CN109206464B - 一种腺苷二磷酸核糖类化合物及其制备方法和生物活性 - Google Patents
一种腺苷二磷酸核糖类化合物及其制备方法和生物活性 Download PDFInfo
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- CN109206464B CN109206464B CN201710551938.6A CN201710551938A CN109206464B CN 109206464 B CN109206464 B CN 109206464B CN 201710551938 A CN201710551938 A CN 201710551938A CN 109206464 B CN109206464 B CN 109206464B
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- isopropylidene
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- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
- C07H19/20—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids
- C07H19/207—Purine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Abstract
本发明公开了一种腺苷二磷酸核糖化合物,其通式如(I)所示,其中各取代基定义详见说明书。此外,本发明还公开了上述化合物的制备方法和用途,本发明的腺苷二磷酸核糖(ADPR)结构类似物具有特异性TRPM2抑制活性。
Description
技术领域
本发明属于医药技术领域,具体地说,涉及一类新型的腺苷二磷酸核糖类化合物及其制备方法和生物活性,本发明公开的化合物具有特异性的TRPM2抑制活性,对其他TRP通道无作用。
背景技术
瞬时受体电位通道(Transient receptor potential channels,TRP channels)超家族是一类非选择性阳离子通道(Nilius等,Genome Biol,2011,12:218),其主要功能是作为细胞的感受器,感受包括伤害、味觉、温度、化学刺激等环境变化(Patapoutian等,NatRev Drug Discov,2009,8:55;Nilius等,Rev Physiol Biochem Pharmacol,2013,164:1;Talavera等,Trends Neurosci,2008,31:287;Eijkelkamp等,Annu Rev Neurosci,2013,36:519)。
TRPM2(Transient receptor potential melastatin 2)通道是TRP超家族的一员,主要通透Ca2+等阳离子,广泛表达于多种细胞并具有多种生理功能。作为细胞的活性氧物种(reactive oxygen species,ROS)感受器,TRPM2通道已经被证明与细胞凋亡、炎症反应、温度调节等一系列生理功能有重要联系(Hara等,Mol Cell,2002,9:163;Luste等,NEngl J Med,1998,338:436;Song等,Science,2016,353:1393;Voets等,Handb ExpPharmacol,2014,223:729)。
活性氧物种ROS在细胞凋亡、肿瘤及慢性疼痛等病生理过程中起着重要的作用。TRPM2最重要的生理功能之一是作为生物体的ROS感受器,通道被ROS激活后,通过介导胞外的Ca2+内流而参与下游的各种正常和疾病生理过程。最早在2002年,Hara等人报道TRPM2参与了ROS诱导的细胞死亡,他们发现对细胞给予H2O2刺激,会激活TRPM2而引起细胞外的钙离子和钠离子内流,形成细胞内阳离子过载,导致细胞的死亡(Hara等,Mol Cell,2002,9:163)。Kaneko等人也发现,H2O2导致的小鼠大脑皮层神经元损伤是由TRPM2介导的,他们发现用H2O2处理过的神经元细胞,会由于胞外Ca2+持续内流而最终导致神经细胞的死亡(Kaneko等,J Pharmacol Sci,2006,101:66)。TRPM2通道在胰岛β细胞里有丰富的表达,TRPM2通道通过调节胰岛β细胞的Ca2+内流,对胰岛素的分泌起着重要的作用(Jiang等,Expert OpinTher Targets,2010,14:973)。Tominaga课题组报道,人体的体温协同细胞内的cADPR可以引起TRPM2通道调控的Ca2+内流,Ca2+内流是胰岛β细胞及其他释放胰岛素细胞系释放胰岛素的必要条件之一(Togashi等,EMBO J,2006,25:1804)。TRPM2通道还能在ROS的作用下使细胞产生趋化因子,介导免疫细胞(如噬中性粒细胞)在炎症部位积累,进而修复感染或受伤的区域(Luste等,N Engl J Med,1998,338:436)。此外,体温调节也是TRPM2通道的重要功能,TRPM2温度感受域是非疼痛温觉(23℃~38℃)。人体的正常体温处于TRPM2温度感受的范围,TRPM2特有的温度感受域能帮助人体识别炎热的环境,从而避免长期处于高热环境导致身体机能损伤(Tan等,Nature,2016,536:460)。
作为ROS感受器,TRPM2通过将ROS转换为钙信号,广泛地调控人体各种生理功能并参与大量疾病的进程,因而成为很多疾病的潜在治疗靶点(Yamamoto等,Pharmaceuticals,2016,9:57),主要包括缺血再灌注损伤(ischemia-reperfusion injury,I/R injury)、阿尔兹海默症(Alzheimer’s disease,AD)、糖尿病等(Weilinger等,Acta Pharmacol Sin,2013,34:39;Forstl等,Eur Arch Psychiatry Clin Neurosci,1999,249:288;Hardy等,Science,2002,297:353;Kahya等,Mol Neurobiol,2016,1;Ostapchenko等,J Neurosci,2015,35:15157)。在中枢神经***,血液再灌注显著提高的氧化压力(oxidative stress)和缺血期间产生的ROS会激活包括TRPM2通道等非选择性阳离子通道,导致神经元细胞的死亡。β-淀粉样蛋白(amyloid beta,Aβ)是阿尔兹海默症最重要的病生理特征,Aβ的沉积被认为具有很高的生理毒性,TRPM2通道介导的Ca2+稳态的扰乱被认为是Aβ产生生理毒性的基础(Laferla等,Nat Rev Neurosci,2002,3:862;Mattson等,Ann N Y Acad Sci,1999,893:154)。TRPM2对胰岛β细胞分泌胰岛素起着重要的作用,胰岛素的分泌与糖尿病的发病机制密切相关,因此TRPM2通道与糖尿病有重要的联系。
TRPM2通道参与调控多种生理功能,是多种疾病的潜在治疗靶点。研究表明,多种涉及该通道的疾病都是由于通道的过度激活所导致的,因此研究该通道的抑制剂,对进一步阐明通道功能,确证其作为多种疾病的潜在治疗靶点有重要意义。
发明内容
本发明人经研究发现了一类新型的腺苷二磷酸核糖(ADPR)结构类似物,它们具有特异性的TRPM2抑制活性,而对其他TRP通道无抑制活性。
本发明的目的是提供一种新的腺苷二磷酸核糖(ADPR)类化合物。
本发明的第二个目的是提供上述化合物的制备方法。
本发明的第三个目的是提供包含上述化合物的药物组合物。
