰曲前列尼尔为棕榈酸(treprostinil palmitil)作为长效释放的前药吸入剂(专利US09255064和US09469600)，用 于治疗肺动脉高压、肺间质疾病关联肺高压和特发性纤维化，目前该项目已经进 入II期临床试验阶段。
因此，寻求探索合适的前药或剂型，进一步改进曲前列尼尔的体内代谢特征， 减少给药剂量和服用频率，降低直接暴露导致的毒副作用有积极的临床价值。
发明内容
本发明针对现有技术存在的问题，提供了一种曲前列尼尔的前体药物，优化 了曲前列尼尔的药代特征，减少给药的剂量和服用频率，提高了药物的有效性和 安全性。
为实现上述目的，本发明采用的技术方案如下：
一方面，本发明提供了一种曲前列尼尔的前体药物或其药学上可接受的盐、 立体异构体，所述前体药物结构如下式I所示：
其中，
R1为氢、烷基、环烷基、烷氧基或芳基；
R2为烷基、环烷基、烷氧基、烷基胺基或羟基；
n为0-6的整数。
另一方面，本发明提供了一种包含上述曲前列尼尔的前体药物或其药学上可 接受的盐的药物组合物。
再一方面，本发明提供了一种上述曲前列尼尔的前体药物或其药学上可接受 的盐或上述药物组合物作为前环列素类似物的应用。
又一方面，本发明提供了一种上述曲前列尼尔的前体药物或其药学上可接受 的盐或上述药物组合物在制备治疗肺动脉高压、慢性动脉闭塞性疾病、特发性肺 纤维化等的药物中的应用。
相对于现有技术，本发明具有以下有益效果：
本发明提供的一系列曲前列尼尔的前体药物，可以与前列素受体特异性结合， 舒张血管平滑肌，可用于治疗肺动脉高压、慢性动脉闭塞性疾病、特发性肺纤维 化等疾病。
本发明提供的曲前列尼尔的前体药物，优化了曲前列尼尔的药代特征和药物 的刺激性，减少给药的剂量和服用频率，提高了药物的有效性和安全性。
附图说明
图1为试验例2低氧性肺动脉高压大鼠体内试验结果。
具体实施方式
下面对本发明进行详细说明。
一方面，本发明提供了一种如下式I所示的曲前列尼尔的前体药物：
或其药学上可接受的盐、立体异构体；
其中，
R1为氢、烷基、环烷基、烷氧基或芳基；
R2为烷基、环烷基、烷氧基、烷基胺基或羟基；
n为0-6的整数，例如n可以为0，1，2，3，4，5或6。
在本发明的一些实施方式中，R1为氢、C1-20烷基、C3-20环烷基、C1-20烷氧 基或C7-20芳基；R2为C1-20烷基、C3-20环烷基、C1-20烷氧基、C1-20烷基胺基或羟 基。
在本发明的一些实施方式中，R1为氢或C1-10烷基；R2为C1-10烷基、C3-7环 烷基、C1-6烷基胺基、羟基或C1-6烷氧基。
在本发明的一些实施方式中，R1为氢、甲基或异丙基；R2为甲基、乙基、 正丙基、异丙基、叔丁基、环丙基、环己基、羟基、甲氧基、乙氧基、丙氧基、 甲胺基、乙胺基、丁氨基、2-甲基丙-1-胺、正己基、正庚基或正辛基；n为0，1， 2或3。
在本发明的一些实施方式中，所述曲前列尼尔的前体药物选自以下任一种结 构：
另一方面，本发明提供了一种包含上述曲前列尼尔的前体药物或其药学上可 接受的盐、立体异构体的药物组合物。
在本发明的一些实施方式中，所述药物组合物进一步包含药学上可接受的辅 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。
在本发明的一些实施方式中，所述药物组合物通常被配制成适合于对患者进 行口服给药、注射给药或吸入给药的剂型。
在本发明的一些实施方式中，所述剂型为口服剂型，例如片剂、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、颗粒剂和 扁囊剂等等。
本发明的药物组合物可根据公开的内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。
再一方面，本发明提供了一种上述曲前列尼尔的前体药物或其药学上可接受 的盐、立体异构体或上述药物组合物作为前环列素类似物的应用。
又一方面，本发明提供了一种上述曲前列尼尔的前体药物或其药学上可接受 的盐、立体异构体或上述药物组合物在制备治疗心血管疾病、脑血管疾病、呼吸 系统疾病等方面的药物中的应用，尤其是在肺动脉高压、慢性动脉闭塞性疾病、 特发性肺纤维化等的药物中的应用。
定义和一般术语
术语“药学上可接受的盐”是指本发明的化合物的有机盐和无机盐。药学上 可接受的盐在所属领域是为我们所熟知的，如文献：Berge et al.,describepharmaceuticallyacceptable salts in detail in J.Pharmacol Sci,1977,66,1-19，所记载的。