CN115991702B - 芳基c-葡萄糖苷衍生物、其制备方法及其用途 - Google Patents
芳基c-葡萄糖苷衍生物、其制备方法及其用途 Download PDFInfo
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- CN115991702B CN115991702B CN202211589504.2A CN202211589504A CN115991702B CN 115991702 B CN115991702 B CN 115991702B CN 202211589504 A CN202211589504 A CN 202211589504A CN 115991702 B CN115991702 B CN 115991702B
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Abstract
本发明公开了一种芳基C‑葡萄糖苷衍生物、其制备方法及其用途。具体提供了如式I所示的芳基C‑葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者的药学上可接受的盐,或前述任一者的溶剂化物。本发明的芳基C‑葡萄糖苷衍生物的肌细胞保护作用、NHE1抑制活性均优于现有技术的恩格列净,且能在较低给药剂量下发挥有效的抗心衰作用,因此可以用于制备抗心衰的药物。本发明化合物结构简单,制备工艺简洁,生产成本低。
Description
技术领域
本发明涉及药物化学和药物治疗学领域,具体涉及芳基C-葡萄糖苷衍生物、其制备方法及其用途。
背景技术
心力衰竭(Heart failure,HF)简称心衰,是心脏收缩和/或舒张功能受损、射血及充盈能力减退导致组织灌注不足的一组临床疾病,其常见的临床症状为呼吸困难、周身疲惫和乏力,并伴有体循环/肺循环淤血及周围水肿等体征。作为多种心血管疾病的后期临床病征,心衰导致的患病率、住院率和死亡率极高,已成为65岁以上老年人住院的主要原因。
心衰的发生发展常受多种因素综合影响,故病理机制较复杂,目前针对它的机制研究发现诱因主要集中于两方面:(1)交感神经系统和/或肾素-血管紧张素-醛固酮系统长期异常激活;(2)促炎与抗炎细胞因子分泌增加,引发持续炎症反应,导致心肌损伤和心功能下降。
随着对心衰发生机制的认识加深,心衰的治疗方案也从“强心、利尿、扩血管”的传统模式逐渐转变成神经内分泌阻断及逆转心室重构等新型手段,包括血管紧张素转化酶抑制剂/血管紧张素Ⅱ受体抑制剂(ACEI/ARB)、醛固酮抑制剂、β-受体阻滞剂等。这些新型手段治疗药物虽然能在一定程度上减缓了心衰患者的临床症状和病死率,但仍然存在不良反应多、需长期用药等临床局限性,且无法显著提高患者的生存质量。相关数据显示,目前心衰患者的5年病死率仍高达50%以上。
近几年,临床研究发现SGLT2抑制剂可降低合并高危心血管糖尿病患者的主要不良心血管事件,有望成为心力衰竭药物治疗领域的新标准。研究表明,SGLT2抑制剂可以通过抑制心肌细胞上I型钠氢转换器(NHE1)发挥心血管保护作用。因此本领域迫切需要研发一种新型的抑制NHE1的芳基C-葡萄糖苷衍生物,用于心衰治疗。
发明内容
本发明的主要目的在于提供一种有效抗心衰,并且抑制NHE1的芳基C-葡萄糖苷衍生物、其制备方法及其用途,具体地,本发明提供了如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者的药学上可接受的盐,或前述任一者的溶剂化物,及其制备方法,以及其在制备a)NHE1抑制剂;和/或b)抗心衰药物中的用途。
本发明是通过下述技术方案来解决上述技术问题:
本发明提供了如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体或其立体异构体)的药学上可接受的盐,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物;
其中,
R1-R3独立地为H、C1-C6烷基或C2-C6炔基;
R4为COOH或CH2OR4-1;R4-1为H或C1-C6烷基;
当R4为CH2OR4-1,R4-1为H时,R1-R3至少有一个为C1-C6烷基或C2-C6炔基;
R5为“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”;
R6为卤素。
在本发明某些优选实施方案中,所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体或其立体异构体)的药学上可接受的盐,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物中的某些基团如下定义,未提及的基团同本发明任一方案所述(简称“在本发明某一方案中”),
R1、R2、R3和R4-1中,所述C1-C6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基,例如甲基、乙基或正丙基。
在本发明某一方案中,R1、R2和R3中,所述C2-C6炔基独立地为乙炔基、丙炔基、炔丙基、1-丁炔基、2-丁炔基或3-丁炔基,例如炔丙基
在本发明某一方案中,R5中,所述“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”为“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-6元杂环烷基”,例如四氢呋喃基,再例如又例如/>
在本发明某一方案中,R6中,所述卤素为F、Cl、Br或I,例如Cl。
在本发明某一方案中,R4为CH2OH,R1-R3至少有一个为C1-C6烷基或C2-C6炔基,其余为H;或者,R4为COOH或CH2OR4-1,R1-R3独立地为H、C1-C6烷基或C2-C6炔基,R4-1为C1-C6烷基;
R5为“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”;
R6为Cl。
在本发明某一方案中,R1-R3独立地为H、甲基、乙基、正丙基或炔丙基。
在本发明某一方案中,R4为COOH、CH2OH或CH2OCH3。
在本发明某一方案中,R5为在本发明某一方案中,R6为Cl。
在本发明某一方案中,如式I所示的芳基C-葡萄糖苷衍生物为如下任一化合物:
本发明还提供了如式I所示的芳基C-葡萄糖苷衍生物的制备方法,其包括以下任一方法:
方法一:
冰浴下,用氧化剂如2,2,6,6-四甲基哌啶氧化物在四氢呋喃/饱和碳酸氢钠溶液中处理恩格列净(EMPA)制备所述芳基C-葡萄糖苷衍生物(I-1),如下流程1所示:
流程1
方法二:
(1)在室温下,EMPA用苯甲醛二甲缩醛和樟脑磺酸在N,N-二甲基甲酰胺(DMF)中处理得中间体式IIA化合物;
(2)在冰浴下,硅烷如叔丁基二甲基氯硅烷和咪唑在DMF中处理式IIA化合物得中间体式IIB化合物;
(3)在室温下,式IIB化合物在无机碱如钠氢的存在下经C1-3碘代烷烃处理,待反应结束后再经90%的醋酸水溶液处理得芳基C-葡萄糖苷衍生物(目标化合物I-2~I-4);所述步骤如流程2所示:
流程2:
方法三:
在室温下,式IIA化合物在无机碱如氢氧化钠的存在下经卤代烃处理,待反应结束后再经90%的醋酸水溶液处理得所述芳基C-葡萄糖苷衍生物(目标化合物I-5、I-6、I-10);所述步骤如流程3所示:
流程3:
方法四:
包括步骤:
(1)在60℃下,将EMPA溶于甲醇中,与2,3-丁二酮和三乙氧基甲烷反应,得中间体式IIC化合物。
(2)在室温下,碘甲烷和氧化银在DMF中处理式IIC化合物,待反应结束后再经80%三氟乙酸处理,得所述芳基C-葡萄糖苷衍生物(目标化合物I-7);所述步骤如流程4所示:
流程4
方法五:
包括步骤:
(1)在60℃下,将EMPA溶于甲醇中,与2,3-丁二酮和三乙氧基甲烷反应,得中间体式IID化合物。
(2)在冰浴下,四氟硼酸和三甲基硅烷化重氮甲烷在二氯甲烷中处理式IID化合物,待反应结束后再经80%三氟乙酸处理得芳基C-葡萄糖苷衍生物(目标化合物I-8);所述步骤如流程5所示:
流程5:
方法六:
在室温下,EMPA用碘甲烷和钠氢在DMF中处理得所述芳基C-葡萄糖苷衍生物(目标化合物I-9);所述步骤如流程6所示:
流程6
本发明还提供了一种药物组合物,其包括:
(1)如本发明任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体或其立体异构体)的药学上可接受的盐,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物;和
(2)药学上可接受的载体或赋形剂。
在本发明某一方案中,所述药物组合物的剂型为口服剂型或非口服剂型。
在本发明某一方案中,所述药物组合物的剂型选自片剂、胶囊剂、颗粒剂、混悬剂、丸剂、溶液剂、糖浆剂和注射剂。
本发明还提供了如本发明任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体或其立体异构体)的药学上可接受的盐,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物或所述药物组合物的用途,其用于制备a)抑制钠氢交换器的抑制剂;和/或b)预防和/或缓解和/或治疗钠氢交换器相关的疾病的药物。
