CN113943266A - 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 - Google Patents
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 Download PDFInfo
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- CN113943266A CN113943266A CN202111366683.9A CN202111366683A CN113943266A CN 113943266 A CN113943266 A CN 113943266A CN 202111366683 A CN202111366683 A CN 202111366683A CN 113943266 A CN113943266 A CN 113943266A
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- Prior art keywords
- beraprost
- acid
- nitric oxide
- oxide donor
- derivative
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Abstract
本发明公开了一系列新化合物，该化合物含有贝前列素和一氧化氮供体，如下式Ⅰ所示，本发明涉及该系列化合物及其药物组合物及用途。
Description
技术领域
本发明属于生物医药领域，具体涉及一种氧化氮供体型贝前列素类衍生物或其可药用盐，其药物组合物及用途。
背景技术
肺高压(Pulmonary Hypertension，PH，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。
目前临床上用于治疗肺动脉高压的主要有内皮素受体拮抗剂(如波生坦)、磷酸酯酶5抑制剂(如西地拉非)、鸟苷酸环化酶激动剂(利奥西呱)、前列环素类似物(如贝前列腺素)和前列环素受体激动剂(赛莱西帕)等几类，这几类药物的作用机制最终都会涉及到一氧化氮(Nitric oxide,NO)和cGMP途径来舒张内皮血管的。
在这些药物中，前列腺素类似物是最有效又最为经典的药物，其中贝前列腺素钠(beraprost sudiam)是这类药物中在临床主要应用的口服制剂，但由于其药代缺陷，需要每日多次给药，因此，有研究者在贝前列腺素的制剂(如缓释片Careload在日本成功上市)和结构(贝前列腺素光学体Esuberaprost三期临床研究失败)上进行了改良。
由于NO在整个作用途径上具有最为关键的作用，但又由于其气体特征且代谢特别快较难给药，因此采用供体(NO donor)模式是开发新药是一种新的尝试，如采用NO供体制备的脂质体气溶胶的长效吸入剂用于PAH的治疗(Nahar K,等,Pharma Res.2016)；ValeantPharma公司开发的拉坦前列腺素硝酸酯就是由拉坦前列腺素酸丁二醇单硝酸酯组成，在治疗青光眼上有着双重作用机制：拉坦前列素酸(latanoprost acid，已上市药物)能作用于葡萄膜巩膜通路，促进房水的排出；丁二醇单硝酸酯(butanediol mononitrate)则能释放一氧化氮(NO)，通过小梁网和许莱姆氏管(Schlemm's canal)，促进房水排出。这种双管齐下新治疗方法在临床试验中得到了验证：和单一给予拉坦前列素相比，拉坦前列腺素硝酸酯能更显著地降低眼压，表现出更好的临床优势，该产品于2017年被FDA批准上市(商品名VYZULTA)。因此，采用前列腺素类加上NO供体模式的修饰，能够通过两个途径药理作用增加药物的有效性，是一个更便捷的新药开发路径。
贝前列腺素除用于肺动脉高压治疗以外，还被尝试用于恶性肿瘤转移(美国United Therap公司开发)、动脉粥样硬化(日本科研Kaken Pharma开发)、高血压(日本科研Kaken Pharma和美国United Therap两个公司分别开发)、糖尿病神经病变(日本科研KakenPharma开发)，以及肾炎和肾衰，脑血管性痴呆(CN 112691109A)，酒精性脂肪肝(HK1219665A)等疾病的治疗。同时，NO供体药物也被用于开发多种疾病如抗炎、心血管疾病的治疗(MegsonIL&WebbDJ,Expert Opin Investig Drugs,2002；KnoxCD等,MK5108,J AmHeart Assoc,2016)。因此，贝前列腺素钠和NO供体均有开发多种治疗药物的可能性。
本发明为一系列一氧化氮供体型贝前列素类衍生物或其可药用盐所开发的药物，该系列化合物进入体内后分解成为贝前列腺素并产生一氧化氮NO，能够产生双重的药理作用，一方面贝前列腺素可以与前列素受体特异性结合，发挥舒张血管平滑肌的作用，另一方面，这些化合物在体内可以释放出的NO分子，同样起到通过内皮细胞cGMP途径舒张血管的作用，两种机制协同增效地达到治疗效果。
这些系列化合物可以用于治疗肺动脉高压、心肌梗死、肾脏疾病、闭塞性动脉硬化等外周血管疾病、和眼科疾病(如糖尿病眼底病变、青光眼等)、骨质疏松、血栓性脉管炎、血栓栓塞疾病等多种疾病的治疗药物中的应用。
发明内容
本申请针对贝前列素钠的清除半衰期短、单日给药次数多、疗效有饱和封顶效应，和NO是气体在溶液中快速分解代谢半衰期短等两者的缺陷，提供了一种贝前列素钠结合NO供体的新系列化合物。
为了实现上述目的，如本发明所述一种如下式Ⅰ所示的一氧化氮供体型贝前列素类衍生物或其可药用盐：
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烷基、环烷基或-C1-C10烷基-芳环-；其中C1-C10烷基、C5-7环烷基或芳环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烷基)-ONO2。
所述环烷基优选为C5-7环烷基，芳环为C5-10芳环。
进一步，所述化合物包括以下任意一种具体结构：
