CN111057059B - 一种苯并二四氢吡咯类化合物或其药学上可接受的盐、及其制备方法和应用 - Google Patents
一种苯并二四氢吡咯类化合物或其药学上可接受的盐、及其制备方法和应用 Download PDFInfo
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- CN111057059B CN111057059B CN201911166962.3A CN201911166962A CN111057059B CN 111057059 B CN111057059 B CN 111057059B CN 201911166962 A CN201911166962 A CN 201911166962A CN 111057059 B CN111057059 B CN 111057059B
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Abstract
本发明公开了一种苯并二四氢吡咯类化合物或其药学上可接受的盐、及其制备方法和应用。本发明的苯并二四氢吡咯类化合物具有式I所示的结构，经体外和体内实验验证，对DPP‑Ⅳ具有非常好的选择性抑制作用，在有效抑制DPP‑Ⅳ活性的同时，对DPP‑VIII和DPP‑IX的活性几乎没有影响，同时钾离子通道抑制率较低，可预见本发明化合物开发成药后毒性会比较低。本发明的苯并二四氢吡咯类化合物与上市的每周口服一次药物奥格列汀相比有相当或有更高的生物利用效率，可预见本发明化合物开发后有望达到较长时间口服一次的治疗效果，大大提高患者的便利性和依从性。并且制备方法简单，原料易得，适合工业化大规模生产。
Description
技术领域
本发明属于医药技术领域，具体涉及一种苯并二四氢吡咯类化合物或其药学上可接受的盐、及其制备方法和应用。
背景技术
糖尿病是由于胰岛素的绝对或相对不足造成血糖升高，从而引发严重的并发症，最终导致病人的致残或致死。临床上将糖尿病分为I型与II型。I型糖尿病是由于胰岛β-细胞被破坏，缺乏胰岛素分泌，从而引发血糖升高，这类患者只能依赖于外源性胰岛素；II型糖尿病是由于胰岛素分泌相对不足或胰岛素作用环节不健全引发高血糖，它的发病率约占所有糖尿病患者人数的90％以上。目前的药物研究主要是针对于2型糖尿病(T2DM)展开的。
促进胰岛β-细胞分泌胰岛素是治疗T2DM的主要手段，但传统降糖药物胰岛素增敏剂(如双胍类，噻唑烷二酮类等)和胰岛素促分泌剂(如磺酰脲类和非磺酰类药物)等在治疗的同时，往往导致低血糖、增加体重、引发心血管的病态反应和β-细胞死亡等副作用。因此，如何减少并发症和不良副作用，已是治疗T2DM的主要方向。
胰高血糖素样肽酶-1(GLP-1)是一种内源性的激素，随着餐后血糖的升高，由小肠中的 L细胞分泌产生，进而刺激胰岛素的分泌。因此，GLP-1的分泌与血糖的摄入量密切相关。基于GLP-1的治疗方案可以有效地控制血糖而不增加体重，不会产生低血糖等不良反应。 GLP-1作为二肽基肽酶-IV(DPP-IV)的底物，半衰期很短，分泌后1-2分钟之内就会被DPP-IV 迅速剪切失活。研究显示，DPP-IV对底物的剪切部位恒定，均为其N端倒数第二位的脯氨酸或丙氨酸。如果抑制DPP-IV的活性，就会间接的提高体内GLP-1的含量，从而引起体内一系列的生理，刺激胰岛素的分泌，达到治疗T2DM的目的。
DPP-IV抑制剂作为一种新的口服抗糖尿病药物，能够阻止肠降血糖素激素的快速降解，提高餐后GLP-1的水平，毒副作用小，药效明显，无论是单独给药还是联合用药，发生低血糖的风险很小，至今为止是比较安全有效的药物，已经成为治疗T2DM的一个新选择。
目前，DPP-IV抑制剂的研究已取得较大的突破，上市的药物有默克公司的Sitagliptin、诺华公司的Vildagliptin、百时美施贵宝公司的Saxagliptin、武田公司的Alogliptin和勃林格殷格翰公司的Linagliptin等，同时还有数十个品种处于临床研究阶段。2015年3月，武田公司的Trelagliptin获准在日本上市，它是一个长效DPP-IV抑制剂，每周口服一次，而市场上同类DPP-4抑制剂需要每天口服一次。同时，默克公司也正在开发一款长效DPP-4抑制剂 Omarigliptin，试验显示每周口服一次，目前该药物临床试验已获得成功，并已在日本申请上市批准。长效DPP-IV抑制剂的用药优势无疑将为糖尿病患者提供了更为方便的治疗选择，有望大幅改善患者的便利性和依从性，将成为DPP-IV抑制剂研究的新方向。