本发明的第四个目的是提供上述化合物的医药用途。
在本发明的实施方案中,本发明提供了一种通式为(I)的化合物或其药学上可接受的盐。
其中,R1是氢原子、氯原子、溴原子、碘原子、氨基、或甲氧基;
R2是氨基、单甲氨基、或二甲氨基;
R3是氢原子、或甲基;
R4和R5都是氢原子,或者R4和R5相连形成异亚丙基即-C(CH3)2-;
R6和R7都是氢原子,或者R6和R7相连形成异亚丙基即-C(CH3)2-;
X是氧原子、亚甲基、二氟亚甲基。
在本发明的实施方案中,本发明提供了一种通式为(I)的腺苷二磷酸核糖类化合物或其药学上可接受的盐,其中,所述的盐选自季铵盐或铵盐,所述季铵盐为(CH3CH2)3N+的盐。
在本发明的优选实施方案中,本发明提供的一种通式为(I)的腺苷二磷酸核糖类化合物或其药学上可接受的盐,其中,通式(I)中,R1为氯原子、溴原子、碘原子、氨基、甲氧基时;R2为氨基;R3为甲基;X为氧原子、亚甲基、二氟亚甲基;R4和R5相连形成异亚丙基即-C(CH3)2-;R6和R7相连形成异亚丙基即-C(CH3)2-。或者,R1为氢原子时,R2为氨基、单甲氨基、二甲氨基;R3为甲基;X为亚甲基;R4和R5相连形成异亚丙基即-C(CH3)2-;R6和R7相连形成异亚丙基即-C(CH3)2-。
在本发明的优选实施方案中,本发明提供的一种通式为(I)的腺苷二磷酸核糖类化合物或其药学上可接受的盐,其中,通式(I)中,R1为氯原子、溴原子、碘原子时,R2为氨基;R3为甲基;X为亚甲基,二氟亚甲基;R4和R5相连形成异亚丙基即-C(CH3)2-;R6和R7都是氢;或者,R1为氢原子时,R2为氨基;R3为甲基;X为亚甲基;R4和R5相连形成异亚丙基即-C(CH3)2-;R6和R7都是氢。
在本发明的优选实施方案中,本发明提供的一种通式为(I)的腺苷二磷酸核糖类化合物或其药学上可接受的盐,其中,通式(I)中R1为氯原子、溴原子、碘原子、氨基、甲氧基时,R2为氨基,R3为氢、甲基,X为氧原子、亚甲基、二氟亚甲基;R4、R5、R6和R7都是氢;或者,R1为氢原子时,R2为氨基、单甲氨基、二甲氨基,R3为氢,X为亚甲基;R4、R5、R6和R7都是氢。
在本发明的优选实施方案中,本发明提供的一种通式为(I)的腺苷二磷酸核糖类化合物或其药学上可接受的盐,所示式(I)化合物为下列式(I’)、式(II’)或式(III’):
在上述式(I’)、(II’)和(III’)中,Me为甲基,R1、R2和R3以及X的定义如上面式(I)中所定义的。
第二方面,本发明还提供了式(I)化合物的制备方法,包括如下步骤:
以三(四正丁基铵)二磷酸即式(II)化合物为原料,与式(III)化合物反应,得到式(IV)化合物;
或者,以三(四正丁基铵)二磷酸即式(II)化合物为原料,与式(V)化合物反应,得到式(VI)化合物;
在上述的式(II)-(VI)化合物中,其中,Ts为对甲苯磺酰基,R1、R2和R3以及X的定义如上面式(I)中所定义的。
在本发明的实施方案中,本发明提供的式(I)化合物的制备方法,其通用制备方案一和制备方案二。
制备方案一:
通用制备方案一的过程为:式(1)化合物与丙酮在对甲苯磺酸的催化下反应1h,形成异亚丙基保护,然后与对甲苯磺酰氯室温反应3h,得到式(2)化合物。式(2)化合物与二磷酸的四正丁基铵盐反应16h得到式(3)化合物。式(3)化合物与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖室温反应48h,即得式(I’)化合物。式(I’)化合物在盐酸作用下得到不同程度脱除保护基的化合物,即式(II’)和式(III’)化合物。
制备方案二:
通用制备方案二的过程为:D-核糖加入甲醇,在乙酰氯催化下室温反应3h,然后在对甲苯磺酸催化下形成异亚丙基保护。然后与对甲苯磺酰氯反应2h,得式(5)化合物。式(5)化合物与二磷酸的四正丁基铵盐反应24h,得式(6)化合物。式(6)化合物与2,3-O-异亚丙基-5-O-对甲苯磺酰基腺苷室温反应36h,即得式(I’)化合物。式(I’)化合物在盐酸作用下得到不同程度脱除保护基的化合物,即式(II’)和式(III’)化合物。
以上两种通用制备方案中的R1,R2,R3和X的定义与通式(I’)、(II’)和(III’)中的定义一致。
第三方面,本发明提供了包含上述腺苷二磷酸核糖类化合物(包括式(I)、式(I’)、式(II’)、式(III’)化合物)或其药学上可接受的盐的药物组合物。
第四方面,本发明提供了上述腺苷二磷酸核糖类化合物(包括式(I)、式(I’)、式(II’)、式(III’)化合物)或其药学上可接受的盐作为特异性TRPM2抑制剂的用途。这里,所述的特异性TRPM2抑制剂的用途,包括用于研究TRPM2通道相关功能和未来治疗TRPM2通道相关的疾病,包括缺血再灌注损伤,阿尔兹海默症等。
本发明的有益效果体现为:本发明的化合物是一类新的化合物,且具有特异性TRPM2抑制活性,可用做TRPM2通道的抑制剂,从而用于研究TRPM2通道相关功能,并可能用于治疗TRPM2通道相关的疾病,例如缺血再灌注损伤和阿尔兹海默症等。
经试验证明,本发明提供的ADPR结构类似物在功能性实验中表现出对TRPM2通道特异性的抑制活性。用稳定表达TRPM2通道的HEK293细胞测试ADPR结构类似物的TRPM2抑制活性,发现其中两个化合物表现出对TRPM2通道的特异性抑制活性,IC50分别为5.4μM和5.7μM,且这两个化合物对其他TRP家族通道包括TRPM7,TRPM8,TRPV1和TRPV3均没有抑制活性。因此本发明提供了TRPM2通道的特异性抑制剂,可用于研究TRPM2通道的相关功能,并可能用于治疗TRPM2通道相关的疾病。
具体实施方式
以下举例用于进一步说明本发明,不以任何形式构成对本发明的限制。
在本发明中,缩写为:
核磁数据由Bruker Avance III 400型核磁共振仪测定,内标为TMS(tetramethylsilane);核磁数据由mestReNova(Ver.6.1.0,Mesrelab Research S.L.)软件处理;高分辨率质谱数据(ESI-TOF)由Bruker Apex IV FTMS型傅立叶离子回旋变换质谱测定;薄层层析硅胶板(上海上邦实业有限公司);柱层析硅胶(200-300目,上海上邦实业有限公司)。所有溶剂、原料和试剂如无说明均为市售分析纯。
实施例1
腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
1a)2’,3’-O-异亚丙基-5’-O-对甲苯磺酰基腺苷
腺苷(5.0g,18.7mmol,1.0eq)、TsOH·H2O(32.2g,187mmol,10.0eq)溶于1L丙酮,室温下搅拌1h。冰浴下向反应液中加饱和NaHCO3溶液,调节pH≥7,旋蒸除去丙酮,过滤得类白色固体,即2’,3’-O-异亚丙基腺苷8.6g,产率99%。上步所得2’,3’-O-异亚丙基腺苷(4.16g,10mmol,1.0eq)、TsCl(2.48g,13mmol,1.3eq)和DMAP(1.83g,15mmol,1.5eq)溶于DCM,室温搅拌3h。减压蒸除溶剂,残留物用EA稀释,依次用饱和NaHCO3溶液,饱和NaCl溶液洗涤,收集有机相用无水Na2SO4干燥。硅胶柱层析(DCM:MeOH=50:1)得白色固体产物3.50g,产率76%。
1b)2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸腺苷
化合物1a(0.65g,1.4mmol,1.0eq)和三(四正丁基铵)亚甲基二磷酸(1.60g,1.7mmol,1.2eq)溶于3mL无水CH3CN,室温搅拌16h。旋蒸除去溶剂,用蒸馏水稀释,通过离子交换柱(Amberlyst A15,NH4 +),收集254nm显色的洗脱液。硅胶柱层析(iPrOH:H2O:aq NH3=8:1:1至6:2:2),得淡黄色泡沫状产物(NH4 +盐)0.52g,产率67%。