本发明所提及的一氧化氮供体型贝前列素类衍生物药学上可接受的盐可以是酸性盐，也可以是碱性盐。酸性盐例如盐酸、氢氟酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸或硝酸，或硫酸氢盐，或者与如下有机酸形成的酸加成盐：例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一烷酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、3-羟基-2-萘甲酸、烟酸、扑酸、果胶酯酸、过硫酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、氨基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、藻酸、马来酸、富马酸、D-葡糖酸、扁桃酸、抗坏血酸、葡庚酸、甘油磷酸、天冬氨酸、磺基水杨酸、半硫酸或硫氰酸。碱性盐例如钠离子、钾离子、N-甲基葡糖胺、二甲基葡糖胺、乙基葡糖胺、赖氨酸、二环己基胺、1,6-己二胺、乙醇胺、葡糖胺、葡甲胺、肌氨酸、丝氨醇、三羟基甲基氨基甲烷、氨基丙二醇、1-氨基-2,3,4-丁三醇。
本申请的又一个技术方案提供了一种含有上述一氧化氮供体型贝前列素类衍生物的药物组合物，其包括通式I所示结构的化合物或其可药用盐，及可药用载体。
所述载体为缓释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、吸附载体、表面活性剂和润滑剂中的任意一种或两种以上的混合物。
所述的药物组合物，优选外用制剂、口服制剂和注射制剂中的任意一种。
所述口服制剂为颗粒剂、胶囊剂和片剂中的任意一种。
本发明所述的一氧化氮供体型贝前列素类衍生物的药物组合物，包括其作为前环列素类似物的应用。
本发明所述的一氧化氮供体型贝前列素类衍生物的药物组合物，包括其在制备治疗肺动脉高压、心肌梗死、肾脏疾病、闭塞性动脉硬化等外周血管疾病、和眼科疾病(如糖尿病眼底病变、青光眼等)、骨质疏松、血栓性脉管炎、血栓栓塞疾病等多种疾病的治疗药物中的应用。
有益效果：与现有技术相比，本发明具有如下优点：
本发明提供一类贝前列素钠和NO供体结合药物，解决了贝前列素钠的清除清除半衰期短、单日给药次数多、疗效有饱和封顶效应，和NO是气体在溶液中快速分解代谢半衰期短等两者的缺陷，新化合物减少原来贝前列腺素给药的剂量和服用频率，同时利用该化合物在体内释放NO分子导致的舒张平滑肌作用，通过双重作用，发挥了两种药物协同作用效果，提高了药物的有效性和安全性。
附图说明
图1表示化合物15体内小鼠低氧性肺动脉高压治疗效果；
图2表示化合物15治疗后小鼠骨密度测定数据；
图3表示化合物15对急性肾衰中肾小管上皮细胞增殖的影响。
具体实施方式
以下结合实施例对本发明作进一步说明。
实施例1
合成路线：
实施例1的合成
将浓硫酸(13mmol)溶于二氯甲烷中，0℃条件下缓慢滴入发烟硝酸(14mmol)，继续反应20min后，将2-溴乙醇(6mmol)加入上述反应液中。0℃条件下继续反应4小时，将该反应液缓慢倒入冰水中，用二氯甲烷(50mL)萃取两次，收集有机相，水洗一次，饱和食盐水洗一次，旋干得产物2-溴乙基硝酸酯。
将贝前列素(60mg)，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67％。1H NMR(300MHz,DMSO-d)δ7.38–7.22(m,2H),7.00(d,J＝5.8Hz,1H),5.85(d,J＝9.5Hz,2H),4.63–4.51(m,2H),4.38(d,J＝12.5Hz,1H),4.23–4.15(m,2H),3.49–3.36(m,2H),2.95–2.76(m,2H),2.61(dq,J＝12.5,2.0Hz,1H),2.56–2.39(m,4H),2.28(d,J＝13.0Hz,1H),2.01–1.99(m,1H),1.95–1.76(m,5H),1.03(d,J＝5.5Hz,3H).ESI-MS m/z:510.2[M+Na]+.
实施例2
参考实施例1的合成方法，可制得实施例2。1H NMR(300MHz,DMSO-d)δ7.35–7.24(m,2H),7.04(ddd,J＝3.7,2.7,1.4Hz,1H),5.88(s,1H),5.82(s,1H),4.71–4.52(m,3H),4.35–4.10(m,6H),2.86(qd,J＝12.3,0.9Hz,2H),2.61(dq,J＝12.5,2.0Hz,1H),2.51–2.37(m,4H),2.36–2.15(m,3H),1.94–1.74(m,6H),1.00(d,J＝5.7Hz,3H).ESI-MS m/z:524.2[M+Na]+.
实施例3
参考实施例1的合成方法，可制得实施例3。1H NMR(300MHz,Methanol-d4)δ7.39–7.22(m,2H),7.04(d,J＝3.1Hz,1H),5.69–5.46(m,2H),4.69–4.52(m,3H),4.31–4.09(m,5H),4.01(d,J＝12.5Hz,1H),2.86(qd,J＝12.3,0.9Hz,2H),2.70(dq,J＝12.5,2.0Hz,1H),2.55(dq,J＝12.3,1.9Hz,1H),2.49–2.38(m,3H),2.28(d,J＝13.0Hz,1H),2.09–1.78(m,10H),1.02(d,J＝5.3Hz,3H).
实施例4
参考实施例1的合成方法，可制得实施例4。1H NMR(300MHz,DMSO-d4)δ7.41–7.24(m,1H),7.07(d,J＝7.4Hz,1H),5.85(d,J＝7.5Hz,1H),4.71–4.51(m,2H),4.28–4.00(m,3H),2.94–2.77(m,1H),2.66(dq,J＝12.5,2.0Hz,1H),2.56–2.37(m,2H),2.28(d,J＝13.0Hz,1H),1.94–1.78(m,5H),1.68–1.54(m,1H),1.02(d,J＝5.5Hz,2H).
