CN117800845A - 一种羟基取代曲前列尼尔衍生物、合成方法及其应用 - Google Patents
一种羟基取代曲前列尼尔衍生物、合成方法及其应用 Download PDFInfo
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- CN117800845A CN117800845A CN202311793556.6A CN202311793556A CN117800845A CN 117800845 A CN117800845 A CN 117800845A CN 202311793556 A CN202311793556 A CN 202311793556A CN 117800845 A CN117800845 A CN 117800845A
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- treprostinil
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- PAJMKGZZBBTTOY-ZFORQUDYSA-N treprostinil Chemical class 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 38
- 238000010189 synthetic method Methods 0.000 title description 18
- 150000001875 compounds Chemical class 0.000 claims abstract description 29
- 239000003814 drug Substances 0.000 claims abstract description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 48
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 claims description 34
- 239000000543 intermediate Substances 0.000 claims description 30
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 27
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- 239000002904 solvent Substances 0.000 claims description 13
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- 125000000217 alkyl group Chemical group 0.000 claims description 8
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- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
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- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 6
- 238000003786 synthesis reaction Methods 0.000 claims description 6
- 125000006705 (C5-C7) cycloalkyl group Chemical group 0.000 claims description 4
- 206010001052 Acute respiratory distress syndrome Diseases 0.000 claims description 4
- 208000031104 Arterial Occlusive disease Diseases 0.000 claims description 4
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 206010016654 Fibrosis Diseases 0.000 claims description 4
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 claims description 4
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- 150000001718 carbodiimides Chemical class 0.000 claims description 4