1c)腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
化合物1b(520mg,1.0mmol,1.0eq)加入3倍摩尔当量40%(w/w)的Bu4NOH溶液,冷冻干燥。所得产物再加入1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖(537mg,1.3mmol,1.3eq)和1mL无水CH3CN,室温搅拌48h。旋蒸除去溶剂,剩余物用蒸馏水稀释,通过离子交换柱(Amberlyst A15,NH4 +),收集254nm显色的洗脱液。硅胶柱层析(iPrOH:H2O:aqNH3=16:1:1至8:1:1),所得产物再用制备HPLC进一步纯化(H2O:CH3CN=3:1),得白色泡沫状产物(NH4 +盐)136mg,产率20%。
1H NMR(400MHz,D2O)δ8.39(s,1H),8.11(s,1H),6.14(d,J=3.3Hz,1H),5.31(dd,J=6.1,3.3Hz,1H),5.13(dd,J=6.1,2.1Hz,1H),4.87(s,1H),4.65(d,J=6.0Hz,1H),4.56(d,J=1.8Hz,1H),4.47(d,J=5.9Hz,1H),4.15(t,J=7.2Hz,1H),4.10–3.91(m,2H),3.83–3.50(m,2H),3.20(s,3H),2.03(t,J=19.1Hz,2H),1.59(s,3H),1.37(s,3H),1.32(s,3H),1.18(s,3H).HRMS(ESI+):C23H36N5O13P2[M+H]+理论值:652.1785;实测值:652.1786.
实施例2
2-氯腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-2-氯腺苷(NH4 +盐),总收率为50%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)165mg,产率23%。
1H NMR(400MHz,D2O)δ8.32(s,1H),6.05(d,J=3.0Hz,1H),5.31(dd,J=6.1,3.0Hz,1H),5.11(dd,J=6.1,2.2Hz,1H),4.84(s,1H),4.60(d,J=6.0Hz,1H),4.53(s,1H),4.44(d,J=6.0Hz,1H),4.08(t,J=7.3Hz,1H),4.05–3.89(m,2H),3.72–3.50(m,2H),3.19(s,3H),2.01(td,J=19.9,1.7Hz,2H),1.59(s,3H),1.38(s,3H),1.32(s,3H),1.17(s,3H).HRMS(ESI+):C23H35N5O14P2Cl[M+H]+理论值:686.1395;实测值:686.1394.
实施例3
2-溴腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-2-溴腺苷(NH4 +盐),总收率为53%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)38mg,产率5%。
1H NMR(400MHz,D2O)δ8.31(s,1H),6.05(d,J=3.3Hz,1H),5.30(dd,J=6.0,3.3Hz,1H),5.09(dd,J=6.0,2.0Hz,1H),4.81(s,1H),4.66–4.46(m,2H),4.39(d,J=5.9Hz,1H),4.20–3.84(m,3H),3.57(ddt,J=11.9,8.6,5.4Hz,2H),3.16(s,3H),1.98(t,J=19.8Hz,2H),1.56(s,3H),1.34(s,3H),1.28(s,3H),1.14(s,3H).HRMS(ESI+):C23H35N5O13P2Br[M+H]+理论值:730.0890;实测值:730.0883.
实施例4
2-甲氧基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-2-甲氧基腺苷(NH4 +盐),总收率为53%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)108mg,产率15%。
1H NMR(400MHz,D2O)δ8.20(s,1H),6.14(d,J=2.8Hz,1H),5.41(dd,J=6.1,2.8Hz),5.16(dd,J=6.1,2.5Hz,1H),4.91(s,1H),4.55–4.51(m,2H),4.18(t,J=7.3Hz,1H),4.05(d,J=5.0Hz,2H),3.91(s,3H),3.71(ddt,J=14.1,10.4,7.0Hz,2H),3.24(s,3H),2.04(t,J=19.7Hz,2H),1.61(s,3H),1.40(s,3H),1.37(s,3H),1.22(s,3H).HRMS(ESI+):C24H38N5O14P2[M+H]+理论值:682.1890;实测值:682.1880.
实施例5
2-氨基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-2-氨基腺苷(NH4 +盐),总收率为23%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)105mg,产率15%。
1H NMR(400MHz,D2O)δ7.99(s,1H),5.91(d,J=3.2Hz,1H),5.20(dd,J=6.1,3.2Hz,1H),5.07(dd,J=6.1,2.3Hz,1H),4.84(s,1H),4.60(d,J=6.0Hz,1H),4.45(m,2H),4.13(t,J=7.3Hz,1H),4.08–3.92(m,2H),3.65(ddt,J=17.8,10.3,7.1Hz,2H),3.16(s,3H),2.01(td,J=19.8,1.7Hz,1H),1.52(s,3H),1.31(s,3H),1.28(s,3H),1.12(s,3H).HRMS(ESI+):C23H37N6O14P2[M+H]+理论值:667.1894;实测值:667.1899.
实施例6
6-甲氨基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-6-甲氨基腺苷(NH4 +盐),总收率为46%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)105mg,产率15%。
1H NMR(400MHz,D2O)δ8.26(s,1H),8.00(s,1H),6.05(d,J=3.3Hz,1H),5.28(dd,J=6.1,3.3Hz,1H),5.10(dd,J=6.1,2.1Hz,1H),4.81(s,1H),4.58(d,J=5.9Hz,1H),4.52(s,1H),4.40(d,J=5.9Hz,1H),4.08(t,J=7.2Hz,1H),4.04–3.93(m,2H),3.60(dtd,J=14.1,10.4,7.0Hz,2H),3.16(s,3H),2.92(s,3H),1.99(td,J=19.9,2.8Hz,2H),1.58(s,3H),1.37(s,3H),1.28(s,3H),1.14(s,3H).HRMS(ESI+):C24H38N5O13P2[M+H]+理论值:666.1941;实测值:666.1946.