实施例5
参考实施例1的合成方法，可制得实施例5。1H NMR(300MHz,DMSO-d4)δ7.37(t,J＝7.5Hz,1H),7.24(dd,J＝7.5,2.0Hz,1H),7.02(d,J＝7.7Hz,1H),5.65–5.42(m,2H),4.71–4.52(m,3H),4.32–4.02(m,6H),2.93–2.77(m,2H),2.66(dq,J＝12.4,2.0Hz,1H),2.52–2.26(m,5H),1.95–1.81(m,5H),1.68–1.59(m,4H),1.53–1.35(m,4H),1.00(d,J＝6.5Hz,3H).
实施例6
实施例6的合成
将贝前列素(60mg)，用2mL无水乙腈溶解，将碘化钾(75mg)、碳酸钾(62mg)加入，室温搅拌10min后，加入2-氯甲基硝酸乙酯(15mg)，置于60℃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，HPLC纯化得实施例6，收率42％。1HNMR(300MHz,DMSO-d)δ7.11–7.01(m,2H),6.95(dq,J＝7.7,1.2Hz,1H),5.90–5.68(m,2H),5.09(s,2H),4.66–4.56(m,2H),4.22–4.09(m,2H),3.87(t,J＝6.2Hz,2H),2.88–2.68(m,3H),2.46(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.11(t,J＝4.7Hz,2H),2.05–1.85(m,3H),1.65(t,J＝2.0Hz,3H),1.02(d,J＝6.8Hz,3H).
实施例7
参考实施例6的合成方法，可制得实施例7。1H NMR(300MHz,DMSO-d)δ7.28–7.08(m,2H),7.05(dq,J＝7.7,1.2Hz,1H),5.89–5.58(m,2H),5.06(q,J＝2.7Hz,2H),4.94(q,J＝4.5Hz,1H),4.37(t,J＝6.1Hz,2H),4.22–4.04(m,2H),3.59(t,J＝6.1Hz,2H),3.43(dd,J＝5.5,4.2Hz,1H),2.92–2.66(m,3H),2.46(t,J＝7.1Hz,2H),2.27–2.16(m,2H),2.16–1.85(m,7H),1.65(t,J＝2.0Hz,3H),1.01(d,J＝6.5Hz,3H).
实施例8
参考实施例6的合成方法，可制得化合物8。ESI-MS m/z:513.3[M+H]+.1H NMR(300MHz,DMSO-d)δ7.25–7.04(m,2H),7.00(dq,J＝7.7,1.0Hz,1H),5.91–5.66(m,2H),4.94(q,J＝4.5Hz,1H),4.57(t,J＝6.2Hz,2H),4.30–4.04(m,4H),3.82(t,J＝6.2Hz,2H),3.72(t,J＝6.2Hz,2H),3.43(dd,J＝5.5,4.2Hz,1H),2.86–2.68(m,3H),2.41(t,J＝7.0Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.18–2.07(m,2H),2.07–1.85(m,3H),1.66(t,J＝2.0Hz,3H),1.01(d,J＝6.9Hz,3H).
实施例9
参考实施例6的合成方法，可制得实施例9。1H NMR(300MHz,DMSO-d)δ7.16–7.02(m,2H),6.95(dq,J＝7.7,1.2Hz,1H),5.98–5.66(m,4H),5.11–4.87(m,3H),4.24–4.03(m,2H),3.43(dd,J＝5.5,4.2Hz,1H),2.77(dqd,J＝30.2,6.5,6.1,1.1Hz,3H),2.46(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.11(t,J＝4.7Hz,2H),2.02–1.87(m,3H),1.55(t,J＝2.0Hz,3H),1.02(d,J＝6.8Hz,3H).
实施例10
参考实施例6的合成方法，可制得实施例10。1H NMR(300MHz,Chloroform-d)δ7.16–7.02(m,2H),6.95(ddt,J＝6.0,2.7,0.9Hz,1H),5.93–5.61(m,4H),4.76–4.42(m,3H),4.29–4.04(m,2H),3.92(d,J＝5.5Hz,1H),3.43(dd,J＝5.5,4.2Hz,1H),2.96–2.63(m,5H),2.45(td,J＝7.0,0.9Hz,2H),2.30–2.06(m,4H),2.06–1.84(m,3H),1.57(t,J＝2.0Hz,3H),1.00(d,J＝6.2Hz,3H).
实施例11
参考实施例1的合成方法，可制得实施例11。1H NMR(300MHz,DMSO-d)δ7.49–7.30(m,2H),7.18–7.02(m,4H),6.97(ddt,J＝7.0,1.9,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),5.52–5.24(m,2H),4.80(d,J＝6.2Hz,1H),4.39–4.02(m,5H),3.42(dd,J＝5.5,4.2Hz,1H),2.89–2.56(m,5H),2.40(t,J＝7.1Hz,2H),2.26–1.85(m,9H),1.61(t,J＝2.0Hz,3H),1.01(d,J＝6.7Hz,3H).
实施例12
参考实施例1的合成方法，可制得实施例12。1H NMR(300MHz,DMSO-d)δ7.13–7.02(m,2H),6.95(ddt,J＝5.5,3.3,0.9Hz,1H),5.89–5.57(m,4H),4.94(dt,J＝5.1,4.3Hz,1H),4.42(qt,J＝10.4,6.1Hz,2H),4.24–4.06(m,2H),3.43(dd,J＝5.5,4.2Hz,1H),2.94–2.63(m,3H),2.63–2.39(m,4H),2.26–1.79(m,9H),1.62(t,J＝2.0Hz,3H),0.99(d,J＝6.8Hz,3H).
