CN110790817A - 一种多肽类化合物、制剂、药物组合物及制备方法、应用 - Google Patents
一种多肽类化合物、制剂、药物组合物及制备方法、应用 Download PDFInfo
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Abstract
本发明公开了一种多肽类化合物、制剂、药物组合物及制备方法、应用，所述多肽类化合物的结构式如通式(I)：
Description
技术领域
本发明涉及医药领域，具体涉及一种多肽类化合物、制剂、药物组合物及制备方法、应用。
背景技术
镇痛药主要作用于中枢或外周神经系统，选择性抑制和缓解各种疼痛，减轻疼痛而致恐惧紧张和不安情绪疼痛的药物。目前全球镇痛市场以阿片类药物和非甾体抗炎药为主，2015 年共占市场总收入的52％以上。据根据美国透明市场研究的一份报告预测，到2025年底全球镇痛市场将达到882亿美元。
阿片样物质受体是一类主要的G蛋白偶联受体，是内源性阿片肽以及阿片类药物结合靶点。阿片受体激活后对神经系统免疫以及内分泌系统具有调节作用，是目前最强且常用的中枢镇痛药。内源性阿片肽是哺乳动物体内天然生成的阿片样活性物质，目前已知的内源性阿片肽大致分为脑啡肽、内啡肽、强啡肽和新啡肽几类。中枢神经系统中存在其相应的阿片受体，即μ、δ和κ受体。μ受体镇痛活性最强，成瘾性也最强，是产生副作用的主要原因。δ受体成瘾性小，镇痛作用也不明显。κ受体(KOR)镇痛活性介于前两者之间。KOR提供了天然的成瘾控制机制，因此，作为受体激动剂的药物具有药物成瘾治疗的潜力。
传统μ阿片样物质受体激动剂(如吗啡及其衍生物)是临床解除剧烈疼痛的主要药物，全世界使用量最大的强效镇痛剂，是治疗慢性关节炎、炎症性神经痛、术后疼痛以及各种癌症引起的中到重度疼痛的最有效的药物。但全身施用传统μ阿片类镇痛药物会产生副作用，如呼吸抑制、药物成瘾、便秘、恶心、意识模糊和产生耐受等。哌啶类(哌替啶，芬太尼类) 也是μ阿片样物质受体激动剂，药理作用与吗啡相同，临床应用与吗啡也相同。但哌替啶镇静、麻醉作用较小，呼吸抑制作用较吗啡弱，不良反应比吗啡小。其他常见的μ阿片样物质受体激动剂包括氨基酮类(美沙酮，右丙氧芬)、环己烷类衍生物(曲马朵)、氨基四氢萘类(地佐辛)。目前还有很多处于临床前和临床阶段μ阿片样物质受体激动剂。
κ阿片样物质受体(KOR)由380个氨基酸组成，强啡肽是其内源性配体。其在感觉神经元、背根神经节细胞和初级传入神经元末梢中均有表达，与痛觉、神经内分泌、情感行为和认知等主要的生理活动。κ阿片样物质受体激动剂与μ阿片样物质受体激动剂不同，其不会导致呼吸抑制和便秘，并且研究表明其成瘾性更低。在机体正常情况下外周施用阿片样物质受体激动剂没有任何镇痛效果，在有炎症或组织损伤时，外周阿片样物质受体功能增强，在施用阿片样物质受体激动剂后发挥镇痛效果。此外，机体对于κ阿片样物质受体激动剂也不容易产生耐受。
血脑屏障由几个部分组成，主要包括沿脑毛细血管壁排列的内皮细胞，包括一个特殊的基底膜)、连续的紧密连接和无细胞旁转运，以及相邻的细胞和活跃的转运分子。由于这种屏障的性质，小的亲脂分子更容易进入中枢神经系统，而大的亲脂化合物进入大脑的可能性较小。因此，在避免中枢神经系统穿透的同时，实现镇痛的目标集中在发现大的/亲水的药效团。
专利WO2013184794报道了一种的全新的多肽类κ阿片样物质受体激动剂。该分子结构中含有D构型氨基酸的四肽，在临床试验中都显示了很强的长效镇痛活性和较小的成瘾性。已经启动的临床适应症包括：急性疼痛，尿毒症瘙痒，腹部手术后疼痛，骨关节炎，髋部、肌肉骨骼疾病，风湿性疾病，术后疼痛，瘙痒症，慢性肾病等。这类多肽药物具有全新的作用机制，为中等至重度疼痛提供了改善的治疗方法。然而临床III期试验显示其会引起高血钠症等一些副作用，因此获得活性更好、副作用更小、成药性更好的新型κ阿片样物质受体激动剂仍然具有吸引力。
发明内容
本发明的目的在于提供一种多肽类化合物，该类多肽类化合物作为κ阿片样物质受体激动剂具有活性更好、副作用更小、成药性更好的优点。
此外，本发明还提供上述由上述多肽类化合物制备的制剂、药物组合物，以及多肽类化合物的制备方法、应用。
本发明通过下述技术方案实现：
一种多肽类化合物，所述多肽类化合物的结构式如通式(I)：
n为0-3中的任意整数；
其中，R1、R2为氢原子、烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基、芳基、芳基烷基、杂芳基、杂芳基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙基氧羰基、C1～C8烷氧羰基、C1～C8酰基、三氟乙酰基、芳基甲酰基、三苯甲基、苄基、2，4-二甲氧基苄基或对甲氧基苄基，所述杂环烷基和杂芳基为含有1到4个选自N、O、S的杂原子；