在本发明某一方案中,所述的钠氢交换器优选地为NHE1。
在本发明某一方案中,所述钠氢交换器相关的疾病包括心力衰竭。
在本发明某一方案中,所述用途中,所述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体或其立体异构体)的药学上可接受的盐,或前述任一者(指前述如式I所示的芳基C-葡萄糖苷衍生物、其互变异构体、其立体异构体或前述任一者的药学上可接受的盐)的溶剂化物或所述药物组合物用于制备具有以下一种或多种作用的药物:
A1)保护心肌细胞;
A2)收缩/舒张期左心室室间隔厚度变厚;
A3)收缩/舒张期左心室后壁厚度变厚;
A4)收缩/舒张期左心室内径变小;
A5)射血分数升高;
A6)短轴缩短率升高。
在本发明某一方案中,所述心肌细胞包括:H9c2、大鼠乳鼠原代心肌细胞。
在本发明某一方案中,所述的心力衰竭包括:射血分数降低的心力衰竭、射血分数保留的心力衰竭。
如无特别说明,本发明所用术语具有如下含义:
本领域技术人员可以理解,根据本领域中使用的惯例,本发明描述基团的结构式中所使用的是指,相应的基团通过该位点与化合物中的其它片段、基团进行连接。
术语“药学上可接受的”是指盐、溶剂、辅料等一般无毒、安全,并且适合于患者使用。所述的“患者”优选哺乳动物,更优选为人类。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于:锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时,可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸,所述无机酸包括但不限于:盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸,所述有机酸包括但不限于:乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时,可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或、Handbook of PharmaceuticalSalts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂化物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂化物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于:水、甲醇、乙醇等。
术语“立体异构体”是指顺反异构体或旋光异构体。这些立体异构体可以通过不对称合成方法或手性分离法(包括但不限于薄层色谱、旋转色谱、柱色谱、气相色谱、高压液相色谱等)分离、纯化及富集,还可以通过与其它手性化合物成键(化学结合等)或成盐(物理结合等)等方式进行手性拆分获得。术语“单一的立体异构体”是指本发明化合物的一种立体异构体相对于该化合物的所有立体异构体的质量含量不低于95%。
当任意变量(例如卤素)在化合物的定义中多次出现时,该变量每一位置出现的定义与其余位置出现的定义无关,它们的含义互相独立、互不影响。因此,若某基团被1个、2个或3个卤素取代,也就是说,该基团可能会被最多3个卤素取代,该位置卤素的定义与其余位置卤素的定义是互相独立的。另外,取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有指定的碳原子数的直链或支链烷基。烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、仲丁基、正戊基、正己基及其类似烷基。
术语“烷氧基”是指基团-O-RX,其中,RX为如上文所定义的烷基。
术语“炔基”是指具有指定碳原子数的一个或多个叁键的直链或支链的烃基(例如C2-C6炔基,又例如C2-C4炔基)。该一个或多个碳碳叁键可以是内部的也可以是末端的,例如叁键在内部的丙炔基或叁键在末端的丙炔基/>等。
术语“杂环烷基”是指具有指定环原子数(例如3-12元)的、指定杂原子数(例如1个、2个或3个)的、指定杂原子种类(N、O和S中的1种、2种或3种)的环状基团,其为单环、桥环或螺环,且每一个环均为饱和的。杂环烷基包括但不限于氮杂环丁烷基、四氢吡咯基、四氢呋喃基、吗啉基和哌啶基等。
术语“芳基”是指C6-C10芳基,例如苯基或萘基。
术语“杂芳基”是指含有杂原子的芳香基团,优选含有1个、2个或3个独立选自氮、氧和硫的芳族环状基团,其为单环或双环,当为双环时,至少有一个环具有芳香性,例如呋喃基、吡啶基、哒嗪基、嘧啶基、吡嗪基、噻吩基、异唑基、噁唑基、二唑基、咪唑基、吡咯基、吡唑基、三唑基、四唑基、噻唑基、异噻唑基、噻二唑基、苯并咪唑基、吲哚基、吲唑基、苯并噻唑基、苯并异噻唑基、苯并唑基、苯并异唑基、喹啉基、异喹啉基等。
术语“药学上可接受的载体”是指生产药品和调配处方时使用的赋形剂和附加剂,是除活性成分以外,包含在药物制剂中的所有物质。可参见中华人民共和国药典(2015年版)四部、或、Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009SixthEdition)。
术语“治疗”指治疗性疗法。涉及具体病症时,治疗指:(1)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现,或(2)改善与病症相关的一种或多种症状、影响或副作用,或者与病症或其治疗相关的一种或多种症状、影响或副作用。
术语“预防”是指获得或发生疾病或障碍的风险降低。
术语“治疗有效量”是指在给予患者时足以有效治疗本文所述的疾病或病症的化合物的量。“治疗有效量”将根据化合物、病症及其严重度、以及欲治疗患者的年龄而变化,但可由本领域技术人员根据需要进行调整。
在所述的用途中,所述抑制钠氢交换器的抑制剂可用于哺乳动物生物体内;也可用于生物体外,主要作为实验用途,例如:作为标准样或对照样提供比对,或按照本领域常规方法制成试剂盒,为钠氢交换器的抑制效果提供快速检测。
本发明的积极进步效果在于:
本发明实验表明本发明的芳基C-葡萄糖苷衍生物的肌细胞保护作用、NHE1抑制活性均优于现有技术的恩格列净,且能在较低给药剂量下发挥有效的抗心衰作用,因此可以用于制备抗心衰的药物。
本发明化合物结构简单,制备工艺简洁,生产成本低。
附图说明
图1为化合物I-2和EMPA处理后心肌细胞结晶紫染色图。
图2为化合物I-2和EMPA处理后心肌细胞结晶紫染色定量图。
图3为化合物I-2和EMPA处理后心肌细胞LDH释放作用图。
图4为化合物I-2、EMPA及阳性药卡立伯来德(Cariporide)处理心肌细胞心肌细胞存活率图。
图5为化合物I-2、EMPA及阳性药卡立伯来德(Cariporide)处理心肌细胞后荧光强度图。
图6为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型心脏超声(M模式)代表性图。
图7为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型心率图。
图8为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型射血分数图。
图9为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型短轴缩短率图。
图10为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室收缩期内径图。
图11为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室舒张期内径图。
图12为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室收缩期后壁厚度图。
图13为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型左心室舒张期后壁厚度图。
图14为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型Masson染色代表性图。
图15为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型Masson染色定量图。
图16为化合物I-2和EMPA处理异丙肾上腺素诱导的心衰小鼠模型心体比。
图17为化合物I-2处理MI诱导的心衰小鼠模型心功能改善的药效生存率图。
图18为化合物I-2处理MI诱导的心衰小鼠模型心脏超声(M模式)代表性图。
图19为化合物I-2处理MI诱导的心衰小鼠模型心率图。
图20为化合物I-2处理MI诱导的心衰小鼠模型射血分数图。
图21为化合物I-2处理MI诱导的心衰小鼠模型短轴缩短率图。
图22为化合物I-2处理MI诱导的心衰小鼠模型左心室舒张期内径图。