但是，这两个药物都可能因安全性原因没有向FDA及在欧洲申请上市。因此，在本领域，期望开发出更多能够长时间有效安全控制血糖的药物，基于此，完成此发明。
发明内容
本发明的目的是提供一种苯并二四氢吡咯类化合物或其药学上可接受的盐和应用。该类化合物是一种有效的DPP-IV抑制剂，能够有效降低血糖，同时不引起体重增加和低血糖等风险，且能达到长时间控制血糖的治疗效果。
为达此目的，本发明采用以下技术方案：
一方面，本发明提供了一种苯并二四氢吡咯类化合物或其药学上可接受的盐，所述的苯并二四氢吡咯类化合物具有式I所示的结构：
其中，R1选自氢、羟基、C1～C6直链或支链的饱和或不饱和烃基、C3～C7环烃基、4～7 元杂环基、C1～C6烷基酰基、C1～C6烷基磺酰基、C1～C6烷基亚磺酰基、C3～C7环胺基酰基、5～7元杂环胺酰基、芳基、苄基、芳基酰基、芳基酰基亚甲基、5～7元杂芳基、5～7元杂芳基亚甲基、5～7元杂芳基酰基或5～7元杂芳基酰基亚甲基；
R2和R3分别独立地选自氢、卤素、氨基、氰基、硝基、C1～C6直链或支链的饱和或不饱和烃基、C3～C7环烃基、4～7元杂环基、C1～C4烷基酰基、C3～C7环胺基酰基、5～7元杂环胺酰基、芳基、苄基、芳基酰基、芳基酰基亚甲基、5～7元杂芳基、5～7元杂芳基亚甲基、 5～7元杂芳基酰基或5～7元杂芳基酰基亚甲基。
优选地，所述的苯并二四氢吡咯类化合物具有式II所示的结构：
其中，R1具有如上述所示的范围；
本发明中，R1～R3中所述C1～C6直链或支链的饱和或不饱和烃基、C1～C4烷基酰基、C3～C7 环烃基、C1～C6烷基酰基、C1～C6烷基磺酰基、C1～C6烷基亚磺酰基、芳基、苄基、芳基酰基、芳基酰基亚甲基、5～7元杂芳基、5～7元杂芳基亚甲基、5～7元杂芳基酰基或5～7元杂芳基酰基亚甲基的碳上的氢被一个或多个R11所取代；所述R11选自卤素、羰基、羟基、氨基、硝基、巯基、氰基、C1～C3烷磺基或C1～C3烷氧基；R1～R3中所述4～7元杂环基的氮上的氢或5～7元杂环胺酰基的氮上的氢被一个或多个R12所取代；所述R12选自C1～C6烷基、C1～C6 烷酰基或C1～C3烷磺基。
当R2和R3选自氢、卤素、氨基、氰基、硝基、C1～C6直链或支链的饱和或不饱和烃基、C3～C7环烃基、4～7元杂环基、C1～C4烷基酰基、C3～C7环胺基酰基、5～7元杂环胺酰基、芳基、苄基、芳基酰基、芳基酰基亚甲基、5～7元杂芳基、5～7元杂芳基亚甲基、5～7元杂芳基酰基或5～7元杂芳基酰基亚甲基；优选地，R1选自氢、C1～C6直链或支链的饱和或不饱和烃基、C3～C7环烃基、C1～C6烷基酰基、C1～C6烷基磺酰基、苄基、芳基酰基、芳基酰基亚甲基、5～7元杂芳基亚甲基或5～7元杂芳基酰基。
优选地，所述苯并二四氢吡咯类化合物选自以下化合物中的任意一种：
本发明包括式I-II化合物的游离形式，也包括其药学上可接受的盐的形式存在。
优选地，所述的苯并二四氢吡咯类化合物的药学上可接受的盐为苯并二四氢吡咯类化合物的酸加成盐或碱加成盐。
当本发明化合物具备游离碱的形式时，使化合物的游离碱形式与药学上可接受的无机或有机酸反应，可以制备本发明化合物的酸加成盐。
优选地，所述苯并二四氢吡咯类化合物的酸加成盐包括但不限于：盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硫酸盐、硝酸盐、乙磺酸盐、甲苯磺酸盐、苯磺酸盐、乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、抗坏血酸盐、水杨酸盐、丙二酸盐、己二酸盐、己酸盐、精氨酸盐、富马酸盐、烟酸盐、邻苯二甲酸盐和草酸盐。
当本发明苯并二四氢吡咯类化合物具备游离酸的形式时，使其游离酸形式与药学上可接受的无机或有机碱反应可以制备本发明化合物的碱加成盐。
优选地，所述苯并二四氢吡咯类化合物的碱加成盐包括但不限于噻吩并嘧啶酮类化合物的锂盐、钠盐、钾盐、钡盐、钙盐、镁盐、铝盐、铁盐、亚铁盐、铜盐、锌盐，和噻吩并嘧啶酮类化合物与吗啉、二乙胺、三乙胺、异丙胺、三甲胺、赖氨酸或组胺酸组成的盐。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
