CN109721555B - 酰化哌嗪类化合物及其用途 - Google Patents
酰化哌嗪类化合物及其用途 Download PDFInfo
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- CN109721555B CN109721555B CN201910008948.4A CN201910008948A CN109721555B CN 109721555 B CN109721555 B CN 109721555B CN 201910008948 A CN201910008948 A CN 201910008948A CN 109721555 B CN109721555 B CN 109721555B
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Abstract
本发明涉及一种酰化哌嗪类化合物及其用途,进一步涉及包含所述化合物的药物组合物。本发明所述化合物或所述药物组合物可以用作二肽基肽酶‑IV(DPP‑IV)抑制剂。
Description
技术领域
本发明属于医药技术领域,具体涉及酰化哌嗪类化合物及其用途,进一步涉及包含所述化合物的药物组合物。所述化合物或所述药物组合物可以用作二肽基肽酶-IV(DPP-IV)抑制剂。
背景技术
糖尿病是由多种致病因素引起的血糖升高的疾病过程。通常来说有两种类型的糖尿病。I型糖尿病,也称或胰岛素依赖型糖尿病(IDDM),主要特点是自身免疫过程损伤胰腺β细胞。II型糖尿病,也称非胰岛素依赖型糖尿病(NIDDM),是长期的、渐进的代谢性疾病,特点是高血糖、高血脂和胰岛素抵抗。典型的症状为多尿、多饮和多食。II型糖尿病更常见,预计到2025年II型糖尿病将影响全球30亿人的健康。
肠促胰素在正常和病理状态下的血糖平衡调节中起到重要的作用。肠促胰素中的胰高血糖素肽(GLP-1)和葡萄糖依赖性促胰岛素多肽在食物摄入后从肠道释放并且对胰岛素的分泌有影响。GLP-1以葡萄糖依赖的方式通过同时促进胰岛素的分泌和减少胰高血糖素的分泌而降低高血糖。同时,GLP-1可以减慢胃排空和作为增饱药物抑制食欲和降低体重。在动物实验中,GLP-1对β细胞有营养的作用,因此增加了有潜力通过增加β细胞的密度和功能来改善疾病过程的可能性。最近研究表明,GLP-1对心血管系统有益处,这一点很重要因为心血管并发症在糖尿病患者人群中是主要的死亡原因之一。总而言之,GLP-1有许多益处,这使它与现有的治疗方法相比有很多不同。然而,GLP-1并没有应用于临床,是因为它可以很快的被体内广泛分布的丝氨酸蛋白酶二肽基肽酶-IV(DPP-IV)降解和失活。因此现在更多的兴趣正集中于对于开发长效的耐肽酶降解的GLP-1的类似物和二肽基肽酶-IV抑制剂。
二肽基肽酶-IV是细胞膜内的糖蛋白和丝氨酸外肽酶,可以从多肽的N端将X-脯氨酸二肽切除掉。DPP-IV广泛分布在人的各个组织中,包括肠道和肠粘膜血管的内皮细胞中。DPP-IV也表达循环系统中的T-淋巴细胞,等同于T细胞激活标志物CD26,从系统模型中得到的数据也表示DPP-IV酶在T-细胞活化过程中具有潜在的共激活的作用。此外,DPP-IV也表现出对于很多免疫调剂的、内分泌的和神经的多肽的降解作用。
DPP-IV抑制剂可以引起未降解的具有生物活性的GLP-1水平的增高,可以为II型糖尿病提供另一种候选的治疗方法。此外,与肠促胰素类似物相比,DPP-IV抑制剂口服有效。抑制DPP-IV的活性可以改善对血糖的控制。DPP-IV抑制剂的优点是可以增加胰岛素的释放同时并没有增加低血糖的风险。然而,作为外肽酶家族中的一员,DPP-IV抑制剂需要高选择性的仅抑制DPP-IV的活性而对其他DPPs.无影响。
用DPP-IV抑制剂来治疗II型糖尿病的原则已经被强有力的证实了。很多DPP-IV抑制剂已经在临床开发的各个阶段,并且有五个上市的药物,包括2006年上市的西他列汀,2007年上市的维达列汀,2009年上市的沙格列汀,2010年上市的阿格列汀和2011年上市的利拉列汀。但目前,仍然存在对于具有优势的活性,稳定性,选择性和药代动力学特性的DPP-IV抑制剂的需求。
发明内容
本发明提供一种具有较好抑制二肽基肽酶-IV(DPP-IV)活性的酰化哌嗪类化合物及其药物组合物,以及所述化合物或所述药物组合物在制备药物中的用途,所述药物用于治疗、预防或减轻糖尿病、视网膜病、糖尿病引起的神经病、肾病、胰岛素抗性、高血糖、高胰岛素血症、肥胖症、高甘油三酯血症、X综合征、动脉粥样硬化、高血压或者高密度脂蛋白水平。
一方面,本发明涉及一种化合物,其为式(I)所示的化合物或式(I)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药,
其中,
R2为F、Cl、Br、I、CN、NH2、OH、-C(=O)NH2、-S(=O)2NH2、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基、5-6个原子组成的杂芳基或-L-R3;
R1和R3各自独立地为-S(=O)qRe、-C(=O)Ra、-C(=O)ORb、-S(=O)2NRcRd、-NRfC(=O)Ra、-NRfS(=O)2Re或-C(=O)NRcRd;
L为C1-6烷基、C2-6烯基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基,其中所述C1-6烷基、C2-6烯基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Ry所取代;
各Ry独立地为D、F、Cl、Br、CN、NO2、OH、-NH2、-C(=O)OH、-C(=O)NH2、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基;
或任意两个Ry和与它们相连的碳原子一起,形成C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基;
各Ra、Rb、Rc、Rd、Re和Rf独立地为H、D、C1-6卤代烷基、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、C3-6环烷基、3-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基;
或Rc、Rd和与它们相连的氮原子一起,形成3-6个原子组成的杂环或5-6个原子组成的杂芳环;
q为0、1或2。
在一些实施例中,R2为F、Cl、Br、I、CN、NH2、OH、-C(=O)NH2、-S(=O)2NH2、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基、5-6个原子组成的杂芳基或-L-R3。
在一些实施例中,R2为F、Cl、Br、I、CN、NH2、OH、-C(=O)NH2、-S(=O)2NH2、甲氧基、乙氧基、乙烯基、烯丙基、丙烯基、炔丙基、1-丙炔基、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基、5-6个原子组成的杂芳基或-L-R3。
在一些实施例中,L为C1-4烷基、C2-4烯基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基,其中所述C1-4烷基、C2-4烯基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Ry所取代。
在一些实施例中,L为甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、丙烯基、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基,其中所述甲基、乙基、正丙基、异丙基、乙烯基、烯丙基、丙烯基、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基和5-6个原子组成的杂芳基各自独立地未被取代或被1、2、3或4个Ry所取代。
在一些实施例中,各Ry独立地为D、F、Cl、Br、CN、NO2、OH、-NH2、-C(=O)OH、-C(=O)NH2、C1-4烷基、C1-4卤代烷基、C1-4烷氧基、C1-4卤代烷氧基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基;
或任意两个Ry和与它们相连的碳原子一起,形成C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基。
在一些实施例中,各Ry独立地为D、F、Cl、Br、CN、NO2、OH、-NH2、-C(=O)OH、-C(=O)NH2、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、三氟甲基、三氟乙基、甲氧基、乙氧基、三氟甲氧基、环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基;
或任意两个Ry和与它们相连的碳原子一起,形成环丙基、环丁基、环戊基、环己基、5-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基。
在一些实施例中,各Ra、Rb、Rc、Rd、Re和Rf独立地为H、D、C1-4卤代烷基、C1-4烷基、C1-4烷氧基、C2-4烯基、C2-4炔基、C3-6环烷基、5-6个原子组成的杂环基、C6-10芳基或5-6个原子组成的杂芳基;
或Rc、Rd和与它们相连的氮原子一起,形成5-6个原子组成的杂环或5-6个原子组成的杂芳环。
在一些实施例中,各Ra、Rb、Rc、Rd、Re和Rf独立地为H、D、三氟甲基、三氟乙基、甲基、乙基、正丙基、异丙基、甲氧基、环丙基、环丁基、环戊基、环己基、3-6个原子组成的杂环基、苯基或5-6个原子组成的杂芳基;
或Rc、Rd和与它们相连的氮原子一起,形成5-6个原子组成的杂环或5-6个原子组成的杂芳环。
在一些实施例中,本发明所述的化合物为式(II)所示的化合物或式(II)所示化合物的立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药,
其中,R1和R2具有本发明所描述的含义。
在一些实施例中,本发明所述的化合物为以下其中之一的化合物,
或其立体异构体、几何异构体、互变异构体、氮氧化物、水合物、溶剂化物、代谢产物、药学上可接受的盐或它们的前药。
另一方面,本发明涉及一种药物组合物,其包含本发明所述的化合物。
在一些实施例中,本发明所述的药物组合物,其进一步包含药学上可接受的载体、赋形剂、辅剂、媒介物或它们的组合。
在一些实施例中,本发明所述的药物组合物进一步包含一种或多种其他活性成分,所述其他活性成分选自ACE抑制剂、肾素抑制剂、血管紧张素II受体拮抗剂、β-受体阻断剂、乙酰水杨酸、利尿剂、钙拮抗剂、他汀类、洋地黄衍生物、钙敏化剂、硝酸盐和抗血栓形成剂。
另一方面,本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备二肽基肽酶-IV(DPP-IV)抑制剂药物的用途。
另一方面,本发明涉及本发明所述的化合物或本发明所述的药物组合物在制备用于预防、治疗或减轻糖尿病、糖尿病视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、肥胖症、高甘油三酯血症、X综合征、动脉粥样硬化或高血压药物的用途。
本发明详细说明书
定义和一般术语
现在详细描述本发明的某些实施方案,其实例由随附的结构式和化学式说明。本发明意图涵盖所有的替代、修改和等同技术方案,它们均包括在如权利要求定义的本发明范围内。本领域技术人员应认识到,许多与本文所述类似或等同的方法和材料能够用于实践本发明。本发明绝不限于本文所述的方法和材料。在所结合的文献、专利和类似材料的一篇或多篇与本申请不同或相矛盾的情况下(包括但不限于所定义的术语、术语应用、所描述的技术,等等),以本申请为准。
应进一步认识到,本发明的某些特征,为清楚可见,在多个独立的实施方案中进行了描述,但也可以在单个实施例中以组合形式提供。反之,本发明的各种特征,为简洁起见,在单个实施方案中进行了描述,但也可以单独或以任意适合的子组合提供。
除非另外说明,本发明所使用的所有科技术语具有与本发明所属领域技术人员的通常理解相同的含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。
除非另外说明,应当应用本文所使用的下列定义。出于本发明的目的,化学元素与元素周期表CAS版,和《化学和物理手册》,第75版,1994一致。此外,有机化学一般原理可参考"Organic Chemistry",Thomas Sorrell,University Science Books,Sausalito:1999,和"March's Advanced Organic Chemistry”by Michael B.Smith and Jerry March,JohnWiley&Sons,New York:2007中的描述,其全部内容通过引用并入本文。
除非另有说明或者上下文中有明显的冲突,本文所使用的冠词“一”、“一个(种)”和“所述”旨在包括“至少一个”或“一个或多个”。因此,本文所使用的这些冠词是指一个或多于一个(即至少一个)宾语的冠词。例如,“一组分”指一个或多个组分,即可能有多于一个的组分被考虑在所述实施方案的实施方式中采用或使用。
本发明所使用的术语“患者”是指人(包括成人和儿童)或者其他动物。在一些实施方案中,“患者”是指人。
术语“包含”为开放式表达,即包括本发明所指明的内容,但并不排除其他方面的内容。
“立体异构体”是指具有相同化学构造,但原子或基团在空间上排列方式不同的化合物。立体异构体包括对映异构体、非对映异构体、构象异构体(旋转异构体)、几何异构体(顺/反)异构体、阻转异构体,等等。
“对映异构体”是指一个化合物的两个不能重叠但互成镜像关系的异构体。
“非对映异构体”是指有两个或多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质,如熔点、沸点、光谱性质和反应性。非对映异构体混合物可通过高分辨分析操作如电泳和色谱,例如HPLC来分离。
本发明所使用的立体化学定义和规则一般遵循S.P.Parker,Ed.,McGraw-HillDictionary of Chemical Terms(1984)McGraw-Hill Book Company,New York;andEliel,E.and Wilen,S.,“Stereochemistry of Organic Compounds”,John Wiley&Sons,Inc.,New York,1994。
本发明公开化合物的任何不对称原子(例如,碳等)都可以以外消旋或对映体富集的形式存在,例如(R)-、(S)-或(R,S)-构型形式存在。在某些实施方案中,各不对称原子在(R)-或(S)-构型方面具有至少50%对映体过量,至少60%对映体过量,至少70%对映体过量,至少80%对映体过量,至少90%对映体过量,至少95%对映体过量,或至少99%对映体过量。