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- 125000003118 aryl group Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- 125000001424 substituent group Chemical group 0.000 claims description 2
- DPKBAXPHAYBPRL-UHFFFAOYSA-M tetrabutylazanium;iodide Chemical compound [I-].CCCC[N+](CCCC)(CCCC)CCCC DPKBAXPHAYBPRL-UHFFFAOYSA-M 0.000 claims description 2
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- 239000002840 nitric oxide donor Substances 0.000 abstract description 9
- 238000001308 synthesis method Methods 0.000 abstract description 7
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Abstract
本发明提出了一种羟基取代曲前列尼尔衍生物、合成方法及其应用,属于药物技术领域。该化合物是含有曲前列尼尔和一氧化氮供体的偶联化合物,如下所示。本发明羟基取代曲前列尼尔衍生物是一类曲前列尼尔和NO供体结合药物,解决了曲前列尼尔疗效较弱及NO给药不便、剂量无法控制等缺陷,并通过两者协同作用提高了药物的有效性和患者的依从性,及药物有效性控制也得到了提高。
Description
技术领域
本发明涉及药物技术领域,具体涉及一种羟基取代曲前列尼尔衍生物、合成方法及其应用。
背景技术
肺动脉高压(PAH)是一类以肺血管阻力升高、右心室衰竭为特征的恶性疾病。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(PGI2)类药物是治疗PAH的靶向药物的重要类型之一,曲前列尼尔(treprositinil)作为一类前列素类似物,由美国联合治疗公司开发并与2002年获得FDA批准上市,其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。曲前列尼尔是目前用于治疗PAH国外内唯一一种具有多种药方式,如皮下、静脉、吸入或口服皮下/静脉给药的前列环素类药物,具有抗血小板和血管扩张的特性,其结构稳定、作用时间比其他几个前列环素更长,是治疗肺动脉高压的优选的药物,有较强的循证医学证据(Nika Skoro-Sajer,Drugs 2012;James C Coons,等,Therapeutic Advances in Respiratory Disease,2021;Steven D Nathan,等,LancentRespiratory Medicine,2021)。
一氧化氮(Nitric oxide,NO)是一种广泛存在于人体内的信使分子,具有多种生理活性,在生理浓度下,可以通过激活平滑肌细胞中的可溶性鸟苷酸环化酶,增加胞内的cGMP水平,从而使得血管舒张,起到调节血压的作用。NO也是用于肺动脉高压和肺栓塞的常用药物(Fernanda Blasina,等,Pulmonary Pharmacology&Therapeutics,2019;JeffreyA.Kline,Am Heart J.2017;),尤其在儿童和新生儿肺高压治疗及晚期住院患者治疗上有特别的优势(Puthiyachirakkal M等,Front Pediatr,2013;Petros AJ和Pierce CM,Paediatr Anaesth,2006),但由于其本身是气体,必须在医院内给药,同时需要采用吸入方式给药,但因患者个体差异较大,剂量较难控制,因此目前在临床上使用逐步减少,只在住院患者和危急状况下还有使用。
由于肺动脉高压发病机制较为复杂,临床上已有两种或三种不同作用机制的药物联合给药方案来提高疗效(White RJ,等,Am J Respir Crit Care Med,2020;VerlindenNJ,等,Pulmonary Circulation 2020)。由于NO和曲前列尼尔各自特殊优势且是分别通过两种第二信使cGMP和cAMP途径来起效的,临床上也有采用联合给药的方式将来提高治疗效果的经验(Stacy Mandras,等,J of Cardiovascular Pharmacol and Therap,2021),但由于两种药物要分别采用不同给药方式(NO必须是在医院吸入,曲前可以是口服或注射或吸入),因此药物使用非常不便,同时,疗效较弱,患者依从度低较难获得理想治疗效果。
发明内容