术语“烷基酰基”指RCO类取代基，其中，R表示烷基。
术语“芳基酰基”指ArCO类取代基，其中，Ar表示芳基。
术语“烷基磺酰基”指RSO2类取代基，其中，R表示烷基。
术语“芳基磺酰基”指ArSO2类取代基，其中，Ar表示芳基。
术语“芳基酰基亚甲基”指ArCOCH2类取代基，其中，Ar表示芳基。
术语“杂芳基酰基亚甲基”指ArCOCH2类取代基，其中，Ar表示杂芳基。
术语“杂芳基亚甲基”指ArCH2类取代基，其中，Ar表示杂芳基。
术语“环胺基酰基”指
术语“杂环胺酰基”指
X代表N,O,S杂原子。
在本发明中，所述C1～C6直链或支链的饱和或不饱和烃基是指含有1、2、3、4、5或6个碳原子的直链或支链的饱和或不饱和烃基；所述C3～C7环烃基是指含有3、4、5、6或7 个碳原子的环状烃基，所述4～7元杂环基是指4元、5元、6元或7元杂环基；所述C1～C4 烷基酰基是指含有1、2、3或4个碳原子的烷基酰基，C3～C7环胺基酰基是指含有3、4、5、 6或7个碳原子的环胺基酰基，5～7元杂环胺酰基是指5元、6元或7元的杂环胺酰基，同理 5～7元杂芳基、5～7元杂芳基亚甲基、5～7元杂芳基酰基以及5～7元杂芳基酰基亚甲基中所述 5～7元同样是指5元、6元或7元的所述基团。
另一方面，本发明提供了如上所述的苯并二四氢吡咯类化合物或其药学上可接受的盐的制备方法，所述制备方法的合成路线如下(主要包括步骤(1)-(5))：
其中：R1、R2、R3定义如上述通式I化合物中所述。
步骤(1)中，将R2、R3取代的四溴甲基苯与三氟乙酰胺反应，得到化合物A；
步骤(2)中，将化合物A在强碱中水解，得到化合物B；
步骤(3)中，将化合物B与2-(2’,5’-二氟苯基)-3-氨基-5-氢化吡喃酮(中间体C)在碱性条件(base)下水解，得到化合物D；
步骤(4)中，将化合物D与X-R1(X＝I、Br、Cl、OTs、OMs、OTf)反应，得到化合物E；
步骤(5)中，将化合物E脱去Boc保护基，得到通式化合物I；
具体合成步骤如下：
步骤(1)中，将R2、R3取代的四溴甲基苯溶于四氢呋喃等有机溶剂，加入4当量的三氟乙酰胺，-5至5℃缓慢加入6当量的钠氢(60wt％in oil)，0℃至室温搅拌30分钟以上，然后再升温至回流搅拌3小时以上，TLC检测无原料后，萃取，水洗，干燥，减压蒸除溶剂，浓缩物用柱层析纯化得到化合物A；
步骤(2)中，将化合物A悬溶于水/甲醇中，室温缓慢加入10当量的氢氧化钠，升温至回流搅拌约两小时，TLC检测无原料后，降温后减压除去甲醇，析出固体，过滤，用水洗涤滤饼，抽干，得到化合物B；
步骤(3)中，将化合物B溶于N,N-二甲基乙酰胺中，加入等当量的苯甲磺酸，再加入等当量的2-(2’,5’-二氟苯基)-3-氨基-5-氢化吡喃酮(中间体C)，-10℃慢慢加入1.1当量的三乙酰氧基硼氢化钠，保持该温度搅拌10至20小时，TLC检测反应完毕后，加入水，用乙酸乙酯萃取三次，合并有机相，有机相依次用水、饱和食盐水洗，干燥，浓缩，所得浓缩物用柱层析纯化，得到化合物D；
步骤(4)中，将化合物D溶于DMF中，加入1.1当量的碱，-10℃至室温滴加入卤代烃或烷(芳)酰基卤或烷(芳)磺酰基卤代物，在室温至100℃搅拌2至6小时，待反应完毕，降至室温，加入水，用乙酸乙酯萃取三次，合并有机相，有机相依次用水、饱和食盐水洗，干燥，浓缩，所得浓缩物用柱层析纯化，得到化合物E；
步骤(5)中，将化合物E溶于甲醇，室温下滴加入饱和氯化氢甲醇溶液，室温搅拌过夜， TLC检测反应完毕后，减压蒸除过量的甲醇和氯化氢，固体用甲醇溶解，加入过量的碳酸氢钠，搅拌2小时以上，过滤除去固体，滤液减压蒸除溶剂，所得浓缩物用柱层析纯化，得到如上述的通式如式I所示的苯并二四氢吡咯类化合物。
上述制备方法中，各步骤中干燥是以无水硫酸镁或无水硫酸钠为干燥剂，干燥30分钟左右。浓缩是采用常压蒸馏、减压蒸馏或者旋转蒸发方法将溶剂蒸干。