药学上可接受的无毒的酸形成的盐包括，但并不限 于，与氨基基团反应形成的无机酸盐，如盐酸盐、氢溴酸盐、磷酸盐、硫酸盐、 高氯酸盐等；和有机酸盐，如乙酸盐、草酸盐、马来酸盐、酒石酸盐、柠檬酸 盐、琥珀酸盐、丙二酸盐等，或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天 冬氨酸盐、苯磺酸盐、苯甲酸盐、重硫酸盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑 磺酸盐、环戊基丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、 反丁烯二酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、己 酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、月桂基 硫酸盐、苹果酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油 酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特 戊酸盐、丙酸盐、硬脂酸盐、硫氰酸盐、对甲苯磺酸盐、十一酸盐、戊酸盐等等。 通过适当的碱得到的盐包括碱金属，碱土金属，铵盐。碱金属或碱土金属盐包括 钠、锂、钾、钙、镁等等。药学上可接受的盐进一步包括适当的、无毒的铵、季 铵盐和抗平衡离子形成的胺阳离子，如卤化物、氢氧化物、羧化物、硫酸化物、 磷酸化物、硝酸化物、C1-8磺酸化物和芳香磺酸化物。
术语“立体异构体”表示具有相同化学构造，但原子或基团在空间上排列方 式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋 转异构体)、几何异构体、(顺/反)异构体、阻转异构体等等。“对映异构体”是 指一个化合物的两个不能重叠但互成镜像关系的异构体。“非对映异构体”是指 有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有 不同的物理性质，如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通 过高分辨分析操作如电泳和色谱，例如HPLC来分离。
术语“烷基”或“烷基基团”表示含1-20个碳原子的饱和直链或支链一价 碳氢化合物原子团。其中所述烷基基团可以独立任选地被一个或多个取代基所取 代。烷基或烷基基团的实例包含但并不限于甲基、乙基、正丙基、异丙基、正丁 基异丁基、仲丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基 -2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2- 戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲 基-2-丁基、3,3-二甲基-2-丁基、正庚基、正辛基等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连，其中烷基基 团具有如本发明所述的含义。烷氧基的实例包含但并不限于，甲氧基、乙氧基、1-丙氧基、2-丙氧基、1-丁氧基、2-甲基-l-丙氧基、2-丁氧基、2-甲基-2-丙氧基、 1-戊氧基、2-戊氧基、3-戊氧基、2-甲基-2-丁氧基、3-甲基-2-丁氧基、3-甲基-l- 丁氧基、2-甲基-l-丁氧基等等。
术语“芳基”表示含有6-20元环的单环，双环或三环的碳环体系，其中， 至少一个环体系是芳香族的，其中每一个环体系包含3-7元环，且只有一个附着 点与分子的其余部分相连。芳基的实例包含但并不限于苯基、萘基和蒽等等。
术语“环烷基”表示指C3-C20环脂肪族环结构；环烷基的实例包括但不限 于，环丙基、环丁基、环戊基、环己基、环庚基、环辛基及类似基团。
术语“烷基胺基”表示基团-NHR或-NRR，其中R表示如上所述的烷基或 环烷基。
术语“羟基”表示-OH。
下面将结合具体实施例对本发明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：
化合物1的合成
将O-TES保护的曲前列尼尔(20mg)，碘化钾(25mg)和碳酸钾(21mg) 用10mL乙腈溶解，室温搅拌10min后，缓慢加入氯乙酸甲酯(15mg)，置于 80℃条件下反应8h，停止反应，旋干溶剂，加入二氯甲烷，水洗两次，饱和食 盐水洗一次，有机相浓缩，经柱层析纯化，浓缩，用THF/水溶解，加入2N HCl， 室温搅拌反应，TLC检测反应完全，旋干溶剂，HPLC纯化得实施例1，收率42％。 1H NMR(300MHz,DMSO-d)δ7.13(t,J＝7.5Hz,1H),7.02–6.96(m,1H),6.88(dd,J＝7.3,2.0Hz,1H),5.35–5.12(m,2H),4.75(s,2H),3.70(d,J＝7.7Hz,2H), 3.06(d,J＝12.8Hz,2H),2.90–2.63(m,2H),2.60–2.37(m,2H),2.12(s,3H),2.09 –1.96(m,2H),1.78–1.67(m,2H),1.61(dd,J＝12.4,1.9Hz,2H),1.59–1.39(m, 4H),1.39–1.27(m,4H),1.11(d,J＝12.5Hz,1H),0.86(t,J＝5.3Hz,3H).ESI-MS m/z:463.6[M+H]+.