所得的任何立体异构体的混合物可以依据组分物理化学性质上的差异被分离成纯的或基本纯的几何异构体,对映异构体,非对映异构体,例如,通过色谱法和/或分步结晶法。
术语“互变异构体”或“互变异构形式”是指具有不同能量的可通过低能垒(lowenergy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中),则可以达到互变异构体的化学平衡。例如,质子互变异构体(protontautomer)(也称为质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化,如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体(valence tautomer)包括通过一些成键电子的重组来进行的互相转化。酮-烯醇互变异构的具体实例是戊烷-2,4-二酮和4-羟基戊-3-烯-2-酮互变异构体的互变。互变异构的另一个实例是酚-酮互变异构。酚-酮互变异构的一个具体实例是吡啶-4-醇和吡啶-4(1H)-酮互变异构体的互变。除非另外指出,本发明化合物的所有互变异构体形式都在本发明的范围之内。
本发明所使用的术语“前药”,代表一个化合物在体内转化为式(I)所示的化合物。这样的转化受前体药物在血液中水解或在血液或组织中经酶转化为母体结构的影响。本发明前体药物类化合物可以是酯,在现有的发明中酯可以作为前体药物的有苯酯类,脂肪族(C1-24)酯类,酰氧基甲基酯类,碳酸酯,氨基甲酸酯类和氨基酸酯类。例如本发明里的一个化合物包含羟基,即可以将其酰化得到前体药物形式的化合物。其他的前体药物形式包括磷酸酯,如这些磷酸酯类化合物是经母体上的羟基磷酸化得到的。关于前体药物完整的讨论可以参考以下文献:T.Higuchi and V.Stella,Pro-drugs as Novel DeliverySystems,Vol.14of the A.C.S.Symposium Series,Edward B.Roche,ed.,BioreversibleCarriers in Drug Design,American Pharmaceutical Association and PergamonPress,1987,J.Rautio et al.,Prodrugs:Design and Clinical Applications,NatureReview Drug Discovery,2008,7,255-270,and S.J.Hecker et al.,Prodrugs ofPhosphates and Phosphonates,Journal of Medicinal Chemistry,2008,51,2328-2345。
“代谢产物”是指具体的化合物或其盐在体内通过代谢作用所得到的产物。一个化合物的代谢产物可以通过所属领域公知的技术来进行鉴定,其活性可以通过如本发明所描述的那样采用试验的方法进行表征。这样的产物可以是通过给药化合物经过氧化,还原,水解,酰氨化,脱酰氨作用,酯化,脱脂作用,酶裂解等等方法得到。相应地,本发明包括化合物的代谢产物,包括将本发明的化合物与哺乳动物充分接触一段时间所产生的代谢产物。
本发明所使用的“药学上可接受的盐”是指本发明化合物的有机盐和无机盐。药学上可接受的盐在所属领域是为我们所熟知的,如文献:S.M.Berge et al.,describepharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences,1977,66:1-19.所记载的。药学上可接受的无毒的酸形成的盐包括,但并不限于,无机酸盐,如盐酸盐,氢溴酸盐,磷酸盐,硫酸盐,高氯酸盐;有机酸盐,如乙酸盐,草酸盐,马来酸盐,酒石酸盐,柠檬酸盐,琥珀酸盐,丙二酸盐;或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括,己二酸盐,藻酸盐,抗坏血酸盐,天冬氨酸盐,苯磺酸盐,苯甲酸盐,重硫酸盐,硼酸盐,丁酸盐,樟脑酸盐,樟脑磺酸盐,环戊基丙酸盐,二葡萄糖酸盐,十二烷基硫酸盐,乙磺酸盐,甲酸盐,反丁烯二酸盐,葡庚糖酸盐,甘油磷酸盐,葡萄糖酸盐,半硫酸盐,庚酸盐,己酸盐,氢碘酸盐,2-羟基-乙磺酸盐,乳糖醛酸盐,乳酸盐,月桂酸盐,月桂基硫酸盐,苹果酸盐,甲磺酸盐,2-萘磺酸盐,烟酸盐,硝酸盐,油酸盐,棕榈酸盐,扑酸盐,果胶酸盐,过硫酸盐,3-苯基丙酸盐,苦味酸盐,特戊酸盐,丙酸盐,硬脂酸盐,硫氰酸盐,对甲苯磺酸盐,十一酸盐,戊酸盐,等等。通过与适当的碱反应得到的盐包括碱金属,碱土金属,铵和N+(C1-4烷基)4的盐。本发明也拟构思了任何包含N的基团的化合物所形成的季铵盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。可以形成盐的碱金属或碱土金属包括钠,锂,钾,钙,镁,等等。药学上可接受的盐进一步包括适当的、无毒的铵,季铵盐和抗平衡离子形成的胺阳离子,如卤化物,氢氧化物,羧化物,硫酸化物,磷酸化物,硝酸化物,C1-8磺酸化物和芳香磺酸化物。
本发明的“溶剂化物”是指一个或多个溶剂分子与本发明的化合物所形成的缔合物。形成溶剂化物的溶剂包括,但并不限于,水,异丙醇,乙醇,甲醇,二甲亚砜,乙酸乙酯,乙酸和氨基乙醇。术语“水合物”是指溶剂分子是水所形成的缔合物。
本发明的“氮氧化物”是指当化合物含几个胺官能团时,可将1个或大于1个的氮原子氧化形成N-氧化物。N-氧化物的特殊实例是叔胺的N-氧化物或含氮杂环氮原子的N-氧化物。可用氧化剂例如过氧化氢或过酸(例如过氧羧酸)处理相应的胺形成N-氧化物(参见Advanced Organic Chemistry,Wiley Interscience,第4版,Jerry March,pages)。尤其是,N-氧化物可用L.W.Deady的方法制备(Syn.Comm.1977,7,509-514),其中例如在惰性溶剂例如二氯甲烷中,使胺化合物与间-氯过氧苯甲酸(MCPBA)反应。
像本发明所描述的,本发明的化合物可以任选地被一个或多个取代基所取代,如上面的通式化合物,或者像实施例里面特殊的例子,子类,和本发明所包含的一类化合物。
术语“任选”或“任选地”是指随后描述的事件或情形可以但不一定出现,即,该描述包括其中所述事件或情形出现的情况以及不出现的情况。
另外,需要说明的是,除非以其他方式明确指出,在本发明中所采用的描述方式“各…独立地为”与“…各自独立地为”和“…独立地为”可以互换,均应做广义理解,其既可以是指在不同基团中,相同符号之间所表达的具体选项之间互相不影响,也可以表示在相同的基团中,相同符号之间所表达的具体选项之间互相不影响。同样的,对于描述方式“…独立任选地”中的“独立”,也应做上述广义理解。
在本说明书的各部分,本发明公开化合物的取代基按照基团种类或范围公开。特别指出,本发明包括这些基团种类和范围的各个成员的每一个独立的次级组合。例如,术语“C1-6烷基”特别指独立公开的甲基、乙基、C3烷基、C4烷基、C5烷基和C6烷基;“C1-4烷基”特指独立公开的C1烷基(甲基)、C2烷基(乙基)、C3烷基(即丙基,包括正丙基和异丙基)、C4烷基(即丁基,包括正丁基、异丁基、仲丁基和叔丁基)。
在本发明的各部分,描述了连接取代基。当该结构清楚地需要连接基团时,针对该基团所列举的马库什变量应理解为连接基团。例如,如果该结构需要连接基团并且针对该变量的马库什基团定义列举了“烷基”或“芳基”,则应该理解,该“烷基”或“芳基”分别代表连接的亚烷基基团或亚芳基基团。
本发明使用的术语“烷基”或“烷基基团”,表示含有1至20个碳原子,饱和的直链或支链的一价烃基基团,其中,所述烷基基团可以任选地被一个或多个本发明描述的取代基所取代。在一些实施方案中,烷基基团含有1-12个碳原子;在另一些实施方案中,烷基基团含有1-6个碳原子,即,C1-6烷基;在又一些实施方案中,烷基基团含有1-4个碳原子,即C1-4烷基;还在一些实施方案中,烷基基团含有1-3个碳原子,即C1-3烷基。在一些实施例中,本发明中所述的C1-6烷基可以为C1-4烷基;在另一些实施例中,本发明中所述的C1-6烷基可以为C1-3烷基。
烷基基团的实例包含,但并不限于,甲基,乙基,丙基(包括正丙基和异丙基),丁基(包括正丁基、异丁基、仲丁基、叔丁基),正戊基,2-戊基,3-戊基,2-甲基-2-丁基,3-甲基-2-丁基,3-甲基-1-丁基,2-甲基-1-丁基,正己基,2-己基,3-己基,2-甲基-2-戊基,3-甲基-2-戊基,4-甲基-2-戊基,3-甲基-3-戊基,2-甲基-3-戊基,2,3-二甲基-2-丁基,3,3-二甲基-2-丁基,正庚基,正辛基,等等。
术语“烯基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp2双键,其中,所述烯基基团可以任选地被一个或多个本发明所描述的取代基所取代,其包括“cis”和“tans”的定位,或者"E"和"Z"的定位。在一实施方案中,烯基基团含有2-6个碳原子,即,C2-6烯基;在另一实施方案中,烯基基团含有2-4个碳原子,即,C2-6烯基。在一些实施例中,本发明中所述的C2-6烯基可以为C2-4烷基;在另一些实施例中,本发明中所述的C2-6烯基可以为C2-3烷基。烯基基团的实例包括,但并不限于,乙烯基(-CH=CH2)、烯丙基(-CH2CH=CH2)、丙烯基(-CH=CH-CH3)等等。
术语“炔基”表示含有2-12个碳原子的直链或支链一价烃基,其中至少有一个不饱和位点,即有一个碳-碳sp三键,其中,所述炔基基团可以任选地被一个或多个本发明所描述的取代基所取代。在一些实施方案中,炔基基团含有2-6个碳原子,即,C2-6炔基;在另一些实施方案中,炔基基团含有2-4个碳原子,即,C2-6炔基。在一些实施例中,本发明中所述的C2-6炔基可以为C2-4炔基;在另一些实施例中,本发明中所述的C2-6炔基可以为C2-3炔基。炔基基团的实例包括,但并不限于,乙炔基(-C≡CH)、炔丙基(-CH2C≡CH)、1-丙炔基(-C≡C-CH3)、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、3-甲基-1-丁炔基、1-己炔基、1-庚炔基、1-辛炔基,等等。
术语“烷氧基”表示烷基基团通过氧原子与分子其余部分相连,其中烷基基团具有如本发明所述的含义。烷氧基基团的实例包括,但并不限于,甲氧基,乙氧基,丙氧基(包括1-丙氧基或2-丙氧基),丁氧基(包括正丁氧基、异丁氧基、仲丁氧基、叔丁氧基)等等。
术语“卤代烷基”或“卤代烷氧基”表示烷基或烷氧基基团被一个或多个卤素原子所取代,这样的实例包含,但并不限于,三氟甲基、三氟甲氧基、氯乙基(例如,2-氯乙基)、三氟乙基(例如,2,2,2-三氟乙基)、2,2-二氟乙基、2-氯-1-甲基乙基等。
术语“氨基”表示基团-NH2。
术语“羧基”表示基团-COOH。
术语“羟基”表示基团-OH。
术语“氰基”表示基团-CN。
术语“硝基”表示基团-NO2。
术语“氧代”代表基团=O。
术语“卤素”是指氟(F)、氯(Cl)、溴(Br)或碘(I)。
术语“烷基氨基”表示基团-NH2被一个或两个烷基所取代,其中所述烷基具有如本发明所述的含义。烷氨基基团的实例包括,但并不限于,甲氨基,二甲氨基等。
术语“环烷基”表示含有3-12个环碳原子的饱和单环、双环或三环体系。在一些实施方案中,环烷基包含3-10个环碳原子,例如C3-10环烷基;在另一些实施方案中,环烷基包含3-8个环碳原子,例如C3-8环烷基;在又一些实施方案中,环烷基包含3-6个环碳原子,例如C3-6环烷基。环烷基基团的实例包括,但并不限于,环丙基、环丁基、环戊基、环己基、环庚基、环辛基,等等;其中,所述的C3-6环烷基包括环丙基、环丁基、环戊基和环己基。所述环烷基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂环基”是指包含3-12个环原子的,饱和或部分不饱和的单环、双环或三环体系,其中至少一个环原子选自氮、硫和氧原子;其中,所述杂环基是非芳香性的,且不包含任何芳香环。除非另外说明,杂环基可以是碳基或氮基,且-CH2-基团可以任选地被-C(=O)-替代。环的硫原子可以任选地被氧化成S-氧化物。环的氮原子可以任选地被氧化成N-氧化物。术语“杂环基”可以与术语“杂环”交换使用。所述杂环基基团可以任选地被一个或多个本发明描述的取代基所取代。杂环基的实例包括,但不限于:环氧乙烷基,氮杂环丁基,氧杂环丁基,硫杂环丁基,吡咯烷基,吡唑烷基,咪唑啉基,咪唑烷基,哌啶基,吗啉基,硫代吗啉基,哌嗪基,等等。所述的杂环基基团可以任选地被一个或多个本发明所描述的取代基所取代。
术语“芳基”表示含有6-14个环原子,或6-12个环原子,或6-10个环原子的单环、双环和三环的碳环体系,其中,至少一个环是芳香族的,且有一个或多个附着点与分子的其余部分相连。术语“芳基”可以和术语“芳香环”或“芳环”交换使用。除非另外说明,基团“C6-10芳基”表示含有6-10个环碳原子的芳基基团。芳基基团的实例可以包括苯基、2,3-二氢-1H-茚基、萘基和蒽基。所述芳基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“杂芳基”表示含有5-12个环原子,或5-10个环原子,或5-6个环原子的单环、双环和三环体系,其中至少一个环是芳香族的,且至少一个环包含1、2、3或4个选自氮、氧、硫的环杂原子,同时,所述杂芳基有一个或多个附着点与分子其余部分相连。当杂芳基基团中存在-CH2-基团时,所述的-CH2-基团可以任选地被-C(=O)-替代。除非另外说明,所述的杂芳基基团可以通过任何合理的位点(可以为CH中的C,或者NH中N)连接到分子其余部分(例如通式中的主体结构)上。术语“杂芳基”可以与术语“杂芳环”或“杂芳族化合物”交换使用。在一些实施方案中,杂芳基为5-10个原子组成的杂芳基,表示杂芳基含有1-9个环碳原子和1、2、3或4个选自O、S和N的环杂原子;在另一些实施方案中,杂芳基为5-6个原子组成的杂芳基,表示杂芳基含有1-5个环碳原子和1、2、3或4个选自O、S和N的环杂原子。这样的实例包括,但并不限于,呋喃基、咪唑基、异噁唑基、噁唑基、吡咯基、吡唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、噻吩基、噻唑基等。所述杂芳基基团可以任选地被一个或多个本发明描述的取代基所取代。
术语“药物组合物”表示一种或多种本文所述化合物或者其生理学上/药学上可以接受的盐或前体药物与其他化学组分的混合物,其他组分例如生理学上/药学上可以接受的载体、赋形剂、稀释剂、粘合剂、填充剂等辅料,以及抗糖尿病试剂、抗高血糖试剂、抗肥胖症试剂、抗高血压试剂、抗血小板试剂、抗动脉粥样硬化试剂或者降脂试剂等附加治疗剂。药物组合物的目的是促进化合物对生物体的给药。
术语“药学上可接受的”是指当给人施用时生理上可耐受的并且一般不产生过敏或类似的不适当的反应,例如肠胃不适、眩晕等的分子实体和组合物。优选地,本文所用的术语“药学上可接受的”是指联邦监管机构或国家政府批准的或美国药典或其他一般认可的药典上列举的在动物中、特别是在人体中使用的。
