CN117736133A - 吡咯磺酰类衍生物、其制备方法及其在医药上的应用 - Google Patents
吡咯磺酰类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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- CN117736133A CN117736133A CN202211109407.9A CN202211109407A CN117736133A CN 117736133 A CN117736133 A CN 117736133A CN 202211109407 A CN202211109407 A CN 202211109407A CN 117736133 A CN117736133 A CN 117736133A
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- hydrogen
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Abstract
本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及在医药上的应用。具体而言,本发明涉及一种通式(I)所示的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合以及作为治疗剂,特别是作为胃酸分泌抑制剂的用途,其通式(I)的各取代基与说明书中的定义相同。
Description
技术领域
本发明涉及一类新的吡咯磺酰类衍生物、其制备方法及含有该衍生物的药物组合以及其作为治疗剂特别是作为胃酸分泌抑制剂和钾离子竞争性酸阻滞剂(P-CABs)的用途。
背景技术
自1988年以来,以奥美拉唑为代表的质子泵抑制剂通过抑制胃酸分泌以治疗消化性溃疡、反流性食管炎和卓-艾综合症等在临床上得到广泛应用。长期的临床应用发现,现有质子泵抑制剂在药代动力学、药效学方面还有局限性。如:给药时间对药效的影响;夜间酸突破起效慢;酸性条件下不稳定(需要配制成肠制剂);对CYP450酶的依赖性(导致个体差异显著)等。
钾竞争性酸阻滞剂(Potassium-Competitive Acid Blockers,P-CABs)通过直接、可逆性的过程竞争性地抑制H+/K+-ATP酶中的K+而产生作用。与传统质子泵抑制剂相比,P-CABs具有亲脂性、弱碱性、解离常数高和在低pH条件下稳定的特点。在酸性环境下,P-CABs以离子化形式与H+/K+-ATP酶结合,阻止H+运送及酸分泌到胃腔中,迅速升高胃中pH值。动物实验和临床研究表明:P-CABs具备起效迅速,在1小时内就能达到最大治疗效果;血药浓度与口服给药剂量线性相关,比较容易达到最佳抑酸效果的优势。
化合物H008,化学名称为1-[5-(2-氟-苯基)-1-{[3-(3-甲氧基丙氧基)苯基]磺酰基}-1H-吡咯-3-基]-N-甲基甲胺,是一种钾离子竞争性酸阻滞剂(P-CABs)。具有用于预防和治疗胃酸相关性疾病,所述疾病包括(但不限于)胃肠道疾病例如消化性溃疡、卓-艾综合症、胃炎、胃溃疡、十二指肠溃疡、非甾体抗炎药引起的溃疡、幽门螺旋杆菌感染、胃食管反流疾病、反流性食管炎等。H008结构如下:
氘代药物是指将药物分子中的部分氢原子替换为氘。由于生物系统的代谢过程复杂,药物在生物体内的药代动力学性质受到多方面因素影响。与相应的非氘代药物相比,氘代药物药代动力学性质的变化表现出极大的偶然性和不可预测性。
尽管目前已公开了一系列钾竞争性酸阻滞剂,但仍需要开发具有对胃酸分泌抑制更好活性、更好的药效学、或更好的药代动力学的化合物。
发明内容
本发明目的在于提供一种新型的具有胃酸分泌抑制更好活性或药效的化合物,及其制备方法,组合物和用途。
本发明第一方面提供一种式(I)所示的化合物或其药学可接受的盐:
其特征在于,式(I)中R1、R2、R3、R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24各自独立地为氢或氘,条件是式(I)化合物含有至少一个为氘。
在一些实施方案中,所述式(I)所示的化合物或其药学可接受的盐,其中R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24各自独立地为氢或氘,条件是R4至R24中至少有一个为氘;R1、R2、R3各自独立地为氢或氘。所述至少有一个为氘,可以R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24中的任选一个、两个、三个、四个、五个、六个、七个、八个、九个、十个、十一个、十二个、十三个、十四个、十五个、十六个、十七个、十八个、十九个、二十个、二十一个为氘。
在一些实施方案中,所述式(I)所示的化合物或其药学可接受的盐,其中R8、R9、R20、R21、R22、R23、R24各自独立地为氢或氘,条件是R8、R9、R20、R21、R22、R23、R24至少有一个为氘;R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19为氢或氘。所述至少有一个为氘,R8、R9、R20、R21、R22、R23、R24中的任选一个、两个、三个、四个、五个、六个、七个为氘。
在一些实施方案中,所述式(I)所示的化合物具有式(II)所示的结构,
其中,Ra选自CH2D、CHD2、CD3;Rb选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地为氢或氘。
在一些实施方案中,Ra为CD3。
在一些实施方案中,Rb为CD3。
在一些实施方案中,Ra和Rb为CD3。
在一些实施方案中,Ra为CD3;R8、R9选自氢或氘。
在一些实施方案中,Ra为CD3;R8、R9同时为氢。
在一些实施方案中,Ra为CD3;R8、R9同时为氘。
在一些实施方案中,Ra为CD3;R20、R21选自氢或氘。
在一些实施方案中,Ra为CD3;R20、R21同时为氢。