本发明的目的在于提出一种羟基取代曲前列尼尔衍生物、合成方法及其应用,针对临床广泛使用曲前列尼尔疗效较弱的缺陷,提供了一种偶联NO供体型曲前列尼尔衍生物或其可药用盐。该类偶联NO供体型曲前列尼尔衍生物或其可药用盐可用于治疗肺动脉高压、呼吸窘迫综合征、动脉闭塞性疾病、器官纤维化、肾病、眼病(如糖尿病眼底病变等)、骨质疏松、血栓性脉管炎、心肌梗死等多种疾病。
本发明的技术方案是这样实现的:
本发明提供一种羟基取代曲前列尼尔衍生物,具有如下式Ⅰ所示结构:
其中,R1、R2分别选自H、且R1、R2不同时为H;其中R3为直链或支链的C1-C10烷基、C5-7环烷基或-C1-C10烷基-芳环-,R4、R5为直链或支链的C1-C10烷基;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。
作为本发明的进一步改进,所述化合物包括以下任意一种结构:
本发明进一步保护一种上述羟基取代曲前列尼尔衍生物的合成方法,包括以下步骤:
S1.起始原料A经取代反应合成得到羧酸硝酸酯中间体B;
S2.原料C经酯化反应合成得到中间体D;
S3.中间体C与中间体B经酯化反应,通过纯化分离得到三类取代中间体E、F或G;
S4.中间体E、F或G经脱保护反应获得产物H、I或J。
作为本发明的进一步改进,
S1取代反应的试剂包括但不限于:硝酸银、浓硝酸,所用溶剂包括但不限于:乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯、二氧六环等;
S2酯化反应所用缩合剂包括但不限于:(1-乙基-3(3-二甲基丙胺)碳二亚胺)、二环己基碳二亚胺、三氟甲磺酸酐、对甲苯磺酸,所用溶剂包括但不限于:乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯、二氧六环等;
S3酯化反应所用缩合剂包括但不限于:(1-乙基-3(3-二甲基丙胺)碳二亚胺)、二环己基碳二亚胺、三氟甲磺酸酐、对甲苯磺酸,所用溶剂包括但不限于:乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯、二氧六环等;
S4脱保护反应所用试剂包括但不限于:三氟乙酸、四丁基氟化铵、四丁基碘化铵、氢氟酸、盐酸、氢氧化钾、氢氧化钠、钯碳等,所用溶剂包括但不限于:乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯、二氧六环、甲醇、乙醇等。
本发明进一步保护一种上述羟基取代曲前列尼尔衍生物为前环列素类似物和一氧化氮偶联的应用。
本发明进一步保护一种上述羟基取代曲前列尼尔衍生物在制备用于治疗肺动脉高压、呼吸窘迫综合征、动脉闭塞性疾病、器官纤维化、肾病、糖尿病眼底病变、骨质疏松、血栓性脉管炎、心肌梗死的治疗药物中的应用。
本发明具有如下有益效果:本发明为一系列曲前列尼尔和NO供体偶联的创新药物,该类药物结合了曲前列尼尔和NO两个特征成分,在体内分解成为曲前列尼尔和NO供体并进而产生NO,一方面提供曲前列尼尔和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,该药物在体内可以释放出NO分子,能够快速起效,由于曲前列尼尔和NO分别通过cGMPS和cAMP不同的作用途径,因此,两者有相互协同增效功能,加强了舒张血管的作用,同时更方便给药,解决了患者依从性问题,能够在疗效上能够更有效治疗肺动脉高压等疾病。这些系列化合物可以用于治疗肺动脉高压、呼吸窘迫综合征、动脉闭塞性疾病、器官纤维化、肾病、眼病(如糖尿病眼底病变等)、骨质疏松、血栓性脉管炎、心肌梗死等多种疾病的治疗药物中的应用。
本发明羟基取代曲前列尼尔衍生物是一类曲前列尼尔和NO供体结合药物,解决了曲前列尼尔疗效较弱及NO给药不便、剂量无法控制等缺陷,并通过两者协同作用提高了药物的有效性和患者的依从性,及药物有效性控制也得到了提高。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍,显而易见地,下面描述中的附图仅仅是本发明的一些实施例,对于本领域普通技术人员来讲,在不付出创造性劳动性的前提下,还可以根据这些附图获得其他的附图。
图1为试验例中各组化合物体外NO释放对比图。
具体实施方式
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。
实施例1:化合物1的制备
合成路线如下:
合成方法如下:
将2-溴丙酸(5mmol)溶于乙腈中,搅拌条件下加入硝酸银(8mmol),60℃条件下反应4小时,TLC监测反应完全,旋干溶剂,加入二氯甲烷,水洗一次,饱和食盐水洗一次,柱层析,得中间体1-B。
将曲前列尼尔(100mg),用10mL二氯甲烷溶解,将2,4-二甲基苄基醇(65mg)、DMAP(25mg)和EDCI.HCl(66mg)按顺序加入,置于室温搅拌反应14h,TLC检测反应完全,将反应混合物用乙酸乙酯稀释,用0.1M盐酸水溶液洗一次,饱和食盐水洗一次,经柱层析,纯化得中间体1-D。