其中，其中，所述的烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基可被选自烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、烯基、炔基、羟基、氨基、硝基、氰基、羧基、酯基、硼酸(酯)基、酰胺基、巯基、脒基、脲基中的一个或多个取代基所取代；
其中，R3、R4、R5、Ra、Rc、Re、Rg为氢原子或C1～C10烷基；
其中，Rb、Rd、Rf、Rh为氢原子、烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基、芳基、芳基烷基、杂芳基、杂芳基、烯基、炔基、羟基、氨基、硝基、氰基、羧基、酯基、硼酸基、硼酸酯基、酰胺基、巯基、脒基或脲基，所述杂环烷基和杂芳基为含有1到4个选自N、O、S的杂原子；
其中，所述的烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、烯基、炔基可被选自烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、烯基、炔基、羟基、氨基、硝基、氰基、羧基、酯基、磺酰基、亚磺酰基、磷酰基、亚磷酰基、(亚)酸酯基、(亚)磷酸酯基、硼酸(酯)基、酰胺基、巯基、脒基、脲基中的一个或多个取代基所取代；
其中，Z为H、任选取代的C1～C12烷基、C1～C8环烷基、芳基、饱和或不饱和的杂环；
其中，R7为H、羟基、氨基、卤素、烯基、炔基、酯基、酰胺基、硝基、氰基、巯基、任选取代的C1～C12烷基、C1～C8环烷基、芳基、饱和或不饱和的杂环；
B(OR6)2为以下取代基中的任一一种：
当
为空时，B(OR6)2和R7与Z直接相连；
其中，
为C1～C12烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、烯基烷基、炔基烷基、酯基、硼酸(酯)基、酰胺基、卤素、硝基、氰基、巯基、羟基、烷氧基、氨基、烯基或炔基中。
本发明所述的多肽类化合物为含有硼酸结构片段的新型多肽类衍生物，其中，含硼化合物具有微妙的特性，能够可逆的与蛋白质靶标作用，硼酸基团与多肽结合，得到的多肽类衍生物作为κ阿片样物质受体激动剂药物，镇痛活性更好，而且由于硼酸基团具有独特的大极性和水溶性特征，脑通透性会更低，因此副作用更少。
优选地，在通式(I)中，R1连同R2、Ra和Rb中的一个或多个原子成环，包括但不限于以下基团：
优选地，在通式(I)中，Rb、Rd、Rf、Rh为以下取代基任一一种：
上述结构式中的取代基可被选自H、卤素、C1～C10烷基、C1～C10烷氧基、C1～C10卤代烷基、氨基、羟基、氰基、硝基、酰胺基、酯基、磺酰基、亚磺酰基、磷酰基、亚磷酰基、酸酯基、亚酸酯基、磷酸酯基、亚磷酸酯基、硼酸基、硼酸酯基、3-10元杂环基、C1～C10 环烷基、C6～C14芳基或C5～C15杂芳基中的一个或多个基团所取代，
其中，X、Y为NH、O、S或Se；n1、n2、n3、n4为0到8中的任意整数。
优选地，在通式(I)中，R1、R2、Rb、Rd、Rf、Rh中的至少一个基团被一个或多个W 基团所取代，
其中，W为被1～10个羟基或氨基或巯基所取代的C1～C10烷基、单糖、由2～20个不同或相同单糖组成的多糖或任选取代的低聚乙二醇。
优选地，在通式(I)中，
包含但不限于以下结构：
其中，m1，m2，m3，m4为0到6中的任意整数。
优选地，所述多肽类化合物的结构式如通式(II)所示：
通式(II)的结构包括但不限于：
一种多肽类化合物的制备方法，包括以下步骤：
步骤1：制备四肽中间体Int-1，制备过程如下：
步骤11：合成中间体Int-1-1：采用DCM溶胀2-CTC Resin一段时间，然后抽掉溶剂获得溶胀树脂，将Fmoc-D-Lys(Boc)-OH和DIEA的DCM混合溶液加入溶胀树脂中，室温条件下反应，再加入甲醇和DIEA，继续反应一段时间后抽干溶剂，再用DCM洗涤获得树脂；
步骤12：合成中间体Int-1-2：将步骤11获得树脂中加入哌啶/DM，室温条件下反应一段时间，再次加入哌啶/DMF，室温条件下反应一段时间后抽干，并用DMF洗涤，直至检测合格，在冰浴条件下分别将Fmoc-D-Leu-OH、HOBT和HBTU加入DMF活化，再加入DIEA 反应一段时间获得活化液，最后将活化液加入树脂中，室温条件下反应一段时间后，用5％的茚三酮显色树脂，树脂变色，抽干溶液并用DMF洗涤，检测合格后抽干溶剂获得中间体 Int-1-2；
步骤13：合成中间体Int-1-3：将步骤12得到的中间体Int-1-2重复步骤12的操作；
步骤14：合成中间体Int-1-4：将步骤13得到的中间体Int-1-3重复步骤12的操作；