在一些实施方案中,Ra为CD3;R20、R21同时为氘。
在一些实施方案中,R20、R21各自独立地为氢或氘,条件是R20、R21至少有一个为氘;Ra、Rb各自独立选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19各自独立地为氢或氘。
在一些实施方案中,R20、R21同时为氘,Ra、Rb各自独立选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19各自独立地为氢或氘。
在一些实施方案中,R8、R9各自独立地为氢或氘,条件是R8、R9至少有一个为氘;Ra、Rb各自独立选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地为氢或氘。
在一些实施方案中,R8、R9同时为氘,Ra、Rb各自独立选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地为氢或氘。
在另一优选实施方案中,氘在氘取代位置的氘同位素含量至少是大于天然氘同位素含(0.015%),优选为大于30%,更优选为大于50%,更优选为大于75%,更优选为大于95%,更优选为大于99%。
根据本发明的化合物或其药学可接受的盐,选自如下化合物或其药学可接受的盐:
本发明第二方面是提供一种药物组合物,包含本发明式(I)所示的化合物或其药学上可接受的盐。
在一些实施方案中,所述药物组合物包含以本发明式(I)所示的化合物或其药学上可接受的盐及药学上可接受的载体。在一些实施方案中,所述药物组合物,本发明所述式(I)所示的化合物或其药学上可接受的盐以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明第三方面是提供如式(I)所示的化合物或其药学上可接受的盐或含有如式(I)所示的化合物或其药学上可接受的盐的药物组合物在作为胃酸分泌抑制剂中的用途。
在一些实施方案中,所述胃酸分泌抑制剂具体为钾竞争性胃酸阻滞剂。
式(I)所示的化合物或其药学上可接受的盐或含有如式(I)所示的化合物或其药学上可接受的盐的药物组合物在制备治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途;或者在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的用途。
所述的消化性溃疡包括胃溃疡、十二指肠溃疡或吻合口溃疡;所述的症状性胃食管反流疾病包括非糜烂性的反流性疾病或无食管炎的胃食管反流疾病。
发明的详细说明
除非有相反陈述,下列用在说明书和权利要求中的术语具有下述含义。氘在氘取代位置的氘同位素含量是大于天然氘同位素含量(0.015%),可以是大于50%,大于75%,大于95%,大于97%,大于99%,大于99.5%。结构式中所述D为氘。
本文中,任何未指定为氘的各原子以其天然同位素丰度存在。
术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐为本发明化合物与无机酸或有机酸的反应而得,无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸、高氯酸等;有机酸包括乙酸、丙酸、丙烯酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、丁二酸、枸橼酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、扁桃酸、琥珀酸或丙二酸等。
“药物组合物”指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分,例如药学上可接受的载体,混合。药物组合物的目的是促进给药给动物的过程。
“药学上可接受的载体”指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分,包括但不限于任何助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
本申请通过对H008化合物进行氘代,得到的化合物具备良好的抑制胃酸分泌作用,并且体外肝微粒体稳定性良好。
具体实施方式
下面更具体地描述本发明式(I)结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易的进行。
以下结合实施例用于进一步描述本发明,但这些实施例并非限制着本发明的范围。
实施例1:
N-((5-(2-氟苯基)-1-((3-(3-(甲氧基-1-1-二氘代)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 1)的制备
步骤1:3-甲氧基-1,1-二氘代丙醇(化合物2)的制备
在0℃下,将LiAlD4(533mg,12.69mmol)分批加入到3-甲氧基丙酸甲酯(1.00g,8.46mmol)的四氢呋喃(10mL)溶液中。添加完成后,将所得混合物升至室温反应2小时终止。反应混合物在0~5℃下缓慢地依次用水(0.5mL)、15%NaOH(0.5mL)和水(1.5mL)淬灭。混合物用乙酸乙酯(60mL)稀释并加入Na2SO4(10.00g)。将混合物在室温搅拌0.5小时并过滤,将滤液浓缩至干,得到产物3-甲氧基-1,1-二氘代丙醇。
步骤2:3-甲氧基丙基-1,1-二氘代-4-甲基苯磺酸酯(化合物3)的制备
室温下,将4-甲基苯磺酰氯(0.93g,3.26mmol)加入到3-甲氧基-1,1-二氘代丙醇(化合物2,0.30g,3.25mmol)、三乙胺(0.99g,9.77mmol)和DMAP(0.04g,0.33mmol)的二氯甲烷(6mL)溶液中,搅拌16小时终止。混合物用己烷(20mL)稀释并过滤,滤液真空浓缩,残余物通过硅胶柱层析色谱法纯化(洗脱液:PE/EtOAc=9/1),得到产物3-甲氧基丙基-1,1-二氘代4-甲基苯磺酸酯。