术语“载体”指与所述化合物一同施用的稀释剂、辅剂、赋形剂或基质。这些药物载体可以是无菌液体,例如水和油类,包括石油、动物、植物或合成来源的,例如花生油、大豆油、矿物油、芝麻油等。水和水性溶液(例如,盐水溶液、葡萄糖水溶液、甘油水溶液)优选用作载体、特别是可注射溶液。适宜的药物载体描述于E.W.Martin的“Remington′sPharmaceutical Sciences”中。
术语“X综合症”,也称作代谢综合症的病症、疾病,其疾患详述于Johannsson etal.,J.Clin.Endocrinol.Metab.,1997,82,727-734中。
本发明中所使用的“本发明的化合物”、“本发明所描述的化合物”、“本发明所述化合物”或类似的表述,均指代本发明中式(I)或式(II)所代表的化合物。
如本发明所使用的术语“治疗”任何疾病或病症,在其中一些实施方案中指改善疾病或病症(即减缓或阻止或减轻疾病或其至少一种临床症状的发展)。在另一些实施方案中,“治疗”指缓和或改善至少一种身体参数,包括可能不为患者所察觉的身体参数。在另一些实施方案中,“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。在另一些实施方案中,“治疗”指预防或延迟疾病或病症的发作、发生或恶化。
本发明给出的任何结构式也意欲表示这些化合物未被同位素富集的形式以及同位素富集的形式。同位素富集的化合物具有本发明给出的通式描绘的结构,除了一个或多个原子被具有所选择原子量或质量数的原子替换。可引入本发明化合物中的示例性同位素包括氢、碳、氮、氧、磷、硫、氟和氯的同位素,如2H,3H,11C,13C,14C,15N,17O,18O,18F,31P,32P,35S,36Cl和125I。
另一方面,本发明所述化合物包括同位素富集的本发明所定义的化合物,例如,其中存在放射性同位素,如3H,14C和18F的那些化合物,或者其中存在非放射性同位素,如2H和13C。该类同位素富集的化合物可用于代谢研究(使用14C)、反应动力学研究(使用例如2H或3H)、检测或成像技术,如正电子发射断层扫描术(PET)或包括药物或底物组织分布测定的单光子发射计算机断层成像术(SPECT),或可用于患者的放疗中。18F富集的化合物对PET或SPECT研究而言是特别理想的。同位素富集的式(I)所示化合物可以通过本领域技术人员熟悉的常规技术或本发明中的实施例和制备过程所描述使用合适的同位素标记试剂替代原来使用过的未标记试剂来制备。
此外,较重同位素特别是氘(即,2H或D)的取代可提供某些治疗优点,这些优点是由代谢稳定性更高带来的。例如,体内半衰期增加或剂量需求降低或治疗指数得到改善带来的。应当理解,本发明中的氘被看作式(I)或式(II)化合物的取代基。可以用同位素富集因子来定义该类较重同位素特别是氘的浓度。本发明所使用的术语“同位素富集因子”是指所指定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物的取代基被指定为氘,该化合物对各指定的氘原子而言具有至少3500(各指定氘原子处52.5%的氘掺入)、至少4000(60%的氘掺入)、至少4500(67.5%的氘掺入),至少5000(75%的氘掺入),至少5500(82.5%的氘掺入)、至少6000(90%的氘掺入)、至少6333.3(95%的氘掺入)、至少6466.7(97%的氘掺入)、至少6600(99%的氘掺入)或至少6633.3(99.5%的氘掺入)的同位素富集因子。本发明可药用的溶剂化物包括其中结晶溶剂可以是同位素取代的例如D2O、丙酮-d6、DMSO-d6的那些溶剂化物。
除非其他方面表明,本发明的化合物的所有互变异构形式都包含在本发明的范围之内。另外,除非其他方面表明,本发明所描述的化合物的结构式包括一个或多个不同的原子的富集同位素。
本发明所使用的任何保护基团、氨基酸和其它化合物的缩写,除非另有说明,都以它们通常使用的、公认的缩写为准,或参照IUPAC-IUBCommission on BiochemicalNomenclature(参见Biochem.1972,11:942-944)。
本发明所述化合物竞争性地拮抗醛甾酮受体(MR),并因此它们可以是治疗和预防与醛甾酮水平提高相关的病症的有用药剂。
本发明包含本发明化合物及其药学上可接受的盐的应用,用于生产医药产品治疗患者与盐皮质激素受体或醛甾酮相关的疾病,包括那些本发明所描述的疾病。本发明包含药物组合物,该药物组合物包括式(I)或式(II)所代表的化合物与至少一种药学上可接受的载体、赋形剂、稀释剂、辅剂、媒介物的结合所需的有效治疗量。
除非其他方面表明,本发明的化合物所有的水合物、溶剂化物和药学上可接受的盐都属于本发明的范围。
具体地说,盐是药学上可接受的盐。术语“药学上可接受的”包括物质或组合物必须是适合化学或毒理学的,与组成制剂的其他组分和用于治疗的哺乳动物有关。
本发明的化合物的盐还包括用于制备或纯化式(I)或式(II)所示化合物的中间体或式(I)或式(II)所示化合物分离的对映异构体的盐,但不一定是药学上可接受的盐。
本发明的化合物的盐可以通过文献上提供的任何合适的方法制备得到,例如,使用无机酸,如盐酸,氢溴酸,硫酸,硝酸和磷酸等等。或者使用有机酸,如乙酸,马来酸,琥珀酸,扁桃酸,富马酸,丙二酸,丙酮酸,草酸,羟乙酸和水杨酸;吡喃糖酸,如葡萄糖醛酸和半乳糖醛酸;α-羟酸,如柠檬酸和酒石酸;氨基酸,如天门冬氨酸和谷氨酸;芳香族酸,如苯甲酸和肉桂酸;磺酸,如对甲苯磺酸,乙磺酸,等等。
本发明化合物的生物活性可通过使用任何常规已知方法评定。适当的检测方法是本领域众所周知的。例如,可以通过适当的常规方法检测本发明化合物的MR拮抗活性、药代动力学活性和/或肝微粒体稳定性等。本发明提供的检测方法仅作为实例呈现且不限制本发明。本发明化合物在至少一种本发明提供的检测方法中具有活性。
本发明化合物的药物组合物、制剂、给药和用途
另一方面,本发明的药物组合物的特点包括式(I)或式(II)所示的酰化哌嗪类化合物,本发明所列出的化合物,或实施例1-11的化合物,和药学上可接受的载体、赋形剂、辅剂、媒介物或它们的组合。本发明的组合物中化合物的量能有效地治疗或减轻患者的与二肽基肽酶-IV(DPP-IV)相关的疾病。
像本发明所描述的,本发明药学上可接受的组合物进一步包含药学上可接受的载体、赋形剂、辅剂、媒介物或它们的组合,这些像本发明所应用的,包括任何溶剂,稀释剂,或其他液体赋形剂,分散剂或悬浮剂,表面活性剂,等渗剂,增稠剂,乳化剂,防腐剂,固体粘合剂或润滑剂,等等,适合于特有的目标剂型。如以下文献所描述的:In Remington:TheScience and Practice of Pharmacy,21st edition,2005,ed.D.B.Troy,LippincottWilliams&Wilkins,Philadelphia,and Encyclopedia of Pharmaceutical Technology,eds.J.Swarbrick and J.C.Boylan,1988-1999,Marcel Dekker,New York,综合此处文献的内容,表明不同的载体可应用于药学上可接受的组合物的制剂和它们公知的制备方法。除了任何常规的载体媒介与本发明的化合物不相容的范围,例如所产生的任何不良的生物效应或与药学上可接受的组合物的任何其他组分以有害的方式产生的相互作用,它们的用途也是本发明所考虑的范围。
可作为药学上可接受载体的物质包括,但并不限于,离子交换剂,铝,硬脂酸铝,卵磷脂,血清蛋白,如人血清蛋白,缓冲物质如磷酸盐,甘氨酸,山梨酸,山梨酸钾,饱和植物脂肪酸的部分甘油酯混合物,水,盐或电解质,如硫酸鱼精蛋白,磷酸氢二钠,磷酸氢钾,氯化钠,锌盐,胶体硅,三硅酸镁,聚乙烯吡咯烷酮,聚丙烯酸脂,蜡,聚乙烯-聚氧丙烯-阻断聚合体,羊毛脂,糖,如乳糖,葡萄糖和蔗糖;淀粉如玉米淀粉和土豆淀粉;纤维素和它的衍生物如羧甲基纤维素钠,乙基纤维素和乙酸纤维素;树胶粉;麦芽;明胶;滑石粉;辅料如可可豆脂和栓剂蜡状物;油如花生油,棉子油,红花油,麻油,橄榄油,玉米油和豆油;二醇类化合物,如丙二醇和聚乙二醇;酯类如乙基油酸酯和乙基月桂酸酯;琼脂;缓冲剂如氢氧化镁和氢氧化铝;海藻酸;无热原的水;等渗盐;林格(氏)溶液;乙醇,磷酸缓冲溶液,和其他无毒的合适的润滑剂如月桂硫酸钠和硬脂酸镁,着色剂,释放剂,包衣衣料,甜味剂,调味剂和香料,防腐剂和抗氧化剂。
本发明的药物组合物可直接给药或随同合适的载体或赋形剂以医药组合物或药物形式给药,这是本领域所熟知的。本发明的治疗方法可包含向有需要的个体施以有效的本发明化合物。在一些实施方案中,所述个体是哺乳动物个体,并且在一些优选实施方案中,所述个体是人类个体。
本发明所述化合物、药物组合物或药物的有效量可通过常规实验容易的测定,最有效和方便的给药途径以及最适当的制剂也可通过常规实验测定。
本发明的化合物的医药剂型可以以速释、控释、缓释或靶药物释放系统形式提供。例如,常用剂型包括溶液和悬浮液、(微)乳液、软膏、凝胶和贴片、脂质体、片剂、糖衣药丸、软壳或硬壳胶囊、栓剂、胚珠、植入物、非晶形或结晶粉末、气溶胶和冻干制剂。视所用的给药途径而定,可能需要特殊装置来施用或给予药物,例如注射器和针、吸入器、泵、注射笔、涂药器或专用瓶(Special flask)。药物剂型常常由药物、赋形剂和容器/密封系统组成。可将一种或多种赋形剂(又称为非活性成分)添加到本发明的化合物中来改善或促进药物的制造、稳定性、给药和安全性,并且可提供获得所需药物释放曲线的方法。因此,添加到药物中的赋形剂类型可视各种因素而定,例如药物的物理和化学特性、给药途径和制备步骤。在该领域中存在药用赋形剂并且包括各种药典中所列的那些。(参见美国药典(U.S.Pharmacopeia,USP)、日本药典(Japanese Pharmacopoeia,JP)、欧洲药典(EuropeanPharmacopoeia,EP)和英国药典(British pharmacopoeia,BP);美国食品与药品管理局(the U.S.Food and Drug Administration,www.fda.gov)药物评价与研究中心(Centerfor Drug Evaluation and Research,CEDR)出版物,例如《非活性组分指南》(InactiveIngredient Guide,1996);Ash和Ash编写的《药物添加剂手册》(Handbook ofPharmaceutical Additives,2002,联合信息资源公司(Synapse Information Resources,Inc.,Endicott NY;etc.)。
本发明化合物的药物剂型可通过本领域中熟知的任一种方法来制造,例如通过常规混合、筛分、溶解、熔化、造粒、制造糖衣药丸、压片、悬浮、挤压、喷雾干燥、研磨、乳化、(纳米/微米级)囊封、包理或冻干工艺。如上文所述,本发明的组合物可包括一种或一种以上生理学上可接受的非活性成分,这些非活性成分会促进活性分子被加工成用于医药用途的制剂。
适当的制剂视所需的给药途径而定。例如,对于静脉注射来说,组合物可配制于水溶液中,必要时使用生理上相容的缓冲剂,包括例如用于调整制剂pH值的磷酸盐、组氨酸或柠檬酸盐,以及诸如氯化钠或右旋糖的张度剂。对于经粘膜或鼻给药来说,可首选半固体、液体制剂或者贴片、可能含有渗透增强剂;所述渗透剂通常为本领域所已知。对于口服给药来说,化合物可配制成液体或固体剂型并作为速释或控释/缓释制剂。用于个体口服摄取的合适剂型包括片剂、药丸、糖衣药丸、硬壳和软壳胶囊、液体、凝胶、糖浆、膏剂、悬浮液和乳液。化合物也可以被配制在直肠组合物中,诸如栓剂或保留灌肠剂,例如含有常规的栓剂基质如可可脂或其它甘油酯。
固体口服剂型可使用赋形剂获得,所述赋形剂包括填充剂、崩解剂、粘合剂(干和湿)、溶解延缓剂、润滑剂、助流剂、抗粘剂、阳离子性交换树脂、湿润剂、抗氧化剂、防腐剂、着色剂和调味剂。这些赋形剂可为合成或天然来源。所述赋形剂的实例包括纤维素衍生物、柠檬酸、磷酸二钙、明胶、碳酸镁、月桂基硫酸镁/月桂基硫酸钠、甘露糖醇、聚乙二醇、聚乙烯吡咯烷酮、硅酸盐、二氧化硅、苯甲酸钠、山梨糖醇、淀粉、硬脂酸或其盐、糖(即右旋糖、蔗糖、乳糖等)、滑石、西黄蓍胶浆(tragacanth mucilage)、植物油(氢化)和蜡。乙醇和水可用作造粒助剂。在某些情况下,需要用例如掩味膜、抗胃酸膜或延缓释放膜来涂覆片剂。常常将天然和合成的聚合物与着色剂、糖和有机溶剂或水组合用于涂覆片剂,从而产生糖衣药丸。当胶囊优于片剂时,可以用兼容的硬壳或软壳胶囊形式递送其药物粉末、悬浮液或溶液。
在一些实施方案中,本发明的化合物可局部给药,例如通过皮肤贴片、半固体或液体制剂,如凝胶、(微)乳液、软膏、溶液、(纳米/微米级)悬浮液或泡沫。药物的皮肤和下层组织渗透可通过以下方式来调节:例如使用渗透增强剂;使用亲脂性、亲水性和两亲性赋形剂的适当选择和组合,包括水、有机溶剂、蜡、油、合成和天然的聚合物、表面活性剂、乳化剂;通过调整pH值;和使用络合剂。例如离子电渗疗法(iontophoresi)的其它技术也可以用于调节本发明的化合物的皮肤渗透。例如在需要以最小全身性暴露局部给药的情形下,将首选透皮或局部给药。
对于通过吸入给药或鼻给药来说,根据本发明使用的化合物以溶液、悬浮液、乳液或半固体气溶胶的形式从加压包或喷雾器中方便地给药,通常借助于推进剂,例如衍生自甲烷和乙烷的卤化碳、二氧化碳或任何其它合适的气体。对于局部气溶胶来说,如丁烷、异丁烯和戊烷等烃是适用的。在加压气溶胶的情况下,适当的剂量单位可通过提供阀门传递计量来测定。可配制用于吸入器或吹入器中的具有例如明胶的胶囊和药筒。这些通常含有化合物与合适粉末基质(如乳糖或淀粉)的粉末混合物。
用于通过注射非经肠给药而配制的组合物通常是无菌的并且可以用单位剂型提供,例如安瓿瓶、注射器、注射笔、或多剂量容器,后者通常含有防腐剂。组合物可采用在油性或水性载体中的悬浮液、溶液或乳液等形式,并且可含有配制试剂,例如缓冲剂、张度剂、粘度增强剂、表面活性剂、悬浮剂和分散剂、抗氧化剂、生物相容性聚合物、鳌合剂和防腐剂。视注射部位而定,所述载体可含有水、合成或植物油和/或有机共溶剂。在某些情况下,例如对于冻干产物或浓缩物,会在给药之前将非经肠制剂重组或加以稀释。提供本发明的化合物的控释或缓释的贮库制剂(depot formulation)可包括纳米/微米级微粒或者纳米/微米级或非微细化晶体的可注射悬浮液。本领域其它熟知的基质,聚(乳酸)、聚(乙醇酸)或其共聚物等聚合物可被用作控释/缓释基质。可以以需要切口的植入物和泵的形式提供其它的贮库型(depot)给药系统。
用于静脉注射的本发明化合物的合适的载体为本领域所熟知并且包括含有碱(如氢氧化钠)的水基溶液,用于形成离子化合物;作为张度剂的蔗糖或氯化钠;例如含有磷酸盐或组氨酸的缓冲剂。可添加如聚乙二醇的共溶剂。这些水基体系能有效溶解本发明的化合物并且在全身性给药后产生低毒性。在不破坏溶解性和毒性特征的情况下,可大大改变溶液体系的组分的比例。此外,可改变组分的特性。举例来说,可使用诸如聚山梨醇酯或泊洛沙姆(poloxamer)的低毒性表面活性剂,也可使用聚乙二醇或其它共溶剂,可添加诸如聚乙烯吡咯烷酮的生物相容性聚合物,并且可用其它糖和多元醇来替代右旋糖。