实施例13
参考实施例1的合成方法，可制得实施例13。1H NMR(500MHz,Chloroform-d)δ7.51–7.30(m,2H),7.19–7.05(m,4H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),5.52–5.31(m,2H),4.94(dt,J＝5.1,4.2Hz,1H),4.22–4.05(m,5H),3.42(dd,J＝5.5,4.2Hz,1H),2.87–2.68(m,3H),2.62(tq,J＝6.5,1.0Hz,2H),2.40(t,J＝7.1Hz,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.16–2.01(m,2H),2.01–1.87(m,3H),1.81–1.60(m,7H),1.02(d,J＝6.7Hz,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,DMSO-d)δ7.22–6.99(m,2H),6.97(ddt,J＝7.3,1.8,0.9Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.29–4.15(m,3H),4.15–4.03(m,3H),3.42(dd,J＝5.5,4.2Hz,1H),2.89–2.66(m,3H),2.40(t,J＝7.0Hz,2H),2.31–2.18(m,2H),2.18–1.84(m,6H),1.76–1.33(m,14H),1.04(d,J＝6.1Hz,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,DMSO-d)δ7.21–7.05(m,2H),6.97(ddt,J＝5.6,3.5,1.1Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.34–4.10(m,5H),3.75(dd,J＝10.5,6.3Hz,1H),3.42(dd,J＝5.5,4.2Hz,1H),2.89–2.66(m,3H),2.41(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.17–1.82(m,7H),1.82–1.59(m,5H),1.59–1.39(m,6H),1.01(d,J＝6.7Hz,3H).
实施例16
参考实施例6的合成方法，可制得化合物16。1H NMR(300MHz,DMSO-d)δ7.13–7.04(m,2H),6.97(ddt,J＝5.7,3.5,1.1Hz,1H),5.87–5.62(m,4H),4.94(dt,J＝5.1,4.3Hz,1H),4.32(t,J＝6.0Hz,2H),4.23–4.05(m,2H),3.92(d,J＝5.5Hz,1H),2.91–2.66(m,3H),2.51–2.32(m,4H),2.26–2.17(m,2H),2.17–1.75(m,9H),1.62(t,J＝2.0Hz,3H),0.99(d,J＝6.1Hz,3H).
实施例17
参考实施例6的合成方法，可制得化合物17。1H NMR(300MHz,DMSO-d)δ7.13–7.00(m,2H),6.96(ddt,J＝6.2,2.9,1.1Hz,1H),5.89–5.63(m,2H),5.04–4.83(m,3H),4.69(d,J＝6.2Hz,1H),4.48–4.28(m,4H),4.22–4.03(m,2H),3.92(d,J＝5.5Hz,1H),2.93–2.60(m,3H),2.40(t,J＝7.1Hz,2H),2.25–2.07(m,4H),2.07–1.86(m,3H),1.57(t,J＝2.0Hz,3H),1.00(d,J＝6.2Hz,3H).
实施例18
参考实施例6的合成方法，可制得化合物18。1H NMR(300MHz,DMSO-d)δ7.18–7.02(m,2H),6.97(ddt,J＝5.6,3.5,1.1Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.71–4.52(m,2H),4.23–4.04(m,6H),3.43(dd,J＝5.5,4.2Hz,1H),2.92–2.66(m,5H),2.40(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.18–1.85(m,7H),1.60(t,J＝2.0Hz,3H),1.04(d,J＝6.8Hz,3H).
实施例19
参考实施例6的合成方法，可制得化合物19。1H NMR(300MHz,DMSO-d)δ7.15–7.02(m,2H),6.97(ddt,J＝7.0,1.9,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.1,4.2Hz,1H),4.61(t,J＝7.1Hz,2H),4.26–4.04(m,6H),3.42(dd,J＝5.5,4.2Hz,1H),2.89–2.67(m,5H),2.39(t,J＝7.0Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.17–1.87(m,5H),1.87–1.73(m,4H),1.60(t,J＝2.0Hz,3H),0.98(d,J＝6.7Hz,3H).
实施例20
参考实施例6的合成方法，可制得化合物20。1H NMR(300MHz,DMSO-d)δ7.13–7.02(m,2H),6.96(ddt,J＝5.5,3.3,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.71–4.51(m,2H),4.40–4.26(m,4H),4.26–4.05(m,2H),3.43(dd,J＝5.5,4.2Hz,1H),2.91–2.63(m,5H),2.40(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.20–1.85(m,5H),1.65(t,J＝2.0Hz,3H),1.02(d,J＝6.7Hz,3H).
实施例21
参考实施例6的合成方法，可制得化合物21。1H NMR(300MHz,DMSO-d)δ7.20–7.10(m,2H),7.01(ddt,J＝5.5,3.3,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),5.25(q,J＝6.6Hz,1H),4.94(dt,J＝5.1,4.3Hz,1H),4.52–4.41(m,2H),4.41–4.26(m,2H),4.26–4.05(m,2H),3.43(dd,J＝5.5,4.2Hz,1H),2.91–2.67(m,3H),2.40(t,J＝7.0Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.17–1.84(m,5H),1.65(t,J＝2.0Hz,3H),1.47(d,J＝6.6Hz,3H),1.00(d,J＝6.2Hz,3H).