1H NMR(400MHz,DMSO)δ7.79(d,J=8.0Hz,2H),7.49(d,J=8.0Hz,2H),3.27(t,J=6.0Hz,2H),3.12(s,3H),2.43(s,3H),1.77(t,J=6.0Hz,2H)。
步骤3:3-(苄氧基)苯磺酸钠(化合物5)的制备
室温下,将3-氨基苯磺酸(10.00g,0.06mol)加入到含有水(100ml)和碳酸钠(2.45g,0.02mol)的溶液中。40℃搅拌至溶液澄清,降温至5℃加入浓HCl(20.00g,0.14mol)和NaNO2(3.98g,0.06mol)溶液(5mL),搅拌2小时。升温至105℃回流8小时终止。减压蒸除溶剂,搅拌下向残余物中加入异丙醇,过滤。滤液减压蒸除异丙醇。将残余物溶解在100mL的水中,加入15%NaOH水溶液调节pH至碱性,缓慢加入苄溴(7.60g,0.04mol)室温反应3小时终止。过滤,浓缩,干燥。得到产物3-(苄氧基)苯磺酸钠。
1H NMR(400MHz,DMSO d6)δ7.52–7.14(m,9H),5.10(s,2H)。
步骤4:3-(苄氧基)苯磺酰氯(化合物6)的制备
将3-(苄氧基)-苯磺酸钠(化合物5,2.79g,0.01mol)加入到N-N-二甲基甲酰胺(0.3mL)和氯化亚砜(25.39g,0.21mol)的混合液中,0-5℃反应15分钟后加热至65℃反应5小时终止。减压浓缩,冰水淬灭。二氯甲烷萃取,合并,干燥,浓缩。残余物使用庚烷打浆,过滤,滤饼干燥得到产物3-(苄氧基)苯磺酰氯。
步骤5:1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛(化合物8)的制备
将t-BuOK(7.11g,0.06mol)添加到5-(2-氟苯)-1H-吡咯-3-甲醛(6.00g,0.03mol)的无水四氢呋喃(180mL)中,并在0℃下反应0.5小时后加入15-crown-5(6.98g,0.03mol)和3-(苄氧基)苯磺酰氯(化合物6,17.90g,0.06mol),室温反应2小时终止。冰水淬灭,乙酸乙酯萃取,合并,干燥,浓缩有机相,粗品通过硅胶柱层析色谱法纯化(洗脱液:PE/EA=8/1),得到产物1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛。
1H NMR(400MHz,DMSO)δ9.86(s,1H),8.56(d,J=1.6Hz,1H),7.57-7.52(m,1H),7.50(t,J=6.0Hz,1H),7.44-7.39(m,5H),7.38–7.34(m,1H),7.27–7.17(m,2H),7.13–7.06(m,2H),7.06–7.02(m,1H),6.67(s,1H),5.09(s,2H)。
步骤6:N-((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)三氘代甲胺(化合物9)的制备
室温下,将1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛(化合物8,0.30g,0.68mmol)加入到三氘代甲胺盐酸盐(0.15g,2.06mmol)的二氯乙烷(10mL)溶液中。室温反应1小时。加入醋酸(0.12g,2.06mmol)和三乙酰氧基硼氢化钠(0.44g,2.06mmol),0℃反应3小时终止。冰水淬灭,乙酸乙酯萃取,合并,浓缩,干燥有机相,粗产物通过硅胶柱层析色谱法纯化(洗脱液:DCM/MeOH=20/1),得到产物N-((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)三氘代甲胺。
1H NMR(400MHz,DMSO)δ9.18(s,1H),7.80(d,J=2.0Hz,1H),7.57–7.50(m,1H),7.48(d,J=8.0Hz,1H),7.46–7.41(m,3H),7.40–7.33(m,2H),7.28–7.18(m,2H),7.10–7.04(m,2H),6.99–6.96(m,1H),6.54(s,1H),5.09(s,2H),3.97(s,2H)。
步骤7:叔丁基((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯(化合物10)的制备
室温下,将Boc2O酸酐(0.96g,4.0mmol)和三乙胺(0.33g,3.0mmol)加入到N-((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)三氘代甲胺(化合物9,1.0g,2.00mmol)的二氯甲烷(20mL)溶液中,室温反应2小时终止。浓缩残余物,通过硅胶柱层析色谱法纯化(洗脱液:PE/EA=7/1),得到产物叔丁基((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯。
LCMS(ESI)calcd for C30H28D3FN2O5S[M+Na]+m/z 576.2,found 576.1。
步骤8:叔丁基(((5-(2-氟苯基)-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯(化合物11)的制备
室温下,将叔丁基((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯(化合物10,0.88g,1.60mmol)加入到Pd/C(0.85g,8.00mmol)的MeOH(40mL)溶液中。H2氛围下室温反应2小时终止。反应液经硅藻土过滤,滤液浓缩,所得粗产物通过硅胶柱层析色谱法(洗脱液:DCM/MeOH=10/1)纯化,得到产物叔丁基(((5-(2-氟苯基)-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯。
LCMS(ESI)calcd for C23H22D3FN2O5S[M+Na]+m/z 486.1,found 486.0。
步骤9:叔丁基(((5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯(化合物12)的制备