实施例7
6-二甲氨基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-6-二甲氨基腺苷(NH4 +盐),总收率为43%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)213mg,产率30%。
1H NMR(400MHz,D2O)δ8.26(s,1H),7.93(s,1H),6.06(d,J=3.4Hz,1H),5.28(dd,J=6.0,3.4Hz,1H),5.10(dd,J=6.1,2.0Hz,1H),4.79(s,1H),4.56(d,J=5.9Hz,1H),4.52(d,J=1.7Hz,1H),4.35(d,J=5.9Hz,1H),4.12–3.92(m,3H),3.70–3.47(m,2H),3.21(s,6H),3.14(s,3H),1.99(td,J=19.9,2.1Hz,2H),1.59(s,3H),1.37(s,3H),1.26(s,3H),1.12(s,3H).HRMS(ESI+):C25H40N5O13P2[M+H]+理论值:680.2098;实测值:680.2089.
实施例8
腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸腺苷,总收率为51%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)216mg,产率30%。
1H NMR(400MHz,D2O)δ8.43(s,1H),8.21(s,1H),6.20(d,J=3.3Hz,1H),5.31(dd,J=6.0,3.2Hz,1H),5.15(dd,J=6.0,1.5Hz,1H),4.92(s,1H),4.69(d,J=6.0Hz,1H,部分被重水峰覆盖),4.60(s,1H),4.53(d,J=6.0Hz,1H),4.19(m,3H),3.87(m,2H),3.24(s,3H),1.60(s,3H),1.38(s,3H),1.34(s,3H),1.20(s,3H).HRMS(ESI+):C23H34F2N5O13P2[M+H]+理论值:688.1596;实测值:688.1605.
实施例9
2-氯腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-2-氯腺苷,总收率为54%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)187mg,产率25%。
1H NMR(400MHz,D2O)δ8.36(s,1H),6.12(d,J=3.4Hz,1H),5.32(dd,J=6.0,3.4Hz,1H),5.14(dd,J=6.0,1.9Hz,1H),4.90(s,1H),4.59(d,J=6.0Hz,1H),4.48(d,J=6.0Hz,1H),4.27–4.15(m,2H),4.11(t,J=7.3Hz,1H),3.91–3.68(m,2H),3.24(s,3H),1.61(s,3H),1.39(s,3H),1.34(s,3H),1.19(s,3H).HRMS(ESI+):C23H33F2N5O13P2Cl[M+H]+理论值:722.1207;实测值:722.1201.
实施例10
2-甲氧基腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-2-甲氧基腺苷,总收率为44%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,纯化,得白色泡沫状产物(NH4 +盐)172mg,产率23%。
1H NMR(400MHz,D2O)δ8.07(s,1H),6.08(d,J=2.8Hz,1H),5.37(dd,J=6.1,2.8Hz,1H),5.12(dd,J=6.1,2.5Hz,1H),4.89(s,1H),4.65(d,J=5.9Hz,1H),4.48(d,J=5.9Hz,1H),4.17(t,J=7.2Hz,1H),4.12(s,1H),3.89–3.74(m,5H),3.21(s,3H),1.58(s,3H),1.38(s,3H),1.33(s,3H),1.18(s,3H).HRMS(ESI+):C24H36F2N5O14P2[M+H]+理论值:718.1702;实测值:718.1690.
实施例11
2-氨基腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-2-氨基腺苷,总收率为27%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)125mg,产率17%。
1H NMR(400MHz,D2O)δ8.06(s,1H),5.96(d,J=3.1Hz,1H),5.21(d,J=6.1,3.1Hz,1H),5.13(dd,J=6.1,2.2Hz,1H),4.92(s,1H),4.54(d,J=5.9Hz,2H),4.55–4.50(m,2H),4.28–4.11(m,3H),3.87(m,2H),3.24(s,3H),1.58(s,3H),1.37(s,3H),1.34(s,3H),1.19(s,3H).HRMS(ESI+):C23H35F2N6O13P2[M+H]+理论值:703.1705;实测值:703.1696.
实施例12
2-氯腺苷-2’,3’-O-异亚丙基-5’-O-焦磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-二磷酸-2-氯腺苷,总收率为40%;再与1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖反应,经纯化,得白色泡沫状产物(NH4 +盐)130mg,产率18%。
1H NMR(400MHz,D2O)δ8.31(s,1H),6.07(d,J=3.4Hz,1H),5.26(dd,J=6.0,3.4Hz,1H),5.10(dd,J=6.1,2.0Hz,1H),4.81(s,1H),4.61–4.50(m,2H),4.42(d,J=5.9Hz,1H),4.14–3.96(m,3H),3.63(dd,J=12.3,5.2Hz,2H),3.14(s,3H),1.55(s,3H),1.33(s,3H),1.29(s,3H),1.14(s,3H).HRMS(ESI+):C22H33N5O14P2[M+H]+理论值:688.1188;实测值:688.1184.
实施例13
2-碘腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
13a)1-O-甲基-2,3-O-异亚丙基-5-O-对甲苯磺酰基核糖
D-核糖(3.5g,23.3mmol,1.0eq)加入30mL无水甲醇,冰浴下滴加乙酰氯(0.14g,1.8mmol,0.08eq),然后室温搅拌3h。反应液用饱和NaHCO3调节pH≥7,旋蒸除去溶剂,得无色透明糖浆。取100mL丙酮,加入原甲酸三乙酯(11mL,10.0g,68mmol,1.0eq)和TsOH·H2O(0.75g,3.9mmol,0.6eq),50℃下搅拌过夜,所得反应液加入上述无色透明糖浆,室温搅拌过夜。旋蒸除去溶剂,剩余物用EA稀释,依次用饱和NaHCO3溶液和饱和NaCl溶液洗涤,收集有机相用Na2SO4干燥。硅胶柱层析(DCM:MeOH=50:1),得无色油状物1.67g,即1-O-甲基-2,3-O-异亚丙基核糖。上述所得产物溶于DCM,加入TsCl(3.1g,16.3mmol,2.0eq)和三乙胺(4mL,31mmol,3.9eq),室温搅拌,薄层色谱监测反应至原料无剩余。旋蒸除去溶剂,剩余物用EA稀释,依次用水和饱和NaCl溶液洗涤,收集有机相用Na2SO4干燥。硅胶柱层析(PE:EA=4:1),得白色固体2.05g,三步总收率25%。
13b)1-O-甲基-2,3-O-异亚丙基-5-O-亚甲基二磷酸核糖
化合物13a(413mg,1.0mmol,1.0eq)及三(四正丁基铵)亚甲基二磷酸(1.1g,1.2mmol,1.0eq),溶于3mL无水CH3CN,室温搅拌24h。旋蒸除去溶剂,剩余物用蒸馏水稀释,通过离子交换柱(Amberlyst A15,NH4 +),收集254nm显色的洗脱液。硅胶柱层析(iPrOH:H2O:aq NH3=8:1:1至6:2:2),得淡黄色泡沫状产物(NH4 +盐)312mg,产率70%。
13c)2’,3’-O-异亚丙基-5’-O-对甲苯磺酰基-2-碘腺苷
参照实施例1中的制备方法,制备2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-2-碘腺苷。2-碘腺苷在TsOH·H2O催化下与丙酮反应,形成异亚丙基保护,然后与TsCl反应得到2’,3’-O-异亚丙基-5’-O-对甲苯磺酰基-2-碘腺苷,收率为72%。
13d)2-碘腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
化合物13b(405mg,1.0mmol,1.0eq)加入3倍摩尔当量40%(w/w)的Bu4NOH溶液,冷冻干燥。所得产物再加入化合物13c(411mg,0.7mmol,0.7eq),并溶于1mL无水CH3CN,室温搅拌36h。旋蒸除去溶剂,剩余物用蒸馏水稀释,通过离子交换柱(Amberlyst A15,NH4 +),收集254nm显色的洗脱液。硅胶柱层析(iPrOH:H2O:aq NH3=16:1:1至8:1:1)。所得产物再用制备HPLC进一步纯化(H2O:CH3CN=3:1)得白色泡沫状产物(NH4 +盐)242mg,产率30%。
1H NMR(400MHz,D2O)δ8.34(s,1H),6.14(d,J=3.1Hz,1H),5.34(dd,J=5.9,3.3Hz,1H),5.15(dd,J=5.9,1.4Hz,1H),4.87(s,1H),4.58(d,J=5.7Hz,2H),4.43(d,J=5.9Hz,1H),4.18–3.91(m,3H),3.75–3.52(m,2H),3.21(s,3H),2.04(t,J=19.8Hz,2H),1.61(s,3H),1.39(s,3H),1.34(s,3H),1.19(s,3H).HRMS(ESI+):C23H35N5O13P2I[M+H]+理论值:778.0751;实测值:778.0750.