步骤15：合成中间体Int-1-5：在室温条件下将Int-1-4加入三氟乙醇/DCM中，反应一段时间后依次进行抽滤、洗涤和浓缩，将浓缩液滴加到甲基叔丁基醚中搅拌沉降得制备四肽中间体Int-1；
步骤2：制备四肽中间体硼酸频哪醇酯；所述硼酸频哪醇酯通过N-保护的硼酸频哪醇酯在酸性或碱性条件下脱除保护基得到；N-保护的硼酸频哪醇酯可直接购买，或可通过将N- 保护的相应的羧酸通过一锅法脱羧硼化反应得到；
步骤3：制备多肽类化合物：
步骤31：将Int-1、HOBT、HBTU和DIEA的DCM溶液于室温下搅拌一段时间，然后加入步骤2制备的体硼酸频哪醇酯，室温反应，反应液依次洗涤、干燥、过滤，浓缩后得到中间体化合物1-1；
步骤32：将酸(TFA或HCl溶液)滴加到中间体化合物1-1的DCM溶液中，室温搅拌，浓缩、纯化，得到多肽类化合物。
所述四肽中间体硼酸频哪醇酯包括Int-2、Int-3和Int-4，以及其它硼酸频哪醇酯。
其中，所述其它硼酸频哪醇酯的制备方法与Int-4类似。
一种由多肽类化合物的制备的制剂，所述制剂包括通式(I)的立体异构体、多晶型物、溶剂合物、代谢物、前药或药学上可接受的盐或酯，以及一种或者多种以上的药学上可接受的载体和/或赋形剂。
药学上可接受的盐，包括胺的碱性残基的无机酸盐或有机酸盐，以及硼酸或羧酸等酸性残基的碱金属盐或有机盐。胺的碱性残基的无机酸盐或有机酸盐，具体的实例包括盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、氨基磺酸盐、硼酸盐、碳酸盐、碳酸氢盐、磷酸盐、六氟磷酸盐和硝酸盐等无机酸的盐，以及甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、琥珀酸盐、己二酸盐、乙醇酸盐、硬脂酸盐、乳酸盐、苹果酸盐、酒石酸盐、硬脂酸盐、柠檬酸盐、抗坏血酸盐、扑酸盐、盐酸盐、草酸盐、马来酸盐、羟基马来酸盐、酒石酸盐、苯乙酸盐、谷氨酸盐、樟脑磺酸盐、苯甲酸盐、水杨酸盐、磺胺酸盐、2-乙酸基苯甲酸盐、富马酸盐、甲苯磺酸盐、甲磺酸盐、乙烷二磺酸盐、草酸盐、羟乙磺酸盐、天冬氨酸盐、环己酸磺酸盐、延胡索酸盐、等有机酸的盐。硼酸或羧酸等酸性残基的碱金属盐或有机盐，具体的实例包括铝盐、钾盐、钙盐、镁盐、锌盐、精氨酸盐、胆碱盐、二乙胺盐、乙醇胺盐、二乙醇胺盐、甘氨酸盐、赖氨酸盐、葡甲胺盐和氨丁三醇盐等。这些盐可通过本领域已知方法制备。
一种包括所述多肽类化合物或所述制剂的药物组合物。
一种由所述多肽类化合物的应用，所述多肽类化合物用于制备治疗和κ阿片样物质受体相关疾病的药物。
相关疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。
疼痛选自神经性疼痛、躯体痛、内脏痛、皮肤痛、关节炎疼痛、肾结石疼痛、子宫痉挛、痛经、子宫内膜异位症、消化不良、外科手术后疼痛、医疗处理后疼痛、头痛、牙痛、颈椎痛、眼部疼痛、耳炎疼痛、胸部痛、腹痛、腰腿痛、痛风、风湿、类风湿、癌症疼痛、胃肠道紊乱相关的疼痛等。
本发明与现有技术相比，具有如下的优点和有益效果：
本发明所述的多肽类化合物为含有硼酸结构片段的新型多肽类衍生物，其中，含硼化合物具有微妙的特性，能够可逆的与蛋白质靶标作用，硼酸基团与多肽结合，得到的多肽类衍生物作为κ阿片样物质受体激动剂药物，镇痛活性更好，而且由于硼酸基团具有独特的大极性和水溶性特征，脑通透性会更低，因此副作用更少。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，下面结合实施例，对本发明作进一步的详细说明，本发明的示意性实施方式及其说明仅用于解释本发明，并不作为对本发明的限定。
实施例1：
制备多肽类化合物TM-1
步骤31：将Int-1(0.545g，0.622mmol)，HOBT(0.201g，1.492mmol)，HBTU(0.566 g，1.492mmol)，和DIEA(0.320g，2.488mmol)的DCM(15mL)溶液于室温下搅拌0.5h，然后加入Int-4的粗品，室温反应2h。反应液分别用饱和氯化铵溶液、水和饱和食盐水洗涤，经无水硫酸钠干燥，过滤浓缩后的粗品经Prep-HPLC纯化，得到中间体化合物1-1；
步骤32：将TFA(1mL)滴加到1-1(500mg)的DCM(2mL)溶液中，室温搅拌1h，浓缩干后的粗品经Prep-HPLC纯化，得到多肽类化合物TM-1的三氟醋酸盐。
制备的TM-1的质谱、核磁表征如下：
ESI-MS(m/z):665.4(M+H+)
1H NMR(400MHz,DMSO-d6+D2O)：δ7.28–7.21(m,10H),4.70-4.59(m,2H),4.42–4.36(m, 1H),4.18-4.11(m,1H),3.98(s,1H),3.13–2.87(m,4H),2.86–2.59(m,4H),1.74–1.09(m,14H), 1.00-0.91(m,1H),0.89-0.84(m,6H).