室温下,将3-甲氧基丙基4-甲基苯磺酸酯(化合物3,0.09g,0.35mmol)加入到叔丁基(((5-(2-氟苯基)-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯(化合物11,0.11g,0.23mmol),碳酸钾(0.07g,0.47mmol)和碘化钾(0.04g,0.23mmol)的DMF(3mL)溶液中,升温至60℃反应16小时终止。反应液水洗,干燥,浓缩,所得粗品经硅胶柱层析色谱法(洗脱液:PE/EA=3:1),得到产物叔丁基(((5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯。
LCMS(ESI)calcd for C27H28D5FN2O6S[M+Na]+m/z 560.1,found 560.1。
步骤10:N-((5-(2-氟苯基)-1-((3-(3-(甲氧基-1-1-二氘代)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP1)的制备
室温下,将HCl/EtOAc(4.0M,,2mL,8mmol)加入到叔丁基(((5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)(三氘代甲基)氨基甲酸酯(化合物12,0.10g,0.18mmol)的EtOAc(2mL)溶液中,室温反应2小时终止。浓缩,得到产物N-((5-(2-氟苯基)-1-((3-(3-(甲氧基-1-1-二氘代)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 1)。
LCMS(ESI)calcd for C22H20D5FN2O4S[M+H]+m/z 438,found 438.10。
1H NMR(400MHz,DMSO)δ9.20(s,2H),7.81(s,1H),7.59–7.43(m,2H),7.28(dd,J=8.4,2.0Hz,1H),7.23(dd,J=16.0,8.4Hz,2H),7.08(t,J=7.2Hz,2H),6.84(d,J=1.6Hz,1H),6.55(s,1H),3.97(s,2H),3.46(t,J=6.0Hz,2H),3.27(d,J=1.2Hz,3H),1.92(t,J=6.0Hz,2H)。
实施例2:N-(5-(2-氟苯基)-1-(3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 2)的制备
参照实施例1的制备方法,得到产物N-(5-(2-氟苯基)-1-(3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 2)。
LCMS(ESI)calcd for C22H22D3FN2O4S[M+H]+m/z 436.2,found 436.2。
1H NMR(400MHz,DMSO-d6)δ9.01(s,2H),7.79(d,J=1.6Hz,1H),7.57–7.50(m,1H),7.47(t,J=8.0Hz,1H),7.29(dd,J=8.0,2.4Hz,1H),7.26–7.19(m,2H),7.12–7.04(m,2H),6.83(t,J=2.0Hz,1H),6.52(d,J=1.8Hz,1H),4.05–3.91(m,2H),3.46(t,J=6.4Hz,1H),3.27(s,2H),1.93(p,J=6.4Hz,1H)。
实施例3:N-((5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 3)的制备
参照实施例1的制备方法,得到产物N-((5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 3)。
LCMS(ESI)calcd for C22H19D6FN2O4S[M+H]+m/z 438.19,found 439.00。
1H NMR(400MHz,DMSO-d6)δ7.54–7.42(m,3H),7.30–7.16(m,3H),7.12–7.08(m,1H),7.06–7.02(m,1H),6.87–6.77(t,1H),6.32(d,J=1.6Hz,1H),3.96(t,J=6.4Hz,2H),3.51(s,2H),3.45(t,J=6.4Hz,2H),1.92(p,J=6.4Hz,2H)。
实施例4:N-((5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 4)的制备
参照实施例1的制备方法,得到产物N-((5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)三氘代甲胺(EXP 4)。
LCMS(ESI)calcd for C22H17D8FN2O4S[M+H]+m/z 440.2,found 441.0。
1H NMR(400MHz,Chloroform-d)δ7.47(d,J=1.6Hz,1H),7.33-7.39(m,1H),7.23-7.27(m,1H),7.19–7.09(m,2H),7.07–6.97(m,3H),6.88(t,J=2.0Hz,1H),6.36(d,J=1.6Hz,1H),3.75(s,2H),3.52(t,J=6.0Hz,2H),1.99(t,J=6.0Hz,2H)。
实施例5:1-(5-(2-氟苯基)-1-(3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 5)的制备
步骤1:3-(三氘代甲氧基)丙基-1,1-二氘代-4-甲苯磺酸酯(化合物17)的制备
参照化合物3的制备方法得化合物3-(三氘代甲氧基)丙基-1,1-二氘代-4-甲苯磺酸酯(化合物17)。
1H NMR(400MHz,DMSO-d6)δ7.84–7.78(m,2H),7.39–7.34(m,2H),3.40(t,J=6.0Hz,2H),2.47(s,3H),1.90(t,J=6.0Hz,2H)。