实施例22
参考实施例6的合成方法，可制得化合物22。1H NMR(300MHz,DMSO-d)δ7.21–7.08(m,2H),7.00(ddt,J＝6.9,1.9,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.54–4.31(m,2H),4.22–4.03(m,6H),3.42(dd,J＝5.5,4.2Hz,1H),2.91–2.62(m,3H),2.49(t,J＝7.0Hz,2H),2.40(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.18–1.82(m,9H),1.55(t,J＝2.0Hz,3H),1.00(d,J＝6.2Hz,3H).
实施例23
参考实施例6的合成方法，可制得化合物23。1H NMR(300MHz,DMSO-d)δ7.17–7.08(m,2H),7.00(ddt,J＝5.6,3.5,1.1Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),5.09–4.87(m,3H),4.27–4.05(m,6H),3.43(dd,J＝5.5,4.2Hz,1H),2.86–2.67(m,3H),2.38(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.17–1.87(m,5H),1.87–1.72(m,4H),1.61(t,J＝2.0Hz,3H),1.01(d,J＝6.7Hz,3H).
实施例24
参考实施例6的合成方法，可制得化合物24。1H NMR(300MHz,DMSO-d)δ7.54–7.38(m,2H),7.30–7.15(m,2H),7.15–7.02(m,2H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),5.97–5.70(m,4H),5.50–5.26(m,2H),4.94(dt,J＝5.1,4.2Hz,1H),4.80(d,J＝6.2Hz,1H),4.26–4.04(m,3H),3.62(q,J＝0.8Hz,2H),2.77(dqd,J＝31.3,6.5,6.1,1.1Hz,3H),2.43(td,J＝7.1,1.0Hz,2H),2.27–1.82(m,7H),1.60(t,J＝2.0Hz,3H),1.04(d,J＝6.6Hz,3H).
实施例25
参考实施例6的合成方法，可制得化合物25。1H NMR(300MHz,DMSO-d)δ8.04(tt,J＝2.2,1.0Hz,1H),7.92(ddd,J＝7.7,2.2,1.1Hz,1H),7.57(ddq,J＝7.9,2.2,1.1Hz,1H),7.47(t,J＝7.8Hz,1H),7.20–7.02(m,2H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),5.89–5.70(m,2H),5.45(t,J＝1.0Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.80(d,J＝6.2Hz,1H),4.46(td,J＝6.0,0.8Hz,2H),4.37(td,J＝6.0,0.8Hz,2H),4.26–4.04(m,3H),3.42(dd,J＝5.5,4.2Hz,1H),2.93–2.62(m,3H),2.41(t,J＝7.0Hz,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.16–1.84(m,5H),1.65(t,J＝2.0Hz,3H),1.02(d,J＝6.6Hz,3H).
实施例26
参考实施例6的合成方法，可制得化合物26。1H NMR(300MHz,DMSO-d)δ8.11–7.84(m,2H),7.65–7.37(m,2H),7.13–7.01(m,2H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),5.92–5.62(m,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.80(d,J＝6.2Hz,1H),4.32–3.95(m,7H),3.45(dd,J＝5.6,4.3Hz,1H),2.89–2.67(m,3H),2.40(t,J＝7.1Hz,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.18–1.85(m,7H),1.61(t,J＝2.0Hz,3H),1.00(d,J＝6.8Hz,3H).
实施例27
参考实施例6的合成方法，可制得化合物27。1H NMR(300MHz,DMSO-d)δ8.05–7.89(m,2H),7.58–7.35(m,2H),7.17–7.04(m,2H),6.97(ddt,J＝6.9,2.0,1.0Hz,1H),5.90–5.65(m,2H),4.94(dt,J＝5.1,4.2Hz,1H),4.80(d,J＝6.2Hz,1H),4.30–4.02(m,7H),3.45(dd,J＝5.6,4.3Hz,1H),2.88–2.66(m,3H),2.49–2.31(m,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.18–1.73(m,9H),1.61(t,J＝2.2Hz,3H),1.01(d,J＝6.4Hz,3H).
实施例28
参考实施例6的合成方法，可制得化合物28。1H NMR(300MHz,DMSO-d)δ7.22–7.06(m,2H),7.00(dtt,J＝5.7,3.5,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.1,4.3Hz,1H),4.62–4.40(m,4H),4.29–4.05(m,4H),3.43(dd,J＝5.5,4.2Hz,1H),2.87–2.67(m,3H),2.55–2.39(m,3H),2.26–2.16(m,2H),2.16–1.85(m,5H),1.66(t,J＝2.1Hz,3H),1.00(d,J＝6.5Hz,3H).
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)δ7.19–7.07(m,2H),7.01(ddt,J＝6.9,1.9,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.56–4.36(m,4H),4.29–4.01(m,4H),3.92(d,J＝5.5Hz,1H),2.91–2.65(m,3H),2.40(t,J＝7.0Hz,2H),2.33–2.17(m,3H),2.17–1.81(m,7H),1.60(t,J＝1.9Hz,3H),0.99(d,J＝6.2Hz,3H).
实施例30
参考实施例6的合成方法，可制得化合物30。1H NMR(300MHz,DMSO-d)δ7.21–7.07(m,2H),7.00(ddt,J＝6.9,1.9,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),5.28–5.02(m,3H),4.94(dt,J＝5.1,4.2Hz,1H),4.74(dd,J＝21.4,5.9Hz,3H),4.23–4.05(m,2H),3.93(dd,J＝5.5,3.9Hz,3H),3.42(dd,J＝5.5,4.2Hz,1H),2.87–2.67(m,3H),2.43(t,J＝7.1Hz,2H),2.21(dp,J＝6.2,2.0Hz,2H),2.18–1.84(m,5H),1.60(t,J＝2.2Hz,3H),1.00(d,J＝6.6Hz,3H).