其中，Int-1的制备过程如下：
步骤11：合成中间体Int-1-1：在室温条件下用DCM(20mL)溶胀2-CTC Resin(取代度为0.993mmol/g，2.000g)，溶胀时间15min，抽掉溶剂，将Fmoc-D-Lys(Boc)-OH(1.120 g，2.4mmol)和DIEA(0.516g，4.0mmol)的DCM(15mL)混合溶液加入溶胀的树脂中，室温条件下反应2h；再加入甲醇(2mL)和DIEA(1mL)，继续反应0.5h；抽干溶剂，再用DCM(30mL)洗三次；最后用DMF(30mL)洗三次后，直接将树脂投下一步反应；
步骤12：向步骤11中得到的产品中加入哌啶/DMF(V/V＝1/4，20mL)，室温条件下反应10min，抽干，再次加入哌啶/DMF(V/V＝1/4，20mL)，室温条件下反应10mim后抽干，并用DMF(30mL)洗5次，检测最后一次洗涤废液pH为中性；在冰浴条件下分别将 Fmoc-D-Leu-OH(1.809g，4.0mmol)，HOBT(0.543g，4.0mmol)和HBTU(1.521g，4.0mmol) 加入DMF(20mL)活化10min，再加入DIEA(0.780g，6mmol)反应5min，最后将活化液加入树脂中，在室温条件下反应2h，用5％的茚三酮显色树脂(在100℃下加热10min)，树脂未变色，抽干溶液并用DMF(30mL)洗涤5次，检测最后一次洗涤废液pH为中性；抽干后直接用于下一步反应；
步骤13：向步骤12中得到的产品中加入哌啶/DMF(V/V＝1/4，20mL)，室温条件下反应10min，抽干，再次加入哌啶/DMF(V/V＝1/4，20mL)，室温条件下反应10mim后抽干，并用DMF(30mL)洗5次，检测最后一次洗涤废液pH为中性；在冰浴条件下分别将 Fmoc-D-Phe-OH(1.547g，4.0mmol)，HOBT(0.543g，4.0mmol)和HBTU(1.521g，4.0mmol) 加入DMF(20mL)活化10min，再加入DIEA(0.780g，6mmol)反应5min，最后将活化液加入树脂中，在室温条件下反应2h，用5％的茚三酮显色树脂(在100℃下加热10min)，树脂未变色，抽干溶液并用DMF(30mL)洗涤5次，检测最后一次洗涤废液pH为中性，抽干直接用于下一步反应；
步骤14：合成中间体Int-1-4：向步骤13中得到的产品中加入哌啶/DMF(V/V＝1/4，20mL)，室温条件下反应10min，抽干，再次加入哌啶/DMF(V/V＝1/4，20mL)，室温条件下反应10 mim后抽干，并用DMF(30mL)洗5次，检测最后一次洗涤废液pH为中性；在冰浴条件下分别将Boc-D-Phe-OH(1.547g，4.0mmol)，HOBT(0.543g，4.0mmol)和HBTU(1.521 g，4.0mmol)加入DMF(20mL)活化10min，再加入DIEA(0.780g，6mmol)反应5min，最后将活化液加入树脂中，在室温条件下反应2h，用5％的茚三酮显色树脂(在100℃下加热10min)，树脂未变色，抽干溶液并用DMF(30mL)洗涤5次，检测最后一次洗涤废液 pH为中性，抽干直接用于下一步反应；
步骤15：在室温条件下将Int-1-4(4.2g)加入三氟乙醇/DCM(50mL，V＝/V＝1/4)在中，在室温条件下反应2h，抽滤，并用DCM(30mL)洗2次，将有机相浓缩到5mL左右；将浓缩液滴加到100mL的甲基叔丁基醚中搅拌沉降得到2.10g产品，经LCMS检测为目标 Int-1。ESI-MS(m/z):754.4(M+H+)
其中，Int-4的制备过程如下：
将TFA(1mL)滴加到1-N-叔丁氧羰基哌啶-4-硼酸频哪醇酯(0.045g，1.1eq)的DCM(2mL)溶液中，室温搅拌0.5h。减压下浓缩干，得到的透明油状物直接投下一步反应。
ESI-MS(m/z):212.3(M+H+)。
实施例2：
制备多肽类化合物TM-2
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.093g；将Int-4替换成吡咯-3-硼酸频哪醇酯；吡咯-3-硼酸频哪醇酯的合成与Int-4类似，由N-叔丁氧羰基-吡咯-3-硼酸频哪醇酯在酸性条件下脱除保护基得到。所得粗品经Prep-HPLC纯化后得到13.3mg目标化合物TM-2的三氟醋酸盐。
制备的TM-2的质谱、核磁表征如下：
ESI-MS(m/z):651.4(M+H+)
1H NMR(400MHz,DMSO)：δ8.76-8.73(m,1H),8.38–8.16(m,2H),8.02(s,3H),7.70(s, 3H),7.39–7.13(m,10H),4.69-4.64(m,1H),4.52-4.43(m,2H),4.02(s,1H),3.44–3.25(m,3H), 3.14-3.02(m,3H),2.96-2.90(m,1H),2.87–2.66(m,3H),2.01-1.92(m,1H),1.71–1.29(m,11H), 0.92-0.87(m,6H).
实施例3：
制备肽类化合物TM-3：
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.090g，将Int-4替换成2,5-二氢-1H-吡咯-3-硼酸频哪醇酯；2,5-二氢-1H-吡咯-3-硼酸频哪醇酯的合成与Int-4类似，由N-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯在酸性条件下脱除保护基得到。所得粗品经Prep-HPLC纯化后得到13.3mg目标化合物TM-3 的三氟醋酸盐。
制备的TM-3的质谱、核磁表征如下：
ESI-MS(m/z):649.4(M+H+)
1H NMR(400MHz,CD3OD):δ7.44–7.12(m,10H),6.58–6.34(m,1H),4.77–4.52(m,3H), 4.48-4.25(m,4H),4.11-4.06(m,1H),3.28–3.18(m,1H),3.06–2.89(m,4H),1.88-1.80(m,1H), 1.79–1.38(m,8H),1.02–0.91(m,6H).
实施例4：
制备肽类化合物TM-4：
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.057g；将Int-4替换成氨基甲基苯硼酸频哪醇酯。氨基甲基苯硼酸频哪醇酯用量为18mg。所得粗品经Prep-HPLC纯化后得到20.1mg目标化合物TM-4的三氟醋酸盐。
制备的TM-4的质谱、核磁表征如下：
ESI-MS(m/z):687.4(M+H+)
1H NMR(400MHz,DMSO):δ8.77-8.72(m,1H),8.49–8.33(m,2H),8.11–7.95(m,5H),7.66 (d,J＝8.8Hz,4H),7.40–7.06(m,12H),4.69-4.64(m,1H),4.49–4.35(m,1H),4.34–4.23(m,3H), 4.01(s,1H),3.19–3.03(m,2H),2.98–2.87(m,1H),2.86–2.69(m,3H),1.78–1.45(m,7H), 1.36–1.25(m,2H),0.97–0.74(m,6H).