实施例2
参考实施例1的合成方法，将氯乙酸甲酯替换为氯丙酸甲酯，可制得化合物 2。1HNMR(300MHz,DMSO-d)δ7.11(t,J＝7.5Hz,1H),7.00–6.85(m,2H),5.45 –5.27(m,2H),4.75(s,2H),3.73(d,J＝7.9Hz,2H),3.01(d,J＝11.8Hz,2H),2.87 –2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.35(s,2H),2.08–1.92(m,3H),1.77–
1.58(m,4H),1.58–1.37(m,4H),1.37–1.27(m,4H),1.17–1.03(m,4H),0.90(t,J＝5.2Hz,3H).ESI-MS m/z:477.3[M+H]+.
实施例3
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯乙酸乙酯，可制得化合 物3。1H NMR(300MHz,DMSO-d)δ7.22(t,J＝7.2Hz,1H),6.97(dd,J＝7.5,2.0 Hz,2H),5.82–5.77(m,1H),4.68(d,J＝1.8Hz,2H),3.77(d,J＝4.9Hz,1H), 3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.85–2.65(m,2H),2.56(d,J＝ 13.0Hz,2H),2.14–1.93(m,5H),1.79–1.59(m,7H),1.59–1.37(m,4H),1.37– 1.26(m,4H),1.11(d,J＝12.5Hz,1H),0.91(t,J＝5.3Hz,3H).ESI-MS m/z:477.3 [M+H]+.
实施例4
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯丙酸乙酯，可制得化合 物4。1H NMR(300MHz,DMSO-d)δ7.07(t,J＝7.7Hz,1H),6.99–6.89(m,2H), 5.84–5.79(m,1H),4.04(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝ 12.8Hz,1H),2.85–2.62(m,2H),2.56(d,J＝13.0Hz,1H),2.38(d,J＝27.7Hz, 3H),2.05–1.93(m,4H),1.80–1.57(m,7H),1.56–1.39(m,4H),1.39–1.26(m, 4H),1.23–1.03(m,4H),0.91(t,J＝5.3Hz,3H).ESI-MS m/z:513.3[M+Na]+.
实施例5
参考实施例1的合成方法，将氯乙酸甲酯替换为氯甲基异丁酸酯，可制得化 合物5。1H NMR(300MHz,DMSO-d)δ7.14(t,J＝7.2Hz,1H),6.97–6.85(m,2H), 4.92–4.61(m,4H),4.18(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝ 12.8Hz,1H),2.85–2.66(m,2H),2.63–2.47(m,2H),2.08–1.90(m,4H),1.81– 1.58(m,4H),1.58–1.38(m,4H),1.38–1.27(m,4H),1.22–1.08(m,7H),0.86(t,J ＝5.2Hz,3H).ESI-MS m/z:491.3[M+H]+.