上述制备方法中，步骤(4)中所述的碱可以是无机碱或有机碱，所述的无机碱选自碳酸钠、碳酸钾、碳酸铯、碳酸氢钠、碳酸氢钾、磷酸钾、磷酸二氢钾、氢氧化钠、氢氧化锂和氢氧化钾中的至少一种，所述的有机碱选自三乙胺、吡啶、二氮杂二环(DBU)和N,N-二异丙基乙胺(DIPEA)中的至少一种；步骤(1)中所述的有机溶剂选自四氢呋喃(THF)、二氯甲烷(DCM)、乙酸乙酯(EA)、乙腈、丙酮、1,4-二氧六环、醇类、乙醚、甲苯、N,N-二甲基甲酰胺(DMF)、N,N-二甲基甲酰胺(DMA)、乙二醇二甲醚和二甲基亚砜(DMSO)中的至少一中；步骤(4)中所述的卤代试剂可以是卤素或N-卤代丁二酰亚胺(NXS，X＝I、 Br、Cl)。
另一方面，本发明提供了一种药物组合物，所述的药物组合物包括作为活性成分的如上所述的苯并二四氢吡咯类化合物或其药学上可接受的盐，以及药学上可接受的载体。
在本发明中，所述药学上可接受的载体，可以是液体、半液体或固体形式，按照适合于所用的给药途径的方式配制，其可以用于体内治疗并具有生物相容性。所述药物组合物可以按照下列给药方式给药：口服、肠胃外、腹膜内、静脉内、透皮、舌下、肌内、直肠、口腔、鼻内、脂质体等方式而制备成各种形式。
口服组合物可以是固体、凝胶或液体。固体制剂的实例包括但不限于片剂、胶囊剂、颗粒剂和散装粉剂。这些制剂可以选择地含有粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂和矫味剂等。粘合剂的实例包括但不限于微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；润滑剂的实例包括但不限于滑石、淀粉、硬脂酸镁、硬脂酸钙、硬脂酸；稀释剂的实例包括但不限于乳糖、蔗糖、淀粉、甘露糖醇、磷酸二钙；助流剂的实例包括但不限于二氧化硅；崩解剂的实例包括但不限于交联羧甲基纤维素钠、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂和羧甲基纤维素。
以肠胃外给予本发明组合物，一般以注射为主，包括皮下、肌内或静脉内注射。注射剂可以被制成任何常规形式，如液体溶液或悬液、适合于在注射之前溶解或悬浮在液体中的固体形式或者乳剂。可用于本发明注射剂的药学上可接收的载体的实例包括但不限于水性载体、非水性载体、抗微生物剂、等渗剂、缓冲剂、抗氧剂、悬浮与分散剂、乳化剂、螯合剂和其它药学上可接受的物质。水性载体的实例包括氯化钠注射液、林格式注射液、等渗葡萄糖注射液、无菌水注射液、葡萄糖与乳酸化林格氏注射液；非水性载体的实例包括植物来源的固定油、棉籽油、玉米油、芝麻油和花生油；抗微生物剂的实例包括间甲酚、苄醇、氯丁醇、苯扎氯铵等；等渗剂的实例包括氯化钠和葡萄糖；缓冲剂包括磷酸盐和柠檬酸盐。
本发明组合物还可以制备成无菌的冻干粉针剂，将化合物溶于磷酸钠缓冲溶液，其中含有葡萄糖或其他适合的赋形剂，随后在本领域技术人员已知的标准条件下将溶液无菌过滤，继之以冷冻干燥，得到所需的制剂。
另一方面，本发明提供了如上所述的苯并二四氢吡咯类化合物或其药学上可接受的盐在制备DPP-IV抑制剂中的应用。
另一方面，本发明提供了如上所述的苯并二四氢吡咯类化合物或其药学上可接受的盐在制备治疗和预防受益于DPP-IV抑制的疾病的药物中的应用。
优选地，所述受益于DPP-IV抑制的疾病选自Ⅱ型糖尿病、糖尿病性脂血异常、葡萄糖耐量减低(IGT)症、禁食血浆葡萄糖减低(IFG)症、代谢性酸中毒、酮症、食欲调节、肥胖症、各种癌症、神经系统病症或免疫系统病症，优选Ⅱ型糖尿病或肥胖症。
与现有技术相比，本发明具有以下有益效果：
(1)本发明的苯并二四氢吡咯类化合物或其药学上可接受的盐，具有新型的化学结构，经体外和体内实验验证，对DPP-IV具有非常好的选择性抑制作用，在有效抑制DPP-IV活性的同时，对DPP-VIII和DPP-IX的活性几乎没有影响，同时钾离子通道抑制率较低，可以预见本发明化合物开发成药后毒性也会比较低。
(2)本发明的苯并二四氢吡咯类化合物经初步药效学研究显示，与上市的每周口服一次药物奥格列汀(MK-3102)相比有更高的体外活性和相当或更高的生物利用效率，可预见本发明化合物开发后有望达到较长时间口服一次的治疗效果，大大提高患者的便利性和依从性。经初步药效和药代研究，显示了体内具有较长时间抑制DPP-IV的功效，可望开发为更长时效的DPP-IV抑制剂。
(3)本发明的苯并二四氢吡咯类化合物的制备方法，具有工艺简单，原料易得，适合工业化大规模生产的特点。
具体实施方式