实施例5：
制备肽类化合物TM-5：
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.075g；将Int-4替换成3,6-二氢-2H-吡啶-5-硼酸频哪醇酯；3,6-二氢-2H-吡啶-5-硼酸频哪醇酯的合成与Int-4类似，由N-叔丁氧羰基-3,6-二氢-2H-吡啶-5-硼酸频哪醇酯在酸性条件下脱除保护基得到。所得粗品经Prep-HPLC纯化后得到22.0mg目标化合物TM-5 的三氟醋酸盐。
制备的TM-5的质谱、核磁表征如下：
ESI-MS(m/z):663.4(M+H+)
1H NMR(400MHz,MeOD)：δ7.52–7.15(m,10H),6.59-6.40(m,1H),4.79–4.64(m,1H), 4.42(dt,J＝10.2,6.1Hz,1H),4.30–3.94(m,3H),3.85–3.53(m,2H),3.32–3.12(m,2H), 3.04-2.91(m,4H),2.27(s,2H),1.97–1.55(m,7H),1.54–1.32(m,2H),1.00-0.95(m,6H).
实施例6：
制备肽类化合物TM-6：
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.075g；将Int-4替换成对氨基苯硼酸频哪醇酯。对氨基苯硼酸频哪醇酯用量为22mg。所得粗品经Prep-HPLC纯化后得到3.0mg目标化合物TM-6的三氟醋酸盐。
制备的TM-6的质谱、核磁表征如下：
ESI-MS(m/z):755.4(M+H+)
1H NMR(400MHz,CD3OD)：δ7.79–7.47(m,4H),7.44–7.12(m,10H),4.79–4.66(m,1H),4.58–4.35(m,2H),4.09-4.06(m,1H),3.05–2.90(m,4H),2.09–1.89(m,1H),1.88–1.61(m, 6H),1.61–1.45(m,2H),1.41–1.34(m,2H),1.06–0.92(m,6H).
实施例7：
制备肽类化合物TM-7：
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.190g；将Int-4替换成Int-2。所得粗品经Prep-HPLC纯化后得到33.0mg 目标化合物TM-7的三氟醋酸盐。
制备的TM-7的质谱、核磁表征如下：
ESI-MS(m/z):705.4(M+H+)
1H NMR(400MHz,DMSO-d6)：δ8.58(dd,J＝160.0,8.2Hz,1H),8.18–7.84(m,3H),7.69(s,2H),7.43–7.14(m,10H),4.83–4.40(m,2H),4.40–4.20(m,1H),4.19–3.66(m,2H),3.18-3.03(m,3H),2.96–2.60(m,5H),1.87–1.58(m,6H),1.57–1.41(m,6H),1.41–1.22(m,10H),0.92-0.84(m,6H).
其中，Int-2的制备过程如下：
步骤221：室温条件下将DIC(0.070g,0.55mmol)，DMAP(0.006，0.05mmol)，N-羟基邻苯二甲酰亚胺(0.098g，0.6mmol)加入到Int-2-1(0.135g，0.5mmol)的DCM(15mL) 溶液中，室温搅拌2h。反应液用20mL DCM稀释后，分别用1N HCl和水洗涤2次，有机相合并后经无水硫酸钠干燥、过滤，浓缩后得到白色固体Int-2-2(0.120g)，直接投下一步反应，所述Int-2-1为7-(叔丁氧羰基)-7-氮杂螺[3.5]壬烷-2-羧酸；
步骤222：合反应瓶A：0℃，氮气保护下，将MeLi(1.6M，1mL)缓慢滴加到联硼酸频哪醇酯(0.420g，1.65mmol)的无水THF(7mL)溶液中，加完继续在0℃搅拌0.5h，再室温搅拌0.5h。
反应瓶B：0℃，氮气保护下，将Int-2-2(0.12g)和溴化镁乙醚络合物(0.129g)溶于无水THF(3mL)中，再加入六水合氯化镍(0.012g)，4,4’-二甲氧基-2,2’-联吡啶(0.014g)和无水THF(3mL)，搅拌0.5h至反应体系呈浅绿色。
0℃将反应瓶A中的溶液一次性加入到反应瓶B中，反应体系变成褐色，0℃搅拌1h，再升到室温搅拌1h。TLC中控Int-2-2反应完毕。反应混合物加入到20mL饱和氯化铵溶液中，搅拌10min，加入25mL的乙酸乙酯萃取分液，水相再用15mL乙酸乙酯萃取；合并的有机相用饱和氯化钠溶液洗涤2次，经无水硫酸钠干燥，过滤浓缩得到0.550g粗品；经柱层析纯化得透明油状物0.11g，ESI-MS(m/z):352.3(M+H+)；
步骤223：将Int-2-3(0.11g，0.313mmol)加入DCM(4mL)中，再加入TFA(2mL)，室温搅拌0.5h后浓缩干，得油状物粗品(Int-2)直接投下一步反应，ESI-MS(m/z):252.3 (M+H+)。
实施例8：
制备肽类化合物TM-8：
本实施例基于实施例1，与实施例1的区别在于：
Int-1用量为0.220g；将Int-4替换成Int-3。所得粗品经Prep-HPLC纯化后得到6.5mg 目标化合物TM-8的三氟醋酸盐。
制备的TM-8的质谱、核磁表征如下：
ESI-MS(m/z):680.4(M+H+)
1H NMR(400MHz,DMSO-d6+D2O)：δ7.41–7.22(m,10H),4.79–4.69(m,1H),4.44-4.42 (m,1H),4.11-4.09(m,2H),3.95–3.57(m,4H),2.99-2.92(m,4H),2.20–2.00(m,2H),1.85– 1.33(m,13H),1.02-0.96(m,,6H).