本发明化合物可全身和/或局部作用。它们可以以适合的方式给药,例如,通过口服给药、经肠胃给药、经肺给药、经鼻给药、舌下给药、经舌给药、含服、直肠给药、真皮给药、经皮给药、结膜给药、耳道给药或作为移植片或支架给药。本发明化合物优选地经口服给药或非经肠给药。
口服给药的适合给药方式如下:根据现有技术工作的方式,迅速释放和/或以改良的方法释放本发明的化合物的给药方式,它们包含结晶和/或无定形和/或溶解的形式的本发明的化合物,例如片剂(未包衣片剂或例如用控制本发明的化合物释放的胃液耐受的或延迟溶解的或不溶性的包衣进行包衣的片剂)、在口腔中迅速碎裂的片剂或薄膜/薄片、薄膜/冻干体、胶囊(例如硬胶囊或软胶囊)、糖衣片剂、颗粒剂、丸剂、粉剂、乳剂、混悬剂、气溶胶或溶液。
非经肠给药可以绕过吸收步骤(例如静脉内、动脉内、贲门内、脊柱内或腰内)或包括吸收(例如:肌内吸收、皮下吸收、皮内吸收、经皮吸收或腹膜内吸收)。适合于非经肠给药的给药形式包括溶液、混悬液、乳液、冻干体或无菌粉体形式的用于注射和输注的制剂。
对于其它给药途径,适合的例子是吸入的药物形式(包括粉体吸入器、喷雾器)、滴鼻剂、溶液或喷雾剂、用于舌、舌下或含服给药的片剂、薄膜/薄片或胶囊、栓剂、耳或眼制剂、阴道胶囊、水混悬液(洗剂、震荡合剂)、亲脂性混悬剂、软膏、霜剂、经皮治疗体系(例如贴片)、乳剂(Milch)、糊剂、泡沫、喷洒粉剂、植入物或支架。
本发明化合物的治疗有效量应当是以整个混合物约0.1至99.5%,优选约0.5至95%重量的浓度存在于上述药物制剂中。
除本发明化合物外,上述药物制剂还可以包含其它药物活性成分。
治疗有效剂量可首先使用本领域中熟知的各种方法来估算。用于动物研究的初始剂量可基于细胞培养测定中所确立的有效浓度。适合于人个体的剂量范围例如可使用从动物研究和细胞培养测定所获得的数据来确定。在某些实施方案中,可以将本发明的化合物制备为用于口服的药剂。本发明的化合物在用于口服的药剂中的示例性的剂量是从约0.01至约100mg/kg(其中kg表示受试者的体重)。在一些实施方案中,药剂包括从约0.01至约20mg/kg(其中kg表示受试者的体重),或者任选地从约0.01至约10mg/kg(其中kg表示受试者的体重),或者任选地从约0.01至约5.0mg/kg(其中kg表示受试者的体重)。在某些实施例中,本发明化合物经肠胃给药,其有效给药剂量为大约0.001-1mg/kg、优选大约0.01-0.5mg/kg体重。
通常用于口服施用的药剂的给药方案是每周三次、每周两次、每周一次、每日三次、每日两次或者每日一次。在某些实施例中,本发明化合物作为活性成分以每24小时约0.001至约50、优选0.001至10mg/kg体重的总量进行给药,为了获得所需的结果,任选可以采用多个单剂量的形式来进行给药。一个单剂量优选地可以包含用量为约0.001至约30、特别是0.001至3mg/kg体重的本发明化合物。
药剂(例如本发明的化合物)的有效量或治疗有效量或剂量指的是引起个体症状改善或存活延长的药剂或化合物的量。所述分子的毒性和治疗功效可在细胞培养物或实验动物中通过标准医药程序来测定,例如通过测定LD50(使群体的50%致死的剂量)和ED50(对群体的50%治疗有效的剂量)。毒性作用与治疗作用的剂量比是治疗指数,可表示为LD50/ED50。优选显示高治疗指数的药剂。
有效量或治疗有效量是将会引发研究人员、兽医、医生或其它临床医生所探求的组织、系统、动物或人类的生物或医学反应的化合物或医药组合物的量。剂量优选在包括极小毒性或无毒性的ED50的循环浓度的范围内。剂量可在这个范围内变化,视所用的剂型和/或所用的给药途径而定。应根据本领域中已知的方法,考虑个体状况的特殊性来选择正确的制剂、给药途径、剂量和给药间隔时间。
剂量和间隔时间可个别地加以调整以提供足以获得所需效果的活性部分的血浆水平;即最小有效浓度(minimal effective concentration,MEC)。各化合物的MEC将有所不同,但可以例如从体外(in vitro)数据和动物实验估算。获得MEC所必需的剂量将视个体特征和给药途径而定。在局部给药或选择性摄取的情况下,药物的有效局部浓度可能与血浆浓度无关。
所施予的药剂或组合物的量可视各种因素而定,包括所治疗个体的性别、年龄和体重、病痛的严重性、给药方式和处方医师的判断。
在需要时,本发明的组合物可以用含有一个或一个以上单位剂型(含有活性成分)的包装或分配装置提供。举例来说,所述包装或装置可包含金属或塑料箔(如发泡包装)或玻璃和橡皮塞。所述包装或分配装置可附有用药说明书。也可以制备包含在相容性医药载体中配制的本发明化合物的组合物,将其置于适当容器中,并且加上用于治疗指定病状的标签。
本发明的化合物可以单独或者,如需要,与其它的活性化合物结合使用。本发明还提供了包括至少一种本发明的化合物和一种或多种进一步的活性物质,特别是用于治疗和/或预防本发明所述的疾病的药物的联合使用。
本发明的化合物作为DPP-IV抑制剂且显示出不能预知的有价值药理学作用范围。它们因此适于用作用于治疗和/或预防人类和动物疾病的药物。DPP-4抑制剂可以增加血液中有活性的内院GIP(葡萄糖依赖性促胰岛素多肽)和GLP-1(胰高血糖素样多肽-1)的浓度,从而促进胰岛素分泌,抑制胰高血糖素异常分泌,减轻胃排空,降低血糖水平。因此,本发明的化合物将应用于糖尿病和相关疾病的预防、治疗或者改善这些疾病的症状。
本发明的化合物将应用于,但绝不限于,使用本发明的化合物或药物组合物的有效量对患者给药来预防、治疗或减轻患者糖尿病和相关疾病,或者糖尿病后期损伤。这样的疾病包括,但并不限于糖尿病,尤其是II型糖尿病,以及糖尿病性视网膜病、糖尿病性神经病、糖尿病性肾病、胰岛素抗性、高血糖、高胰岛素血症、肥胖症、高脂血症,尤其是高甘油三酯血症、X综合症、动脉粥样硬化或高血压。
本发明的化合物除了对人类治疗有益以外,还可应用于兽医治疗宠物、引进品种的动物和农场的动物,包括哺乳动物,啮齿类动物等等。另外一些动物的实例包括马、狗和猫。在此,本发明的化合物包括其药学上可接受的衍生物。
本发明的化合物可以单独使用或,如果需要的话与其它活性成分结合使用。本发明进一步涉及包括至少一种本发明的化合物和一种或多种另一种活性成分(特别是用于治疗和/或预防上述病症)的药物。用于组合的合适的活性成分例如且优选地是:
·DPP-IV抑制剂,例如,西格列汀(sitagliptin)、维格列汀(vidagliptin)、阿格列汀(alogliptin)、利格列汀(linagliptin)及沙格列汀(saxagliptin);
·双胍类药物,例如,苯乙双胍、二甲双胍(metformin);
·磺酰脲类药物,例如,醋磺环已脲、氯磺丙脲(diabinese)、格列本脲(glibenclamide,优降糖)、格列吡嗪(glipizide,吡磺环已脲)、格列齐特(gliclazide,达美康)、格列美脲(glimepiride)、格列戊脲(glipentide)、格列喹酮(gliquidone)、妥拉磺脲、甲苯磺丁脲及氯茴苯酸(meglitinide);
·格列奈类药物,例如,瑞格列奈及那格列奈;
·α-葡萄糖苷水解酶抑制剂,例如,阿卡波糖(acarbose);
·α-葡萄糖苷酶抑制剂,例如,酯解素、卡格列波糖(camiglibose)、乙格列酯(emiglitate)、米格列醇(miglitol)、伏格列波糖(voglibose)、普那米星(pradimicin)及沙玻制菌素(salbostatin);
·PPAR激动剂,例如,巴拉列酮(balaglitazone)、环格列酮(ciglitazone)、达格列酮(darglitazone)、恩格列酮(englitazone)、爱沙列酮(isaglitazone)、吡格列酮(pioglitazone)、罗格列酮(rosiglitazone)及曲格列酮(troglitazone);
·PPARα/γ双激活剂,例如,CLX-0940、GW-1536、GW-1929、GW-2433、KRP-297、L-796449、LR-90、MK-0767及SB-219994;
·胰高血糖素样肽-1(GLP-1)激动剂,例如,乙先素-3(exendin-3)及乙先素-4(exendin-4);
·蛋白质酪氨酸磷酸酶-1B(PTP1B)抑制剂,例如,曲度奎明、海提索萃取物及由Zhang,S.等人,现代药物发现,12(9/10),373-381(2007)所公开的化合物;
·钠-葡萄糖协同转运蛋白2(SGLT2)抑制剂,例如达格列净(Dapagliflozin)、恩格列净(Empagliflozin)、坎格列净(Canagliflozin)、Ipragliflozin(ASP-1941)、Tofogliflozin、Luseogliflozin及荣格列净。
·胰岛素、胰岛素拟似物、肝糖磷酸化酶抑制剂;
·VPAC2受体激动剂;
·葡糖激酶活化剂;
·糖原磷酸化酶抑制剂或者葡糖-6-磷酸酶抑制剂;
·αP2抑制剂;
·乙酰基-CoA羧化酶-2(ACC-2)抑制剂;
·磷酸二酯酶(PDE)-10抑制剂;
·二酰基甘油酰基转移酶(DGAT)1或2抑制剂;
·葡萄糖转运载体4(GLUT4)调节剂;
·谷氨酰胺-果糖-6-磷酸酰胺转移酶(GFAT)抑制剂。。
一般合成过程
在本说明书中,如果在化学名称和化学结构间存在任何差异,结构是占优的。
一般地,本发明的化合物可以通过本发明所描述的方法制备得到,除非有进一步的说明,其中取代基的定义如式(I)或式(II)所示。下面的反应方案和实施例用于进一步举例说明本发明的内容。
所属领域的技术人员将认识到:本发明所描述的化学反应可以用来合适地制备本发明的其他化合物,且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如,根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成,如适当的保护干扰基团,通过利用其他已知的试剂除了本发明所描述的,或将反应条件做一些常规的修改。另外,本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
化合物的结构是通过核磁共振(1H-NMR、13C-NMR或/和19F-NMR)来确定的。1H-NMR、13C-NMR、19F-NMR化学位移(δ)以百万分之一(ppm)的单位给出。1H-NMR、13C-NMR、19F-NMR的测定是用Bruker Ultrashield-400核磁共振谱仪和Bruker Avance III HD 600核磁共振谱仪,测定溶剂为氘代氯仿(CDCl3)、氘代甲醇(CD3OD或MeOH-d4)或者氘代二甲基亚砜(DMSO-d6)。用TMS(0ppm)或氯仿(7.25ppm)作为参照标准。当出现多重峰的时候,将使用下面的缩写:s(singlet,单峰),d(doublet,双峰),t(triplet,三重峰),m(multiplet,多重峰),br(broadened,宽峰),dd(doublet of doublets,双二重峰),dt(doublet of triplets,双三重峰),td(triplet of doublets,三双重峰),brs(broadened singlet,宽单峰)。偶合常数J,单位用赫兹(Hz)表示。
制备纯化或制备拆分一般使用Novasep pump 250高效液相色谱仪。
LC-MS的测定用Agilen-6120Quadrupole LC/MS质谱仪。
柱层析一般使用青岛海洋化工300目~400目硅胶为载体。
本发明的起始原料是已知的,并且可以在市场上购买到得,购买自上海韶远公司(Shanghai Accela Company)、安耐吉公司(Energy Company)、百灵威公司(J&K)、天津阿法埃莎公司(Alfa Company)等公司,或者可以采用或者按照本领域已知的方法来合成。
实施例中无特殊说明,反应均在氮气氛围下进行;
氮气氛围是指反应瓶连接一个约1L容积的氮气气球或钢釜;
氢气氛围是指反应瓶连接一个约1L容积的氢气气球或者是一个约1L容积的不锈钢高压反应釜;
实施例中若无特殊说明,溶液是指水溶液;
实施例中若无特殊说明,反应温度为室温;
实施例中若无特殊说明,室温为20℃~30℃。
实施例中的反应进程的监测采用薄层色谱法(TLC),反应所使用的展开剂的体系有:二氯甲烷和甲醇体系,二氯甲烷和乙酸乙酯体系,石油醚和乙酸乙酯体系,溶剂的体积比根据化合物的极性不同而进行调节。
柱层析的洗脱剂的体系包括:A:石油醚和乙酸乙酯体系,B:二氯甲烷和乙酸乙酯体系,C:二氯甲烷和甲醇体系。溶剂的体积比根据化合物的极性不同而进行调节,也可以加入少量的氨水和醋酸等进行调节。
HPLC是指高效液相色谱;
HPLC的测定使用安捷伦1260高压液相色谱仪(Eclipse Plus C18,4.6×150mm,5um色谱柱);
HPLC测试条件:柱温:35℃ PDA:210nm,254nm
流动相:A相:0.1%磷酸B相:乙腈流速:1.0mL/min
流动相梯度如表A所示:
表A
时间 | 流动相A的梯度 | 流动相B的梯度 |
0min | 90% | 10% |
7min | 85% | 15% |
20min | 10 | 90 |
25min | 10 | 90 |
生物测试试验中的分析用的LC/MS/MS系统包括Agilent 1200系列真空脱气炉,二元注射泵,孔板自动采样器,柱恒温箱,带电喷雾电离(ESI)源的Agilent G6430三级四级杆质谱仪。定量分析在MRM模式下进行,MRM转换的参数如表B所示:
表B
分析使用Agilent XDB-C18,2.1×30mm,3.5μM柱,注入5μL样品。分析条件:流动相为0.1%的甲酸水溶液(A)和0.1%的甲酸甲醇溶液(B)。流速为0.4mL/min。流动相梯度如表C所示:
表C
时间 | 流动相B的梯度 |
0.5min | 5% |
1.0min | 95% |
2.2min | 95% |
2.3min | 5% |
5.0min | 终止 |
此外,用于分析的还有Agilent 6330系列LC/MS/MS光谱仪,配备有G1312A二元注射泵,G1367A自动采样器和G1314C UV检测器;LC/MS/MS光谱仪采用ESI放射源。使用标准液对每一个分析物进行合适的阳离子模型处理和MRM转换进行最佳的分析。在分析期间使用Capcell MP-C18柱,规格为:100×4.6mm I.D.,5μM(Phenomenex,Torrance,California,USA)。流动相是5mM醋酸铵,0.1%甲醇水溶液(A):5mM醋酸铵,0.1%甲醇乙腈溶液(B)(70/30,v/v);流速为0.6mL/min;柱温保持在室温;注入20μL样品。
下面简写词的使用贯穿本发明:
下列合成方案描述了制备本发明公开化合物的步骤。其中,除非另外说明,R1和R2具有如本发明所述的含义。
合成方案
合成方案1
化合物(I-A)可以通过合成方案1所描述的方法制备得到。化合物(I-a)与化合物(I-b)在缩合剂(例如,2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯)存在的条件下发生缩合反应得到化合物(I-c)。化合物(I-c)脱除氨基上的保护基Boc,得到式(I-A)所示结构的化合物。