下面通过具体实施方式来进一步说明本发明的技术方案。本领域技术人员应该明了，所述实施例仅仅是帮助理解本发明，不应视为对本发明的具体限制。
在以下的实施例中，样品的分析数据由以下仪器测定：核磁共振由Bruker AMX-400型核磁共振仪测定，TMS(四甲基硅烷)为内标，化学位移单位为ppm，耦合常数单位为Hz；质谱由Agilent1200/MSD质谱仪测定。
柱层析用硅胶200-300目(青岛海洋化工厂生产)；TLC硅胶板为烟台化工厂生产的HSGF-254型薄层层析预制板；石油醚沸程为60-90℃；采用紫外灯，碘缸显色。
除另有说明外，以下实施例中使用的初始原料、反应试剂等均为市售产品。实验中所用试剂及溶剂均按反应具体情况处理。
本发明中使用的试剂缩写字母为本领域常用的表达方式，含义如下：
DCM：二氯甲烷，DIEA：N,N-二异丙基乙胺，DMA：N,N-二甲基乙酰胺，DME：乙二醇二甲醚，DMF：N,N-二甲基甲酰胺，EA：乙酸乙酯，NBS：N-溴代丁二酰亚胺，PE：石油醚，TEA：三乙胺，THF：四氢呋喃，GP-AMC：甘氨酸-脯氨酸-7-氨基-4-三氟甲基香豆素。
实施例1化合物1的合成
合成路线：
合成化合物1-1：
四溴甲基苯(9.0g,20mmol)溶于200mL四氢呋喃，加入三氟乙酰胺(9.0g,80mmol)，0℃缓慢加入钠氢(4.8g,120mmol,60wt％in oil)，渐渐升温至室温搅拌30分钟，然后升温至回流搅拌3小时，TLC检测无原料后，反应液中加入300mL乙酸乙酯稀释，有机相依次用200mL水和饱和食盐水洗涤一次，然后用无水硫酸镁干燥，抽滤，滤液减压蒸除溶剂后，所得浓缩物用柱层析(200-300目硅胶，洗脱液为石油醚/乙酸乙酯，体积比为4:1)纯化得白色固体(化合物1-1)6.0g，产率85％；
MS:353.1[M+H+]。
合成化合物1-2：
将化合物1-1(5.3g,15mmol)悬溶于100mL体积比为1:1的水/甲醇混合溶剂中，室温下慢慢加入氢氧化钠(6.0g,150mmol)，升温至回流，搅拌约2小时，TLC检测无原料后，降温后减压蒸除去甲醇，析出固体，过滤，用水洗涤滤饼，抽干，得到泥黄色固体(化合物1-2)2.0g，产率82％；
1H-NMR(400MHz，DMSO-d6):δ7.08(2H,s),4.00(8H,s)；MS:161.2[M+H+]。
合成化合物1-3：
将化合物1-2(1.9g,12mmol)溶于10mL N,N-二甲基乙酰胺中，室温依次加入苯甲磺酸 (1.9g,12mmol)和2-(2’,5’-二氟苯基)-3-氨基-5-氢化吡喃酮(3.9g,12mmol)，-10℃慢慢加入三乙酰氧基硼氢化钠(2.8g,13mmol)，保持该温度搅拌20小时，TLC检测反应完毕后，加入水 30mL，用乙酸乙酯萃取三次(50mL×3)，合并有机相，有机相依次用等体积的水洗涤三次，饱和食盐水洗涤一次，无水硫酸镁干燥，过滤，滤液减压浓缩，所得浓缩物用柱层析(200-300 目硅胶，洗脱液为二氯甲烷/甲醇，体积比为15:1)纯化，得到黄色固体(化合物1-3)3.0g，产率53％；
MS:472.2[M+H+]。
合成化合物1-4：
将化合物1-3(2.36g,5.0mmol)溶于10mL DMF中，加入三乙胺(0.55g,5.5mmol)，0℃滴加甲磺酰氯(0.63g,5.5mmol)，渐渐升温至室温搅拌2小时，TLC检测反应完毕后，加入水 30mL，用乙酸乙酯萃取三次(50mL×3)，有机相依次用等体积的水洗涤三次，饱和食盐水洗涤一次，无水硫酸镁干燥，过滤，滤液减压浓缩，所得浓缩物用柱层析(200-300目硅胶，洗脱液为二氯甲烷/甲醇，体积比为20:1)纯化，得到白色固体(化合物1-4)2.2g，产率81％；
MS:550.2[M+H+]。
合成化合物1：
将化合物1-4(1.6g,3mmol)溶于20mL甲醇，室温下缓慢加入等体积饱和氯化氢甲醇溶液，室温搅拌过夜，TLC检测反应完毕后，减压蒸除过量的甲醇和氯化氢，固体用甲醇溶解，加入碳酸氢钠调至pH值为8，搅拌2小时以上，过滤除去固体，滤液减压蒸除溶剂，所得浓缩物用柱层析(200-300目硅胶，洗脱液为二氯甲烷/甲醇，体积比10:1)纯化，得到浅黄色固体(化合物1)1.2g，产率88％；