实施例14
2-溴腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例13中的制备方法,制备1-O-甲基-2,3-O-异亚丙基-5-O-二氟亚甲基二磷酸核糖,收率为70%;再与2’,3’-O-异亚丙基-5’-O-对甲苯磺酰基-2-溴腺苷反应,经纯化,得白色泡沫状产物(NH4 +盐)242mg,产率30%。
1H NMR(400MHz,D2O)δ8.29(s,1H),6.08(d,J=3.3Hz,1H),5.30(dd,J=6.0,3.4Hz,1H),5.12(dd,J=6.0,2.1Hz,1H),4.86(s,1H),4.55(dd,J=7.3,4.1Hz,2H),4.44(d,J=5.9Hz,1H),4.22–4.11(m,2H),4.08(dd,J=14.4,7.1Hz,1H),3.93–3.66(m,2H),3.20(s,3H),1.59(s,3H),1.38(s,3H),1.31(s,3H),1.16(s,3H).HRMS(ESI+):C23H33F2N5O13P2Br[M+H]+理论值:766.0702;实测值:766.0696.
实施例15
2-碘腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
参照实施例13中的制备方法,制备1-O-甲基-2,3-O-异亚丙基-5-O-二氟亚甲基二磷酸核糖;再与2’,3’-O-异亚丙基-5’-O-对甲苯磺酰基-2-碘腺苷反应,经纯化,得白色泡沫状产物(NH4 +盐)378mg,产率45%。
1H NMR(400MHz,D2O)δ8.26(s,1H),6.11(d,J=3.4Hz,1H),5.30(dd,J=6.0,3.4Hz,1H),5.12(dd,J=6.0,2.1Hz,1H),4.86(s,1H),4.53(d,J=6.2Hz,2H),4.41(d,J=5.9Hz,1H),4.25–4.10(m,2H),4.06(t,J=7.3Hz,1H),3.88–3.64(m,2H),3.20(s,3H),1.59(s,3H),1.38(s,3H),1.31(s,3H),1.16(s,3H).HRMS(ESI+):C23H33F2N5O13P2I[M+H]+理论值:814.0563;实测值:814.0566.
实施例16
16a)腺苷-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
16b)腺苷-5’-O-亚甲基二磷酸核糖
取实施例1中化合物1c(65mg,1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7。反应液用制备HPLC分离纯化(50mmol NH4HCO3:CH3CN:=20:1至1:2),反复冻干三次得白色泡沫状产物16a(NH4 +盐),产率32%。HPLC分离纯化还得到化合物16b,用制备HPLC分离纯化(50mmol TEAA:CH3CN=20:1至4:1),反复冻干三次得白色泡沫状产物16b(Et3N+盐),产率25%。
16a 1H NMR(400MHz,D2O)δ8.48(s,1H),8.14(s,1H),6.01(d,J=5.5Hz,1H),4.85(s,1H),4.66(t,J=5.5Hz,1H),4.60(d,J=6.0Hz,1H),4.45–4.41(m,2H),4.26(d,J=6.0Hz,1H),4.17–4.02(m,3H),3.68(ddd,J=24.3,14.1,7.2Hz,2H),3.18(s,3H),2.09(t,J=20.0Hz,2H),1.24(s,3H),1.11(s,3H).31P NMR(162MHz,D2O)δ17.0(m).13C NMR(101MHz,D2O)δ156.3,153.8,150.2,140.1,117.7,112.8,108.5,87.1,85.0,84.9,84.1,83.9,81.0,74.3,70.2,64.2,63.6,54.7,25.1,23.5.HRMS(ESI+):C20H32N5O13P2[M+H]+理论值:612.1472;实测值:612.1462.
16b 1H NMR(400MHz,D2O)δ8.49(s,1H),8.18(s,1H),6.06(d,J=5.6Hz,1H),5.20(5.27,d,J=4.1Hz,0.4H,5.14,d,J=2.1Hz,0.6H),4.73(s,1H,部分被重水峰覆盖),4.56–4.46(m,1H),4.32(d,J=3.1Hz,1H),4.29–4.23(m,1H),4.17–4.09(m,3H),4.05–3.88(m,3H),2.16(ddd,J=27.5,14.3,5.0Hz,2H).HRMS(ESI+):C16H26N5O13P2[M+H]+理论值:558.1001;实测值:558.1001.
实施例17
17a)2-氯腺苷-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
17b)2-氯腺苷-5’-O-亚甲基二磷酸核糖
取实施例2的化合物(72mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例16的纯化方式,得17a(NH4 +盐),产率32%和17b(Et3N+盐),产率22%。
17a 1H NMR(400MHz,D2O)δ8.41(s,1H),5.91(d,J=5.3Hz,1H),4.84(s,1H,部分被重水峰覆盖),4.64(t,J=5.2Hz,1H),4.57(d,J=6.0Hz,1H),4.44(d,J=6.0Hz,1H),.4.41(t,J=4.4Hz,1H)4.25(d,J=2.5Hz,1H),4.16–3.98(m,3H),3.72–3.58(m,2H),3.18(s,3H),2.08(t,J=19.9Hz,2H),1.26(s,3H),1.12(s,3H).HRMS(ESI+):C20H31N5O13P2Cl[M+H]+理论值:646.1082;实测值:646.1081.