图23为化合物I-2处理MI诱导的心衰小鼠模型左心室收缩期内径图。
图24为化合物I-2处理MI诱导的心衰小鼠模型左心室舒张期后壁厚度图。
图25为化合物I-2处理MI诱导的心衰小鼠模型左心室收缩期后壁厚度。
图26为化合物I-2对MI诱导的心衰小鼠模型Masson染色代表性图。
图27为化合物I-2对MI诱导的心衰小鼠模型Masson染色定量图。
图28为化合物I-2对MI诱导的心衰小鼠模型心体比图。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。
一、制备实施例
实施例1(2S,3S,4R,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-3,4,5-三羟基四氢-2H-吡喃-2-羧酸(目标化合物I-1)的制备
将恩格列净(EMPA,2.00g,4.44mmol)溶于50mL的无水THF中和50mL饱和NaHCO3混合溶剂中,0℃加入2,2,6,6-四甲基哌啶氧化物(TEMPO,139mg,887μmol)和溴化钾(KBr,106mg,887μmol),恒温15min后,滴加50mL的次氯酸钠溶液,继续反应1h,停止反应,反应加入50mL的水稀释,用2M的稀盐酸调节pH至2-3左右,加入乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V甲醇:V二氯甲烷=1:5),得到产物白色固体,收率52%。1H NMR(400MHz,DMSO-d6)δ12.74(s,1H),7.39(d,J=8.2Hz,1H),7.31(d,J=2.0Hz,1H),7.21(dd,J=8.3,2.1Hz,1H),7.13–7.07(m,2H),6.86–6.79(m,2H),5.15(s,1H),5.02–4.91(m,2H),4.11(d,J=9.4Hz,1H),3.99(d,J=4.3Hz,2H),3.89–3.69(m,5H),3.46(t,J=9.3Hz,1H),3.30(t,J=8.8Hz,2H),3.24–3.15(m,1H),2.17(m,1H),1.97–1.88(m,1H).13C NMR(151MHz,DMSO-d6)δ173.03,155.94,139.91,138.23,132.46,131.99,131.37,130.12,129.20,127.98,115.63,81.23,79.27,78.53,77.39,74.78,72.76,72.66,66.86,38.06,32.91.HRMS(ESI)m/z cacld C23H25ClO8Na+[M+Na]+487.1130,found487.1134.
实施例2(4aR,6S,7R,8R,8aS)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-苯基六氢吡喃[3,2-d][1,3]二噁英-7,8-二醇(式IIA所示化合物)的制备
将恩格列净(EMPA,2.00g,4.44mmol)溶于35mL的无水DMF中,室温下加入苯甲醛二甲缩醛((dimethoxymethyl)benzene,810mg,5.32mmol)和(+)-10-樟脑磺酸(CAS,100mg),N2保护,110℃反应3h,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯:V石油醚=1:10),得到产物白色固体,收率90%。1H NMR(400MHz,DMSO-d6)δ7.47(dd,J=6.8,2.9Hz,2H),7.43–7.37(m,4H),7.31(d,J=2.1Hz,1H),7.23(dd,J=8.2,2.1Hz,1H),7.15–7.08(m,2H),6.84(d,J=8.7Hz,2H),5.62(s,1H),5.36(s,1H),5.18(d,J=6.0Hz,1H),4.97(td,J=4.6,2.3Hz,1H),4.28–4.15(m,2H),4.00(d,J=4.0Hz,2H),3.87(dd,J=10.0,4.6Hz,1H),3.84–3.79(m,1H),3.78–3.66(m,3H),3.56–3.49(m,3H),3.29(s,1H),2.19(dtd,J=14.3,8.2,6.3Hz,1H),1.94(dt,J=12.5,5.6Hz,1H).13C NMR(151MHz,DMSO-d6)δ155.98,139.44,138.46,138.29,132.70,131.95,131.16,130.16,129.35,129.30,128.49,127.76,126.83,115.66,101.15,82.02,81.48,77.40,75.70,74.72,72.75,70.86,68.46,66.86,38.03,32.91.HRMS(ESI)m/z cacldC30H31ClO7Na+[M+Na]+561.1651,found 561.1658.
实施例3((4aR,6R,7S,8R,8aR)-8-((叔丁基二甲基硅烷基)氧基)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-苯基六氢吡喃[3,2-d][1,3]二噁英-7-醇(式IIB所示化合物)的制备
将式IIA所示化合物(2.10g,3.90mmol)溶于35mL无水DMF中,0℃加入咪唑(Imidazole,1.06g,15.58mmol),恒温15min后加入叔丁基二甲基氯硅烷(tert-Butyldimethylsilyl chloride,763mg,5.06mmol),70℃反应6h。加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯:V石油醚=1:5),得到白色固体,收率55%。1H NMR(400MHz,DMSO-d6)δ7.47–7.43(m,2H),7.43–7.35(m,4H),7.32(d,J=2.1Hz,1H),7.25(dd,J=8.3,2.1Hz,1H),7.14–7.08(m,2H),6.86–6.82(m,2H),5.64(s,1H),5.14(d,J=7.6Hz,1H),4.97(ddd,J=6.4,4.3,2.0Hz,1H),4.25(d,J=9.5Hz,1H),4.19(dd,J=10.1,4.5Hz,1H),4.06–3.95(m,2H),3.90–3.80(m,2H),3.78–3.67(m,4H),3.61–3.50(m,2H),3.29(dt,J=9.6,8.1Hz,1H),2.19(dtd,J=13.5,8.2,6.3Hz,1H),1.98–1.89(m,1H),0.82(s,9H),0.04(s,3H),0.01(s,3H).
实施例4(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-5-甲氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-2)的制备
将式IIB所示化合物(650mg,0.995mmol)溶于10mL无水THF中,加入钠氢(NaH(60%),26.3mg,1.09mmol)和碘甲烷(Iodomethane,211.8mg,1.49mmol),室温反应12h,停止反应,蒸干溶剂,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯:V石油醚=1:10),得到白色固体。紧接着将白色固体溶于10mL90%的醋酸水溶液中,60℃反应12h,冷却至室温,将反应液倒入冰水中,用饱和NaHCO3溶液调节pH至中性,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯),得到终产物白色固体,收率35%。1H NMR(400MHz,DMSO-d6)δ7.40(d,J=8.2Hz,1H),7.35(d,J=2.1Hz,1H),7.28(dd,J=8.2,2.1Hz,1H),7.10(d,J=8.2Hz,2H),6.83(d,J=8.2Hz,2H),5.12(d,J=5.1Hz,1H),5.03(d,J=4.6Hz,1H),4.99–4.91(m,1H),4.47(t,J=5.8Hz,1H),4.06–3.97(m,4H),3.92–3.64(m,6H),3.44(dt,J=11.5,5.6Hz,1H),3.39–3.33(m,1H),2.95(s,3H),2.88(t,J=9.2Hz,1H),2.18(dtd,J=14.2,8.1,5.8Hz,1H),1.92(tt,J=8.9,3.5Hz,1H).13C NMR(151MHz,DMSO-d6)δ155.95,139.93,138.21,132.45,131.99,131.35,130.15,129.17,127.84,115.63,88.68,81.70,81.23,77.39,74.54,72.75,70.10,66.86,61.58,60.55,38.07,32.91.HRMS(ESI)m/zcacld C24H29ClO7Na+[M+Na]+487.1494,found 487.1504.