下面的实施例可以对本发明做进一步的描述,然而,这些实施例不应作为对本发明的范围的限制。
实施例
制备实施例
实施例1 2-氨基-2-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]乙酸乙酯的异构体1-1、异构体1-2、异构体1-3和异构体1-4
异构体1-1、异构体1-2、异构体1-3和异构体1-4分别为以下其中之一的结构:
步骤1 2-(二苯亚甲基氨基)-2-吡嗪-2-基-乙酸乙酯1b
将2-氯吡嗪(18mL,200mmol)1a加入到2-(二苯亚甲基氨基)乙酸乙酯(51g,190mmol)与碳酸铯(6.5g,20mmol)的N,N-二甲基甲酰胺(250mL)溶液中,加热至65℃反应48小时。反应液冷却至室温,加入水(200mL),用乙酸乙酯(400mL×2)萃取,合并的有机相用水(500mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=5/1]纯化,得到标题化合物1b(48g,产率69%),为棕色油状物。
MS(ESI,pos.ion)m/z:346.2[M+H]+。
步骤2 2-氨基-2-吡嗪-2-基-乙酸乙酯盐酸盐1c
将盐酸(140mL,420mmol,3mol/L)加入到2-(二苯亚甲基氨基)-2-吡嗪-2-基-乙酸乙酯1b(48.0g,140mmol)的乙酸乙酯(420mL)溶液中,室温反应5小时。减压浓缩除去溶剂,残留物用乙酸乙酯(500mL)打浆,过滤,收集滤饼,得到标题化合物1c(31g,产率100%),为棕色固体。
MS(ESI,pos.ion)m/z:182.1[M+H]+。
步骤3 2-(叔丁氧基羰基氨基)-2-(吡嗪-2-基)-乙酸乙酯1d
0℃下,将二碳酸二叔丁酯(0.67mL,2.9mmol)缓慢滴加到2-氨基-2-吡嗪-2-基-乙酸乙酯盐酸盐1c(0.51g,2.8mmol)与三乙胺(0.79mL,5.6mmol)的四氢呋喃(10mL)溶液中,反应液室温反应20小时。减压浓缩除去溶剂,残留物溶于二氯甲烷(40mL),用饱和碳酸氢钠溶液(50mL)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=5/1]纯化,得到标题化合物1d(0.49g,产率62%),为黄色油状物。
步骤4 2-(叔丁氧基羰基氨基)-2-(哌嗪-2-基)-乙酸乙酯1e
将10%钯/碳(0.4g,0.37mmol)加入到2-(叔丁氧基羰基氨基)-2-(吡嗪-2-基)-乙酸乙酯1d(2.0g,7.11mmol)的乙醇(25mL)与乙酸乙酯(10mL)的混合溶液中,置换氢气,室温氢化反应30小时。过滤,滤液浓缩,残余物经硅胶柱层析[乙酸乙酯/甲醇(v/v)=5/1]纯化,得到标题化合物1e(1.1g,产率54%),为黄色固体。
MS(ESI,pos.ion)m/z:288.2[M+H]+。
步骤5 3-[1-(叔丁氧基羰基氨基)-2-乙氧基-2-羰基-乙基]哌嗪-1-甲酸苄酯1f
0℃下,将氯甲酸苄酯(0.49mL,3.4mmol)的二氯甲烷溶液(2mL)加入到2-(叔丁氧基羰基氨基)-2-(哌嗪-2-基)-乙酸乙酯1e(1.0g,3.5mmol)与三乙胺(0.75mL,5.2mmol)的二氯甲烷(15mL)溶液中,室温反应4小时。加入水(10mL),用二氯甲烷(15mL×2)萃取,合并的有机相用饱和氯化钠溶液(15mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=1/1]纯化,得到标题化合物1f(1.5g,产率100%),为无色油状物。
MS(ESI,pos.ion)m/z:422.3[M+H]+。
步骤6 3-[1-(叔丁氧基羰基氨基)-2-乙氧基-2-羰基-乙基]-4-甲磺酰基-哌嗪-
1-甲酸苄酯1g
0℃下,将甲磺酰氯(0.3mL,4.0mmol)缓慢滴加到3-[1-(叔丁氧基羰基氨基)-2-乙氧基-2-羰基-乙基]哌嗪-1-甲酸苄酯1f(1.35g,3.2mmol)与三乙胺(0.67mL,4.8mmol)的二氯甲烷(15mL)溶液中,室温反应2小时。向反应液中加入水(10mL)淬灭反应,用乙酸乙酯(20mL×3)萃取,合并的有机相用饱和氯化钠溶液(15mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=5/1]纯化,得到标题化合物1g(1.44g,产率100%),为无色油状物。
MS(ESI,pos.ion)m/z:522.3[M+Na]+。
步骤7 2-(叔丁氧基羰基氨基)-2-(1-甲磺酰基哌嗪-2-基)乙酸乙酯1h
将氢氧化钯/碳(0.15g,1.07mmol)加入到3-[1-(叔丁氧基羰基氨基)-2-乙氧基-2-羰基-乙基]-4-甲磺酰基-哌嗪-1-甲酸苄酯1g(1.44g,2.88mmol)的乙醇(30mL)溶液中,置换氢气,加热至80℃氢化反应18小时。过滤浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物1h(0.74g,产率70%),为无色油状物。
MS(ESI,pos.ion)m/z:366.2[M+H]+。
步骤8 2-(叔丁氧基羰基氨基)-2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-
三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]乙酸乙酯的异构体1i1和异构体1i2
异构体1i1和异构体1i2分别为以下其中之一的结构:
0℃下,将三乙胺(0.85mL,6.1mmol)加入到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(0.74g,2.2mmol)、2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(0.93g,2.4mmol)与2-(叔丁氧基羰基氨基)-2-(1-甲磺酰基哌嗪-2-基)乙酸乙酯1h(0.74g,2.0mmol)的二氯甲烷(15mL)溶液中,室温反应24小时。减压浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到的化合物经IC柱[正己烷/乙醇(v/v)=40/60]制备拆分得异构体1i1(保留时间:15.997min,0.50g,产率37%)和异构体1i2(保留时间:17.497min,0.20g,产率15%),均为白色固体。
MS(ESI,pos.ion)m/z:581.3[M-Boc+H]+。
步骤9 2-氨基-2-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-
哌嗪-2-基]乙酸乙酯的异构体1-1、异构体1-2、异构体1-3和异构体1-4
0℃下,将氢化氢的乙醇溶液(8mL,2mol/L)滴入2-(叔丁氧基羰基氨基)-2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]乙酸乙酯1i1(500mg,0.74mmol)的乙醇(1mL)溶液中,室温反应1小时。减压浓缩除去溶剂,残余物溶于二氯甲烷/甲醇/水(v/v/v=4/1/5,20mL)中,用饱和碳酸氢钠溶液调节pH=8,随后用二氯甲烷/甲醇(v/v=4/1,10mL×5)萃取,合并的有机相用无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到的化合物再经IC柱[正己烷(0.1%二乙胺)/乙醇(v/v)=30/70]制备得异构体1-1(129mg,产率36%,HPLC:97.5%)和异构体1-2(134mg,产率38%,HPLC:95.2%),均为白色固体。
MS(ESI,pos.ion)m/z:481.2[M+H]+;
异构体1-1:1H NMR(600MHz,CDCl3)δ(ppm)7.06(dd,1H),6.91(dt,1H),4.58(d,1H),4.40(d,1H),4.16(tdd,2H),3.78(m,3H),3.54(dd,2H),3.21(dt,2H),2.85(d,3H),2.70(m,2H),2.55(dd,1H),2.45(dd,1H),1.28(t,3H);
异构体1-2:1H NMR(600MHz,CDCl3)δ(ppm)7.11(dd,1H),6.91(dt,1H),4.55(d,1H),4.38(d,1H),4.16(qd,2H),3.77(m,2H),3.54(dd,2H),3.23(m,2H),2.85(d,4H),2.76(m,2H),2.51(m,1H),2.41(m,1H),1.28(t,3H)。
以1i2(200mg,0.29mmol)为代替1i1,经上述实验方法制备得到异构体1-3(33mg,产率:24%,HPLC:93.7%)和异构体1-4(21mg,产率:15%,HPLC:96.3%),均为白色固体。
MS(ESI,pos.ion)m/z:481.2[M+H]+;
异构体1-3:1H NMR(400MHz,CDCl3)δ(ppm)7.32(d,1H),6.95(d,1H),4.22(m,3H),3.91(dd,2H),3.66(dd,4H),3.41-3.17(m,4H),3.07(s,3H),3.01-2.85(m,1H),2.85-2.73(m,1H),1.41-1.28(m,3H);
异构体1-4:1H NMR(400MHz,CDCl3)δ(ppm)7.34(s,1H),6.95(s,1H),4.50-4.03(m,3H),3.84(d,2H),3.66(d,2H),3.49(d,3H),3.28(s,3H),3.08(s,3H),2.89(d,1H),2.75(s,1H),1.34-1.26(m,3H)。
实施例22-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]乙酸乙酯的异构体2-1和异构体2-2
异构体2-1和异构体2-2分别为以下其中之一的结构:
步骤1(2E)-2-(4-苄基哌嗪-2-亚基)乙酸乙酯2b
0℃下,将4-氯-3羰基-丁酸乙酯(3.38mL,25mmol)加入到N'-苄基乙基-1,2-二氨2a(5.7mL,38mmol)的甲醇(25mL)溶液中,室温反应1小时。减压浓缩除去溶剂,残余物溶于乙酸乙酯(100mL)中,分别用水(50mL×2)和饱和氯化钠溶液(50mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=8/1]纯化,得到标题化合物2b(2.3g,产率35.3%),为黄色固体。
MS(ESI,pos.ion)m/z:261.10[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)8.65(s,1H),7.35(m,5H),4.41(s,1H),4.15(q,2H),3.58(s,2H),3.83(t,2H),3.21(s,2H),2.70(t,2H),1.26(t,3H)。
步骤2 2-(哌嗪-2-基)乙酸乙酯2c
将10%钯/碳(0.09g,0.08mmol)加入到(2E)-2-(4-苄基哌嗪-2-亚基)乙酸乙酯2b(0.47g,1.8mmol)的甲醇(15mL)溶液中,置换氢气,60℃加热氢化(4.0MPa)反应12小时。过滤,用甲醇(10mL×2)洗涤滤饼,滤液浓缩,残余物经硅胶柱层析[乙酸乙酯/甲醇(v/v)=10/1]纯化,得到标题化合物2c(0.18g,产率54%),为白色固体。
MS(ESI,pos.ion)m/z:173.30[M+H]+。
步骤3 2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]哌嗪-
2-基]乙酸乙酯2d
0℃下,将三乙胺(0.45mL,3.2mmol)加入到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(0.35g,1.1mmol)、2-哌嗪-2-基乙酸乙酯2c(0.18g,1.0mmol)与2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(0.48g,1.2mmol)的二氯甲烷(15mL)溶液中,室温反应1小时。加水(5mL)淬灭反应,分液,有机相用饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物(0.45g,产率88.0%),为白色固体。
MS(ESI,pos.ion)m/z:487.90[M+H]+。
步骤4 2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-甲
磺酰基-哌嗪-2-基]乙酸乙酯的异构体2e1和异构体2e2
异构体2e1和异构体2e2分别为以下其中之一的结构:
0℃下,将甲磺酰氯(0.08mL,1mmol)的二氯甲烷(0.5mL)溶液缓慢加入到2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]哌嗪-2-基]乙酸乙酯2d(0.45g,0.92mmol)与三乙胺(0.19mL,1.4mmol)的二氯甲烷(15mL)溶液中,室温反应30分钟。加水(5mL)淬灭反应,用乙酸乙酯(30mL×2)萃取,合并的有机相用饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,得到的固体HPLC普通柱和IC柱[正己烷/乙醇(v/v)=70/30]制备分离,得到标题化合物异构体2e1(52mg,产率10%)和异构体2e2(63mg,产率12%),均为白色固体。
步骤5 2-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-
基]乙酸乙酯的异构体2-1和异构2-2
0℃下,将氯化氢的乙醇溶液(1.5mL,2mol/L)加入到2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]乙酸乙酯的异构体2e1(52mg,0.09mmol)的二氯甲烷(0.3mL)溶液中,室温反应1小时。减压浓缩除去溶剂,残余物溶于乙酸乙酯(20mL),用饱和碳酸氢钠溶液调节pH=9,分液,有机相用饱和氯化钠(20mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[乙酸乙酯/甲醇(v/v)=10/1]纯化,得到标题化合物异构体2-1(26mg,产率60%,HPLC:96.0%),为白色固体。
异构体2-1:
MS(ESI,pos.ion)m/z:465.90[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)δ7.24(m,1H),6.98(m,1H),4.51(m,2H),4.11(m,2H),3.90(d,1H),3.75(m,2H),3.41-3.23(m,2H),3.10(m,3H),2.95(s,3H),2.80(m,1H),2.69-2.53(m,3H),1.29(t,3H)。