1H-NMR(400MHz，CDCl3):δ7.15-7.14(1H,m),7.10(2H,s),7.07-6.96(1H,m),7.07-6.96 (1H,m),4.67(4H,s),4.29-4.21(2H,m),4.03-3.96(4H,dd,J＝4.0Hz,16.0Hz),3.75-3.72(2H,br), 3.64-3.40(2H,t,J＝10.4Hz),2.95-2.88(1H,m),2.86(3H,s),2.50-2.47(1H,m),1.86-1.83(2H, m)；MS:450.1[M+H+]。
实施例2化合物2的合成
以中间体1-3(化合物1-3)为原料，用三氟甲磺酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物2，后两步收率62％；MS:504.1[M+H+]。
实施例3化合物3的合成
以中间体1-3为原料，用原料异丙基磺酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物3，后两步收率65％；MS:477.1[M+H+]。
实施例4化合物4的合成
以中间体1-3为原料，用原料环丙基磺酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物4，后两步收率67％；MS:476.1[M+H+]。
实施例5化合物5的合成
以中间体1-3为原料，用原料对甲苯磺酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物5，后两步收率67％；MS:526.2[M+H+]。
实施例6化合物6的合成
以中间体1-3为原料，用原料碘甲烷替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物6，后两步收率58％；MS:386.2[M+H+]。
实施例7化合物7的合成
以中间体1-3为原料，用原料三氟碘甲烷替换实施例1中的原料甲磺酰氯，参考实施例1 中后两步的合成方法，合成化合物7，后两步收率51％；MS:440.1[M+H+]。
实施例8化合物8的合成
以中间体1-3为原料，用原料对氟苄溴替换实施例1中的原料甲磺酰氯，参考实施例1 中后两步的合成方法，合成化合物8，后两步收率64％；MS:480.2[M+H+]。
实施例9化合物9的合成
以中间体1-3为原料，用原料乙酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物9，后两步收率66％；MS:414.2[M+H+]。
实施例10化合物10的合成
以中间体1-3为原料，用原料三氟乙酰氯替换实施例1中的原料甲磺酰氯，参考实施例1 中后两步的合成方法，合成化合物10，后两步收率64％；MS:468.1[M+H+]。
实施例11化合物11的合成
以中间体1-3为原料，用原料噻吩-1-甲酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物11，后两步收率60％；MS:482.1[M+H+]。
实施例12化合物12的合成
以中间体1-3为原料，用原料对氟苯甲酰氯替换实施例1中的原料甲磺酰氯，参考实施例1中后两步的合成方法，合成化合物12，后两步收率61％；MS:494.2[M+H+]。
实施例13化合物13的合成
用原料1，4-二氟四溴甲基苯和碘甲烷分别替换实施例1中的原料四溴甲基苯和甲磺酰氯，参考实施例1的合成方法，合成化合物13，总收率24％；MS:422.2[M+H+]。
实施例14化合物14的合成
用原料1，4-二氯四溴甲基苯和碘甲烷分别替换实施例1中的原料四溴甲基苯和甲磺酰氯，参考实施例1的合成方法，合成化合物14，总收率21％；MS:454.1[M+H+]。
实施例15化合物15的合成
用原料1，4-二溴四溴甲基苯和碘甲烷分别替换实施例1中的原料四溴甲基苯和甲磺酰氯，参考实施例1的合成方法，合成化合物15，总收率20％；MS:544.0[M+H+]。
实施例16体外活性实验
本发明提供的化合物1-15对DPP-IV的抑制率可以用DPP-IV-GloTM蛋白水解酶的均相发光检测系统(DPP-IV-GloTMProtease Assay，Promega cat#G8350)测得。