实施例5(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-5-乙氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-3)的制备
除以碘乙烷替换碘甲烷外,其他步骤与实施例4相同,得终产物白色固体,收率31%。1H NMR(400MHz,CD3OD)δ7.39–7.35(m,1H),7.30(d,J=7.0Hz,2H),7.12–7.08(m,2H),6.82–6.77(m,2H),4.97(ddt,J=6.1,4.0,1.8Hz,1H),4.11–4.02(m,3H),3.97–3.91(m,2H),3.91–3.84(m,3H),3.69(dd,J=12.0,5.4Hz,1H),3.49(t,J=8.7Hz,1H),3.43–3.34(m,3H),3.01(t,J=9.1Hz,1H),2.81(dq,J=9.1,7.1Hz,1H),2.21(dtd,J=13.5,8.4,5.9Hz,1H),2.12–2.04(m,1H),0.79(t,J=7.0Hz,3H).13C NMR(151MHz,DMSO-d6)δ155.95,139.98,138.34,132.47,132.07,131.11,130.03,129.28,127.59,115.63,83.95,81.49,79.95,78.14,77.38,72.73,70.91,67.39,66.85,61.73,37.91,32.88,15.64.HRMS(EI)m/zcacld C25H31ClO7 +[M]+478.1753,found 478.1754.
实施例6(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-5-丙氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-4)的制备
除以碘丙烷替换碘甲烷外,其他步骤与实施例4相同,白色固体,收率24%。1H NMR(400MHz,DMSO-d6)δ7.40(d,J=8.2Hz,1H),7.33(d,J=2.0Hz,1H),7.27(dd,J=8.2,2.1Hz,1H),7.12–7.06(m,2H),6.85–6.79(m,2H),5.04(dd,J=9.9,5.1Hz,2H),4.96(dt,J=6.2,3.0Hz,1H),4.48(t,J=5.8Hz,1H),4.05–3.98(m,3H),3.86(dd,J=10.1,4.6Hz,1H),3.80(t,J=7.7Hz,1H),3.76–3.66(m,3H),3.47–3.41(m,2H),3.25–3.14(m,3H),2.95(t,J=9.1Hz,1H),2.72(dt,J=9.1,6.9Hz,1H),2.23–2.13(m,1H),1.92(dt,J=12.6,5.8Hz,1H),1.10(q,J=7.1Hz,2H),0.49(t,J=7.4Hz,3H).13C NMR(151MHz,DMSO-d6)δ155.94,139.95,138.35,132.48,132.09,131.29,130.02,129.26,127.80,115.60,83.95,81.54,80.08,78.33,77.38,73.89,72.73,71.00,66.85,61.75,37.90,32.88,23.07,10.67.HRMS(EI)m/z cacld C26H33ClO7 +[M]+492.1909,found 492.1912.
实施例7(2R,3S,4S,5R,6S)-6-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-4-甲氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-5)的制备
将式IIA所示化合物(2.10g,3.90mmol)溶于35mL无水THF中,加入NaOH(312mg,7.79mmol)和碘甲烷(Iodomethane,1.11g,7.79mmol),50℃反应4h,冷却至室温,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯:V石油醚=1:5),得到白色固体。接着将白色固体(200mg)溶于10mL 90%的醋酸水溶液中,60℃反应12h,冷却至室温,将反应液倒入冰水中,用饱和NaHCO3溶液调节pH至中性,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯),得到最终产物白色固体,收率76%。1H NMR(400MHz,DMSO-d6)δ7.37(d,J=8.2Hz,1H),7.33(d,J=2.0Hz,1H),7.23(dd,J=8.2,2.1Hz,1H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.11(d,J=5.4Hz,1H),5.00(d,J=6.5Hz,1H),4.96(ddt,J=6.3,4.0,1.8Hz,1H),4.46(t,J=5.8Hz,1H),4.01–3.95(m,3H),3.86(dd,J=10.1,4.6Hz,1H),3.80(dd,J=8.2,7.0Hz,1H),3.77–3.65(m,3H),3.52(s,3H),3.43(dd,J=12.0,6.0Hz,1H),3.27–3.13(m,3H),3.04(t,J=8.3Hz,1H),2.18(dtd,J=16.4,8.2,6.2Hz,1H),1.96–1.88(m,1H).13CNMR(151MHz,DMSO-d6)δ155.95,139.93,138.22,132.46,131.99,131.36,130.15,129.18,127.84,115.63,88.69,81.70,81.24,77.39,74.54,72.75,70.11,66.86,61.59,60.56,38.08,32.91.HRMS(EI)m/z cacld C24H29ClO7 +[M]+464.1596,found 464.1598.
实施例8(2R,3R,4S,5S,6S)-2-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2-(羟甲基)-4,5-二甲氧基四氢-2H-吡喃-3-醇(目标化合物I-6)的制备
除将式IIA所示化合物的量调整为400mg外,其他步骤与实施例7相同,白色固体,收率74%。1H NMR(400MHz,DMSO-d6)δ7.41(d,J=8.2Hz,1H),7.36(d,J=2.1Hz,1H),7.29(dd,J=8.2,2.1Hz,1H),7.12–7.07(m,2H),6.86–6.80(m,2H),5.20(d,J=5.8Hz,1H),4.96(ddt,J=6.4,4.0,1.8Hz,1H),4.50(t,J=5.8Hz,1H),4.07(d,J=9.5Hz,1H),4.00(s,2H),3.86(dd,J=10.1,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.65(m,3H),3.52(s,3H),3.44(dt,J=11.7,5.9Hz,1H),3.31–3.20(m,2H),3.14(t,J=8.6Hz,1H),2.95(t,J=9.2Hz,1H),2.90(s,3H),2.23–2.12(m,1H),1.92(h,J=5.5Hz,1H).13C NMR(151MHz,DMSO-d6)δ155.96,139.46,138.62,132.74,132.02,131.20,130.09,129.44,127.70,115.65,88.16,85.00,81.57,79.79,77.39,72.73,70.27,66.85,61.47,60.46,59.81,37.94,32.89.HRMS(EI)m/zcacld C25H31ClO7 +[M]+478.1753,found 478.1759.