17b 1H NMR(400MHz,D2O)δ8.38(s,1H),5.90(d,J=5.3Hz,1H),5.17(5.24,d,J=4.0Hz,0.4H,5.10s,0.6H),4.65(t,J=5.0Hz,1H),4.44(d,J=4.1Hz,1H),4.27(s,1H),4.22(t,J=5.2Hz,1H),4.07(s,3H),3.99–3.72(m,3H),2.11(td,J=19.9,7.7Hz,2H).HRMS(ESI+):C16H25N5O13P2Cl[M+H]+理论值:592.0613;实测值:592.0619.
实施例18
2-溴腺苷-5’-O-亚甲基二磷酸核糖
取实施例3的化合物(77mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7。反应液用制备HPLC分离纯化(50mmol TEAA:CH3CN:=20:1至4:1),反复冻干三次得白色泡沫状产物(Et3N+盐),产率39%。
1H NMR(400MHz,D2O)δ8.38(s,1H),5.93(d,J=5.4Hz,1H),5.17(5.24,d,J=4.1Hz,0.4H,5.11,d,J=2.1Hz,0.6H),4.66(t,J=5.2Hz,1H),4.45(t,J=4.5Hz,1H),4.28(d,J=3.0Hz,1H),4.23(t,J=5.2Hz,1H),4.12–4.02(m,3H),3.99–3.85(m,3H),2.11(td,J=19.8,8.3Hz,2H).HRMS(ESI+):C16H25N5O13P2[M+H]+理论值:636.0107;实测值:636.0103.
实施例19
2-甲氧基腺苷-5’-O-亚甲基二磷酸核糖
取实施例4的化合物(72mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率40%。
1H NMR(400MHz,D2O)δ8.26(s,1H),5.99(d,J=5.3Hz,1H),5.22(5.28,d,J=4.1Hz,0.4H,5.15,d,J=2.1Hz,0.6H),4.78(t,J=5.2Hz,1H),4.53(t,J=4.7Hz,1H),4.33–4.22(m,2H),4.18–4.04(m,3H),4.03–3.85(m,3H),3.93(s,3H),2.14(td,J=19.9,8.1Hz,2H).HRMS(ESI+):C17H28N5O14P2[M+H]+理论值:588.1108;实测值:588.1102.
实施例20
2-氨基腺苷-5’-O-亚甲基二磷酸核糖
取实施例5的化合物(70mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率35%。
1H NMR(400MHz,D2O)δ8.13(s,1H),5.82(d,J=5.5Hz,1H),5.20(5.26,d,J=4.1Hz,0.4H,5.13,d,J=2.1Hz,0.6H),4.62(m,2H),4.50–4.39(m,2H),4.30–3.84(m,6H),2.31–2.04(m,2H).HRMS(ESI+):C16H27N6O13P2[M+H]+理论值:573.1111;实测值:573.1132.
实施例21
6-甲氨基腺苷-5’-O-亚甲基二磷酸核糖
取实施例6的化合物(70mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率33%。
1H NMR(400MHz,D2O)δ8.38(s,1H),8.07(s,1H),5.98(d,J=5.6Hz,1H),5.17(5.23,d,J=4.1Hz,0.4H,5.11,d,J=2.0Hz,0.6H),4.68(1H,部分被重水峰覆盖),4.47–4.43(m),4.30–4.20(m,2H),4.15–3.97(m,3H),4.00–3.83(m,3H),2.96(s,3H),2.12(ddd,J=24.0,13.9,6.1Hz,2H).HRMS(ESI+):C17H28N5O13P2[M+H]+理论值:572.1159;实测值:572.1152.
实施例22
6-二甲氨基腺苷-5’-O-亚甲基二磷酸核糖
取实施例7的化合物(72mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率36%。
1H NMR(400MHz,D2O)δ8.31(s,1H),7.95(s,1H),5.95(d,J=5.5Hz,1H),5.14(5.20,d,J=4.1Hz,0.4H,5.08,d,J=2.0Hz,0.6H),4.68–4.62(m,1H),4.46–4.40(m,1H),4.27–4.17(m,2H),4.09–4.06(m,3H),3.96–3.80(m,3H),3.21(s,6H),2.10(td,J=19.9,7.8Hz,2H).HRMS(ESI+):C18H30N5O13P2[M+H]+理论值:586.1315;实测值:586.1326.
实施例23
腺苷-5’-O-二氟亚甲基二磷酸核糖
取实施例8的化合物(72mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率39%。
1H NMR(400MHz,D2O)δ8.50(s,1H),8.23(s,1H),6.20(d,J=5.9Hz,1H),5.23(5.30,d,J=4.0Hz,0.4H,5.17,d,J=2.0Hz,0.6H),4.72(1H,部分被重水峰覆盖),4.53–4.46(m,1H),4.33(s,1H),4.30–4.20(m,3H),4.20–3.92(m,4H).19F NMR(376MHz,D2O)δ-118.7(dd,J=102.3,63.1Hz).HRMS(ESI+):C16H24F2N5O13P2[M+H]+理论值:594.0814;实测值:594.0792.
实施例24
24a)2-氯腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
24b)2-氯腺苷-5’-O-二氟亚甲基二磷酸核糖
取实施例9的化合物(76mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例16的纯化方式,得白色泡沫状产物24a(NH4 +盐),产率29%和白色泡沫状产物24b(Et3N+盐),产率32%。
24a)1H NMR(400MHz,D2O)δ8.36(s,1H),5.92(d,J=5.7Hz,1H),4.86(s,1H),4.67–4.60(m,1H),4.56(d,J=6.0Hz,1H),4.46(d,J=5.9Hz,1H),4.40(dd,J=5.0,3.8Hz,1H),4.26(d,J=1.7Hz,1H),4.23–4.16(m,2H),4.10(t,J=7.3Hz,1H),3.93–3.72(m,2H),3.19(s,3H),1.27(s,3H),1.13(s,3H).HRMS(ESI+):C20H29F2N5O13P2Cl[M+H]+理论值:682.0894;实测值:682.0886.
24b)1H NMR(400MHz,D2O)δ8.41(s,1H),5.97(d,J=5.7Hz,1H),5.22(5.29,d,J=4.1Hz,0.4H,5.14,d,J=2.2Hz,0.6H),4.65(t,J=5.4Hz,1H),4.50–4.43(m,1H),4.31(d,J=2.4Hz,1H),4.28–4.20(m,3H),4.19–3.89(m,4H).HRMS(ESI+):C16H23F2N5O13P2Cl[M+H]+理论值:628.0424;实测值:628.0441.
实施例25
2-甲氧腺苷-5’-O-二氟亚甲基二磷酸核糖
取实施例10的化合物(76mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率35%。
1H NMR(400MHz,D2O)δ8.17(s,1H),5.95(d,J=5.7Hz,1H),5.19,(5.26,d,J=4.1Hz,0.4H,5.12,d,J=2.0Hz,0.6H),4.79–4.73(m,1H),4.47(dd,J=8.8,4.7Hz,1H),4.29–4.15(m,4H),4.13–3.89(m,4H),3.84(s,3H).HRMS(ESI+):C17H26F2N5O14P2[M+H]+理论值:624.0920;实测值:624.0937.