步骤2:1-(1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯烷-3-基)-N-甲基甲胺(化合物13)的制备
室温下,将1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-甲醛(化合物8,0.40g,0.92mmol)加入到甲胺甲醇溶液(~30%质量分数;0.29g,2.75mmol)的甲醇(10mL)溶液中,氮气保护下,室温反应1小时。0℃下加入AcOH(0.17g,2.75mmol)和三乙酰氧基硼氢化钠(0.78g,3.67mmol)反应3小时终止。冰水淬灭,乙酸乙酯萃取。合并,干燥,浓缩有机相,粗品通过硅胶柱层析色谱法纯化(洗脱液:DCM/MeOH=20/1),得到产物1-(1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺。
LCMS(ESI)calcd for C25H23FN2O3S[M+H]+m/z 451,found 451.1。
步骤3:叔丁基((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸酯(化合物14)的制备
室温下,将Boc2O酸酐(0.22g,1.00mmol)和TEA(0.08g,0.70mmol)加入到1-(1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)-N-甲基甲胺(化合物13,0.23g,0.5mmol)的二氯甲烷(4mL)溶液中。室温反应2小时终止。浓缩反应液,残余物通过硅胶柱层析色谱法纯化(洗脱液:PE/EA=7:1),得到产物((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯。
LCMS(ESI)calcd for C30H31FN2O5S[M+Na]+m/z 573.1,found 573.2。
步骤4:制备中间体((5-(2-氟苯基)-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(化合物15)
室温下,将化合物((1-((3-(苄氧基)苯基)磺酰基)-5-(2-氟苯基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(化合物14,0.35g,0.63mmol)和Pd/C(0.34g,3.17mmol)溶入到甲醇(8mL)溶液中,在H2下室温反应2小时终止。过滤,滤液浓缩,粗产物通过硅胶柱层析色谱法(洗脱液:DCM/MeOH=10:1)纯化,得到产物((5-(2-氟苯基)-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯。
1H NMR(400MHz,DMSO)δ7.59–7.48(m,2H),7.47–7.45(m,2H),7.38–7.36(m,1H),7.25–7.10(m,4H),6.27(s,1H),4.17(s,2H),2.72(s,3H),1.51(s,9H)。
步骤5:((5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(化合物16)的制备
室温下,将3-(三氘代甲氧基)丙基-1,1-二氘代-4-甲苯磺酸酯(化合物17,0.05g,0.20mmol)加入到((5-(2-氟苯基)-1-((3-羟基苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(化合物15,0.08g,0.16mmol)、碳酸钾(0.05g,0.32mmol)和碘化钾(0.03g,0.16mmol)的N-N二甲基甲酰胺(2mL)溶液中,55℃下反应16小时终止,加水稀释,用乙酸乙酯萃取。合并,干燥,浓缩有机相,粗品经硅胶柱层析(洗脱液:PE/EA=3/1)纯化,得产物((5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯。
LCMS(ESI)calcd for C27H28D5FN2O6S[M+H]+m/z 538,found 538.20.
步骤6:1-(5-(2-氟苯基)-1-(3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 5)的制备
室温下,将TFA(0.5ml)加入到((5-(2-氟苯基)-1-((3-(3-(甲氧基-d3)丙氧基-1,1-d2)苯基)磺酰基)-1H-吡咯-3-基)甲基)(甲基)氨基甲酸叔丁酯(化合物16,0.06g,0.11mmol)的二氯甲烷(2mL)溶液中,室温反应1小时终止。加水稀释,饱和碳酸氢钠水溶液调pH至8~9,二氯甲烷萃取。合并,干燥,浓缩有机相,粗产物通过硅胶制备板(洗脱液:DCM/MeOH=15/1)纯化,得到产物1-(5-(2-氟苯基)-1-(3-(3-(三氘代甲氧基)丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 5)。
LCMS(ESI)calcd for C22H20D5FN2O4S[M+H]+m/z 438,found 438.10.
1H NMR(400MHz,DMSO-d6)δ7.53–7.42(m,3H),7.26–7.18(m,3H),7.10(td,J=7.2,1.6Hz,1H),7.07–7.02(m,1H),6.83(t,J=2.0Hz,1H),6.33(d,J=1.6Hz,1H),3.52(s,2H),3.45(t,J=6.0Hz,2H),2.26(s,3H),1.91(t,J=6.0Hz,2H)。
实施例6:1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲酰胺(EXP 6)的制备