实施例9(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-(((S)-四氢呋喃-3-基)氧基)苄基)苯基)-6-(羟甲基)-4-(丙-2-炔-1-基氧基)四氢-2H-吡喃-3,5-二醇(目标化合物I-10)的制备
除以溴丙炔替换碘甲烷外,其他步骤与实施例7相同,白色固体,收率63%。1H NMR(400MHz,DMSO-d6)δ7.40–7.32(m,2H),7.23(dd,J=8.3,2.1Hz,1H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.17(d,J=4.8Hz,1H),5.04(d,J=6.3Hz,1H),4.99–4.93(m,1H),4.49(t,J=5.8Hz,1H),4.44(d,J=2.5Hz,2H),4.05–3.92(m,3H),3.86(dd,J=10.1,4.6Hz,1H),3.83–3.77(m,1H),3.76–3.64(m,3H),3.44(dt,J=11.5,5.8Hz,1H),3.36(t,J=2.4Hz,1H),3.24(ddd,J=19.0,8.2,5.6Hz,4H),2.18(dtd,J=14.2,8.2,6.2Hz,1H),1.92(dt,J=12.7,5.8Hz,1H).13C NMR(151MHz,DMSO-d6)δ155.95,139.74,138.25,132.54,131.98,131.41,130.16,129.21,127.89,115.63,86.00,81.79,81.64,81.21,77.39,76.95,74.52,72.76,70.19,66.86,61.52,59.77,38.10,32.91.HRMS(EI)m/z cacldC26H29ClO7 +[M]+488.1596,found 488.1599.
实施例10(4aS,5S,7R,8R,8aS)-5-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-2,3,8-三甲氧基-2,3-二甲基六氢-5H-吡喃并[3,4-b][1,4]二噁英-7-基)甲醇(式IIC-1所示化合物)的制备
将恩格列净(EMPA,3.00g,6.65mmol)溶于20mL甲醇中,室温下加入2,3-丁二酮(2,3-Butanedione,1.5mL,17.25mmol)、三乙氧基甲烷(triethoxymethane,3.6mL,21.62mmol)与三氟化硼乙醚(Boron trifluoride etherate,1.92mL),60℃反应4h,自然冷却至室温,加入9mL三乙胺,反应0.5h,停止反应,蒸干溶剂,硅胶柱层析分离纯化(V石油醚:V乙酸乙酯=2:1),得到白色固体,收率42%。将上述白色固体(350mg,619.41μmol)、氧化银(Silver oxide,143.54mg,619.41μmol)与碘甲烷(Iodomethane,158.25mg,1.11μmol)溶于5mL DMF中,室温反应8h,停止反应,加入乙酸乙酯,然后硅藻土抽滤,再加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯:V石油醚=1:3),得到式IIC-1化合物,白色固体,收率51%。1H NMR(400MHz,DMSO-d6)δ7.41(d,J=8.2Hz,1H),7.33(d,J=2.1Hz,1H),7.28(dd,J=8.2,2.1Hz,1H),7.08(d,J=8.5Hz,2H),6.85–6.78(m,2H),4.96(td,J=4.6,2.2Hz,1H),4.66(dd,J=6.6,5.0Hz,1H),4.30(d,J=9.7Hz,1H),3.99(d,J=2.0Hz,2H),3.89–3.70(m,5H),3.62(dd,J=11.3,5.1Hz,1H),3.55–3.50(m,1H),3.49(s,3H),3.36(dd,J=7.2,3.0Hz,1H),3.32(m,1H),3.30–3.24(m,1H),3.21(s,3H),2.56(s,3H),2.18(dtd,J=14.2,8.2,6.2Hz,1H),1.96–1.87(m,1H),1.18(s,3H),1.00(s,3H).
实施例11(2S,3R,4R,5S,6R)-2-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-6-(羟甲基)-5-甲氧基四氢-2H-吡喃-3,4-二醇(目标化合物I-7)的制备
将式IIC-1所示化合物(170mg)加入到5mL的80%的三氟乙酸水溶液,室温反应2h,用NaOH水溶液调节溶液pH至碱性,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V甲醇:V二氯甲烷=1:30),得到终产物,白色固体,收率40%。1H NMR(400MHz,DMSO-d6)δ7.37(d,J=8.2Hz,1H),7.33(d,J=2.0Hz,1H),7.23(dd,J=8.2,2.1Hz,1H),7.11(d,J=8.5Hz,2H),6.85–6.81(m,2H),5.12(d,J=5.3Hz,1H),4.96(td,J=4.6,2.3Hz,1H),4.90(d,J=5.8Hz,1H),4.57(dd,J=6.4,5.0Hz,1H),4.04–3.95(m,3H),3.86(dd,J=10.1,4.6Hz,1H),3.80(t,J=7.8Hz,1H),3.77–3.71(m,2H),3.66–3.58(m,1H),3.49(s,1H),3.46(s,3H),3.38(td,J=8.8,5.4Hz,1H),3.23(dd,J=10.2,4.5Hz,1H),3.11(td,J=9.1,5.9Hz,1H),3.03(t,J=9.3Hz,1H),2.23–2.13(m,1H),1.97–1.89(m,1H).13C NMR(151MHz,DMSO-d6)δ155.95,139.99,138.22,132.41,132.00,131.24,130.14,129.16,127.80,115.63,80.97,80.30,80.04,78.52,77.39,75.38,72.75,66.86,61.26,60.19,38.08,32.91.HRMS(EI)m/z cacld C24H29ClO7 +[M]+464.1596,found464.1603.
实施例12(2S,3R,4R,5S,6R)-2-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-6-(甲氧基甲基)四氢-2H-吡喃-3,4,5-三醇(目标化合物I-8)的制备
将恩格列净(EMPA,3.00g,6.65mmol)溶于20mL甲醇中,室温下加入2,3-丁二酮(2,3-Butanedione,1.5mL,17.25mmol)、三乙氧基甲烷(triethoxymethane,3.6mL,21.62mmol)与三氟化硼乙醚(Boron trifluoride etherate,1.92mL),60℃反应4h,自然冷却至室温,加入9mL三乙胺,反应0.5h,停止反应,蒸干溶剂,硅胶柱层析分离纯化(V石油醚:V乙酸乙酯=2:1),得到白色固体,收率36%。将上述白色固体(250mg,619.41μmol)与四氟硼酸(42%inwater,Tetrafluoroborate,73μL)溶于5mL二氯甲烷中,0℃滴加三甲基硅烷化重氮甲烷(Trimethylsilanated diazomethane,0.25mL),20min后再滴加0.13mL三甲基硅烷化重氮甲烷,20min后再滴加0.06mL三甲基硅烷化重氮甲烷,20min后再滴加0.06mL三甲基硅烷化重氮甲烷,恢复室温反应0.5h,停止反应,加入水和二氯甲烷萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,得到白色固体,收率54%。将上述白色固体(130mg)溶于5mL的80%的三氟乙酸水溶液,室温反应2h,停止反应,用NaOH水溶液调节溶液pH至碱性,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V甲醇:V二氯甲烷=1:30),得到终产物,产物白色固体,收率42%。1H NMR(400MHz,DMSO-d6)δ7.38(d,J=8.2Hz,1H),7.27(d,J=2.1Hz,1H),7.19(dd,J=8.2,2.1Hz,1H),7.13–7.08(m,2H),6.86–6.80(m,2H),5.06(d,J=5.5Hz,1H),5.00(d,J=4.8Hz,1H),4.98–4.94(m,1H),4.86(d,J=5.7Hz,1H),4.01–3.96(m,3H),3.86(dd,J=10.0,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.70(m,2H),3.57(d,J=10.5Hz,1H),3.44–3.35(m,2H),3.27–3.22(m,1H),3.21(s,3H),3.12(dtd,J=11.6,9.2,5.7Hz,2H),2.18(dtd,J=14.2,8.2,6.3Hz,1H),1.93(dt,J=12.6,5.7Hz,1H).13C NMR(151MHz,DMSO-d6)δ155.96,140.01,138.32,132.41,131.96,131.08,130.19,129.20,127.70,115.63,81.15,80.00,78.71,77.39,75.06,72.75,72.69,70.71,66.86,58.97,38.03,32.91.HRMS(EI)m/z cacld C24H29ClO7 +[M]+464.1596,found464.1604.