该系统含有DPP-IV底物Gly-Pro-氨基萤光素和萤光素酶活性检测的缓冲液系统，检测原理为：DPPIV-GloTM被DPP-IV切割后会激活萤光素酶反应，产生“glow-type”型发光信号，再用Turner VeritasTM微孔板发光光度计检测发光信号即可表征DPP-IV的活性。
实验目的：测定本发明化合物1-15对DPP-IV酶的抑制活性以及选择性抑制作用。
实验材料：DPP-IV酶、DPP-VIII酶、DPP-IX酶、GP-AMC(BioMol)、黑色96孔板、超级酶标仪；DPP-IV和DPP-VIII的分析缓冲液：100mmol/L Tris/HCl buffer,pH 8.0,0.1mg/mLBSA； DPP-IX的分析缓冲液：100mmol/L Tris/HCl buffer,pH 7.4,0.1mg/mL BSA。
实验方法：
a、酶活性的确定：
将GP-AMC稀释于各自的缓冲液中，浓度为100μmol/L，每孔25μL；酶梯度稀释，起始浓度分别为DPP-VIII、DPP-IX：0.01μg/μL,DPP-IV：0.01mU/μL，按5倍稀释，每孔25μL，混匀；37℃，360/460nm测定荧光值的动态变化，测定30分钟；以吸光度呈直线上升、S/B≥5的酶浓度为使用浓度。
b、抑制剂活性测定：
所有酶、抑制剂、GP-AMC均用分析缓冲液配制，设置无化合物对照、无酶液对照。按酶的使用浓度配制酶液，每孔25μL；梯度稀释抑制剂(10倍或5倍稀释)，每孔25μL，混匀；加入稀释好的GP-AMC溶液50μL，混匀；37℃反应20分钟，360/460nm测定荧光值。
c、数据分析：用GraphPad-Prism软件分析。
实验结果：本发明化合物1-15对三种酶的抑制活性数据如下表1所示。
表1体外活性与选择性数据
实验结果说明：与对照药奥格列汀相比，本发明化合物对DPP-IV具有非常好的选择性抑制作用，化合物对DPP-IV的抑制率均与对照药相当或更好。表中数据还显示，在有效抑制 DPP-IV活性的同时，本发明化合物对DPP-VIII和DPP-IX的活性几乎没有影响，可以预见本发明化合物开发成药后毒性将可能比较低。
实施例17体外对hERG的抑制作用
实验材料：受试化合物1和化合物6，hERG/HEK293稳定细胞株(购自南京金斯瑞生物科技有限公司金斯瑞)。
实验方法：将化合物1或化合物6溶解于适量DMSO中，配制成100mM储存液，溶液澄清透明；将储存液分装冻存于-70℃，备用。实验时，将储存液用细胞外液梯度稀释为检测浓度。稳定表达hERG通道的HEK293细胞培养于35mm培养皿中，在37℃/5％CO2培养箱中放置至少24小时后用于实验。每次实验取出一个培养皿，用细胞外液清洗两次，放置于倒置显微镜载物台上。全细胞膜片钳实验在室温下进行，所用硼硅玻璃微电极尖端电阻为 3～5MΩ。形成全细胞记录模式后，将膜电位钳制在-80mV，每隔30s给予细胞+50mV去极化电压刺激，持续2s后复极化至-50mV，持续3s，即可引出hERG尾电流。去极化电压刺激前，先给予细胞50ms，-50mV复极化电压，该电压下记录的电流作为计算hERG尾电流的基线。只有达到记录标准的细胞才会被应用于待测化合物的检测。加入化合物前，hERG尾电流在细胞外液中至少稳定记录3分钟。灌流给药后当hERG尾电流幅值变化小于<5％时，被认为药物作用达到稳态。如果电流在6分钟内未达到稳态，则亦结束该浓度化合物检测。
实验结果如下表2所示。
表2对hERG通道的抑制(％)
| 化合物名称 | 30μM抑制率(％) |
| 化合物1 | 2.96 |
| 化合物6 | 15.85 |
实验结果表明，化合物1和化合物6对hERG的抑制较弱，可预测本发明所述化合物成药后无心脏毒性。
实施例18大鼠药代动力学评价
动物：SD雄性大鼠(5-7周龄，性别：雄，体重200-230g，购自上海斯莱克实验动物中心)。
步骤：禁食过夜。实验当天3只SD大鼠分别灌胃5mg·kg-1化合物，分别于给药前及给药后 15min，30min，45min，1h，2h，4h，8h，12h和24h，由颈静脉采血0.20mL，置于EDTA 试管中。血液样品采集后加入含内标(维拉帕米，5.00ng/mL和格列本脲，50.0ng/mL)的乙腈，剧烈涡旋后13000rpm离心10min。取上清进行LC-MS/MS检测。