以2e2(63mg,0.11mmol)代替2e1,经上述实验方法制备得到相应的异构体2-2(24mg,产率46%,HPLC:87.4%),为白色固体。
异构体2-2:
MS(ESI,pos.ion)m/z:466.30[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.24(m,1H),6.98(m,1H),4.60-4.30(m,2H),3.89-3.75(m,2H),3.70(d,3H),3.41(t,1H),3.25(m,2H),3.12(t,2H),2.90(s,3H),2.82(t,1H),2.81-2.62(m,3H),1.28(t,3H)。
实施例32-氨基-2-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]乙酸乙酯的异构体3-1、异构体3-2、异构体3-3和异构体3-4
异构体3-1、异构体3-2、异构体3-3和异构体3-4分别为以下其中之一的结构:
步骤1(E)-2-甲基丁-2-烯酸甲酯3b
将浓硫酸(2.7mL,51mmol)缓慢加入到(E)-2-甲基丁-2-烯酸3a(5.0g,49.9mmol)的甲醇溶液中(30mL)中,68℃加热反应7小时。反应液冷却至室温,加水(25mL)淬灭反应,用二氯甲烷(25mL×2)萃取,合并的有机相分别用饱和碳酸氢钠溶液(20mL×2)和饱和氯化钠溶液(20mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,得到标题化合物3b(4.0g,产率70%),为无色油状物。
1H NMR(400MHz,CDCl3)δ(ppm)6.87(m,1H),3.73(s,3H),1.84(s,3H),1.79(d,3H)。
步骤2(E)-4-溴-2-甲基-丁-2-烯酸甲酯3c
将N-溴代丁二酰亚胺(1.7g,9.6mmol)分批加入到(E)-2-甲基丁-2-烯酸甲酯3b(1.0g,8.8mmol)和过氧化苯甲酰(0.32g,1.3mmol)的四氯化碳(20mL)溶液中,加热至78℃,反应4小时。加入无水硫酸钠,过滤,用石油醚洗涤滤饼(5mL×2),滤液浓缩,残余物溶于乙酸乙酯(20mL),依次用硫代硫酸钠溶液(10mL×2)、水(10mL×2)和饱和氯化钠溶液(10mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=50/1]纯化,得到标题产物3c(1.2g,产率71%),为无色油状物。
1H NMR(400MHz,CDCl3)δ(ppm):6.98(m,1H),4.03(d,2H),3.76(s,3H),1.98(s,3H)。
步骤3N-苄基-N'-三苯甲基-乙-1,2-二胺3e
0℃下,将[氯(二苯)甲基]苯(1.8g,6.5mmol)的二氯甲烷溶液(15mL)加入N-苄基乙-1,2-二氨3d(0.9mL,5.9mmol)与三乙胺(1.0mL,7.2mmol)的乙腈(3mL)溶液中,室温反应1小时。过滤,用二氯甲烷(5mL×2)洗涤滤饼,收集滤液浓缩,得到标题化合物3e(2.3g,产率100%),为淡黄色固体。
步骤42-(4-苄基哌嗪-2-基)异丙酸甲酯3f
将碳酸钾(1.72g,12.4mmol)与碘化钾(0.04g,0.22mmol)加入到N-苄基-N'-三苯甲基-乙-1,2-二胺3e(3.62g,9.22mmol)的乙腈(12mL)溶液中,剧烈搅拌10分钟后,加入(E)-4-溴-2-甲基-丁-2-烯酸甲酯3c(1.20g,6.22mmol),室温反应13小时。过滤,滤饼依次用乙腈(5mL)和二氯甲烷(10mL)洗涤,收集滤液浓缩,残余物溶于甲醇(10mL),加入氯化氢的乙醇(2mL,2mol/L)溶液,加热至90℃回流反应1.5小时。减压浓缩除去溶剂,向残余物中加入水(20mL),用1N盐酸调节pH=3,用乙酸乙酯(15mL×2)萃取,合并的有机相用饱和氯化钠溶液(10mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物3f(0.44g,产率27%),为黄色油状物。
步骤5 2-(4-苄基-1-甲磺酰基-哌嗪-2-基)异丙酸甲酯3g
0℃下,将甲磺酰氯(0.14mL,1.8mmol)的二氯甲烷(0.5mL)溶液缓慢加入到2-(4-苄基哌嗪-2-基)异丙酸甲酯3f(0.44g,1.7mmol)与三乙胺(0.35mL,2.5mmol)的二氯甲烷(15mL)溶液中,室温反应30分钟。用水(5mL)淬灭反应,乙酸乙酯(30mL×2)萃取,合并的有机相用饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,得到标题化合物3g(0.41g,产率73%),为黄褐色油状物。
MS(ESI,pos.ion)m/z:341.3[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.36-7.27(m,5H),4.01(dd,1H),3.74(dd,1H),3.70(s,1H),3.58(d,1H),3.54(s,2H),3.45-3.15(m,3H),2.91(d,3H),2.85-2.67(m,2H),2.18(d,2H),1.24(d,2H),1.01(d,1H)。
步骤6 2-(1-甲磺酰基哌嗪-2-基)异丙酸甲酯3h
将10%钯/碳(0.08g)加入到2-(4-苄基-1-甲磺酰基-哌嗪-2-基)异丙酸甲酯3g(0.41g,1.2mmol)的甲醇(15mL)溶液中,置换氢气,60℃加热氢化(4.0MPa)反应10小时。过滤,用甲醇(5mL×2)洗涤滤饼,收集滤液浓缩,残余物经硅胶柱层析[乙酸乙酯/甲醇(v/v)=10/1]纯化,得到标题化合物3h(0.24g,产率81%),为白色固体。
1H NMR(400MHz,CDCl3)δ(ppm)4.05(dd,1H),3.71(m,4H),3.61-3.32(m,2H),3.11(m,1H),3.04-2.92(m,4H),2.91-2.77(m,2H),1.28(d,2H),1.22(d,1H)。
步骤7 2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-甲
磺酰基-哌嗪-2-基]异丙酸甲酯的异构体3i1、异构体3i2、异构体3i3和异构体3i4
异构体3i1、异构体3i2、异构体3i3和异构体3i4分别为以下其中之一的结构:
0℃下,将三乙胺(0.41mL,2.9mmol)加入到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(0.35g,1.1mmol)、2-(1-甲磺酰基哌嗪-2-基)异丙酸甲酯3h(0.24g,0.96mmol)与2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(0.44g,1.1mmol)的二氯甲烷(12mL)溶液中,室温反应1小时。加水(2mL)淬灭反应,分液,有机相用饱和氯化钠(10mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物3i(0.41g,产率76%),通过制备得到四个异构体(3i1:69mg,3i2:40mg,3i3:40mg,3i4:65mg),均为白色固体。
MS(ESI,pos.ion)m/z:588.8[M+Na]+。
步骤8 2-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-
基]异丙酸甲酯的异构体3-1、异构体3-2、异构体3-3和异构体3-4
0℃下,将氯化氢的乙醇溶液(1.6mL,2mol/L)加入到2-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]异丙酸甲酯的异构体3i1(69mg,0.12mmol)的二氯甲烷(0.4mL)溶液中,室温反应1小时。减压浓缩除去溶剂,残余物溶于乙酸乙酯(20mL),用饱和碳酸氢钠溶液调节pH=9,分液,有机相用饱和氯化钠溶液(5mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[乙酸乙酯/甲醇(v/v)=10/1]纯化,得到标题化合物的异构体3-1(48mg,产率85%,HPLC:88.96%),为白色固体。
MS(ESI,pos.ion)m/z:466.3[M+H]+;
异构体3-1:1H NMR(400MHz,CDCl3)δ(ppm)7.25(m,1H),6.98(m,1H),4.50(dd,1H),4.20(dd,1H),3.80(m,2H),3.75(s,3H),3.66(m,2H),3.33(m,1H),3.11(m,2H),2.99(s,3H),2.98(m,1H),2.88-2.73(m,2H),2.59(d,1H),1.23(d,3H)。
分别以3i2(40mg,0.07mmol)、3i3(40mg,0.07mmol)和3i4(65mg,0.11mmol)代替3i1,经上述实验方法制备得到相应的异构体3-2(26mg,产率80%,HPLC:97.39%)、异构体3-3(28mg,产率85%,HPLC:98.23%)和异构体3-4(45mg,产率85%,HPLC:96.52%),均为白色固体。
MS(ESI,pos.ion)m/z:466.2[M+H]+;
异构体3-2:1H NMR(400MHz,CDCl3)δ(ppm)7.24(m,1H),6.97(m,1H),4.70(dd,1H),4.13-4.03(dd,1H),3.81(m,2H),3.70(s,3H),3.65(m,1H),3.35-3.17(m,3H),3.10(m,1H),2.96(m,1H),2.90(s,3H),2.84(m,1H),2.81-2.66(m,1H),2.60(d,1H),1.30(d,3H);
异构体3-3:1H NMR(400MHz,CDCl3)δ(ppm)7.22(m,1H),7.00(m,1H),4.70(d,1H),4.08(dd,1H),3.85-3.74(m,2H),3.71(s,3H),3.63(m,1H),3.24(m,2H),3.15(m,1H),3.06(m,1H),2.98(m,1H),2.90(s,3H),2.82(m,1H),2.71(m,1H),2.62(m,1H),1.30(d,3H);
异构体3-4:1H NMR(400MHz,CDCl3)δ(ppm)7.24(m,1H),6.96(m,1H),4.51(t,1H),4.25-4.10(m,1H),3.79(m,2H),3.74(s,3H),3.68(m,1H),3.34(m,1H),3.25(m,1H),3.18(m,1H),3.06(m,1H),2.99(s,3H),2.97-2.90(m,1H),2.90-2.79(m,1H),2.72(m,1H),2.57(m,1H),1.22(d,3H)。
实施例4 1-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]环丙基甲酸甲酯的异构体4-1和异构体4-2
异构体4-1和异构体4-2分别为以下其中之一的结构:
步骤1 1-(哌啶-2-基)-环丙基腈4b
将2-氟哌啶4a(6mL,74.20mmol)和环丙基腈(5.74mL,77.9mmol)溶于干燥的甲苯(60mL),氮气保护,0℃下,缓慢加入双(三甲基硅基)氨基钠(39mL,78mmol),自然恢复至室温下搅拌反应4小时。0℃下,缓慢滴加饱和氯化铵溶液(100mL)淬灭反应,用乙酸乙酯(300mL×2)萃取,合并的有机相用饱和氯化钠溶液(200mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=5/1]纯化,得到淡黄色固体4b(1.34g,产率12%)。
MS(ESI,pos.ion)m/z:146.1[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)9.01(d,J=1.3Hz,1H),8.49(d,J=2.4Hz,1H),8.46-8.42(m,1H),1.85-1.80(m,4H)。
步骤2 1-(哌啶-2-基)-环丙基甲酸4c
将氢氧化钠溶液(20%,12mL)缓慢滴加到1-(哌啶-2-基)-环丙基腈4b(1.32g,9.09mmol)的甲醇(25mL)溶液中,升温至75℃回流反应24小时。反应液冷却至室温,用6N盐酸调节pH至2,用乙酸乙酯(30mL×2)萃取,合并的有机相用饱和氯化钠溶液(30mL)洗涤,无水硫酸钠干燥,抽滤浓缩,得到标题化合物4c(1.38g,产率92%),为淡黄色固体。
MS(ESI,neg.ion)m/z:163.1[M-H]-。
步骤31-(哌啶-2-基)-环丙基甲酸甲酯4d
将浓硫酸(0.35mL,6.6mmol)加入到1-(哌啶-2-基)-环丙基甲酸4c(0.83g,5.1mmol)的甲醇(25mL)溶液中,66℃加热反应8小时。反应液冷却至室温,减压浓缩,加入水(100mL),用乙酸乙酯(50mL×3)萃取,合并的有机相用饱和氯化钠溶液(100mL)洗涤,无水硫酸钠干燥,抽浓浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=5/1]纯化,得到标题化合物4d(0.79g,产率88%),为淡黄色油状物。
1H NMR(400MHz,CDCl3)δ(ppm)8.85(d,J=1.2Hz,1H),8.48-8.44(m,1H),8.42(d,J=2.5Hz,1H),3.70(s,3H),1.73(q,J=4.0Hz,2H),1.51(q,J=4.1Hz,2H)。
步骤4 1-(哌嗪-2-基)-环丙基甲酸甲酯4e
将10%钯/碳(0.074g)加入到1-(哌啶-2-基)-环丙基甲酸甲酯4d(0.74g,4.2mmol)的甲醇(15mL)溶液中,置换氢气,66℃下氢化(6MPa)反应24小时。过滤,滤液浓缩,得到标题化合物4e(0.53g,产率70%)。
MS(ESI,pos.ion)m/z:185.2[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm)3.65(s,3H),3.02(d,J=12.7Hz,1H),2.96-2.84(m,2H),2.82-2.71(m,2H),2.69-2.64(m,1H),2.51(dd,J=10.5,2.8Hz,1H),2.11(s,2H),1.25-1.21(m,2H),0.95-0.87(m,1H),0.87-0.78(m,1H)。
步骤5叔丁基3-(1-甲氧基羰基环丙基)哌嗪-1-甲酸甲酯4f
0℃下,将二碳酸二叔丁酯(1.0mL,4.4mmol)的二氯甲烷(5mL)溶液缓慢滴加到1-(哌嗪-2-基)-环丙基甲酸甲酯4e(0.80g,4.3mmol)和三乙胺(1.2mL,8.6mmol)的二氯甲烷(15mL)溶液中,室温下反应1小时。将反应液浓缩,用乙酸乙酯(50mL)溶解,依次用水(50mL)和饱和氯化钠溶液(50mL)洗涤,无水硫酸钠干燥,抽浓浓缩,得到标题化合物4f(1.23g,产率99%),为淡黄色油状物。