实施例26
2-氨基腺苷-5’-O-二氟亚甲基二磷酸核糖
取实施例11的化合物(73mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率39%。
1H NMR(400MHz,D2O)δ8.18(s,1H),5.90(d,J=6.1Hz,1H),5.24(5.31,d,J=4.2Hz,0.4H,5.16,d,J=2.3Hz,0.6H),4.65(1H,部分被重水峰覆盖),4.53–4.44(m,1H),4.29(d,J=6.3Hz,1H),4.26(d,J=4.4Hz,3H),4.20–3.96(m,4H).HRMS(ESI+):C16H25F2N6O13P2[M+H]+理论值:609.0923;实测值:609.0928.
实施例27
2-氯腺苷-5’-O-焦磷酸核糖
取实施例12的化合物(70mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率33%。
1H NMR(400MHz,D2O)δ8.34(d,J=3.6Hz,1H),5.92(d,J=5.7Hz,1H),5.18(5.25,d,J=4.1Hz,0.4H,5.12,d,J=1.9Hz,0.6H),4.64(t,J=5.2Hz,1H),4.44(t,J=4.2Hz,1H),4.30(s,1H),4.21(t,J=5.2Hz,1H),4.13(d,J=3.1Hz,2H),3.99(m,4H).HRMS(ESI+):C15H23N5O14P2Cl[M+H]+理论值:594.0405;实测值:594.0406.
实施例28
2-碘腺苷-5’-O-亚甲基二磷酸核糖
取实施例13的化合物(81mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例18的纯化方式,得白色泡沫状产物(Et3N+盐),产率39%。
1H NMR(400MHz,D2O)δ8.34(s,1H),5.95(d,J=5.3Hz,1H),5.18(5.25,d,J=4.0Hz,0.4H,5.11,d,J=2.0Hz,0.6H),4.67(d,J=5.3Hz,1H),4.46(t,J=4.5Hz,1H),4.32–4.26(m,1H),4.24(t,J=5.3Hz,1H),4.15–4.02(m,3H),4.01–3.84(m,3H),2.12(td,J=19.9,8.4Hz,2H).HRMS(ESI+):C16H25N5O13P2I[M+H]+理论值:683.9969;实测值:683.9969.
实施例29
29a)2-溴腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
29b)2-溴腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基核糖
29c)2-溴腺苷-5’-O-二氟亚甲基二磷酸核糖
取实施例14的化合物(80mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7。反应液用制备HPLC分离纯化(50mmol NH4HCO3:CH3CN:=20:1至1:2),得化合物29a和29b,反复冻干三次得白色泡沫状产物29a(NH4 +盐),产率33%,白色泡沫状产物29b(NH4 +盐),产率28%。HPLC分离纯化还得到化合物29c,进一步用制备HPLC分离纯化(50mmolTEAA:CH3CN:=20:1至1:4),反复冻干三次得白色泡沫状产物29c(Et3N+盐),产率24%。
29a 1H NMR(400MHz,D2O)δ8.37(s,1H),5.94(d,J=5.6Hz,1H),4.88(s,1H),4.69–4.61(t,J=5.2Hz,1H),4.57(d,J=6.0Hz,1H),4.47(d,J=5.9Hz,1H),4.42(dd,J=5.0,3.8Hz,1H),4.28(d,J=1.8Hz,1H),4.22(d,J=4.5Hz,2H),4.11(t,J=7.3Hz,1H),3.90–3.73(m,2H),3.21(s,3H),1.29(s,3H),1.14(s,3H).HRMS(ESI+):C20H29F2N5O13P2Br[M+H]+理论值:726.0389;实测值:726.0404.
29b 1H NMR(400MHz,D2O)δ8.30(s,1H),5.89(d,J=5.4Hz,1H),4.74(1H,部分被重水峰覆盖),4.58(t,J=5.2Hz,1H),4.43–4.34(m,1H),4.24(d,J=2.9Hz,1H),4.18(s,2H),4.11(dd,J=6.1,5.0Hz,1H),4.07–3.87(m,4H),3.23(s,3H).19F NMR(376MHz,D2O)δ-118.7(t,J=82.4Hz).HRMS(ESI+):C17H25F2N5O13P2Br[M+H]+:686.0076;实测值:686.0051.
29c 1H NMR(400MHz,D2O)δ8.27(s,1H),5.88(d,J=5.3Hz,1H),5.16(5.23,s,0.4H,5.09,s,0.6H),4.57(t,J=5.2Hz,1H),4.44–4.34(m,1H),4.23(d,J=3.1Hz,1H),4.17(s,3H),4.12–3.83(m,4H,).HRMS(ESI+):C16H23F2N5O13P2Br[M+H]+理论值:671.9919;实测值:671.9941.
实施例30
30a)2-碘腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖
30b)2-碘腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基核糖
30c)2-碘腺苷-5’-O-二氟亚甲基二磷酸核糖
取实施例15的化合物(85mg,0.1mmol)溶于1mL的0.8M HCl,冰浴下搅拌8h。用稀氨水调节pH=7,参照实施例29的纯化方式,得白色泡沫状产物30a(NH4 +盐),产率29%,白色泡沫状产物30b(NH4 +盐),产率30%,白色泡沫状产物30c(Et3N+盐),产率25%。
30a 1H NMR(400MHz,D2O)δ8.27(s,1H),5.91(d,J=5.4Hz,1H),4.84(s,1H),4.61(t,J=5.2Hz,1H),4.52(d,J=6.0Hz,1H),4.44–4.36(m,2H),4.25(d,J=2.2Hz,1H),4.21–4.18(m,2H),4.08(t,J=7.3Hz,1H),3.86–3.69(m,2H),3.18(s,3H,CH3),1.26(s,3H),1.11(s,3H).HRMS(ESI+):C20H29F2N5O13P2I[M+H]+理论值:774.0250;实测值:774.0237.
30b 1H NMR(400MHz,D2O)δ8.21(s,1H),5.87(d,J=5.1Hz,1H),4.70(1H,部分被重水峰覆盖),4.54(t,J=5.1Hz,1H),4.42–4.32(m,1H),4.21(d,J=3.3Hz,1H),4.19–4.05(m,3H),4.05–3.84(m,4H),3.20(s,3H).19F NMR(376MHz,D2O)δ-118.8(t,J=82.2Hz).HRMS(ESI+):C17H25F2N5O13P2I[M+H]+理论值:733.9937;实测值:733.9949.
30c 1H NMR(400MHz,D2O)δ8.25(s,1H),5.90(d,J=5.3Hz,1H),5.12(5.23,s,0.4H,5.09,s,0.6H),4.57(t,J=5.2Hz,1H),4.42–4.37(m,1H),4.24(d,J=3.1Hz,1H),4.18(s,2H),4.11–3.81(m,5H).HRMS(ESI+):C16H23F2N5O13P2I[M+H]+理论值:719.9780;实测值:719.9762.