其中，Int-3的制备过程如下：
步骤231：室温条件下将DIC(0.3g,1.1eq)，DMAP(0.027g,0.1eq)，N-羟基邻苯二甲酰亚胺(0.42g,1.2eq)加入到Int-3-1(1.0g,1eq)的DCM(15ml)溶液中，室温搅拌2h。反应液用 20ml DCM稀释后，用1N HCl和水个洗涤2次，经无水硫酸钠干燥后，过滤，浓缩，得白色固体Int-3-2(1.29g)，直接投下一步反应，所述Int-3-1为4-(叔丁氧羰基氨基)-1-芴甲氧羰基哌啶-4-羧酸；ESI-MS(m/z):612.2(M+H+)；
步骤232：反应瓶A：0℃，氮气保护下，将MeLi(1.6M，4ml，3eq)缓慢滴加到联硼酸频哪醇酯(1.798g，3.3eq)的无水THF(7ml)溶液中，加完继续在0℃搅拌0.5h，再室温搅拌0.5h。
反应瓶B：0℃，氮气保护下，将Int-3-2(1.29g)和溴化镁乙醚络合物(0.545g，1eq)溶于无水THF(7ml)中，再加入六水合氯化镍(0.05g，0.1eq)，4,4’-二甲氧基-2,2’-联吡啶(0.06g， 0.13eq)和无水THF(7ml)，搅拌0.5h至反应体系呈浅绿色。
0℃将反应瓶A中的溶液一次性加入到反应瓶B中，反应体系变成褐色，0℃搅拌1h，再升到室温搅拌1h。TLC中控Int-3-2反应完毕。反应混合物加入到50ml饱和氯化铵溶液中，搅拌10min，加入50ml的乙酸乙酯萃取分液，水相再用25ml乙酸乙酯萃取；合并的有机相用饱和氯化钠溶液洗涤2次，经无水硫酸钠干燥，过滤浓缩得到3.00g粗品；经柱层析纯化得透明油状物0.650g，收率：55％；ESI-MS(m/z):549.3(M+H+)
步骤233：将Int-3-3(0.08g，0.146mmol)和甲胺甲醇溶液(4M，4mL)于室温下搅拌0.5h，减压下浓缩干，得到的油状物粗品为Int-3，直接投下一步反应；ESI-MS(m/z):327.2(M+H+)。
本发明采用的溶胀CTC树脂的溶剂、洗涤树脂所用溶剂和缩合条件所用溶剂包括但不限于DCM，THF，DMF，DMA，NMP，DMSO中的单一或者混合溶剂；所述氨基酸保护基以及侧链保护基除了芴甲氧羰基、叔丁氧羰基，还包括苄氧羰基、甲氧羰基、乙氧羰基、三氟乙酸基、对甲氧基苄基、烯丙氧羰基等；所述缩合剂包括但不限于HATU、HBTU、HCTU、 EDCI、PyBOP、CDI、HOBT等。
四肽中间体Int-1的制备过程如下所示：
硼酸类中间体Int-2、Int-3、Int-4的制备中所用的一般合成流程如下所示：
目标化合物TM-1～TM-8的制备中所用的一般合成流程如下所示：
本发明所使用的物料缩写含义如表1所示：
对上述实施例中制备的部分多肽类衍生物进行生物学评价
1、对κ-阿片样物质受体的激动活性及选择性
Forskolin(毛猴素)能够刺激人κ(或μ，或δ)-阿片样物质受体高表达细胞株HEK293 细胞cAMP的释放，κ-阿片受体激动剂能够抑制Forskolin刺激的κ-阿片样物质受体高表达细胞株HEK293细胞cAMP的释放，但不影响Forskolin刺激的μ(或δ)-阿片样物质受体高表达细胞株HEK293细胞cAMP的释放。通过测定实施化合物对腺苷酸环化酶活性的抑制能力，来确定本发明的化合物作为κ-阿片样物质受体激动剂的效能。
细胞培养：将稳定表达人κ(或μ，或δ)-阿片样物质受体高表达细胞株HEK293细胞于含有10％FBS的DMEM培养基种培养。
刺激：将待测化合物按4被梯度浓度稀释为10个浓度梯度，转移50nl到384孔板总然后加入10nl Forskolin。将细胞消化、重选、计数后加入10ul的细胞悬液(5X105cell/mL), 轻轻混匀，23℃下孵育60分钟。
检测：采用cAMP检测试剂盒(Cisbio)，按说明书加入cAMP D2和抗cAMP化合物缀合物，将其再室温下孵育1小时。用envisiong(Perkon Elmer)读板，使用四参数方程拟合得到EC50。
实验结果:如表2所示，所有受试化合物的激动活性(EC50)均低于nM级别，且对κ-阿片样物质受体具有优异的选择性。
表2化合物对κ-阿片样物质受体的激动活性及选择性(EC50)
2、对细胞色素P 450氧化酶的抑制
将含有细胞色素P450的人肝微粒体(0.253mg/mL蛋白)与测试化合物(0.05-50μM)、 CYPs底物(10μM对乙酰氨基酚、5μM双氯芬酸、30μM美芬妥因、5μM氢溴酸右美沙芬、 2μM米达唑仑)、1.0mM NADP在37℃温育10分钟。将萘黄酮、磺胺苯吡唑、N-3-苄基尼凡、奎尼定、酮康唑作作为参比抑制剂。结果如表3所示，受试化合物的IC50均大于50uM。
表3化合物的细胞色素P 450CYP同工酶抑制活性(IC50)
3、化合物的膜透过性
Caco-2细胞系是培养中分化的人结肠腺癌细胞系，用于模拟人小肠的上皮衬。使用标准测试中的Caco-2细胞膜层在膜透过性测试中检测本发明的化合物。可以在穿越培养于96孔聚碳酸酯膜过滤器上的细胞单层的顶到底侧(A-B)方向来确定表观透过性系数(Papp)。化合物于5μM浓度下在接受侧保持在pH 7.4，将测试板温和振荡在37℃温育120分钟。在时间为零时从供应侧取样，在温育过程结束时从供应侧和接受侧取样。以HPLC-MS/MS分析样品。随后根据接受侧中化合物的出现率来计算P app值(表示为10-6cm/秒)。可以以下述方程来计算P app：
Papp＝(VA×[drug]acceptor)/(Area×Time×[drug]initial,donor)
其中P app是表观透过性；VA是接受侧体积，Area是膜表面积，[drug]initial,donor 是零时的供应侧浓度，[drug]acceptor是温育过程结束时接受侧化合物浓度，Time是总温育时间。
表4化合物膜透过性
以上所述的具体实施方式，对本发明的目的、技术方案和有益效果进行了进一步详细说明，所应理解的是，以上所述仅为本发明的具体实施方式而已，并不用于限定本发明的保护范围，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
1.一种多肽类化合物，其特征在于，所述多肽类化合物的结构式如通式(I)：
n为0-3中的任意整数；
其中，R1、R2为氢原子、烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基、芳基、芳基烷基、杂芳基、杂芳基、邻苯二甲酰基、对甲苯磺酰基、邻硝基苯磺酰基、对硝基苯磺酰基、叔丁氧羰基、苄氧羰基、9-芴甲氧羰基、烯丙氧羰基、三甲基硅乙基氧羰基、C1～C8烷氧羰基、C1～C8酰基、三氟乙酰基、芳基甲酰基、三苯甲基、苄基、2，4-二甲氧基苄基或对甲氧基苄基，所述杂环烷基和杂芳基为含有1到4个选自N、O、S的杂原子；