步骤6叔丁基3-(1-甲氧基羰基环丙基)-4-(甲磺酰基)哌嗪-1-甲酸甲酯4g
0℃下,将甲磺酰氯(0.10mL,1mmol)的二氯甲烷(0.5mL)溶液缓慢滴加到叔丁基3-(1-甲氧基羰基环丙基)哌嗪-1-甲酸甲酯4f(0.185g,0.650mmol)和三乙胺(0.18mL,1.3mmol)的二氯甲烷(4mL)溶液中,室温反应30分钟。加水(4mL)淬灭反应,用乙酸乙酯(20mL)萃取,有机相用饱和氯化钠溶液(20mL)洗涤,用无水硫酸钠干燥,抽滤浓缩,得到标题化合物4g(0.163g,产率69%),为无色油状物。
MS(ESI,pos.ion)m/z:263.2[M-Boc+H]+。
1H NMR(400MHz,CDCl3)δ(ppm)3.90-3.71(m,4H),3.68(s,3H),3.63-3.25(m,3H),2.92(s,3H),1.48(s,9H),1.36-1.30(m,2H),1.13-0.84(m,2H)。
步骤7 1-(1-甲磺酰基哌嗪-2-基)环丙基甲酸甲酯4h和1-(1-甲磺酰基哌嗪-2-
基)丁酸甲酯4i
0℃下,将氯化氢的乙醇溶液(20mL,2mol/L)缓慢滴加到叔丁基3-(1-甲氧基羰基环丙基)-4-(甲磺酰基)哌嗪-1-甲酸甲酯4g(1.66g,4.58mmol)的二氯甲烷(6mL)溶液中,室温反应1小时。加入用乙酸乙酯(20mL),用饱和碳酸氢钠溶液调pH至9,减压浓缩除去溶剂,残余物经硅胶柱层析[乙酸乙酯/甲醇(v/v)=5/1]纯化,得到标题化合物4h(0.10g,产率8.4%)和4i(0.19g,16%),均为淡黄色油状物。
MS(ESI,pos.ion)m/z:263.2[M+H]+。
步骤8 1-[4-[(3R)-3-(叔丁氧羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-(1-甲
磺酰基哌嗪-2-基)]环丙基甲酸甲酯4j
0℃下,将三乙胺(0.38mL,2.7mmol)缓慢滴加到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(0.32g,0.96mmol),1-(1-甲磺酰基哌嗪-2-基)环丙基甲酸甲酯4h(0.23g,0.88mmol)和2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(0.40g,1.0mmol)的二氯甲烷(12mL)溶液中,室温反应1小时。加水(10mL)淬灭反应,分液,有机相用饱和氯化钠溶液(10mL)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物4j(0.49g,产率97%),为白色固体。
MS(ESI,pos.ion)m/z:578.3[M+H]+。
步骤9 1-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-
基]环丙基甲酸甲酯4
0℃下,将氯化氢的乙醇溶液(17mL,2mol/L)缓慢滴加到1-[4-[(3R)-3-(叔丁氧羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-(1-甲磺酰基哌嗪-2-基)]环丙基甲酸甲酯4j(0.764g,1.32mmol)的二氯甲烷(5mL)溶液中,室温反应1小时。反应液浓缩,加入乙酸乙酯(100mL)溶解,用饱和碳酸氢钠溶液调pH至9,分液,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到标题化合物4(0.42g,产率66%),为白色固体。
MS(ESI,pos.ion)m/z:478.3[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.34-7.24(m,1H),7.03-6.93(m,1H),4.32-4.20(m,1H),4.08-3.93(m,1H),3.92-3.78(m,2H),3.78-3.56(m,5H),3.55-3.40(m,1H),3.38-3.20(m,1H),3.20-3.06(m,1H),3.02-2.89(m,3H),2.83-2.52(m,2H),1.45-1.30(m,2H),1.25-1.07(m,1H),1.04-0.81(m,2H)。
步骤10 1-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-
基]环丙基甲酸甲酯的异构体4-1和异构体4-2
将1-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]环丙基甲酸甲酯4经IC柱[正己烷/乙醇(v/v)=70/30]制备分离得到异构体4-1(43mg,产率6.8%,HPLC:93.7%)和4-2(45mg,产率7.1%,HPLC:98.8%),均为白色固体。
实施例51-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]丁酸甲酯5
以4i代替4h,经实施例4步骤8和步骤9描述的实验方法制备得到化合物5(0.131g,HPLC:99.2%),为白色固体。
MS(ESI,pos.ion)m/z:480.3[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.16-7.06(m,1H),7.00-6.90(m,1H),4.73(d,J=14.0Hz,1H),4.08(d,J=10.8Hz,1H),3.85-3.76(m,1H),3.70(s,3H),3.65-3.55(m,1H),3.25-3.15(m,1H),2.95(d,J=14.0Hz,1H),2.89(s,3H),2.86-2.73(m,2H),2.72-2.60(m,1H),2.50-2.43(m,1H),2.43-2.33(m,1H),2.32-2.15(m,2H),1.85-1.75(m,1H),1.75-1.65(m,1H),0.93-0.86(m,3H)。
实施例6(E)-3-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]丙-2-烯酸乙酯6
步骤1 O4-叔丁基O1-(9H-芴-9-基甲基)2-(羟甲基)哌嗪-1,4-二羧酸酯6b
在0℃下,将碳酸钠(0.99g,9.2mmol)与芴甲氧羰酰氯(1.5g,5.6mmol)加入到3-(羟甲基)哌嗪-1-甲酸叔丁基酯6a(1.0g,4.6mmol)的二氧六环(15mL)与水(5mL)溶液中,室温反应12小时。减压浓缩除去溶剂,残留物溶于乙酸乙酯(50mL),分液,有机相用饱和氯化钠溶液(20mL)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经经硅胶柱层析[石油醚/乙酸乙酯(v/v)=3/1]纯化,得到标题化合物6b(1.6g,产率79%),无色油状物。
1H NMR(400MHz,CDCl3)δ(ppm)7.79(d,J=7.5Hz,2H),7.58(d,J=7.4Hz,2H),7.43(t,J=7.4Hz,2H),7.33(dd,J=19.4,12.0Hz,2H),4.53(s,2H),4.25(t,J=6.1Hz,1H),4.20-3.26(m,6H),2.93(d,J=45.9Hz,3H),1.91(s,1H),1.48(s,9H)。
步骤2 O4-叔丁基O1-(9H-芴-9-基甲基)2-甲酰基哌嗪-1,4-二羧酸酯6c
将2-碘酰基苯甲酸(4.0g,14.0mmol)加入到O4-叔丁基O1-(9H-芴-9-基甲基)2-(羟甲基)哌嗪-1,4-二羧酸酯6b(1.5g,3.4mmol)的二氯甲烷(40mL)溶液中,室温反应48小时。过滤,滤液浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=4/1]纯化,得到标题化合物6c(1.18g,产率79%),为无色油状物。
步骤3 O4-叔丁基O1-(9H-芴-9-基甲基)2-[(E)-3-乙氧基-3-氧代-丙-1-烯基]哌
嗪-1,4-二羧酸酯6d
将乙氧甲酰基亚甲基三苯基膦(9.6g,27.6mmol)的四氢呋喃(80mL)溶液加入O4-叔丁基O1-(9H-芴-9-基甲基)2-甲酰基哌嗪-1,4-二羧酸酯6c(8.0g,18.0mmol)的四氢呋喃(20mL)溶液中,室温反应4小时。减压浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=5/1]纯化,得到标题化合物6d(8.0g,产率86%),为无色油状物。
MS(ESI,pos.ion)m/z:529.3[M+Na]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.78(d,J=7.5Hz,2H),7.56(d,J=7.3Hz,2H),7.41(td,J=7.3,2.8Hz,2H),7.32(dd,J=16.4,9.1Hz,2H),6.77(d,J=12.9Hz,1H),6.03-5.64(m,1H),4.95-4.41(m,3H),4.31-3.76(m,6H),3.00(tt,J=98.9,49.5Hz,3H),1.48(s,9H),1.31(t,J=7.1Hz,3H)。
步骤4 3-[(E)-3-乙氧基-3-氧代-丙-1-烯基]哌嗪-1-甲酸叔丁基酯6e
将哌啶(4.0mL,40.0mmol)加入到O4-叔丁基O1-(9H-芴-9-基甲基)2-[(E)-3-乙氧基-3-氧代-丙-1-烯基]哌嗪-1,4-二羧酸酯6d(4.0g,7.90mmol)的N,N-二甲基甲酰胺(12mL)溶液中,室温反应15分钟。加水(20mL)淬灭反应,用二氯甲烷/甲醇的混合溶液(v/v=10/1,20mL×3)萃取,合并的有机相用饱和氯化钠溶液(30mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经经硅胶柱层析[石油醚/乙酸乙酯(v/v)=1/1]纯化,得到标题化合物6e(1.6g,产率71%),为无色油状物。
MS(ESI,pos.ion)m/z:324.0[M+K]+;
1H NMR(400MHz,CDCl3)δ(ppm)6.87(dd,J=15.9,5.8Hz,1H),6.05(dd,J=15.9,1.2Hz,1H),4.22(q,J=7.1Hz,2H),4.13-3.83(m,2H),3.44-3.34(m,1H),3.03(d,J=11.5Hz,1H),2.96-2.85(m,1H),2.79(td,J=11.3,2.8Hz,1H),2.67(s,1H),1.48(s,9H),1.29(dd,J=13.7,6.6Hz,4H)。
步骤5 3-[(E)-3-乙氧基-3-氧代-丙-1-烯基]-4-(甲磺酰基)哌嗪-1-甲酸叔丁基
酯6f
0℃下,将三乙胺(1.6mL,11.5mmol)与甲磺酰氯(0.9mL,12.0mmol)依次滴入3-[(E)-3-乙氧基-3-氧代-丙-1-烯基]哌嗪-1-甲酸叔丁基酯6e(1.6g,5.6mmol)的二氯甲烷(15mL)溶液中,室温反应12小时。冷却至0℃,用水(20mL)淬灭反应,二氯甲烷(20mL×2)萃取,合并的有机相用饱和氯化钠溶液(20mL×2)洗涤,无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=3/1]纯化,得到标题化合物6f(1.39g,产率68%),为黄色油状物。
MS(ESI,pos.ion)m/z:385.0[M+Na]+。
步骤6(E)-3-(1-甲磺酰基哌嗪-2-基)丙-2-烯酸乙酯6g
0℃下,将三氟乙酸(3.0mL,40.0mmol)加入到3-[(E)-3-乙氧基-3-氧代-丙-1-烯基]-4-(甲磺酰基)哌嗪-1-甲酸叔丁基酯6f(1.39g,3.84mmol)的二氯甲烷(10mL)溶液中,室温反应3小时。减压浓缩除去溶剂,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到标题化合物6g(0.3g,产率30%),为黄色固体。
MS(ESI,pos.ion)m/z:263.0[M+H]+。
步骤7(E)-3-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酰基]-1-
甲磺酰基-哌嗪-2-基]丙-2-烯酸乙酯6h
0℃下,将N,N-二异丙基乙胺(0.5mL,2.8mmol)与2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(0.60g,1.6mmol)加入到(E)-3-(1-甲磺酰基哌嗪-2-基)丙-2-烯酸乙酯6g(0.28g,1.07mmol)的四氢呋喃(8mL)溶液中,室温反应20分钟后,加入(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(0.57g,1.7mmol),室温反应12小时。减压浓缩除去溶剂,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=2/1]纯化,得到标题化合物6h(0.45g,产率73%),为白色固体。
MS(ESI,pos.ion)m/z:600.3[M+Na]+。
步骤8(E)-3-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-
2-基]丙-2-烯酸乙酯6
0℃下,将三氟乙酸(1.0mL,13.0mmol)加入(E)-3-[4-[(3R)-3-(叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酮]-1-甲磺酰基-哌嗪-2-基]丙-2-烯酸乙酯6h(0.45g,0.78mmol)的二氯甲烷(10mL)溶液中,室温反应12小时。减压浓缩除去溶剂,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到标题化合物6(0.28g,产率75%),为无色油状物。
MS(ESI,pos.ion)m/z:477.8[M+H]+;
1H NMR(400MHz,DMSO-d6)δ(ppm)7.66-7.19(m,2H),7.04-6.66(m,1H),6.04(t,J=16.0Hz,1H),4.59(d,J=13.5Hz,1H),4.52-4.31(m,1H),4.18-4.01(m,2H),4.00-3.77(m,1H),3.64-3.43(m,2H),3.20(d,J=8.6Hz,2H),3.17-3.08(m,2H),3.07-2.91(m,4H),2.66(dd,J=13.4,5.1Hz,1H),2.56(dd,J=17.8,10.1Hz,1H),2.46-2.22(m,2H),1.23-1.13(m,3H)。
实施例7 3-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]丙酸乙酯7