将中间体1-D(0.1mmol),中间体1-B(0.15mmol),EDCI.HCl(0.2mmol)和HOBT(0.2mmol)用二氯甲烷溶解,室温搅拌4小时,TLC监测反应完全,旋干溶剂,柱层析纯化得中间体1-E。
将中间体1-E(0.1mmol)用二氯甲烷(2mL)溶解,加入三氟乙酸(1mL)搅拌反应,室温反应2小时后,旋干溶剂,经HPLC纯化得化合物1,收率18%。1H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.78(dd,J=8.0,1.4Hz,2H),5.05(dt,J=5.6,4.5Hz,1H),4.80–4.67(m,2H),4.63(t,J=7.1Hz,2H),3.57–3.45(m,1H),3.36(d,J=6.8Hz,1H),2.95(d,J=7.2Hz,2H),2.87–2.71(m,4H),2.32–2.23(m,1H),2.20(dtd,J=7.9,6.2,2.9Hz,1H),2.11–1.96(m,3H),1.83–1.65(m,2H),1.63–1.51(m,2H),1.47–1.36(m,4H),1.36–1.24(m,4H),0.94–0.80(m,3H)。
实施例2:化合物2的制备
合成路线如下:
参考中间体1-B的合成方法,将原料1-A替换为2-A可制得中间体2-B。
将中间体1-D(0.1mmol),中间体2-B(0.15mmol),EDCI.HCl(0.2mmol)和HOBT(0.2mmol)用二氯甲烷溶解,室温搅拌6小时,TLC监测反应完全,旋干溶剂,经HPLC纯化可得中间体2-C。
参考实施例1的合成方法,将原料替换为2-C可制得化合物2。1H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.90–6.66(m,2H),4.72(d,J=4.8Hz,2H),4.58(p,J=5.5Hz,1H),4.32(t,J=5.9Hz,2H),4.04–3.92(m,1H),2.96(d,J=7.2Hz,2H),2.88–2.61(m,2H),2.46–2.26(m,3H),2.26–2.04(m,2H),1.99–1.72(m,9H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.56(tdd,J=7.2,4.6,1.8Hz,2H),1.44–1.22(m,6H),0.97–0.69(m,3H)。
实施例3:化合物3的制备
参考实施例1的合成方法,将原料替换为4-溴丁酸可制得化合物3。1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.94–6.54(m,2H),5.02(ddd,J=5.7,5.0,4.2Hz,1H),4.88–4.60(m,2H),4.44(td,J=6.1,2.5Hz,2H),3.70–3.45(m,1H),3.36(d,J=6.8Hz,1H),2.95(d,J=7.2Hz,2H),2.89–2.70(m,2H),2.50(t,J=7.1Hz,2H),2.27(dddd,J=10.8,9.8,5.4,2.8Hz,1H),2.20(dtd,J=7.9,6.4,2.9Hz,1H),2.13–1.93(m,5H),1.84–1.67(m,2H),1.67–
1.50(m,2H),1.45–1.35(m,4H),1.35–1.19(m,4H),0.96–0.70(m,3H)。
实施例4:化合物4的制备
参考实施例2的合成方法,将原料替换为4-溴丁酸可制得化合物4。1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.94–6.66(m,2H),4.81–4.64(m,2H),4.58(p,J=5.5Hz,1H),4.44(td,J=6.1,2.5Hz,2H),4.08–3.88(m,1H),2.96(d,J=7.2Hz,2H),2.88–2.64(m,2H),2.49(t,J=7.1Hz,2H),2.39(d,J=5.3Hz,1H),2.23–2.01(m,4H),1.96–1.86(m,2H),1.86–1.72(m,3H),1.66(tdd,J=6.6,5.5,1.0Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.43–1.18(m,6H),1.00–0.60(m,3H)。
实施例5:化合物5的制备
参考实施例2的合成方法,将原料替换为6-溴己酸可制得化合物5。1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.94–6.68(m,2H),4.72(d,J=4.8Hz,2H),4.58(p,J=5.5Hz,1H),4.29(t,J=6.0Hz,2H),4.14–3.80(m,1H),2.96(d,J=7.2Hz,2H),2.87–2.62(m,2H),2.39(d,J=5.3Hz,1H),2.31(t,J=6.8Hz,2H),2.23–2.04(m,2H),1.99–1.87(m,2H),1.87–1.72(m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.62–1.43(m,6H),1.43–1.23(m,6H),0.99–0.72(m,3H)。