实施例31
参考实施例6的合成方法，可制得化合物31。1H NMR(300MHz,DMSO-d)δ7.15–7.04(m,2H),6.97(ddt,J＝6.9,1.9,1.0Hz,1H),5.78(qd,J＝15.6,6.2Hz,2H),5.11(p,J＝5.6Hz,1H),4.94(dt,J＝5.0,4.2Hz,1H),4.68(d,J＝5.6Hz,2H),4.27–4.02(m,5H),3.84(d,J＝5.5Hz,2H),3.56–3.29(m,3H),2.86–2.63(m,3H),2.40(t,J＝7.1Hz,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.17–1.88(m,7H),1.61(t,J＝2.2Hz,3H),0.99(d,J＝6.6Hz,3H).
实施例32
合成方法
将贝前列素(60mg)，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纯化得实施例32，收率40％。1H NMR(300MHz,DMSO-d)δ7.94–7.73(m,2H),7.69–7.50(m,3H),7.13–7.02(m,2H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),6.11–5.95(m,2H),5.89–5.64(m,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.80(d,J＝6.2Hz,1H),4.22–4.03(m,3H),3.45(dd,J＝5.6,4.3Hz,1H),2.88–2.65(m,3H),2.43(t,J＝7.1Hz,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.18–1.84(m,5H),1.61(t,J＝2.1Hz,3H),1.00(d,J＝6.2Hz,3H).
实施例33
参考实施例32的合成方法，可制得化合物33。1H NMR(300MHz,DMSO-d)δ8.04–7.90(m,2H),7.73–7.49(m,3H),7.17–7.02(m,2H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),5.93–5.61(m,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.63(td,J＝6.2,1.0Hz,2H),4.43(t,J＝6.2Hz,2H),4.27–4.00(m,3H),3.45(dd,J＝5.6,4.3Hz,1H),2.88–2.62(m,3H),2.40(t,J＝7.1Hz,2H),2.29–1.86(m,7H),1.55(t,J＝2.1Hz,3H),1.01(d,J＝6.2Hz,3H).
实施例34
参考实施例32的合成方法，可制得化合物34。1H NMR(300MHz,DMSO-d)δ8.12–7.91(m,2H),7.70–7.54(m,3H),7.17–7.04(m,2H),6.97(ddt,J＝7.0,2.0,1.0Hz,1H),5.89–5.63(m,2H),4.94(dt,J＝5.0,4.2Hz,1H),4.80(d,J＝6.2Hz,1H),4.43(t,J＝6.1Hz,2H),4.24–4.03(m,5H),3.45(dd,J＝5.6,4.3Hz,1H),2.88–2.67(m,3H),2.40(t,J＝7.1Hz,2H),2.27–1.85(m,9H),1.57(t,J＝1.9Hz,3H),0.99(d,J＝6.6Hz,3H).
实施例35
参考实施例32的合成方法，可制得化合物35。1H NMR(300MHz,DMSO-d)δ8.04–7.84(m,2H),7.70–7.52(m,3H),7.16–7.04(m,2H),6.97(ddt,J＝7.3,1.8,0.9Hz,1H),5.90–5.63(m,2H),4.94(dt,J＝5.1,4.2Hz,1H),4.47–4.31(m,2H),4.24–4.00(m,5H),3.45(dd,J＝5.6,4.3Hz,1H),2.89–2.62(m,3H),2.48–2.34(m,2H),2.21(dp,J＝5.9,2.0Hz,2H),2.20–1.87(m,5H),1.87–1.72(m,4H),1.62(t,J＝1.8Hz,3H),0.99(d,J＝6.2Hz,3H).
试验例1、化合物的体外NO释放测试
采用Griess法利用释放的NO在水溶液中被瞬间氧化称NO2-，NO2-和Griess试剂形成复合物，此复合物在540nm下有强的紫外吸收，从而确定化合物的NO释放量。
1)、溶液的配制：空白溶液：10mL DMSO和190mL PBS混合；Griess试剂：磺胺(4.0g)、N-(1-萘基)乙二胺二盐酸盐(0.2g)和10mL 85％的H3PO4溶于90mL蒸馏水中，搅拌至澄清溶液；L-半胱氨酸溶液：L-半胱氨酸精确称量后，加入一定量的PBS，配制称200μM的溶液；受试化合物溶液：受试化合物精确称量，用DMSO溶解并稀释至浓度为1mM，然后用PBS稀释，使其浓度为200μM。
2)、标准曲线方程的制定：用空白溶液分别配制亚硝酸钠标准溶液浓度：0，0.78，1.56，3.13，6.25，12.5，25，50，100μmol/L，各个浓度每次取150μL，分别加入50μL的Griess试剂混匀，在37℃恒温摇床中孵化30min后，酶标仪于540nm处测定各管吸光度，分别减去空白溶液读数后回归得标准曲线方程。