试验例
本发明的ADPR结构类似物对TRPM2通道的选择性抑制作用,其他TRP通道包括TRPM7,TRPM8,TRPV1,TRPV3。药理活性测定使用了全细胞膜片钳技术(Whole-cell patch),其相应的步骤如下。
1.细胞准备
过表达TRPM2通道的细胞系。四环素(1μg/ml)诱导稳定表达人源TRPM2的HEK293细胞系12~36h后,用含有10%牛血清,50units/mL青霉素,50mg/mL链霉素的DMEM/F-12(Gibco)培养基,在5%CO2及37℃条件下进行孵育。
其他过表达TRP通道的细胞系。测试的24~48h前,人源TRPM7、TRPM8、TRPV1和TRPV3的质粒利用Lipofectamine 2000瞬时转入HEK293T细胞,并用含有10%牛血清,100units/mL青霉素,100mg/mL链霉素的DMEM(Gibco)的培养基,在5%CO2及37℃条件下进行孵育。
2.电生理测试
测试前的细胞保存于细胞外液(in mM,147NaCl,2KCl,1MgCl2,2CaCl2,10HEPES,and 13glucose,pH 7.4)。电极在充满电极内液(in mM,147NaCl,0.05EGTA,1MgCl2,10HEPES,and 0.5ADPR,pH=7.3)后电阻保持在3~5MΩ。
1)化合物TRPM2抑制活性测试
将待测化合物(实施例9制备的产物)加入细胞外液或者细胞内液,使其最终浓度为100μM。测试用于激活TRPM2的ADPR浓度为100μM。
首先进行化合物胞外抑制活性测试。通过电极向细胞内给予ADPR,并检测到平稳电流。此时在细胞外给予待测化合物(100μM)灌流,时间至少为60s,记录电流大小的变化,记录方式为电压斜坡模式记录(RAMP),500ms时间内电压从-100mV变化到+100mV,正常钳制电压为0mV,每5s为一个ramp。最后,将细胞外液置换为pH=5.0的溶液,阻断电流。
然后进行化合物细胞内抑制活性测试。通过电极向细胞内同时给ADPR(100μM)和待测化合物(100μM),记录电流大小的变化,记录方式为电压斜坡模式记录(RAMP),500ms时间内电压从-100mV变化到+100mV,正常钳制电压为0mV,每5s为一个ramp。最后,将细胞外液置换为pH=5.0的溶液,阻断电流。
2)化合物TRP通道选择性测试
选择性测试方法与活性测试方法类似,将待测化合物(实施例9制备的产物)加入细胞内液,使其最终浓度为100μM,测试其在细胞内对TRP通道的抑制活性。
测试待测化合物的TRPM7抑制活性,将细胞置于细胞外液(in mM,145NaCl,2CaCl2,1MgCl2,5KCl,10D-glucose,10HEPES),并通过电极向细胞给予待测化合物(100μM)。然后向细胞外液加入Ca2+和Mg2+,最终浓度均为100μM,记录电流大小的变化。最后,向细胞外液加入最终浓度为2mM的Ca2+和1mM的Mg2+阻断电流。
测试待测化合物的TRPM8抑制活性,将细胞置于细胞外液(in mM,130NaCl,5KCl,10D-glucose,10HEPES,1.2MgCl2and 1.5CaCl2),并通过电极向细胞给予待测化合物(100μM)。然后向细胞外液加入薄荷醇,最终浓度为1mM,记录电流大小的变化。最后,向细胞外液加入最终浓度为100μM的2-APB阻断电流。
测试待测化合物的TRPV1抑制活性,将细胞置于细胞外液(in mM,130NaCl,5KCl,10D-glucose,10HEPES,1.2MgCl2and 1.5CaCl2),并通过电极向细胞给予待测化合物(100μM)。然后向细胞外液加入辣椒素,最终浓度为10μM,记录电流大小的变化。最后,向细胞外液加入最终浓度为100μM的钌红阻断电流。
测试待测化合物的TRPV3抑制活性,将细胞置于细胞外液(130mM NaCl,0.2mMEDTA),并通过电极向细胞给予待测化合物(100μM)。然后向细胞外液加入2-APB,最终浓度为100μM。最后,将细胞外液的2-APB洗脱阻断电流。
3.活性结果
活性结果如下表所示:
这两个化合物在100μM浓度下对TRPM7,TRPM8,TRPV1和TRPV3均没有抑制活性,因此本发明的ADPR结构类似物对TRPM2通道具有选择性抑制活性。
Claims (6)
1.下列化合物或其药学上可接受的盐:
腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氯腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-溴腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-甲氧基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氨基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
6-甲氨基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-异亚丙基核糖;
6-二甲氨基腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-异亚丙基核糖;
腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氯腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-甲氧基腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氨基腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氯腺苷-2’,3’-O-异亚丙基-5’-O-焦磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-碘腺苷-2’,3’-O-异亚丙基-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-溴腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-碘腺苷-2’,3’-O-异亚丙基-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
腺苷-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氯腺苷-5’-O-亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氯腺苷-5’-O-亚甲基二磷酸核糖;
2-溴腺苷-5’-O-亚甲基二磷酸核糖;
2-甲氧基腺苷-5’-O-亚甲基二磷酸核糖;
2-氨基腺苷-5’-O-亚甲基二磷酸核糖;
6-甲氨基腺苷-5’-O-亚甲基二磷酸核糖;
6-二甲氨基腺苷-5’-O-亚甲基二磷酸核糖;
腺苷-5’-O-二氟亚甲基二磷酸核糖;
2-氯腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-氯腺苷-5’-O-二氟亚甲基二磷酸核糖;
2-甲氧腺苷-5’-O-二氟亚甲基二磷酸核糖;
2-氨基腺苷-5’-O-二氟亚甲基二磷酸核糖;
2-氯腺苷-5’-O-焦磷酸核糖;
2-碘腺苷-5’-O-亚甲基二磷酸核糖;
2-溴腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-溴腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基核糖;
2-溴腺苷-5’-O-二氟亚甲基二磷酸核糖;
2-碘腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基-2”,3”-O-异亚丙基核糖;
2-碘腺苷-5’-O-二氟亚甲基二磷酸-1”-O-甲基核糖;或
2-碘腺苷-5’-O-二氟亚甲基二磷酸核糖。
2.如权利要求1所述的化合物或其药学上可接受的盐,其中,所述的盐选自季铵盐或铵盐,所述季铵盐为(CH3CH2)3N+的盐。
5.包含权利要求1至4中任一项所述的化合物或其药学上可接受的盐的药物组合物。
6.权利要求1至4中任一项所述的化合物或其药学上可接受的盐、或者权利要求5所述的药物组合物在制备作为TRPM2抑制剂药物中的用途。
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Chemical evidence in favor of a stabilized oxocarbonium-ion intermediate in the NAD+ glycohydrolase-catalyzed reactions;Tarnus, Celine,et al.;《Bioorganic Chemistry》;19881231;第38-51页 * |
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