实施例6
参考实施例1的合成方法，将氯乙酸甲酯替换为新戊酸氯甲酯，可制得化合 物6。1H NMR(300MHz,DMSO-d)δ7.15(t,J＝7.2Hz,1H),7.01(t,J＝7.5Hz, 1H),6.89(dd,J＝7.3,2.0Hz,1H),5.25–5.04(m,2H),4.86–4.73(m,2H),4.04(d, J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.84–2.66(m, 2H),2.56(d,J＝13.0Hz,1H),2.07–1.93(m,2H),1.86–1.67(m,4H),1.61(dd,J＝ 12.4,1.9Hz,2H),1.58–1.37(m,4H),1.31(dd,J＝3.8,0.8Hz,4H),1.13–1.07(m, 10H),0.89(t,J＝5.5Hz,3H).ESI-MS m/z:505.3[M+H]+.
实施例7
参考实施例1的合成方法，将氯乙酸甲酯替换为氯丁酸甲酯，可制得化合物 7。1HNMR(300MHz,DMSO-d)δ7.17(t,J＝7.2Hz,1H),7.02–6.91(m,2H),5.29 –5.02(m,2H),4.75–4.66(m,2H),4.18(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H), 3.06(d,J＝12.8Hz,1H),2.86–2.68(m,2H),2.56(d,J＝13.0Hz,1H),2.46–2.28 (m,3H),2.08–1.92(m,4H),1.78–1.59(m,6H),1.58–1.48(m,2H),1.48–1.38 (m,2H),1.38–1.25(m,4H),1.11(d,J＝12.5Hz,1H),1.04–0.84(m,6H).ESI-MS m/z:513.3[M+Na]+.
实施例8
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯丁酸乙酯，可制得化合 物8。1H NMR(300MHz,DMSO-d)δ7.15(t,J＝7.3Hz,1H),7.01–6.91(m,2H), 5.81–5.74(m,1H),4.79–4.59(m,2H),4.15(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz, 1H),3.06(d,J＝12.8Hz,1H),2.88–2.63(m,2H),2.56(d,J＝13.0Hz,1H),2.36– 2.20(m,3H),2.08–1.94(m,4H),1.82–1.57(m,9H),1.57–1.39(m,4H),1.31(dd, J＝3.8,0.8Hz,4H),1.14(d,J＝9.5Hz,1H),1.01–0.84(m,6H).ESI-MS m/z: 503.3[M+H]+.
实施例9
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯乙基异丁酸酯，可制得 化合物9。1H NMR(300MHz,DMSO-d)δ7.13(t,J＝7.2Hz,1H),7.03–6.92(m, 2H),5.83–5.74(m,1H),4.79–4.60(m,2H),4.19(d,J＝5.2Hz,1H),3.63(d,J＝ 4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.84–2.67(m,2H),2.61–2.46(m,2H),2.12 –1.94(m,4H),1.82–1.57(m,7H),1.57–1.37(m,4H),1.31(dd,J＝3.8,0.8Hz, 4H),1.25–1.06(m,7H),0.89(t,J＝5.3Hz,3H).ESI-MS m/z:505.3[M+H]+.
实施例10
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯乙基新戊酸酯，可制得 化合物10。1H NMR(300MHz,DMSO-d)δ7.15(t,J＝7.0Hz,1H),7.03–6.85(m, 2H),5.86–5.74(m,1H),4.78–4.54(m,2H),4.04(d,J＝5.1Hz,1H),3.77(d,J＝ 4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.85–2.66(m,2H),2.56(d,J＝13.0Hz,1H), 2.05–1.93(m,4H),1.82–1.57(m,7H),1.57–1.36(m,4H),1.31(dd,J＝3.8,0.8 Hz,4H),1.13–1.03(m,10H),0.89(t,J＝5.3Hz,3H).ESI-MS m/z:541.3[M+ Na]+.
实施例11
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯乙基环己烷甲酸酯，可 制得化合物11。1H NMR(300MHz,DMSO-d)δ7.08(dd,J＝7.8,7.2Hz,1H),7.02 –6.84(m,2H),5.77–5.64(m,1H),4.80–4.56(m,2H),4.15(d,J＝5.1Hz,1H), 3.77(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.83–2.65(m,2H),2.56(d,J＝ 13.0Hz,1H),2.39(d,J＝17.9Hz,2H),2.07(d,J＝13.0Hz,2H),2.01–1.87(m, 4H),1.84–1.67(m,7H),1.67–1.26(m,16H),1.11(d,J＝12.5Hz,1H),0.92(t,J＝ 5.3Hz,3H).ESI-MS m/z:545.4[M+H]+.