实施例6:化合物1的制备
参考实施例1的合成方法,将原料替换为6-溴己酸可制得化合物6。1H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.91–6.64(m,2H),5.14–5.00(m,1H),4.72(d,J=4.8Hz,2H),4.32(t,J=5.9Hz,2H),3.59–3.42(m,1H),3.36(d,J=6.8Hz,1H),2.95(d,J=7.2Hz,2H),2.89–2.69(m,4H),2.35–2.23(m,1H),2.20(dtd,J=7.9,6.3,2.9Hz,1H),2.13–1.93(m,3H),1.93–1.65(m,6H),1.65–1.48(m,2H),1.48–1.19(m,8H),0.95–0.70(m,3H)。
实施例7:化合物7的制备
参考实施例2的合成方法,将原料替换为7-溴庚酸可制得化合物7。1H NMR(500MHz,Chloroform-d)δ7.07(t,J=7.9Hz,1H),6.88–6.67(m,2H),4.72(d,J=4.8Hz,2H),4.58(p,J=5.5Hz,1H),4.29(t,J=6.0Hz,2H),4.15–3.89(m,1H),2.96(d,J=7.2Hz,2H),2.87–2.66(m,2H),2.38(d,J=5.3Hz,1H),2.31(t,J=7.0Hz,2H),2.21–2.06(m,2H),1.98–1.88(m,2H),1.88–1.82(m,1H),1.82–1.74(m,4H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.56(tdd,J=7.2,4.6,1.8Hz,2H),1.53–1.25(m,12H),0.96–0.81(m,3H)。
实施例8:化合物8的制备
参考实施例1的合成方法,将原料替换为7-溴庚酸可制得化合物8。1H NMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.92–6.70(m,2H),5.25–4.89(m,1H),4.72(d,J=4.8Hz,2H),4.29(t,J=6.0Hz,2H),3.63–3.44(m,1H),3.36(d,J=6.8Hz,1H),2.95(d,J=7.2Hz,2H),2.88–2.68(m,2H),2.37–2.20(m,3H),2.16(dtd,J=7.9,6.4,2.9Hz,1H),2.12–1.93(m,3H),1.88–1.64(m,4H),1.64–1.46(m,6H),1.46–1.36(m,4H),1.36–1.18(m,4H),1.01–0.83(m,3H)。
实施例9:化合物9的制备
合成路线如下:
将中间体1-D(0.1mmol),中间体1-B(0.3mmol),EDCI.HCl(0.4mmol)和HOBT(0.4mmol)用二氯甲烷溶解,室温搅拌6小时,TLC监测反应完全,旋干溶剂,经HPLC纯化可得中间体3-A。参考实施例1的合成方法,可制得化合物9。1H NMR(500MHz,Chloroform-d)δ7.11(t,J=7.8Hz,1H),6.90–6.65(m,2H),5.28–4.98(m,1H),4.82–4.65(m,2H),4.63–4.26(m,3H),2.96(d,J=7.3Hz,2H),2.89–2.64(m,6H),2.37–2.21(m,1H),2.16(dtd,J=7.9,6.3,3.0Hz,1H),2.10–1.96(m,3H),1.82–1.71(m,2H),1.71–1.60(m,4H),1.45–1.19(m,6H),0.96–0.76(m,3H)。
实施例10:化合物10的制备
参考实施例2的合成方法,将原料替换为8-溴辛酸可制得化合物10。1H NMR(500MHz,Chloroform-d)δ7.09(t,J=7.9Hz,1H),6.89–6.65(m,2H),4.88–4.62(m,2H),4.58(p,J=5.5Hz,1H),4.40–4.14(m,2H),4.02(qd,J=5.5,4.6Hz,1H),2.96(d,J=7.2Hz,2H),2.87–2.62(m,2H),2.38(d,J=5.3Hz,1H),2.35–2.24(m,2H),2.22–2.06(m,2H),1.97–1.88(m,2H),1.88–1.71(m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.52–1.45(m,2H),1.42(qd,J=6.7,0.7Hz,2H),1.39–1.22(m,10H),0.94–0.80(m,3H)。