实施例13(2S,3S,4R,5R,6R)-2-(4-氯-3-(4-((((S)-四氢呋喃-3-基)氧基)苄基)苯基)-3,4,5-三甲氧基-6-(甲氧基甲基)四氢-2H-吡喃(目标化合物I-9)的制备
将恩格列净(EMPA,1.00g,2.22mmol)、氢化钠(Sodium hydride,234.17mg,9.76mmol)与碘甲烷(Iodomethane,1.57g,11.09mmol)溶于10mL DMF中,室温反应4h,停止反应,加入水和乙酸乙酯萃取,有机相经饱和食盐水和硫酸钠干燥处理后蒸干,硅胶柱层析分离纯化(V乙酸乙酯:V石油醚=1:5),得到产物终产物,白色固体,收率94%。1H NMR(400MHz,DMSO-d6)δ7.42(d,J=8.2Hz,1H),7.28(d,J=2.1Hz,1H),7.23(dd,J=8.2,2.1Hz,1H),7.12–7.07(m,2H),6.83(d,J=8.7Hz,2H),4.96(ddt,J=6.4,4.0,1.8Hz,1H),4.08(d,J=9.5Hz,1H),4.00(s,2H),3.86(dd,J=10.0,4.6Hz,1H),3.82–3.77(m,1H),3.76–3.71(m,2H),3.52(s,3H),3.47(d,J=3.4Hz,2H),3.44(s,3H),3.42–3.39(m,1H),3.27(d,J=8.9Hz,1H),3.24(s,3H),3.10(t,J=9.2Hz,1H),2.99(t,J=9.2Hz,1H),2.90(s,3H),2.18(dtd,J=13.4,8.2,6.2Hz,1H),1.96–1.88(m,1H).13C NMR(151MHz,DMSO-d6)δ156.00,139.05,138.83,132.83,131.93,130.94,130.16,129.55,127.46,115.66,87.89,85.12,79.86,79.71,78.52,77.39,72.73,71.72,66.85,60.41,60.13,59.88,59.01,37.88,32.90.HRMS(EI)m/z cacld C27H35ClO7 +[M]+506.2066,found 506.2069.
二、药效评价
效果实施例1本发明芳基C-葡萄糖衍生物对心肌细胞的保护作用
大鼠心肌细胞(H9c2)购买于中国科学院干细胞库。心肌细胞用高糖DMEM(含10%胎牛血清,1%青霉素/链霉素)培养基,并置于37℃,5% CO2的培养箱中培养。待心肌细胞基本长满细胞培养皿(10cm)后,用胰酶将细胞消化下来,并以8000个/孔的细胞密度种到96孔板中,每孔100uL。培养过夜后,将用DMEM培养基稀释后的药物溶液加到板中,每孔100μL。在细胞培养箱中孵育48h。
去除DMEM培养基,用PBS洗1次。化合物用无糖无血清的DMEM稀释至目标浓度,加入到板中,进行糖剥夺(Glucose deprivation,GD)处理。GD 36-48h后,观察细胞存活状态(模型组(即DMSO组)存活率控制在50%为宜,能够较好的突出化合物的细胞保护作用),用cck8检测细胞存活率。其中对照组为正常培养组,未加药(未加DMSO)且细胞未进行糖剥夺处理,其存活率作为100%。表中的化合物和DMSO组的细胞均进行了糖剥夺处理,活性数据如表1和2所示。
表1化合物I-1~I-10在GD模型下对心肌细胞的保护作用(0.1μM~50μM)
数据为平均值±SD,n=3,####p<0.0001vs对照组,*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs DMSO组。在每个化合物不同浓度下的存活率中,第一次出现星号的浓度表示最低起效浓度,第二次出现星号的浓度表示最大药效浓度。
表2化合物I-1~I-10在GD模型下对心肌细胞的保护作用(100μM~400μM)
数据为平均值±SD,n=3,####p<0.0001vs对照组,*p<0.05,**p<0.01,***p<0.001,****p<0.0001vs DMSO组。在每个化合物不同浓度下的存活率中,第一次出现星号的浓度表示最低起效浓度,第二次出现星号的浓度表示最大药效浓度。
由表格数据可以看出,I-2~I-8衍生物对心肌细胞的最大保护作用均明显优于阳性药恩格列净,化合物I-1在400μM浓度下的细胞保护作用优于恩格列净,化合物I-9在50μM浓度下的细胞保护作用优于恩格列净,化合物I-10最大细胞保护作用据恩格列净相当,但起效浓度较恩格列净降低5倍。综上所述,本发明所涉及的化合物均表现出优于EMPA的抗心衰作用,特别是化合物I-2起效浓度降至1μM,较恩格列净的低效浓度降低50倍,是具有潜力的抗心衰候选化合物。
效果实施例2优选衍生物在大孔板中的心肌细胞保护作用
为进一步验证这类衍生物的抗心衰药效,将H9c2细胞种到24孔板中,贴壁后加入用DMEM配制的EMPA和化合物I-2稀释液,预给药48h。移除高糖DMEM,用PBS洗一次,加入用无糖无血清的DMEM配制的EMPA和化合物I-2稀释液,缺糖处理48h。取50uL培养基至96孔板中,用LDH检测试剂盒检测培养基中LDH的释放。其中,NG组未进行糖剥夺处理;DMSO组和给药组均进行GD处理。
图1、2和3中,数据为平均值±SD,t检验,#P<0.05,##P<0.01,###P<0.001,####P<0.0001vs NG,*P<0.05,**P<0.01,***P<0.001,****P<0.0001vs DMSO。
实验结果如图3,化合物I-2在50μM和100μM浓度下LDH的释放都低于恩格列净组,说明其细胞保护作用要优于恩格列净。
将培养基移除,细胞置于冰上,用预冷的PBS洗两次,每次3~5分钟。用预冷的甲醇于-20℃固定10分钟。移除甲醇,恢复至室温,加入足量的0.5%结晶紫染色液,室温孵育10分钟。移除结晶紫,用清水清洗细胞,直至不褪色。将细胞置于37℃烘箱烘干,显微镜进行拍照,Image J进行染色定量。
实验结果如图1和图2所示。与LDH释放的结果一致,I-2给药组的细胞存活率要高于恩格列净处理组,进一步说明化合物I-2抗心衰药效要优于恩格列净。
效果实施例3优选的衍生物对NHE1的抑制作用
1、实验原理
在本实验中,我们通过NH4Cl溶液将细胞内的环境调成酸性,pH值下降。当移除NH4Cl后,细胞内的H+外流,使胞内pH恢复正常水平,如果化合物抑制NHE1,那么胞内H+无法外流,导致细胞内的pH仍处于较低的水平,胞内pH水平可以通过荧光探针检测。BCECF AM是一种可以穿透细胞膜的荧光染料。BCECF AM本身没有荧光,进入细胞后可以被细胞内的酯酶剪切成BCECF,从而被滞留在细胞内。BCECF在适当的pH值情况下可以被激发形成绿色荧光。检测时激发波长为488nm,发射波长为535nm,且荧光强度随着pH的增加而增大。
本实施例中应用到的阳性药为卡立伯来德(Cariporide,Car)、EMPA。卡立伯来德如下式所示:
2、实验步骤
(1)在检测pH变化之前,先检测化合物在高浓度下是否对细胞存活造成影响。用HBSS将化合物稀释成目标浓度。待检测的细胞(长满)去除培养基,HBSS洗3次,加入稀释后的化合物,37℃孵育30min,用cck8检测细胞存活率。
(2)取适量BCECF AM(S1006,Beyotime)母液,用HBSS稀释至10μM的工作液;
(3)对于待检测的培养细胞(长满),去除培养液,用HBSS洗3次;
(4)每孔加入50μL的BCECF AM工作液。将待测化合物与80mM的NH4Cl溶液1:1混合,然后每孔加入50μL的化合物与NH4Cl混合溶液;
(5)37℃,孵育30min进行荧光探针装载;
(6)随后用HBSS洗涤3次,每孔再加入100μL HBSS,用多功能荧光酶标仪(激发488nm,发射波长535nm)定量检测BCECF AM的荧光,以确定细胞内PH值的变化。
实验结果如图4和图5所示。其中,图4表明,阳性药Cariporide、EMPA、化合物I-2在200μM和500μM的浓度下处理细胞30分钟没有产生细胞毒性,图5表明化合物I-2在同等浓度下对NHE1的抑制活性要优于EMPA。