参照实施例5的制备方法,得到产物1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基-1,1-二氘代)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲酰胺(EXP 6)。
LCMS(ESI)calcd for C22H23D2FN2O4S[M+H]+m/z 434.2,found 435.3。
1H NMR(600MHz,DMSO-d6)δ7.59(d,J=1.7Hz,1H),7.51(dq,J=7.9,3.3,2.8Hz,1H),7.46(t,J=8.1Hz,1H),7.27(dd,J=8.3,2.6Hz,1H),7.25–7.19(m,2H),7.11–7.08(m,1H),7.06(dd,J=7.8,1.7Hz,1H),6.82(t,J=2.3Hz,1H),6.38(d,J=1.8Hz,1H),3.74(s,2H),3.46(s,2H),3.26(s,3H),2.38(s,3H),1.91(t,J=6.2Hz,2H)。
实施例7:1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基-二氘代甲胺(EXP 7)的制备
步骤1:1H-吡咯-3-氘代甲醛(化合物19)的制备
0℃氮气保护下,将N,N-二甲基甲酰胺-d7(1.20g,15.00mmol)的二氯甲烷溶液(8mL)滴加到草酰氯(1.9g,15.0mmol)的二氯甲烷溶液(50mL)中,0℃反应0.5小时后,将1-(三异丙基硅基)-1H吡咯(化合物18,2.68g,12.00mmol)迅速加入到反应体系中,50℃回流0.5小时。浓缩反应液并加入1.0M的NaOH溶液(50mL),室温反应12小时终止。乙酸乙酯萃取,有机相水洗,干燥,过滤和浓缩。粗品经硅胶柱层析分离纯化(洗脱液:PE/EA=3/1)得1H-吡咯-3-氘代甲醛。
1H NMR(400MHz,DMSO-d6)δ11.64(brs,1H),7.64(dt,J=3.3,1.6Hz,1H),7.01–6.85(m,1H),6.46(dt,J=2.6,1.4Hz,1H)。
步骤2:5-溴-1H-吡咯-3-氘代甲醛(化合物20)的制备
室温氮气保护下,将化合物1H-吡咯-3-氘代甲醛(化合物19,0.96g,10.00mmol)溶解在四氢呋喃(15mL)中。冷却至-78℃,缓慢滴加N-溴代琥珀酰亚胺(0.96g,10.00mmol)的N-N-二甲基甲酰胺(6mL)溶液,-78℃下反应1小时后终止。升温至-10℃,冰水淬灭,乙酸乙酯萃取,有机相水洗,干燥,浓缩。粗品经硅胶柱层析(洗脱液:PE/EA=4/1)纯化得产物5-溴-1H-吡咯-3-氘代甲醛。
1H NMR(400MHz,DMSO-d6)δ12.39(s,1H),7.70(d,J=1.8Hz,1H),6.51(d,J=1.8Hz,1H)。
步骤3:5-(2-氟苯基)-1H-吡咯-3-氘代甲醛(化合物21)的制备
室温下,将5-溴-1H-吡咯-3-氘代甲醛(化合物20,0.15g,0.86mmol),邻氟苯硼酸(0.15g,1.07mmol),四-(三苯基膦)钯(0.05g,0.04mmol)和碳酸钠(0.23g,2.14mmol)溶入到乙二醇二甲醚(5mL)和水(2mL)的混合溶液中。氮气保护100℃反应4小时终止。乙酸乙酯萃取,有机相经水洗,干燥,过滤和浓缩。粗产品经硅胶柱层析(洗脱液:PE/EA=3/1)纯化得到产物5-(2-氟苯基)-1H-吡咯-3-氘代甲醛。
LCMS(ESI)calcd for C11H7DFNO[M+H]+m/z 191,found 190.1。
1H NMR(400MHz,DMSO-d6)δ12.14(s,1H),7.82(dd,J=3.3,1.6Hz,1H),7.78(td,J=7.9,1.7Hz,1H),7.36–7.25(m,3H),6.89(td,J=2.8,1.6Hz,1H)。
步骤4:5-(2-氟苯基)-1-(3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-氘代甲醛(化合物22)的制备
在0℃下,将叔丁醇钾的四氢呋喃溶液(1.0mol/L,1.05mL,1.05mmol)加入到5-(2-氟苯基)-1H-吡咯-3-氘代甲醛(0.10g,0.52mmol)的四氢呋喃(5mL)溶液中,反应半小时。加入15-冠-5(0.23g,1.05mmol)和3-(3-甲氧基丙氧基)-苯磺酰氯(化合物23,0.28g,1.05mmol),室温反应2小时终止。冰水淬灭,乙酸乙酯萃取,合并有机相经水洗,干燥,过滤和浓缩得粗品。粗品经硅胶柱层析(洗脱液:PE/EA=6/1)纯化得到产物5-(2-氟苯基)-1-(3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-氘代甲醛。
LCMS(ESI)calcd for C21H19DFNO5S[M+H]+m/z 419,found 419.1。
步骤5:1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基-二氘代甲胺(化合物EXP 7)的制备
0℃氮气保护下,将甲胺的甲醇溶液(1.0M,0.47mL)和醋酸(0.03g,0.47mmol)缓慢滴加至5-(2-氟苯基)-1-(3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-氘代甲醛(化合物22,0.07g,0.15mmol)的甲醇(2mL)溶液中。室温反应1小时后缓慢加入硼氘化钠(0.03g,0.63mmol),并在0℃下反应2小时终止。冰水淬灭,用乙酸乙酯萃取。合并,干燥,过滤和浓缩有机相。粗品通过硅胶制备板进行纯化(洗脱液:DCM/MeOH=10/1),得产物1-(5-(2-氟苯基)-1-((3-(3-甲氧基丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基-二氘代甲胺(EXP7)。
LCMS(ESI)calcd for C22H23D2FN2O4S[M+H]+m/z 435,found 435.1。