3)、受试化合物的测试：将配好的受试化合物溶液和L-半胱氨酸溶液各取2.5mL混合，在37℃恒温摇床中孵化120min，每个15min各取混合液150μL，分别加入50μL的Griess试剂混匀，在37℃恒温摇床中再孵化30min后，酶标仪于540nm处测定各管吸光度，分别减去空白溶液读数后将数值代入标准曲线方程，即求得NO释放量。
通过测试，本发明的部分化合物数据如表1所示，测试结果显示本发明所述一氧化氮供体型贝前列素类衍生物或其可药用盐具备良好的NO释放效果。
表1.实施例化合物NO释放效果
试验例2、低氧性肺动脉高压大鼠体内试验
1)、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。所有对照组在正常环境下饲养，给药干预组和模型组在低压低氧舱内饲养(气压50kPa，氧浓度10％)。
2)、实验步骤，化合物15使用DMSO/solutol/water(10/10/80)溶解制成澄清溶液，给药干预组从低氧第2天开始，灌胃给药化合物化合物15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。
3)、实验结果，与对照组相比，模型组大鼠的mPAP明显升高，给药化合物15的干预组mPAP较模型组降低，具备良好低氧性肺动脉高压治疗效果。图1结果表示一氧化氮供体型贝前列素类衍生物化合物15体内小鼠低氧性肺动脉高压治疗效果。
试验例3、骨质疏松的治疗作用
1)、试验材料；1.动物清洁级C57BL/6品系，8-10周龄未孕雌性小鼠购自扬州大学。2.主要试剂及仪器，补佳乐(戊酸雌二醇片，拜耳公司)；小鼠骨钙素(osteocalcin，OC)酶联免疫检测试剂盒、碱性磷酸酶(alkaline phosphatase，ALP)测试盒、抗酒石酸酸性磷酸酶(StrACP)测试盒(以上试剂盒均购于南京建成)。双能X线骨密度仪(HOLOGIC)；ECLIPSE 50i显微镜(Nikon)；MUTISKANMK3型酶标仪(Thermo)；组织切片设备(含KD-TS3D1型生物组织自动脱水机(浙江科迪)、TB-718型生物组织自动包埋机(湖北泰维)、R138型轮转式切片机(湖北泰维)、TK-212型自动恒温漂片仪(湖北泰维)、TK-213型自动恒温烘片仪(湖北泰维)等)。
2)、试验方法：a动物分组，随机法将雌性小鼠分为4组，即假手术组，模型组，阳性药组，测试药物组。b绝经后骨质疏松症小鼠模型的制备，水合氯醛麻醉小鼠后取卧位摘除卵巢。假手术组仅摘除卵巢附近同样体积的脂肪组织。卵巢切除后第4-8天进行阴道涂片检查以确定卵巢切除是否完全。c给药方式，术后第3天给药，阳性对照药(补佳乐0.1mL/10g灌胃给药)，假手术组、模型组给予等体积的0.9％氯化钠溶液，连续灌胃给药28d。d结果测试：第28天后行血液及骨组织取材。测试如下指标：(1)骨密度的测定，取腰椎L4-6用双能X线骨密度仪测定骨密度。(2)骨组织形态的观察，取胫骨HE染色法观察骨组织形态学变化，主要测试骨小梁体积比(bone volume/tissue volume，BV/TV)、骨小梁数目(trabecular bonenumber，Tb.N)和骨小梁分离度(trabecular separation，Tb.sp)为定量评价指标。(3)小鼠血清中生物指标物ALP、StrACP、OC、E 2含量的测定，采用眼球摘除法取血，用试剂盒及酶联反应吸附测定法。e所有数据采用SPSS20.0软件分析。
3)试验结果：与模型组比较，测试化合物能有效升高小鼠的腰椎骨密度各指标、骨钙素含量显著降低；血清中碱性磷酸酶和酸性磷酸酶含量均显著降低，表明化合物能够改善雌激素缺乏诱导的骨质疏松症中的相关指标。
其中，图2显示一氧化氮供体型贝前列素类衍生物化合物15治疗后小鼠骨密度测定数据。表2和表3显示化合物15治疗后小鼠骨形态定量指标数据和血清中骨代谢指标数据情况。
表2.骨形态定量指标数据
表3.小鼠血清中骨代谢指标
试验例4、急性肾衰的肾小管保护作用
1)、试验材料，甘油(麦克林公司)；CCK-8试剂盒、Annexin V-PE细胞凋亡检测试剂盒、超氧化物歧化酶活性检测试剂盒、丙二醛检测试剂盒(碧云天生物科技公司)；一抗半胱氨酸天冬氨酸蛋白酶、caspase3和9、B淋巴细胞瘤-2基因、Bcl-2相关X蛋白(BAX，抗兔)、TGF-β1、smad3(美国abcam)。蛋白凝胶成像仪、酶标仪和流式细胞仪(贝克曼库尔特公司，CytoFLEX型)。清洁级SD大鼠购于鼠均购自扬州大学。
2)、试验方法，采用建立大鼠后肢注射甘油急性肾衰模型，24h后导致大鼠血清中BUN、Cr水平升高，肾间质血管坏死、炎性细胞浸润，视为模型建立成功。取模型动物部分肾组织做体外培养，分离肾小管上皮细胞的分离及鉴定，并加入测试药物共培养(0-24小时)后，测定多种生化指标和凋亡情况的变化。所有数据采用统计分析。
3)、试验结果，与对照组相比，模型动物细胞在培养(3、6、12、24h)后OD 450、MDA活性、BCL2蛋白水平降低，SOD活性、细胞凋亡率，caspase3、caspase9、BAX、TGF-b1、Smad3蛋白水平升高；与模型组相比，测试化合物在细胞培养6h后能导致OD 450升高，并减低细胞凋亡率、SOD活性、BCL2、TGF-β1、Smad3蛋白水平(P<0.05)，并升高MDA活性、caspase3、caspase9、BAX蛋白水平。结论测试化合物可促进急性肾衰大鼠的肾小管上皮细胞增殖、抑制凋亡，抑制氧化应激，通过抑制促凋亡蛋白的表达从而减缓急性肾衰肾小管上皮细胞的损伤。
其中图3表示化合物15治疗急性肾衰小鼠的肾小管增殖情况，表4和表5化合物15治疗急性肾衰小鼠的肾小管细胞MDA、SOD和细胞凋亡率、细胞凋亡蛋白和TGF-β1、Smad3的影响情况。