实施例12
参考实施例1的合成方法，将氯乙酸甲酯替换为1-氯-2-甲基丙基异丁酸酯， 可制得化合物12。1H NMR(300MHz,DMSO-d)δ7.15(t,J＝7.5Hz,1H),7.04– 6.86(m,2H),5.65–5.47(m,1H),4.68(d,J＝1.8Hz,2H),4.04(d,J＝5.1Hz,1H), 3.77(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.84–2.66(m,2H),2.65–2.47 (m,2H),2.19(d,J＝29.5Hz,2H),2.09–1.90(m,4H),1.84–1.67(m,2H),1.67– 1.38(m,6H),1.36–1.19(m,10H),1.19–0.99(m,7H),0.94(t,J＝5.3Hz,3H). ESI-MS m/z:533.3[M+H]+.
实施例13
合成路线
化合物13的合成
将甲氨(2mmol)溶于二氯甲烷中，0℃条件下，加入N,N,N’,N’-四甲基-1,8- 萘二胺(2.2mmol)，搅拌2min后，滴入氯甲酸氯甲酯(2.2mmol)，室温反 应过夜。TLC检测反应完全，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥， 旋干溶剂。取上述制得化合物(0.2mmol)和O-TES保护曲前列尼尔(0.1mmol) 和DIPEA(0.2mmol)，用二氯甲烷溶解，室温搅拌两小时后，TLC检测反应 完全，水洗两次，饱和食盐水洗一次，无水硫酸钠干燥，经柱层析浓缩，用THF/ 水溶解，加入2N HCl，室温搅拌反应，TLC检测反应完全，旋干溶剂，HPLC 纯化得化合物13，收率51％。1H NMR(300MHz,DMSO-d)δ7.13(t,J＝7.5Hz, 1H),7.04–6.87(m,2H),5.29(d,J＝2.0Hz,2H),4.73–4.61(m,2H),4.18(d,J＝ 5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.87–2.65(m,5H), 2.56(d,J＝13.0Hz,1H),2.07–1.93(m,4H),1.76–1.58(m,4H),1.58–1.37(m, 4H),1.36–1.25(m,4H),1.11(d,J＝12.5Hz,1H),0.95(t,J＝5.3Hz,3H).ESI-MS m/z:478.3[M+H]+.
实施例14
参考实施例13的合成方法，可制得化合物14。1H NMR(300MHz,DMSO-d) δ7.15(t,J＝7.2Hz,1H),7.04–6.91(m,2H),5.30(d,J＝2.0Hz,2H),4.73–4.66 (m,2H),4.04(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.26–3.13(m,2H),3.06 (d,J＝12.8Hz,1H),2.87–2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.07–1.90(m, 4H),1.78–1.66(m,2H),1.61(dd,J＝12.4,1.9Hz,2H),1.57–1.38(m,4H),1.38– 1.26(m,4H),1.17–1.04(m,4H),0.96(t,J＝5.3Hz,3H).ESI-MS m/z:492.3[M+ H]+.
实施例15
参考实施例13的合成方法，可制得化合物15。1H NMR(300MHz,DMSO-d) δ7.14(t,J＝7.0Hz,1H),7.03–6.88(m,2H),5.30(d,J＝1.1Hz,2H),4.82–4.66 (m,2H),4.15(d,J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H), 2.85–2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.10–1.91(m,2H),1.84–1.69(m, 2H),1.68–1.37(m,8H),1.31(dd,J＝3.8,0.8Hz,4H),1.11(d,J＝12.5Hz,1H), 1.04–0.89(m,6H).ESI-MS m/z:506.3[M+H]+.
实施例16
参考实施例13的合成方法，可制得化合物16。1H NMR(300MHz,DMSO-d) δ7.14(t,J＝7.2Hz,1H),7.00–6.80(m,2H),5.30(d,J＝1.0Hz,2H),4.83–4.71 (m,2H),3.77(d,J＝4.9Hz,1H),3.69–3.55(m,2H),3.31(d,J＝12.3Hz,1H),3.06 (d,J＝12.8Hz,1H),2.85–2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.09–1.90(m, 4H),1.83–1.68(m,2H),1.67–1.37(m,6H),1.31(dd,J＝3.8,0.8Hz,4H),1.11(d, J＝12.5Hz,1H),1.00–0.78(m,9H).ESI-MS m/z:520.3[M+H]+.