1H NMR(400MHz,DMSO-d6)δ7.62(d,J=1.8Hz,1H),7.56–7.48(m,1H),7.46(t,J=8.0Hz,1H),7.27(dd,J=8.2,2.1Hz,1H),7.25–7.18(m,2H),7.15–7.02(m,2H),6.83(t,,J=2.0Hz,1H),6.42(d,J=1.7Hz,1H),3.96(t,J=6.4Hz,2H),3.46(t,J=6.4Hz,2H),3.26(s,3H),2.38(s,3H),1.89-1.96(m,2H)。
实施例8:1-(5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 8)的制备
参照实施例5的制备方法,得到产物1-(5-(2-氟苯基)-1-((3-(3-(三氘代甲氧基)丙氧基)苯基)磺酰基)-1H-吡咯-3-基)-N-甲基甲胺(EXP 8)。
LCMS(ESI)calcd for C22H22D3FN2O4S[M+H]+m/z 436,found 436.2。
实施例9 H+,K+-ATPase生物学评价
下面的体外筛选试验是用来评价本发明化合物对于H+,K+-ATPase酶活性抑制作用的。
(1)实验材料和仪器:
1)兔胃粘膜微粒体(富含H+,K+-ATPase,自提)
2)5-三磷酸腺苷ATP
3)孔雀石绿
4)钼酸铵
5)缬氨霉素
(2)实验步骤:
试剂准备:
1)化合物用DMSO溶解配制成合适的浓度;
2)3M NaCl:称取8.76g氯化钠,加水溶解后,定容至50mL,4℃保存。
3)缓冲液1:50mmol/L HEPEs-Tris,pH=6.5,5mmol/L氯化镁,10μmol/L 缬氨霉素;
4)缓冲液2:50mmol/L HEPEs-Tris,pH=6.5,5mmol/L氯化镁,10μmol/L 缬氨霉素,5mmol/L氯化钾;
5)ATP:用缓冲液1稀释ATP至5mM;
6)孔雀石绿溶液:0.12%孔雀石绿溶于2.5mol/L硫酸,7.5%(V/V)钼酸铵和11%Tween20(V/V)使用时按100:25:2比例混合;
7)兔胃黏膜微粒体(富含H+,K+-ATPase),提取方法为蔗糖梯度离心:把兔胃用分别自来水,3M NaCl溶液洗净,然后用滤纸除去表面水分。加入预冷的匀浆缓冲液(4ml/g组织),于组织匀浆机中匀浆2-5min。匀浆后,如果有较大的组织颗粒,可离心(600g,10min)去除,然后将上清移至干净的离心管中20000g离心30min后,然后将上清移至干净的离心管中,进一步离心,100000g离心90min,收集沉淀;利用匀浆液悬浮沉淀,吹散均匀,利用Bradford法测蛋白浓度,调整浓度为10mg/ml;等比例加入7.5%Ficoll分层液,100000g离心60min后,将中层(H+,K+-ATPase enriched gastric membranes)收集于洁净离心管中,利用匀浆液4-5倍稀释,继续100000g离心90min,收集沉淀;利用匀浆液悬浮沉淀,玻璃匀浆器匀浆均匀,利用Bradford法测蛋白浓度,调整浓度22.5mg/ml。冻于-80℃备用。
实验过程:
向45μL缓冲液2中加入5μL的胃粘膜微粒体(H+,K+-ATPase),再加入5μL的化合物溶液,然后加入5μL 5mM的ATP启动反应,在37℃预反应30min。加入15μL孔雀石绿溶液终止反应,室温平衡20min,在620nm处读吸收光值。
同时,进行相同体积,不加氯化钾的反应(缓冲液1)作为背景,在计算酶活性时减去。
化合物IC50值通过不同浓度下的抑制率计算得到。
表1 化合物对H+,K+-ATPase活性的半数抑制浓度(IC50,nM)
H008 | EXP 1 | EXP 2 | EXP 3 | EXP 6 | EXP 7 | EXP8 |
50.81 | 28.66 | 54.14 | 57.72 | 37.82 | 35.03 | 90.36 |
如表1所示,本发明所述的化合物对H+,K+-ATPase具有优异的抑制活性。
实施例10肝微粒体稳定性评价
(1)实验材料:
1)肝微粒体(种属人)
2)磷酸氢二钾
3)磷酸二氢钾
4)β-NADPH
(2)实验步骤:
溶液配制:
1)本品化合物:取化合物10mM储备液,再用乙腈稀释成100μM的测试化合物工作溶液,待用。
2)称取一定量的β-NADPH,加入适量氯化镁溶液溶解成一定浓度溶液待用。
3)按照下面“实验温孵体系的构成”比例,制备温孵体系混合溶液(不含β-NADPH)。实验温孵体系的构成:
MgCl2-PB溶液:最终浓度3mM
肝微粒体(mg蛋白/mL):待测物0.5mg/mL,咪达唑仑0.2mg/mL
本品化合物:最终浓度1μM
β-NADPH:最终浓度1mM
实验过程:
从-80℃冰箱中取出肝微粒体,置于37℃水浴恒温振荡器上预温孵3min,融化待用。
0min样品:加入240μL乙腈沉淀剂,再加入40μL NADPH溶液(阴性对照组加入40μL氯化镁溶液)。
其他样品:加入40μL NADPH溶液启动反应(阴性对照组加入40μL氯化镁溶液),37℃水浴孵育5,15,30,60min后加入240μL乙腈沉淀剂。
阳性对照组:加入40μL NADPH溶液启动反应,37℃水浴孵育5,15min后加入240μL乙腈沉淀剂。
所有样品涡旋并离心,取上清液150μL加入150μL水,涡旋混匀,LC-MS/MS进样分析(质谱条件:ESI源正离子模式,维拉帕米Q1/Q3 Masses:455/165.2Da;液相条件:色谱柱ACQUITY UPLC HSS T3(2.1*50mm,1.8μm),流动相:A5%乙腈-95%水溶液(0.2%甲酸)、B100%乙腈(0.1%甲酸)溶液,流速0.4ml/min,进样体积2μL,保留时间1.34min)。
(3)实验结果:化合物半衰期(t1/2)
本发明提供结构如式I所示化合物对人肝微粒体代谢稳定性的结果如下:
表2 化合物的代谢稳定性
H008 | EXP 1 | EXP 2 | EXP 3 | EXP 4 | EXP5 | EXP 6 | EXP 7 | EXP8 |