其中，R3、R4、R5、Ra、Rc、Re、Rg为氢原子或C1～C10烷基；
其中，Rb、Rd、Rf、Rh为氢原子、烷基、烷氧基、卤代烷基、环烷基，环烷基烷基、杂环烷基、杂环烷基、芳基、芳基烷基、杂芳基、杂芳基、烯基、炔基、羟基、氨基、硝基、氰基、羧基、酯基、硼酸基、硼酸酯基、酰胺基、巯基、脒基或脲基，所述杂环烷基和杂芳基为含有1到4个选自N、O、S的杂原子；
其中，Z为H、任选取代的C1～C12烷基、C1～C8环烷基、芳基、饱和或不饱和的杂环；
其中，R7为H、羟基、氨基、卤素、烯基、炔基、酯基、酰胺基、硝基、氰基、巯基、任选取代的C1～C12烷基、C1～C8环烷基、芳基、饱和或不饱和的杂环；
B(OR6)2为以下取代基中的任一一种：
-B(OH)2 --B(OMe)2 -B(OEt)2
-B(OPh)2 -B(OiPr)2
Ri＝H，Me，Et，iPr，tBu，Ph，Bn；
当为空时，B(OR6)2和R7与Z直接相连；
其中，
为C1～C12烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、烯基烷基、炔基烷基、酯基、硼酸(酯)基、酰胺基、卤素、硝基、氰基、巯基、羟基、烷氧基、氨基、烯基或炔基中。
2.根据权利要求1所述的一种多肽类化合物，其特征在于，在通式(I)中，R1连同R2、Ra和Rb中的一个或多个原子成环，包括但不限于以下基团：
3.根据权利要求1所述的一种多肽类化合物，其特征在于，在通式(I)中，Rb、Rd、Rf、Rh为以下取代基任一一种：
上述结构式中的取代基可被选自H、卤素、C1～C10烷基、C1～C10烷氧基、C1～C10卤代烷基、氨基、羟基、氰基、硝基、酰胺基、酯基、磺酰基、亚磺酰基、磷酰基、亚磷酰基、酸酯基、亚酸酯基、磷酸酯基、亚磷酸酯基、硼酸基、硼酸酯基、3-10元杂环基、C1～C10环烷基、C6～C14芳基或C5～C15杂芳基中的一个或多个基团所取代，
其中，X、Y为NH、O、S或Se；n1、n2、n3、n4为0到8中的任意整数。
4.根据权利要求1所述的一种多肽类化合物，其特征在于，在通式(I)中，R1、R2、Rb、Rd、Rf、Rh中的至少一个基团被一个或多个W基团所取代，
其中，W为被1～10个羟基或氨基或巯基所取代的C1～C10烷基、单糖、由2～20个不同或相同单糖组成的多糖或任选取代的低聚乙二醇。
5.根据权利要求1所述的一种多肽类化合物，其特征在于，在通式(I)中，
包含但不限于以下结构：
其中，m1，m2，m3，m4为0到6中的任意整数。
6.根据权利要求1所述的一种多肽类化合物，其特征在于，所述多肽类化合物的结构式如通式(II)所示：
7.一种如权利要求1-6任一项所述多肽类化合物的制备方法，其特征在于，包括以下步骤：
步骤1：制备四肽中间体Int-1，制备过程如下：
步骤11：合成中间体Int-1-1：采用DCM溶胀2-CTC Resin一段时间，然后抽掉溶剂获得溶胀树脂，将Fmoc-D-Lys(Boc)-OH和DIEA的DCM混合溶液加入溶胀树脂中，室温条件下反应，再加入甲醇和DIEA，继续反应一段时间后抽干溶剂，再用DCM洗涤获得树脂；
步骤12：合成中间体Int-1-2：将步骤11获得树脂中加入哌啶/DM，室温条件下反应一段时间，再次加入哌啶/DMF，室温条件下反应一段时间后抽干，并用DMF洗涤，直至检测合格，在冰浴条件下分别将Fmoc-D-Leu-OH、HOBT和HBTU加入DMF活化，再加入DIEA反应一段时间获得活化液，最后将活化液加入树脂中，室温条件下反应一段时间后，用5％的茚三酮显色树脂，树脂变色，抽干溶液并用DMF洗涤，检测合格后抽干溶剂获得中间体Int-1-2；
步骤13：合成中间体Int-1-3：将步骤12得到的中间体Int-1-2重复步骤12的操作；
步骤14：合成中间体Int-1-4：将步骤13得到的中间体Int-1-3重复步骤12的操作；
步骤15：合成中间体Int-1-5：在室温条件下将Int-1-4加入三氟乙醇/DCM中，反应一段时间后依次进行抽滤、洗涤和浓缩，将浓缩液滴加到甲基叔丁基醚中搅拌沉降得制备四肽中间体Int-1；
步骤2：制备四肽中间体硼酸频哪醇酯；所述硼酸频哪醇酯通过N-保护的硼酸频哪醇酯在酸性或碱性条件下脱除保护基得到；
步骤3：制备多肽类化合物：
步骤31：将Int-1、HOBT、HBTU和DIEA的DCM溶液于室温下搅拌一段时间，然后加入步骤2制备的体硼酸频哪醇酯，室温反应，反应液依次洗涤、干燥、过滤，浓缩后得到中间体化合物1-1；
步骤32：将酸滴加到中间体化合物1-1的DCM溶液中，室温搅拌，浓缩、纯化，得到多肽类化合物。
8.一种由权利要求1-6任一项所述多肽类化合物的制备的制剂，其特征在于，所述制剂包括通式(I)的立体异构体、多晶型物、溶剂合物、代谢物、前药或药学上可接受的盐或酯，以及一种或者多种以上的药学上可接受的载体和/或赋形剂。
9.一种包括权利要求1所述多肽类化合物或权利要求8所述制剂的药物组合物。
10.一种由权利要求1-6任一项所述多肽类化合物的应用，其特征在于，所述多肽类化合物用于制备治疗和κ阿片样物质受体相关疾病的药物。
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| CN113461775A (zh) * | 2021-08-23 | 2021-10-01 | 成都诺和晟泰生物科技有限公司 | 一种多肽化合物的制备方法 |
| WO2021197283A1 (en) * | 2020-04-03 | 2021-10-07 | Chengdu Sintanovo Biotechnology Co., Ltd. | Synthetic peptide amide compound and its use in the field of medicine |
| WO2022218250A1 (zh) * | 2021-04-12 | 2022-10-20 | 四川海思科制药有限公司 | 肽酰胺类化合物制备用于治疗瘙痒的药物中的用途 |
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| CN113072617B (zh) * | 2021-03-30 | 2023-08-08 | 成都诺和晟泰生物科技有限公司 | 一种多肽化合物及其应用 |