将10%钯/碳(0.1g)加入(E)-3-[4-[(3R)-3-氨基-4-(2,4,5-三氟苯基)丁酰基]-1-甲磺酰基-哌嗪-2-基]丙-2-烯酸乙酯6(0.14g,0.29mmol)的甲醇(10mL)溶液中,置换氢气,氢化反应12小时。过滤,滤液浓缩,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到标题化合物7(0.10g,产率70%,HPLC:91.0%),为无色油状物。
MS(ESI,pos.ion)m/z:480.8[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.10(dd,J=16.9,8.6Hz,1H),6.94(dd,J=16.4,9.2Hz,1H),4.63-4.53(m,1H),4.16(dq,J=14.3,7.1Hz,2H),4.03(s,1H),3.80-3.65(m,2H),3.57(s,1H),3.37(dd,J=13.4,3.6Hz,1H),3.19(dt,J=27.2,13.5Hz,2H),2.96(s,3H),2.88(d,J=13.9Hz,1H),2.80(dd,J=13.4,6.0Hz,1H),2.69(dt,J=13.7,6.9Hz,1H),2.58-2.27(m,5H),2.10-1.87(m,2H),1.27(s,3H)。
实施例8(3R)-3-氨基-1-[(1S,4S)-2-甲磺酰基-2,5-二氮杂双环[2.2.1]庚烷-5-基]-4-(2,4,5-三氟苯基)丁-1-酮8
步骤1(1S,4S)-2-甲磺酰基-2,5-二氮杂二环[2.2.1]庚烷-5-甲酸叔丁基酯8b
0℃下,将三乙胺(0.21mL,1.5mmol)与甲磺酰氯(0.1mL,1mmol)加入到(1S,4S)2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁基酯8a(0.2g,1mmol)的四氢呋喃(5mL)溶液中,室温反应20小时。过滤,滤液浓缩,得到标题化合物8b(0.36g,产率100%),为白色固体。
步骤2(1S,4S)-2-甲磺酰基-2,5-二氮杂二环[2.2.1]庚烷盐酸盐8c
0℃下,将氯化氢的乙醇溶液(4mL,2.0mol/L)加入到(1S,4S)-2-甲磺酰基-2,5-二氮杂二环[2.2.1]庚烷-5-甲酸叔丁基酯8b(0.15g,0.54mmol)的乙醇(2mL)溶液中,室温反应1小时。减压浓缩除去溶剂,得到标题化合物8c(0.12g,产率100%),为白色固体。
步骤3 N-[(R)-3-[(1S,4S)-2-甲磺酰基-2,5-二氮杂二环[2.2.1]庚烷-5-基)-3-
氧代-1-[(2,4,5-三氟苯基)甲基]丙基]氨基甲酸叔丁基酯8d
0℃下,将三乙胺(0.24mL,1.7mmol)加入到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(190mg,0.57mmol)、2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(260mg,0.68mmol)与(1S,4S)-2-甲磺酰基-2,5-二氮杂二环[2.2.1]庚烷盐酸盐8c(120mg,0.56mmol)的二氯甲烷(5mL)溶液中,室温反应24小时。减压浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物8d(0.16g,产率58%),为白色固体。
MS(ESI,pos.ion)m/z:492.2[M+H]+。
步骤4(3R)-3-氨基-1-[(1S,4S)-2-甲磺酰基-2,5-二氮杂双环[2.2.1]庚烷-5-
基]-4-(2,4,5-三氟苯基)丁-1-酮8
0℃下,将氯化氢的乙醇溶液(5mL,2.0mol/L)滴入N-[(R)-3-[(1S,4S)-2-甲磺酰基-2,5-二氮杂二环[2.2.1]庚烷-5-基)-3-氧代-1-[(2,4,5-三氟苯基)甲基]丙基]氨基甲酸叔丁基酯8d(100mg,0.2mmol)的乙醇(1mL)溶液中,室温反应1小时。减压浓缩除去溶剂,残余物溶于二氯甲烷/甲醇/水(v/v/v=4/1/5,20mL)中,用饱和碳酸氢钠调节pH>7,分液,水相用二氯甲烷/甲醇萃取(v/v=4/1,10mL×3),合并的有机相用无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到标题化合物8(71mg,产率90%,HPLC:94.4%),为白色固体。
MS(ESI,pos.ion)m/z:392.2[M+H]+;
1H NMR(600MHz,CDCl3)δ(ppm)7.10(dd,1H),6.94(dd,1H),5.00(s,1H),4.55(s,1H),3.64(dd,2H),3.56-3.37(m,3H),2.93(d,3H),2.85-2.65(m,2H),2.35(dd,1H),2.21-2.10(m,3H),1.93(d,2H)。
实施例9(3R)-3-氨基-1-[(1S,4S)-2-(2,2,2-三氟乙酰基)-2,5-二氮杂双环[2.2.1]庚烷-5-基]-4-(2,4,5-三氟苯基)丁-1-酮9
步骤1(1S,4S)-5-(2,2,2-三氟乙酰基)-2,5-二氮杂二环[2.2.1]庚烷-2-甲酸叔
丁酯9a
0℃下,将三氟乙酸酐(0.16mL,1.1mmol)加入2,5-二氮杂二环[2.2.1]庚烷-2-甲酸叔丁基酯8a(0.20g,1.0mmol)与三乙胺(0.43mL,3.1mmol)的四氢呋喃(8mL)溶液中,反应5小时。反应液加入乙酸乙酯(20mL)稀释,用水(10mL×3)洗涤,无水硫酸钠干燥,抽滤浓缩,得到标题化合物9a(0.28g,产率93%),为黄色油状物。
步骤2 1-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-2,2,2-三氟乙酮盐酸盐
9b
0℃下,将氯化氢的乙醇溶液(5mL,2.0mol/L)加入到(1S,4S)-5-(2,2,2-三氟乙酰基)-2,5-二氮杂双环[2.2.1]庚烷-2-甲酸叔丁酯9a(0.28g,0.94mmol)的乙醇(0.5mL)溶液中,室温反应1小时。减压浓缩除去溶剂,得到标题化合物9b(0.24g,产率100%),为黄色油状物。
步骤3N-[(1R)-3-羰基-3-[(1S,4S)-2-(2,2,2-三氟乙酰基)-2,5-二氮杂双环
[2.2.1]庚烷-5-基]-1-[(2,4,5-三氟苯基)甲基]丙基]氨基甲酸叔丁基酯9c
0℃下,将三乙胺(0.4mL,3.0mmol)加入到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(350mg,1.1mmol)、2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(440mg,1.1mmol)与1-[(1S,4S)-2,5-二氮杂双环[2.2.1]庚烷-2-基]-2,2,2-三氟乙酮盐酸盐9b(240mg,0.94mmol)的二氯甲烷(10mL)溶液中,室温反应24小时。减压浓缩,残余物经硅胶柱层析[100%乙酸乙酯]纯化,得到标题化合物9c(0.31g,产率64%),为黄色固体。
MS(ESI,pos.ion)m/z:410.3[M-Boc+H]+。
步骤4(3R)-3-氨基-1-[(1S,4S)-2-(2,2,2-三氟乙酰基)-2,5-二氮杂双环
[2.2.1]庚烷-5-基]-4-(2,4,5-三氟苯基)丁-1-酮9
0℃下,将氯化氢的乙醇溶液(4mL,2.0mol/L)滴入到N-[(1R)-3-羰基-3-[(1S,4S)-2-(2,2,2-三氟乙酰基)-2,5-二氮杂双环[2.2.1]庚烷-5-yl]-1-[(2,4,5-三氟苯基)甲基]丙]氨基甲酸叔丁基酯9c(0.21g,41mmol)的乙醇(0.5mL)溶液中,室温反应1.5小时。减压浓缩除去溶剂,残余物溶于二氯甲烷/甲醇/水(v/v/v=9/1/10,40mL)中,用饱和碳酸氢钠溶液调节pH>7,分液,水相用二氯甲烷/甲醇萃取(v/v=9/1,20mL×2),合并的有机相用无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=9/1]纯化,得到标题化合物9(71mg,产率42%,HPLC:99.9%),为白色固体。
MS(ESI,pos.ion)m/z:410.9[M+H]+;
1H NMR(400MHz,CDCl3)δ(ppm)7.18(m,1H),6.92(td,1H),5.02(d,1H),4.83-4.52(m,1H),4.23(s,2H),3.79(dd,1H),3.72-3.58(m,2H),3.55(dd,1H),3.52-3.38(m,1H),3.08-2.83(m,2H),2.75-2.31(m,2H),2.10-1.85(m,2H)。
实施例10(3R)-3-氨基-1-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-4-(2,4,5-三氟苯基)丁-1-酮10
步骤1N-[(1R)-3-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-3-氧代-1-
[(2,4,5-三氟苯基)甲基]丙基]氨基甲酸叔丁酯10b
0℃下,将三乙胺(0.32mL,2.3mmol)加入到(3R)-3-((叔丁氧基羰基氨基)-4-(2,4,5-三氟苯基)丁酸(252mg,0.76mmol)、2-(7-偶氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(353mg,0.91mmol)与2-甲磺酰基-5,6-二氢-4H-吡咯[3,4-c]吡唑对甲苯磺酸盐10a(272mg,0.76mmol)的二氯甲烷(5mL)溶液中,室温反应5小时。减压浓缩,残余物经硅胶柱层析[石油醚/乙酸乙酯(v/v)=1/1]纯化,得到标题化合物10b(0.28g,产率74%),为白色固体。
MS(ESI,pos.ion)m/z:403.2[M-Boc+H]+。
步骤2(3R)-3-氨基-1-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-4-(2,4,
5-三氟苯基)丁-1-酮10
将N-[(1R)-3-(2-甲磺酰基-4,6-二氢吡咯[3,4-c]吡唑-5-基)-3-氧代-1-[(2,4,5-三氟苯基)甲基]丙基]氨基甲酸叔丁酯10b(104mg,0.21mmol)溶于乙酸乙酯(4mL),加入氯化氢的乙酸乙酯溶液(7mL,2.0mol/L),室温反应3.5小时。减压浓缩除去溶剂,残余物溶于二氯甲烷/甲醇/水(v/v/v=9/1/10,20mL)中,用饱和碳酸氢钠溶液调节pH>7,分液,水相用二氯甲烷/甲醇萃取(v/v=9/1,20mL×2),合并的有机相用无水硫酸钠干燥,抽滤浓缩,残余物经硅胶柱层析[二氯甲烷/甲醇(v/v)=10/1]纯化,得到标题化合物10(41mg,产率49%,HPLC:96.6%),为白色固体。
MS(ESI,pos.ion)m/z:403.2[M+H]+。
1H NMR(400MHz,CDCl3)δ(ppm)7.86(d,J=5.6Hz,1H),7.12(dd,J=16.5,9.2Hz,1H),6.95(td,J=9.6,6.8Hz,1H),4.61(dq,J=13.2,8.7Hz,4H),3.66(d,J=4.4Hz,1H),3.37(d,J=5.8Hz,3H),2.92-2.81(m,1H),2.71-2.77(m,1H),2.49-2.56(m,7.9Hz,1H),2.47-2.37(m,1H)。
活性测试实施例
一、DPP-IV酶抑制试验
测试目的:下面的方法是用来测定本发明化合物对DPP-IV酶的抑制活性。
试验材料:DPP-IV酶,购自R&D,Catalog No.1180-SE。
试验方法:
将待测化合物溶解在适量的DMSO中,制成100mM的母液分装在EP管中,保存在-20℃。实验时,按照所需浓度用测活缓冲液稀释。加不同浓度的样品4μL于384孔板,再加入4μL一定浓度的DPP-IV。参考说明书,选底物Gly-Pro-AMC浓度为10μM。首先将底物配制成16mM的母液,保存在-20℃供使用。实验时将16mM的母液经测活缓冲液稀释成所需浓度。DPP-IV的测活缓冲液为25mM的Tris,pH 8.0。用测活缓冲液稀释底物母液,加4μL于384孔板至终浓度。整个过程在冰浴条件下进行。测活体系中的成分加样完全后离心。放置于多功能酶标仪Infinite F200中,每30sec记录一个荧光值,共记录20个值。读完之后,直接用酶标仪的软件计算Slope(V0),取线性范围内数据。对测得反应速度与相应抑制剂浓度进行分析,抑制百分数为I(%)=(V0-Vi)/V0x100%。Vi代表不同抑制剂浓度时的反应初速度,V0代表没有抑制剂时的反应初速度,以Vi/V0表示抑制剂的抑制程度。以所加抑制剂的浓度为横坐标,以Vi/V0的值为纵坐标,做出相应曲线,采用Graph Pad Prism统计分析软件计算IC50。
试验结果:其结果如表1所示:
表1:本发明实施例提供的化合物对DPP-IV的抑制活性
化合物编号 | DPP-IV IC50/nM |
2-1 | 4.66 |
2-2 | 5.71 |
3-1 | 3.16 |
3-3 | 8.801 |
4-1 | 12.58 |
4-2 | 8.352 |
5 | 7.93 |
6 | 27.65 |
8 | 14.13 |
9 | 17.18 |
10 | 16.09 |
结论:本发明化合物对DPP-IV活性有明显抑制作用。
在本说明书的描述中,参考术语“一个实施例”、“一些实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中,对上述术语的示意性表述不必须针对的是相同的实施例或示例。而且,描述的具体特征、结构、材料或者特点可以在任一个或多个实施例或示例中以合适的方式结合。此外,在不相互矛盾的情况下,本领域的技术人员可以将本说明书中描述的不同实施例或示例以及不同实施例或示例的特征进行结合和组合。
尽管上面已经示出和描述了本发明的实施例,可以理解的是,上述实施例是示例性的,不能理解为对本发明的限制,本领域的普通技术人员在本发明的范围内可以对上述实施例进行变化、修改、替换和变型。
Claims (3)
1.一种化合物,其具有以下其中之一的结构:
或其药学上可接受的盐。
2.一种药物组合物,其包含权利要求1所述的化合物,任选地,进一步包含药学上可接受的辅剂。
3.一种使用权利要求1所述的化合物或权利要求2所述的药物组合物在制备抑制二肽基肽酶-IV(DPP-IV)药物中的用途,其中,所述药物用于预防、治疗或减轻糖尿病、糖尿病视网膜病、糖尿病性神经病、糖尿病性肾病、高胰岛素血症、肥胖症、高甘油三酯血症、X综合征、动脉粥样硬化或高血压。
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