实施例17
合成路线
将O-TES保护曲前列尼尔(0.1mmol)、1,2-乙二醇单乙酸酯(0.11mmol) 和DCC(0.2mmol)及DMAP(0.02mmol)用二氯甲烷溶解，反应过夜，TLC 检测反应完全。旋干溶剂，经柱层析纯化浓缩，用THF/水溶解，加入2N HCl， 室温搅拌反应，TLC检测反应完全，旋干溶剂，HPLC纯化得化合物17。1H NMR (300MHz,DMSO-d)δ7.09(t,J＝7.3Hz,1H),7.05–6.91(m,2H),4.78(s,2H), 4.39–4.13(m,5H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.84–2.65 (m,2H),2.56(d,J＝13.0Hz,1H),2.09–1.90(m,7H),1.75–1.57(m,4H),1.57–1.37(m,4H),1.37–1.27(m,4H),1.11(d,J＝12.5Hz,1H),0.94(t,J＝5.3Hz,3H). ESI-MSm/z:477.3[M+H]+.
实施例18
参考实施例17的合成方法，可制得化合物18。1H NMR(300MHz,DMSO-d) δ7.10(t,J＝7.4Hz,1H),7.01–6.89(m,2H),4.77(d,J＝2.2Hz,2H),4.27–4.11 (m,5H),3.77(d,J＝4.9Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H), 2.84–2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.14(d,J＝1.4Hz,3H),2.09–1.91 (m,7H),1.78–1.25(m,12H),1.11(d,J＝12.5Hz,1H),0.99(t,J＝5.3Hz,3H). ESI-MS m/z:513.3[M+Na]+.
实施例19
参考实施例17的合成方法，可制得化合物19。1H NMR(300MHz,DMSO-d) δ7.12(t,J＝7.5Hz,1H),7.05–6.90(m,2H),4.87–4.61(m,2H),4.21–4.11(m, 5H),3.77(d,J＝4.9Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.84 –2.66(m,2H),2.56(d,J＝13.0Hz,1H),2.05–1.95(m,7H),1.89(d,J＝0.7Hz, 4H),1.84–1.67(m,2H),1.67–1.39(m,6H),1.31(dd,J＝3.8,0.8Hz,4H),1.14(d, J＝9.4Hz,1H),0.89(t,J＝5.8Hz,3H).ESI-MSm/z:505.3[M+H]+.
实施例20
参考实施例17的合成方法，可制得化合物20。1H NMR(300MHz,DMSO-d) δ7.14(t,J＝7.2Hz,1H),7.04–6.88(m,2H),4.77(s,2H),4.38–4.14(m,5H),4.04 (d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.86–2.65(m, 2H),2.56(d,J＝13.0Hz,1H),2.39(d,J＝16.5Hz,3H),2.08–1.94(m,4H),1.79– 1.57(m,4H),1.57–1.37(m,4H),1.37–1.26(m,4H),1.22–1.06(m,4H),0.95(t,J ＝5.8Hz,3H).ESI-MS m/z:513.3[M+Na]+.
实施例21
参考实施例17的合成方法，可制得化合物21。1H NMR(300MHz,DMSO-d) δ7.11(t,J＝7.4Hz,1H),7.03–6.90(m,2H),4.79(s,2H),4.39–4.14(m,5H),4.04 (d,J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.84–2.64(m, 2H),2.63–2.48(m,2H),2.09–1.91(m,4H),1.85–1.67(m,2H),1.67–1.37(m, 6H),1.31(dd,J＝3.8,0.8Hz,4H),1.28–1.06(m,7H),0.97(t,J＝5.4Hz,3H). ESI-MS m/z:505.3[M+H]+.
实施例22
参考实施例17的合成方法，可制得化合物22。1H NMR(300MHz,DMSO-d) δ7.15(t,J＝7.2Hz,1H),7.04–6.92(m,2H),4.86(s,2H),4.28–4.10(m,5H),4.04 (d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.86–2.67(m, 2H),2.56(d,J＝13.0Hz,1H),2.39(d,J＝16.7Hz,3H),2.25–2.10(m,3H),2.09– 1.90(m,4H),1.83–1.69(m,2H),1.67–1.26(m,10H),1.18–1.03(m,4H),0.94(t, J＝5.8Hz,3H).ESI-MS m/z:505.3[M+H]+.