实施例11:化合物11的制备
参考实施例2的合成方法,将原料替换为9-溴壬酸可制得化合物11。1H NMR(500MHz,Chloroform-d)δ7.09(t,J=7.9Hz,1H),6.96–6.45(m,2H),4.81–4.65(m,2H),4.58(p,J=5.5Hz,1H),4.29(t,J=6.1Hz,2H),4.02(qd,J=5.5,4.6Hz,1H),2.96(d,J=7.2Hz,2H),2.87–2.65(m,2H),2.38(d,J=5.3Hz,1H),2.31(t,J=7.1Hz,2H),2.22–2.05(m,2H),1.99–1.87(m,2H),1.87–1.72(m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.60–1.38(m,6H),1.38–1.19(m,12H),1.00–0.73(m,3H)。
实施例12:化合物12的制备
参考实施例1的合成方法,将原料替换为7-溴庚酸可制得化合物12。1HNMR(500MHz,Chloroform-d)δ7.07(t,J=7.9Hz,1H),6.92–6.60(m,2H),5.14–5.02(m,1H),4.72(d,J=4.8Hz,2H),4.29(t,J=6.0Hz,2H),3.59–3.41(m,1H),3.37(d,J=6.6Hz,1H),2.95(d,J=7.2Hz,2H),2.87–2.69(m,2H),2.37–2.21(m,3H),2.16(dtd,J=7.9,6.4,2.9Hz,1H),2.11–1.92(m,3H),1.84–1.65(m,4H),1.64–1.54(m,2H),1.54–1.20(m,14H),0.99–0.56(m,3H)。
实施例13:化合物13的制备
参考实施例2的合成方法,将原料替换为10-溴代癸酸可制得化合物13。1H NMR(500MHz,Chloroform-d)δ7.11(t,J=7.9Hz,1H),6.92–6.57(m,2H),4.80–4.62(m,2H),4.58(p,J=5.5Hz,1H),4.29(t,J=6.1Hz,2H),4.06(qd,J=5.5,4.6Hz,1H),2.95(dd,J=7.3,1.1Hz,2H),2.83–2.63(m,2H),2.38(d,J=5.3Hz,1H),2.28(t,J=7.0Hz,2H),2.22–2.06(m,2H),1.97–1.87(m,2H),1.86–1.73(m,5H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.53–1.39(m,4H),1.39–1.19(m,14H),0.98–0.65(m,3H)。
实施例14:化合物14的制备
参考实施例2的合成方法,将原料替换为6-溴己酸可制得化合物14。1H NMR(500MHz,Chloroform-d)δ7.10(t,J=7.9Hz,1H),6.91–6.59(m,2H),5.09(td,J=5.4,4.2Hz,1H),4.83–4.62(m,2H),4.57(p,J=5.6Hz,1H),4.29(t,J=6.1Hz,4H),2.94(d,J=7.2Hz,2H),2.89–2.60(m,2H),2.34–2.23(m,5H),2.20(dtd,J=8.0,6.2,3.0Hz,1H),2.11–1.95(m,3H),1.82–1.72(m,6H),1.70–1.61(m,4H),1.61–1.43(m,8H),1.43–1.21(m,6H),1.02–0.72(m,3H)。
实施例15:化合物15的制备
参考实施例2的合成方法,将原料替换为4-溴环己烷-1-甲酸可制得化合物15。1HNMR(500MHz,Chloroform-d)δ7.07(t,J=7.9Hz,1H),6.88–6.58(m,2H),4.79–4.62(m,3H),4.58(p,J=5.5Hz,1H),4.18–3.76(m,1H),2.96(d,J=7.2Hz,2H),2.86–2.65(m,2H),2.47–2.31(m,2H),2.21–2.04(m,2H),2.01–1.72(m,13H),1.67(tdd,J=6.9,5.5,1.6Hz,2H),1.56(tdd,J=7.2,4.6,1.8Hz,2H),1.43–1.20(m,6H),0.96–0.74(m,3H)。
实施例16:化合物16的制备
参考实施例1的合成方法,将原料替换为3-溴-2-甲基丙酸可制得化合物16。1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.91–6.66(m,2H),5.00(ddd,J=5.7,4.9,4.3Hz,1H),4.82–4.63(m,2H),4.37(d,J=6.4Hz,2H),3.61–3.44(m,1H),3.36(d,J=6.8Hz,1H),3.02–2.71(m,5H),2.36–2.14(m,2H),2.14–1.92(m,3H),1.87–1.65(m,2H),1.65–1.48(m,2H),1.51–1.37(m,4H),1.37–1.17(m,7H),0.96–0.66(m,3H)。