41min | 88min | 60min | 90min | 55min | 52min | 46min | 52min | 32min |
如表2所示,与H008相比,本发明所述的化合物在人肝微粒体中的代谢稳定性显著提高。表明本发明化合物具有更好的药代动力学性质,具有更好的安全性和有效性。
实施例11化合物H008、EXP 1,EXP 2,EXP 3对组胺诱导的胃酸分泌作用研究
实验材料
1)动物
SD大鼠,SPF级,雄性。
2)药物及试剂
化合物H008、EXP 1、EXP 2、EXP 3,临用前用去离子水溶解至所需浓度的澄清药液。
0.9%氯化钠溶液
组胺二盐酸盐
水合氯醛
NaOH,临用前用纯水配成0.1mol/L的NaOH溶液。
3)仪器
电子天平
离心机
碱式滴定管
方法与结果
取体重180-220g的SPF级SD大鼠,将动物按体重随机分成6组,包括受试化合物H008、EXP1、2、3组,剂量均为2mg/kg,阴性对照组(等容积去离子水)和模型对照组(等容积去离子水),每组12只。禁食24h,不禁水。24h后,受试化合物H008、EXP1、2、3组采取灌胃给药,给药容积为1ml/100g,各组均给药一次,阴性对照组和模型对照组灌胃给予等体积的去离子水。之后将大鼠用水合氯醛300mg/kg(1ml/100g)麻醉后,固定在大鼠板上,自胸骨剑突下沿腹中线切开腹壁,切口约2~3cm,在左侧肋缘部位,用指轻轻往上一推,使胃暴露于切口。在幽门下穿一线将幽门结扎(邻近的其它血管不结扎),然后缝合腹壁切口。动物于灌胃受试化合物或去离子水1h后皮下给予组胺二盐酸盐(30mg/10ml/kg)。给予组胺3h后用过量CO2窒息处死大鼠,取胃,收集内容物,3000rpm/min离心10min,用0.1mol/L的NaOH滴定酸液至pH7.0,计算3h期间的总酸。结果见表3。
表3 受试化合物对组胺诱导的胃酸分泌作用
组别 | 剂量(mg/kg) | 抑酸率% |
阴性对照 | / | / |
模型对照 | / | / |
H008 | 2 | 62.15 |
EXP 1 | 2 | 78.35 |
EXP2 | 2 | 73.40 |
EXP3 | 2 | 76.03 |
如表3所示,对比H008,相同剂量下本申请化合物抑制大鼠胃酸分泌的作用更强。
上面已经详细描述了本专利的部分组成,但对于本领域技术人员显而易见的是,阐述这种详细描述仅是为了说明示例性实施方式,而不应理解为限制本专利的范围。因此,本公开的实质范围由所附权利要求及其同等方案限定。
Claims (10)
1.一种式(I)所示的化合物或其药学可接受的盐,
其中,R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21、R22、R23、R24各自独立地为氢或氘,条件是R4至R24中至少有一个为氘;R1、R2、R3各自独立地为氢或氘。
2.根据权利要求1所述的化合物或其药学可接受的盐,其特征在于,R8、R9、R20、R21、R22、R23、R24各自独立地为氢或氘,条件是R8、R9、R20、R21、R22、R23、R24中至少有一个为氘;R1、R2、R3、R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19为氢或氘。
3.根据权利要求1所述的化合物或其药学可接受的盐,其特征在于,所述式(I)化合物具有式(II)所示的结构,
其中,Ra选自CH2D、CHD2、CD3;Rb选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地为氢或氘;
或者R20、R21各自独立地为氢或氘,条件是R20、R21至少有一个为氘;Ra、Rb各自独立选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19各自独立地为氢或氘;优选为R20、R21均为氘;
或者R8、R9各自独立地为氢或氘,条件是R8、R9至少有一个为氘;Ra、Rb各自独立选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地为氢或氘;优选为R8、R9均为氘。
4.根据权利要求1所述的化合物或其药学可接受的盐,其特征在于,
所述式(I)化合物具有式(II)所示的结构,
Ra选自CH2D、CHD2、CD3;Rb选自CH3、CH2D、CHD2、CD3;R4、R5、R6、R7、R8、R9、R10、R11、R12、R13、R14、R15、R16、R17、R18、R19、R20、R21各自独立地为氢或氘。
5.根据权利要求4所述的化合物或其药学可接受的盐,其特征在于,所述Rb选自CH2D、CHD2、CD3。
6.根据权利要求4所述的化合物或其药学可接受的盐,其特征在于,所述R8、R9、R20、R21各自独立地为氢或氘,条件是R8、R9、R20、R21至少有一个为氘;优选为R8、R9至少有一个为氘;更优选为R20、R21至少有一个为氘。
7.根据权利要求1所述的化合物或其药学可接受的盐,其特征在于,所述化合物选自如下化合物或其药学可接受的盐:
8.一种药用组合物,包含权利要求1所述的化合物或其药学上可接受的盐,以及药学上可接受的载体。
9.权利要求1~7任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备胃酸分泌抑制剂的药物中的用途。
10.权利要求1~7任一项所述的化合物或其药学上可接受的盐或权利要求8所述的药物组合物在制备治疗或预防消化性溃疡、卓-艾综合症、胃炎、糜烂性食管炎、反流性食管炎、症状性胃食管反流疾病、巴雷特食管炎、功能性消化不良、幽门螺旋杆菌感染、胃癌、胃MALT淋巴瘤、非甾体抗炎药引起的溃疡或手术后应激导致的胃酸过多或溃疡的药物中的用途;或者
在制备抑制用于消化性溃疡、急性应激性溃疡、出血性胃炎或侵入性应激造成的上消化道出血的药物中的用途。
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