实施例23
参考实施例23的合成方法，可制得化合物23。1H NMR(300MHz,DMSO-d) δ7.07(dd,J＝7.9,7.1Hz,1H),7.01–6.90(m,2H),5.03–4.86(m,2H),4.73(s, 2H),4.29(d,J＝4.9Hz,1H),4.07(d,J＝2.5Hz,2H),3.69–3.49(m,3H),3.06(d,J ＝12.8Hz,1H),2.86–2.67(m,2H),2.65–2.46(m,2H),2.23–2.02(m,4H),1.87(s, 2H),1.82–1.68(m,4H),1.66–1.38(m,6H),1.37–1.04(m,11H),0.94(t,J＝5.8 Hz,3H).ESI-MS m/z:563.4[M+H]+.
实施例24
参考实施例13的合成方法，可制得化合物24。1H NMR(300MHz,DMSO-d) δ7.15(t,J＝7.5Hz,1H),6.99(t,J＝7.2Hz,1H),6.90(d,J＝7.3Hz,1H),5.82(s, 1H),4.80–4.52(m,2H),4.18(d,J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J ＝12.8Hz,1H),2.85–2.62(m,5H),2.56(d,J＝13.0Hz,1H),2.06–1.91(m,4H), 1.80–1.38(m,11H),1.38–1.25(m,4H),1.13(d,J＝7.5Hz,1H),0.95(t,J＝5.4 Hz,3H).ESI-MS m/z:514.3[M+Na]+.
实施例25
参考实施例17的合成方法，可制得化合物25。1H NMR(300MHz,DMSO-d) δ7.09(t,J＝7.4Hz,1H),7.04–6.90(m,2H),4.77(s,2H),4.32(d,J＝12.4Hz,1H), 4.27–4.12(m,4H),4.04(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝ 12.8Hz,1H),2.88–2.65(m,5H),2.56(d,J＝13.0Hz,1H),2.11–1.92(m,4H), 1.80–1.57(m,4H),1.57–1.27(m,8H),1.16(d,J＝9.5Hz,1H),0.93(t,J＝5.8Hz, 3H).ESI-MS m/z:514.2[M+Na]+.
实施例26
参考实施例17的合成方法，可制得化合物26。1H NMR(300MHz,DMSO-d) δ7.07(t,J＝7.2Hz,1H),7.04–6.91(m,2H),4.88–4.70(m,2H),4.30–4.12(m, 5H),4.04(d,J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.88 –2.65(m,5H),2.56(d,J＝13.0Hz,1H),2.23–2.08(m,3H),2.06–1.90(m,4H), 1.84–1.70(m,2H),1.67–1.37(m,6H),1.31(dd,J＝3.8,0.8Hz,4H),1.14(d,J＝ 7.4Hz,1H),0.89(t,J＝5.8Hz,3H).ESI-MS m/z:528.3[M+Na]+.
实施例27
参考实施例17的合成方法，可制得化合物27。1H NMR(300MHz,DMSO-d) δ7.07(t,J＝7.3Hz,1H),7.04–6.90(m,2H),4.87(s,2H),4.15(d,J＝4.4Hz,5H), 4.04(d,J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.86– 2.65(m,5H),2.56(d,J＝13.0Hz,1H),2.04–1.96(m,4H),1.89(d,J＝4.2Hz,4H), 1.83–1.69(m,2H),1.67–1.37(m,6H),1.31(dd,J＝3.8,0.8Hz,4H),1.12(d,J＝ 10.5Hz,1H),0.92(t,J＝5.5Hz,3H).ESI-MSm/z:520.3[M+H]+.