实施例17:化合物17的制备
参考实施例2的合成方法,将原料替换为2,2-二溴乙酸可制得化合物17。1H NMR(500MHz,Chloroform-d)δ7.09(t,J=7.9Hz,1H),6.91–6.67(m,2H),4.88–4.66(m,2H),4.65–4.38(m,5H),4.02(qd,J=5.5,4.6Hz,1H),3.10(p,J=6.4Hz,1H),2.96(d,J=7.2Hz,2H),2.88–2.60(m,2H),2.38(d,J=5.3Hz,1H),2.26–2.05(m,2H),1.98–1.88(m,2H),1.88–1.72(m,3H),1.67(tdd,J=6.8,5.5,1.2Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.44–1.21(m,6H),1.04–0.53(m,3H)。
实施例18:化合物18的制备
参考实施例2的合成方法,将原料替换为4-溴-3-甲基丁酸可制得化合物18。1HNMR(500MHz,Chloroform-d)δ7.08(t,J=7.9Hz,1H),6.90–6.63(m,2H),4.72(d,J=4.8Hz,2H),4.60(p,J=5.5Hz,1H),4.26–4.14(m,2H),4.10–3.91(m,1H),2.96(d,J=7.2Hz,2H),2.85–2.68(m,2H),2.42–2.23(m,4H),2.21–2.08(m,2H),1.96–1.87(m,2H),1.87–1.75(m,3H),1.66(tdd,J=6.9,5.5,1.4Hz,2H),1.56(tdd,J=7.3,4.6,1.8Hz,2H),1.40–1.27(m,6H),1.26–1.20(m,3H),0.96–0.76(m,3H)。
实施例19:化合物19的制备
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合成路线如下:
中间体4-A的合成可参考文献Molecules,2012,17,7556-7568.制得。
将中间体1-D(0.1mmol),中间体4-A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纯化得中间体4-B。
参考实施例2的合成方法,可制得化合物19。1H NMR(500MHz,Chloroform-d)δ7.92–7.73(m,2H),7.73–7.49(m,3H),7.10(t,J=7.9Hz,1H),6.78(td,J=7.9,1.1Hz,2H),6.11–5.95(m,2H),5.17(td,J=5.4,4.2Hz,1H),4.81–4.64(m,2H),4.61(p,J=5.5Hz,1H),4.37(d,J=6.4Hz,2H),3.55(s,2H),3.02–2.88(m,2H),2.88–2.66(m,3H),2.34–1.97(m,5H),1.79–1.68(m,2H),1.68–1.54(m,4H),1.44–1.19(m,9H),0.99–0.73(m,3H)。
实施例20:化合物20的制备
参考实施例19的合成方法,可制得化合物20。1HNMR(500MHz,Chloroform-d)δ7.77–7.67(m,2H),7.67–7.55(m,3H),7.10(t,J=7.9Hz,1H),6.78(td,J=7.9,1.2Hz,2H),5.17(td,J=5.4,4.2Hz,1H),4.82–4.68(m,2H),4.68–4.46(m,5H),4.37(d,J=6.4Hz,2H),3.51(s,2H),3.05–2.88(m,2H),2.88–2.64(m,3H),2.36–2.18(m,2H),2.18–2.09(m,1H),2.09–1.98(m,2H),1.81–1.68(m,2H),1.65(tdd,J=7.3,6.5,5.1Hz,4H),1.43–1.19(m,9H),0.95–0.77(m,3H)。
实施例21:化合物1的制备
参考实施例19的合成方法,可制得化合物21。1H NMR(500MHz,Chloroform-d)δ7.92–7.74(m,2H),7.69–7.47(m,3H),7.10(t,J=7.9Hz,1H),6.78(td,J=7.9,1.1Hz,2H),5.17(td,J=5.4,4.2Hz,1H),4.83–4.65(m,2H),4.61(p,J=5.5Hz,1H),4.42–4.32(m,4H),4.21(t,J=6.1Hz,2H),3.51(s,2H),3.06–2.88(m,2H),2.88–2.64(m,3H),2.36–1.96(m,7H),1.85–1.68(m,2H),1.68–1.55(m,4H),1.46–1.17(m,9H),1.00–0.62(m,3H)。