其中,图4和图5中,数据为平均值±SD,t检验,*P<0.05,**P<0.01,***P<0.001,****P<0.0001vs DMSO。
效果实施例4优选的衍生物体内抗心衰作用
1、实验原理
盐酸异丙肾上腺素是建立心力衰竭模型常用的诱导剂。皮下注射盐酸异丙肾上腺素会使小鼠心率加快、心肌持续强烈收缩,使心肌耗氧量增大,加重心脏负荷,最终引起心力衰竭。
2、实验方法
将平均体重在21-22g左右的C57/6J雄鼠分为5组分别为对照组(Sham)、模型组(Vehicle)、恩格列净30mg/kg组、恩格列净10mg/kg组、化合物I-2 10mg/kg组,每组8只小鼠。每天上午灌胃给药,对照组和模型组给等量溶媒(5%DMSO+95%水)。模型组和给药组中,盐酸异丙肾上腺素每天皮下注射两次,上午和晚上,第1-2天每次剂量为40mg/kg,第3-7天每次剂量为20mg/kg,第8-14天剂量为10mg/kg,对照组注射等量不含盐酸异丙肾上腺素的生理盐水。第15天采用Visual-Sonics Vevo 3100小动物高分辨率显微超声成像系统评价各组实验小鼠的心脏结构及功能,取3个心动周期,测量收缩期室间隔厚度(IVSs)、舒张期室间隔厚度(IVSd)、左心室收缩期内径(LVIDs)、左心室舒张期内径(LVIDd)、左心室收缩期后壁厚度(LVPWs)、左心室舒张期后壁厚度(LVPWd),计算射血分数(EF)、短轴缩短率(FS),用Graph Pad软件进行数据处理,计算显著性差异(Unpaired t-test)。
3、结果
如图6~16所示,模型组的小鼠心功能显著减退,收缩/舒张期左心室室间隔厚度和后壁厚度明显变薄,内径变大,射血分数和短轴缩短率降至正常范围以下(射血分数正常小鼠参考值为55-85%,短轴缩短率正常小鼠参考值为30-50%),心肌纤维化显著增加。恩格列净30mg/kg剂量给药组能有效的改善盐酸异丙肾上腺素造成的心功能减退及纤维化,但10mg/kg的剂量并不能明显改善心功能,而化合物I-2在10mg/kg剂量就能明显改善小鼠的心功能,降低心肌纤维化程度,说明化合物I-2在体内起效剂量要低于恩格列净,同等剂量下药效由于恩格列净。
其中,图6至图13中,数据为平均值±SD,t检验,#P<0.05,##P<0.01,###P<0.001,####P<0.0001vs sham,*P<0.05,**P<0.01,***P<0.001,****P<0.0001vs vehicle。图14至图16中,数据为平均值±SD,t检验,#P<0.05,##P<0.01,###P<0.001,####P<0.0001vs sham,*P<0.05,**P<0.01,***P<0.001,****P<0.0001vs vehicle。
效果实施例5
1、实验原理
冠脉结扎后导致心肌梗死与心肌肥厚,最终过渡到心力衰竭,可用于评价长期服用药物对心衰的预防作用。
2、实验方法
C57/6J雄鼠分为2组,DMSO处理组和I-2处理组,每组20只,左前降支冠状动脉结扎手术前DMSO或I-2分别预给药1周,每天灌胃给药,I-2组给予10mg/kg的化合物I-2,DMSO组给予相同体积的含5%DMSO的水溶液。1周后进行手术建模,流程入下:开启小动物气体麻醉机,将小鼠放入气体麻醉机chamber中,待小鼠全身放松昏迷后,将小鼠取出,固定在自制鼠板上,用脱毛膏将小鼠的左胸部和脖子处的皮毛脱掉,快速切开下巴以下的肌肉组织,找到气管,将连有呼吸机和麻醉机的插管经口腔插到气管中,辅助呼吸。在小鼠心脏部位第3、4肋间隙位置沿着腋窝与胸骨下端连线做1.5cm的切口,钝性分离胸大肌肉与肋骨外肌肉,于第3~4肋间穿破肋间隙,用自制撑开器撑开胸腔,剥开心包。在光源下,于左心耳右下缘可见左冠状动脉,以左心耳下缘水平线为标志,在线下2mm处以7-0手术丝线结扎冠脉,进针深度1mm左右,避免刺破心脏。结扎完毕,可见左心室前壁颜色由鲜红变为暗紫至苍白色,快速将心脏推入胸腔,盖上心包膜,挤出胸内气体,依次将肋骨、皮肤缝合,脖子处伤口缝合,用碘伏消毒伤口,待小鼠苏醒。术后不再给予药物干预,术后记录小鼠的生存率,并绘制生存曲线,并在第9天分别进行心功能检测以及心肌梗死面积和纤维化面积的检测。
3、结果
如图17-28所示,I-2在10mg/kg的剂量下可明显提高术后小鼠的生存率,显著改善术后小鼠的心功能、心肌肥厚以及心肌纤维化,而在我们以前的研究中,EMPA在10mg/kg的剂量下无法提高术后小鼠的生存率。该实验进一步说明,I-2的抗心衰药效优于EMPA。
其中,图17至图25中,数据为平均值±SD,t检验,*P<0.05,**P<0.01,***P<0.001,****P<0.0001vs DMSO。图26至图28中,数据为平均值±SD,t检验,*P<0.05,**P<0.01,***P<0.001,****P<0.0001vs DMSO。
Claims (12)
1.如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐;
其中,
R1-R3独立地为H或C1-C6烷基;
R4为CH2OH,R1-R3至少有一个为C1-C6烷基,其余为H;
或者,R4为CH2OR4-1,R1-R3独立地为H,R4-1为C1-C6烷基;
其中排除:R4为CH2OH时,R1-R3均为C1-C6烷基的情形;
R5为“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”;
R6为卤素。
2.如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐,其特征在于,所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种:
(1)R1、R2、R3和R4-1中,所述C1-C6烷基独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基;
(2)R5中,所述“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”为“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-6元杂环烷基”;
(3)R6中,所述卤素为F、Cl、Br或I。
3.如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐,其特征在于,所述的如式I所示的芳基C-葡萄糖苷衍生物满足下述条件中的一种或多种:
(1)R1、R2、R3和R4-1中,所述C1-C6烷基独立地为甲基、乙基或正丙基;
(2)R5中,所述“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”为四氢呋喃基;
(3)R6中,所述卤素为Cl。
4.如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐,其特征在于,
R5中,所述“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”为
5.如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐,其特征在于,
R5中,所述“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”为
6.如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐,其特征在于,R4为CH2OH,R1-R3至少有一个为C1-C6烷基,其余为H;或者,R4为CH2OR4-1,R1-R3独立地为H,R4-1为C1-C6烷基;
其中排除R4为CH2OH,R1-R3均为C1-C6烷基的情形;
R5为“杂原子选自N、O和S中的1种、2种或3种,杂原子数为1、2或3个的3-12元杂环烷基”;
R6为Cl。
7.如权利要求1所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐,其特征在于,如式I所示的芳基C-葡萄糖苷衍生物为如下任一化合物:
8.如权利要求7所述的如式I所示的芳基C-葡萄糖苷衍生物的制备方法,其包括以下任一方法:
方法二:
(1)在室温下,EMPA用苯甲醛二甲缩醛和樟脑磺酸在N,N-二甲基甲酰胺中处理得中间体式IIA化合物;
(2)在冰浴下,叔丁基二甲基氯硅烷和咪唑在DMF中处理式IIA化合物得中间体式IIB化合物;
(3)在室温下,式IIB化合物在无机碱钠氢的存在下经R1I处理,待反应结束后再经90%的醋酸水溶液处理得如式I-2~I-4所示的芳基C-葡萄糖苷衍生物;如流程2所示:
流程2:
方法三:
在室温下,式IIA化合物在无机碱氢氧化钠的存在下经卤代烃处理,待反应结束后再经90%的醋酸水溶液处理得如式I-5、I-6所示的芳基C-葡萄糖苷衍生物;如流程3所示:
流程3:
方法四:
包括步骤:
(1)在60℃下,将EMPA溶于甲醇中,与2,3-丁二酮和三乙氧基甲烷反应,得中间体式IIC化合物;
(2)在室温下,碘甲烷和氧化银在DMF中处理式IIC化合物,待反应结束后再经80%三氟乙酸处理,得如式I-7所示的芳基C-葡萄糖苷衍生物;如流程4所示:
流程4
方法五:
包括步骤:
(1)在60℃下,将EMPA溶于甲醇中,与2,3-丁二酮和三乙氧基甲烷反应,得中间体式IID化合物;
(2)在冰浴下,四氟硼酸和三甲基硅烷化重氮甲烷在二氯甲烷中处理式IID化合物,待反应结束后再经80%三氟乙酸处理得如式I-8所示芳基C-葡萄糖苷衍生物;如流程5所示:
流程5:
9.一种药物组合物,其特征在于,所述药物组合物包括:
(1)如权利要求1-7任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐;和
(2)药学上可接受的载体或赋形剂。
10.如权利要求1-7任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐或如权利要求9所述药物组合物的用途,其用于制备a)抑制钠氢交换器的抑制剂和/或b)预防和/或缓解和/或治疗钠氢交换器相关的疾病的药物。
11.如权利要求10所述的用途,其特征在于,所述的钠氢交换器为NHE1;
和/或,所述钠氢交换器相关的疾病为心力衰竭。
12.如权利要求1-7任一项所述的如式I所示的芳基C-葡萄糖苷衍生物、其立体异构体或前述任一者的药学上可接受的盐或如权利要求9所述药物组合物用于制备具有以下一种或多种作用的药物的用途:
A1)保护心肌细胞;
A2)收缩/舒张期左心室室间隔厚度变厚;
A3)收缩/舒张期左心室后壁厚度变厚;
A4)收缩/舒张期左心室内径变小;
A5)射血分数升高;
A6)短轴缩短率升高。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996036628A1 (en) * | 1995-05-19 | 1996-11-21 | Biota Scientific Management Pty. Ltd. | 6-carboxamido dihydropyran derivatives |
US20060009400A1 (en) * | 2004-07-06 | 2006-01-12 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
US20060074031A1 (en) * | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim International Gmbh | D-pyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
CN1930141A (zh) * | 2004-03-16 | 2007-03-14 | 贝林格尔·英格海姆国际有限公司 | 吡喃葡萄糖基取代的苯基衍生物、含该化合物的药物、其用途及其制造方法 |
CN102159206A (zh) * | 2008-09-19 | 2011-08-17 | 诺瓦提斯公司 | 糖苷衍生物及其作为sglt抑制剂的用途 |
CN103864737A (zh) * | 2012-12-17 | 2014-06-18 | 天津药物研究院 | 含脱氧葡萄糖结构的苯基c-葡萄糖苷衍生物及其制备方法和用途 |
WO2015158206A1 (zh) * | 2014-04-14 | 2015-10-22 | 上海迪诺医药科技有限公司 | C-芳基糖苷衍生物、其药物组合物、制备方法及应用 |
-
2022
- 2022-12-09 CN CN202211589504.2A patent/CN115991702B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1996036628A1 (en) * | 1995-05-19 | 1996-11-21 | Biota Scientific Management Pty. Ltd. | 6-carboxamido dihydropyran derivatives |
CN1930141A (zh) * | 2004-03-16 | 2007-03-14 | 贝林格尔·英格海姆国际有限公司 | 吡喃葡萄糖基取代的苯基衍生物、含该化合物的药物、其用途及其制造方法 |
US20060009400A1 (en) * | 2004-07-06 | 2006-01-12 | Boehringer Ingelheim International Gmbh | D-xylopyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
US20060074031A1 (en) * | 2004-10-01 | 2006-04-06 | Boehringer Ingelheim International Gmbh | D-pyranosyl-substituted phenyl derivatives, medicaments containing such compounds, their use and process for their manufacture |
CN102159206A (zh) * | 2008-09-19 | 2011-08-17 | 诺瓦提斯公司 | 糖苷衍生物及其作为sglt抑制剂的用途 |
CN103864737A (zh) * | 2012-12-17 | 2014-06-18 | 天津药物研究院 | 含脱氧葡萄糖结构的苯基c-葡萄糖苷衍生物及其制备方法和用途 |
WO2015158206A1 (zh) * | 2014-04-14 | 2015-10-22 | 上海迪诺医药科技有限公司 | C-芳基糖苷衍生物、其药物组合物、制备方法及应用 |
CN105001213A (zh) * | 2014-04-14 | 2015-10-28 | 上海迪诺医药科技有限公司 | C-芳基糖苷衍生物、其药物组合物、制备方法及应用 |
Non-Patent Citations (3)
Title |
---|
C-芳基糖苷类SGLT2抑制剂的合成研究进展;杜铁奇;郑亿;朱灵龙;钟为慧;;浙江化工;第46卷(第9期);第19-23页 * |
Efficient synthesis of empagliflozin, an inhibitor of SGLT-2, utilizing an AlCl3- promoted silane reduction of a β-glycopyranoside;Wang X J等;Org. Lett.;第16卷;第4090-4093页 * |
Structural repurposing of SGLT2 inhibitor empagliflozin for strengthening anti-heart failure activity with lower glycosuria;Yixiang Xu等;Acta Pharmaceutica Sinica B;第13卷(第4期);第1671-1685页 * |
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