结果：采用Pharsight Phoenix 6.3中的非房室模型计算药代动力学参数，实验结果如表3所示。
表3大鼠药代动力学评价结果
结论：本发明化合物与阳性对照药奥格列汀相比，在大鼠上具有更高的最大血药浓度和暴露量，及更长的半衰期，具备长效降糖的潜质。
申请人声明，本发明通过上述实施例来说明本发明的苯并二四氢吡咯类化合物或其药学上可接受的盐、及其制备方法和应用，但本发明并不局限于上述实施例，即不意味着本发明必须依赖上述实施例才能实施。所属技术领域的技术人员应该明了，对本发明的任何改进，对本发明产品各原料的等效替换及辅助成分的添加、具体方式的选择等，均落在本发明的保护范围和公开范围之内。
Claims (6)
1.一种苯并二四氢吡咯类化合物或其药学上可接受的盐，其特征在于，所述苯并二四氢吡咯类化合物选自下述化合物中的任意一种：
2.根据权利要求1所述的苯并二四氢吡咯类化合物或其药学上可接受的盐，其特征在于，所述的苯并二四氢吡咯类化合物的药学上可接受的盐为苯并二四氢吡咯类化合物的酸加成盐或碱加成盐；
所述的酸加成盐选自盐酸盐、氢溴酸盐、氢碘酸盐、磷酸盐、硫酸盐、硝酸盐、乙磺酸盐、甲苯磺酸盐、苯磺酸盐、乙酸盐、马来酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、抗坏血酸盐、水杨酸盐、丙二酸盐、己二酸盐、己酸盐、精氨酸盐、富马酸盐、烟酸盐、邻苯二甲酸盐和草酸盐中的至少一种；所述的碱加成盐选自苯并二四氢吡咯类化合物的锂盐、钠盐、钾盐、钡盐、钙盐、镁盐、铝盐、铁盐、亚铁盐、铜盐、锌盐，和苯并二四氢吡咯类化合物与吗啉、二乙胺、三乙胺、异丙胺、三甲胺、赖氨酸或组胺酸组成的盐中的至少一种。
3.一种制备权利要求1或2所述的苯并二四氢吡咯类化合物或其药学上可接受的盐的方法，其特征在于，所述的苯并二四氢吡咯类化合物的合成路线如下所示：
其中，式I所述的苯并二四氢吡咯类化合物选自下述化合物中的任意一种：
步骤(1)中，将R2、R3取代的四溴甲基苯与三氟乙酰胺反应，得到化合物A；
步骤(2)中，将化合物A在强碱中水解，得到化合物B；
步骤(3)中，将化合物B与2-(2’,5’-二氟苯基)-3-氨基-5-氢化吡喃酮中间体C在碱性条件下水解，得到化合物D；
步骤(4)中，将化合物D与X-R1反应，X＝I、Br、Cl、OTs、OMs或OTf，得到化合物E；
步骤(5)中，将化合物E脱去Boc保护基，得到如权利要求1所述的苯并二四氢吡咯类化合物。
4.根据权利要求3所述的制备方法，其特征在于，步骤(1)中的有机溶剂选自四氢呋喃、二氯甲烷、乙酸乙酯、乙腈、丙酮、1,4-二氧六环、醇类、乙醚、甲苯、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、乙二醇二甲醚和二甲基亚砜中的至少一种。
5.一种药物组合物，其特征在于，所述药物组合物包括作为活性成分的如上所述的权利要求1或2所述的苯并二四氢吡咯类化合物或其药学上可接受的盐，以及药学上可接受的载体。
6.权利要求1或2所述的苯并二四氢吡咯类化合物或其药学上可接受的盐在制备DPP-IV抑制剂中的应用，所述的DPP-IV抑制剂用于制备代谢性疾病的药物，所述的代谢性疾病为Ⅱ型糖尿病、糖尿病性脂血异常、葡萄糖耐量减低症、禁食血浆葡萄糖减低症、代谢性酸中毒、酮症、食欲调节、肥胖症、各种癌症、神经系统病症或免疫系统病症。
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| WO1999009032A1 (en) * | 1997-08-13 | 1999-02-25 | Merck & Co., Inc. | Carbapenems with naphthosultam derivative linked via methylene |
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| CN105085530A (zh) * | 2014-05-23 | 2015-11-25 | 四川海思科制药有限公司 | 三元稠合环取代的氨基六元环类衍生物及其在医药上的应用 |
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