| CN113624898B (zh) * | 2021-08-23 | 2023-08-25 | 成都诺和晟泰生物科技有限公司 | 一种手性镇痛类多肽药物的纯化方法 |
Family Cites Families (15)
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| US7399869B2 (en) | 2005-05-19 | 2008-07-15 | Genentech, Inc. | Fibroblast activation protein inhibitor compounds and methods |
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| US7842662B2 (en) * | 2006-11-10 | 2010-11-30 | Cara Therapeutics, Inc. | Synthetic peptide amide dimers |
| US20150150935A1 (en) * | 2012-06-05 | 2015-06-04 | Cara Therapeutics, Inc. | Peripheral kappa receptor agonists for reducing pain and inflammation |
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| WO2016181408A2 (en) | 2015-05-11 | 2016-11-17 | Cadila Healthcare Limited | NOVEL SHORT-CHAIN PEPTIDES AS KAPPA (κ) OPIOID RECEPTORS (KOR) AGONIST |
| CN107098876B (zh) * | 2016-02-23 | 2021-04-06 | 江苏恒瑞医药股份有限公司 | 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用 |
| CN107098871B (zh) * | 2016-02-23 | 2021-07-02 | 江苏恒瑞医药股份有限公司 | 苯基丙酰胺类衍生物、其制备方法及其在医药上的应用 |
| WO2017214076A1 (en) | 2016-06-06 | 2017-12-14 | The Johns Hopkins University | Peptides having tetrahedral mimicking groups as inhibitors of rhomboid proteases |
| UA123737C2 (uk) * | 2016-06-07 | 2021-05-26 | Джянгсу Хенгруй Медісін Ко., Лтд. | Похідне фенілпропанаміду та спосіб отримання, та його фармацевтичне застосування |
| JP6794602B2 (ja) | 2016-09-27 | 2020-12-02 | シチュアン ケルン−バイオテック バイオファーマシューティカル カンパニー リミテッド | ポリアミド化合物及びその使用 |
| CN109879934B (zh) * | 2017-12-06 | 2020-12-08 | 江苏恒瑞医药股份有限公司 | 一种苯基丙酰胺类衍生物的盐及其制备方法 |
| CN110790817A (zh) * | 2019-11-12 | 2020-02-14 | 成都诺和晟泰生物科技有限公司 | 一种多肽类化合物、制剂、药物组合物及制备方法、应用 |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2021093695A1 (en) * | 2019-11-12 | 2021-05-20 | Chengdu Sintanovo Biotechnologv Co., Ltd. | Polypeptide compound, pharmaceutical composition, preparation method and application thereof |
| US11643436B2 (en) * | 2019-11-12 | 2023-05-09 | Chengdu Sintanovo Biotechnology Co., Ltd. | Polypeptide compound, pharmaceutical composition, preparation method and application thereof |
| WO2021197283A1 (en) * | 2020-04-03 | 2021-10-07 | Chengdu Sintanovo Biotechnology Co., Ltd. | Synthetic peptide amide compound and its use in the field of medicine |
| CN113493490A (zh) * | 2020-04-03 | 2021-10-12 | 成都诺和晟泰生物科技有限公司 | 一种合成肽酰胺类化合物及其在医药领域的用途 |
| CN113493490B (zh) * | 2020-04-03 | 2024-03-12 | 成都诺和晟泰生物科技有限公司 | 一种合成肽酰胺类化合物及其在医药领域的用途 |
| WO2022218250A1 (zh) * | 2021-04-12 | 2022-10-20 | 四川海思科制药有限公司 | 肽酰胺类化合物制备用于治疗瘙痒的药物中的用途 |
| CN113461775A (zh) * | 2021-08-23 | 2021-10-01 | 成都诺和晟泰生物科技有限公司 | 一种多肽化合物的制备方法 |
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| CN111233974A (zh) | 2020-06-05 |
| EP3825322A1 (en) | 2021-05-26 |
| CN111233974B (zh) | 2021-02-26 |
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