表4.化合物15对急性肾衰中肾小管上皮细胞MDA、SOD和细胞凋亡率的影响
表5.化合物15对急性肾衰中肾小管上皮细胞凋亡蛋白和TGF-β1、Smad3的影响
| 组别 | caspase3 | caspase9 | BCL2 | BAX | TGF-β1 | Smad3 |
| 对照组 | 0.31±0.08 | 0.39±0.12 | 1.07±0.13 | 0.29±0.09 | 0.33±0.02 | 0.11±0.01 |
| 模型组 | 1.27±0.19 | 0.88±0.2 | 0.08±0.02 | 1.17±0.17 | 0.91±0.09 | 0.57±0.08 |
| 200μg/mL化合物15组 | 0.28±0.06 | 0.48±0.1 | 0.56±0.11 | 0.32±0.12 | 0.24±0.05 | 0.19±0.07 |
试验例5、抗血小板聚集作用
1)实验材料：ADP，肾上腺素，胶原蛋白(拜力生物)
2)实验方法：由健康受试者提供的血液样本，将血液用3.8％的柠檬酸溶液混合，160r/min离心，得到富血小板血浆。为校准数据，获得的富血小板血浆会进一步在2000r/min离心，获得贫血小板血浆，于-20℃的冰箱内储存备用。使用Bornl’s浊度法进行测试。将225μL富血小板血浆加入反应杯，将实施例化合物配置成50nM溶液(25mM Tris-acetate和120mM NaCl)，将25μL实施例化合物溶液加入，37℃条件下共孵育2min后，加入5μL的ADP(终浓度2μM)进行血小板聚集诱导。为了评估血小板聚集程度，吸光度最大值取空白组ADP加入10min后数据，从而计算出各实施例化合物抑制ADP诱导的血小板聚集的抑制率。由下表6数据可知，本申请实施例所述化合物都具备良好的抑制ADP诱导的血小板聚集的效果。
表6.实施例化合物抑制ADP诱导的血小板聚集
| 化合物 | 血小板聚集抑制率(％) | 化合物 | 血小板聚集抑制率(％) |
| 1 | 78 | 19 | 69 |
| 2 | 66 | 20 | 45 |
| 3 | 57 | 21 | 81 |
| 4 | 43 | 22 | 52 |
| 5 | 64 | 23 | 56 |
| 6 | 39 | 24 | 47 |
| 7 | 44 | 25 | 35 |
| 8 | 61 | 26 | 22 |
| 9 | 52 | 27 | 35 |
| 10 | 54 | 28 | 47 |
| 11 | 67 | 29 | 56 |
| 12 | 42 | 30 | 52 |
| 13 | 61 | 31 | 67 |
| 14 | 48 | 32 | 55 |
| 15 | 92 | 33 | 82 |
| 16 | 81 | 34 | 35 |
| 17 | 59 | 35 | 44 |
| 18 | 66 |
对于本领域技术人员，本公开不只局限于前述说明性实施例，在不脱离其必要属性的情况下能以其它特定形式体现。因此期望认为，所有方面均作为说明性而不是限制性、对所附权利要求进行参考的实施例而不是前述实施例，引用文献只是针对附加的权利要求而不是上述的实例，以及落入权利要求等效性的含义和范围之内的所有变化因此预期包含于此。
本说明书中列举的所有专利、专利申请和文献参考均在此以其全部内容引入作为参考。在不一致的情况下，包括定义的本公开将是有说服力的。
Claims (9)
1.一种如下式Ⅰ所示的一氧化氮供体型贝前列素类衍生物或其可药用盐：
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烷基、环烷基或-C1-C10烷基-芳环-；其中C1-C10烷基、C5-7环烷基或芳环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烷基)-ONO2。
2.根据权利要求1所述的一氧化氮供体型贝前列素类衍生物或其可药用盐，其特征在于，所述环烷基为C5-7环烷基，芳环为C5-10芳环。
3.根据权利要求1或2所述的一氧化氮供体型贝前列素类衍生物或其可药用盐，其特征在于，其包括以下任意一种结构：
4.一种权利要求1～3任一项所述的一氧化氮供体型贝前列素类衍生物或其可药用盐，作为前环列素类似物的应用。
5.一种权利要求1～3任一项所述的一氧化氮供体型贝前列素类衍生物或其可药用盐，在制备治疗肺动脉高压、心肌梗死、肾脏疾病、闭塞性动脉硬化等外周血管疾病、和眼科疾病(如糖尿病眼底病变、青光眼等)、骨质疏松、血栓性脉管炎、血栓栓塞疾病等多种疾病的治疗药物中的应用。
6.一种药物组合物，其特征在于包含权利要求1～3任一项所述的一氧化氮供体型贝前列素类衍生物或其可药用盐和药物可接受的载体。
7.根据权利要求6所述的药物组合物，其特征在于，所述载体为缓释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、吸附载体、表面活性剂和润滑剂中的任意一种或两种以上的混合物。
8.根据权利要求6～7任一项所述的药物组合物，其特征在于，所述药物组合物为外用制剂、口服制剂和注射制剂中的任意一种。
9.根据权利要求8所述的一种药物组合物，其特征在于，所述口服制剂为颗粒剂、胶囊剂和片剂中的任意一种。
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| WO2024082470A1 (zh) * | 2022-10-17 | 2024-04-25 | 广州楷石医药有限公司 | 一种前列地尔偶联一氧化氮供体药物及其应用 |
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