试验例1:体外NO释放测试
试验材料:空白溶液为DMSO和PBS混合;Griess试剂按照如下方式配置: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;受试化合物(本专利实施例化合物4、化合物6、化合物8、化合物11、化合物15和化合物21)溶液配置:受试化合物精确称量后用DMSO溶解并用PBS稀释使其浓度为200μM。
试验方法,标准曲线方程的制定:用空白溶液分别配制0-100μmol/L亚硝酸钠标准溶液,与Griess试剂混匀,在37℃恒温摇床中孵化30min后,于540nm处测定吸光值,分别减去空白溶液读数后回归获得标准曲线方程。
试验测试:受试化合物溶液和L-半胱氨酸溶液混合,在37℃恒温摇床中孵化120min,后与Griess试剂混匀,在37℃恒温摇床中再孵化30min后,测定540nm处吸光值,按照标准曲线方程,计算NO释放量。
试验结果:实验结果如图1所示,表明实施例化合物具备良好的NO释放效果。
试验例2:抗血小板聚集作用
实验材料:ADP(adenosine diphosphate,二磷酸腺苷),肾上腺素,胶原蛋白,血小板聚集功能检测试剂盒(cat#5393)。
实验方法:采用健康人血样制备富血小板血浆。使用Bornl’s浊度法进行测试。将225μL富血小板血浆加入反应杯,将配置成1.8-1800nM溶液(25mM Tris-acetate和120mMNaCl)受试化合物(本专利实施例化合物)溶液25μL加入,37℃条件下共孵育2min后,加入终浓度2μM的ADP诱导血小板聚集。评估化合物抑制ADP诱导的血小板聚集的抑制率。
试验结果:结果见表1。
表1实施例化合物抑制ADP诱导的血小板聚集
化合物编号 | 抑制率(IC50,nM) | 化合物编号 | 抑制率(IC50,nM) |
1 | 15 | 12 | 6.4 |
2 | 11 | 13 | 9.4 |
3 | 12 | 14 | 6.8 |
4 | 9.1 | 15 | 7.7 |
5 | 9.9 | 16 | 5.2 |
6 | 4.9 | 17 | 9.0 |
7 | 5.7 | 18 | 4.5 |
8 | 10 | 19 | 11 |
9 | 12 | 20 | 18 |
10 | 16 | 21 | 17 |
11 | 13 | 曲前列尼尔 | 34 |
由上表可知,实施例化合物具备良好的抑制ADP诱导的血小板聚集的效果。
以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。
Claims (6)
1.一种羟基取代曲前列尼尔衍生物,其特征在于,具有如下式Ⅰ所示结构:
其中,R1、R2分别选自H、且R1、R2不同时为H;其中R3为直链或支链的C1-C10烷基、C5-7环烷基或-C1-C10烷基-芳环-,R4、R5为直链或支链的C1-C10烷基;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所述羟基取代曲前列尼尔衍生物,其特征在于,所述化合物选自以下任意一种结构:
3.一种如权利要求1或2所述羟基取代曲前列尼尔衍生物的合成方法,其特征在于,包含以下步骤:
起始原料A经取代反应合成得到羧酸硝酸酯中间体B;
S2.原料C经酯化反应合成得到中间体D;
S3.中间体C与中间体B经酯化反应,通过纯化分离得到三类取代中间体E、F或G;
S4.中间体E、F或G经脱保护反应获得产物H、I或J。
4.根据权利要求3所述的合成方法,其特征在于,所述步骤中:
S1取代反应的试剂选自硝酸银或浓硝酸,所用溶剂选自乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯或二氧六环;
S2酯化反应所用缩合剂选自(1-乙基-3(3-二甲基丙胺)碳二亚胺)、二环己基碳二亚胺、三氟甲磺酸酐或对甲苯磺酸,所用溶剂选自乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯或二氧六环;
S3酯化反应所用缩合剂选自(1-乙基-3(3-二甲基丙胺)碳二亚胺)、二环己基碳二亚胺、三氟甲磺酸酐或对甲苯磺酸,所用溶剂选自乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯或二氧六环;
S4脱保护反应所用试剂选自三氟乙酸、四丁基氟化铵、四丁基碘化铵、氢氟酸、盐酸、氢氧化钾、氢氧化钠或钯碳,所用溶剂选自乙腈、二氯甲烷、氯仿、丙酮、乙酸乙酯、甲苯、二氧六环、甲醇或乙醇。
5.一种如权利要求1或2所述羟基取代曲前列尼尔衍生物为前环列素类似物和一氧化氮偶联的应用。
6.一种如权利要求1或2所述羟基取代曲前列尼尔衍生物在制备用于治疗肺动脉高压、呼吸窘迫综合征、动脉闭塞性疾病、器官纤维化、肾病、糖尿病眼底病变、骨质疏松、血栓性脉管炎或心肌梗死的治疗药物中的应用。
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