实施例28
参考实施例1的合成方法，可制得化合物28。1H NMR(300MHz,DMSO-d) δ7.11(t,J＝7.2Hz,1H),7.04–6.76(m,2H),5.28–5.00(m,2H),4.74(d,J＝2.4 Hz,2H),4.15(d,J＝5.1Hz,1H),3.77(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H), 2.87–2.64(m,2H),2.56(d,J＝13.0Hz,1H),2.39(d,J＝18.8Hz,3H),2.09–1.92 (m,4H),1.84–1.69(m,2H),1.69–1.22(m,18H),1.14(d,J＝11.4Hz,1H),0.97(t, J＝5.9Hz,6H).ESI-MS m/z:555.3[M+Na]+.
实施例29
参考实施例1的合成方法，可制得化合物29。1H NMR(300MHz,DMSO-d) δ7.17–7.05(m,1H),7.05–6.86(m,2H),5.31–4.97(m,2H),4.74(d,J＝2.4Hz, 2H),4.15(d,J＝5.1Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz,1H),2.85 –2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.47–2.28(m,3H),2.08–1.93(m,4H), 1.86–1.67(m,2H),1.66–1.22(m,20H),1.15(d,J＝8.2Hz,1H),1.08–0.93(m, 6H).ESI-MS m/z:569.3[M+Na]+.
实施例30
参考实施例1的合成方法，可制得化合物30。1H NMR(300MHz,DMSO-d) δ7.08(dd,J＝7.8,7.2Hz,1H),7.01–6.89(m,2H),5.28–5.00(m,2H),4.74(d,J＝ 2.4Hz,2H),4.29(d,J＝4.9Hz,1H),3.63(d,J＝4.9Hz,1H),3.06(d,J＝12.8Hz, 1H),2.82–2.65(m,2H),2.56(d,J＝13.0Hz,1H),2.45–2.26(m,3H),2.07(d,J＝ 13.0Hz,2H),1.84–1.64(m,3H),1.64–1.34(m,8H),1.34–1.20(m,14H),1.17(d, J＝5.2Hz,1H),1.04–0.94(m,6H).ESI-MS m/z:561.3[M+H]+.
试验例1、本申请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)，EDTA-K2真空采血管，生理 盐水。
实验所用SD雄性大鼠均购自扬州大学，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
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实施例化合物的药代动力学参数
由实施例化合物的药代学数据可知，相对于曲前列尼尔17％的口服生物利用度，1h半衰 期及0.5h达峰时间(Chinese Journal of New Drugs 2014，23，2585-2589)，本发明实施例化合 物生物利用度显著提高。本发明化合物具备优异的口服给药潜力，同时达峰时间和半衰期也得 到显著改善。
试验例2、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8，13，19和25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8，13，19和25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8， 13，19和25的干预组mPAP较模型组降低。
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 (10)
1.一种如下式I所示的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体：
其中，
R1为氢、C1-20烷基、C3-20环烷基、C1-20烷氧基或C7-20芳基；R2为C1-20烷基、C3-20环烷基、C1-20烷氧基、C1-20烷基胺基或羟基；n为0-6的整数。
2.根据权利要求1所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体，其特征在于，R1为氢或C1-10烷基；R2为C1-10烷基、C3-7环烷基、C1-6烷基胺基、羟基或C1-6烷氧基。
3.根据权利要求1所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体，其特征在于，R1为氢、甲基或异丙基。
4.根据权利要求1所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体，其特征在于，R2为甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环己基、羟基、甲氧基、乙氧基、丙氧基、甲胺基、乙胺基、丁氨基、2-甲基丙-1-胺、正己基、正庚基或正辛基；n为0，1，2或3。
5.根据权利要求1所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体，其特征在于，所述式I选自以下任一种结构：
6.一种药物组合物，包含权利要求1-5任一项所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体及药学上可接受的辅料。
7.根据权利要求6所述的药物组合物，其特征在于，所述药物组合物为口服给药、注射给药或吸入给药的剂型。
8.根据权利要求7所述的药物组合物，其特征在于：所述药物组合物为口服给药剂型，所述剂型包括片剂、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。
9.权利要求1-5任一项所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体或权利要求6-7任一项所述的药物组合物作为前环列素类似物的应用。
10.权利要求1-5任一项所述的曲前列尼尔的前体药物或其药学上可接受的盐、立体异构体或权利要求6-7任一项所述的药物组合物在制备治疗肺动脉高压、慢性动脉闭塞性疾病、特发性肺纤维化的药物中的应用。
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