CN113493490A - 一种合成肽酰胺类化合物及其在医药领域的用途 - Google Patents
一种合成肽酰胺类化合物及其在医药领域的用途 Download PDFInfo
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- CN113493490A CN113493490A CN202010258951.4A CN202010258951A CN113493490A CN 113493490 A CN113493490 A CN 113493490A CN 202010258951 A CN202010258951 A CN 202010258951A CN 113493490 A CN113493490 A CN 113493490A
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Abstract
本发明公开了一种多肽类衍生物,属于医药领域,具体涉及到一种含有硼酸基团的多肽类衍生物及其制备方法,并且公开了其在预防和治疗由κ阿片样物质受体引起的各种疾病的药物中的用途。
Description
技术领域
本发明涉及医药领域,具体涉及一种合成肽酰胺类化合物、其制备方法和在医药领域的用途。
背景技术
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。
吗啡等μ阿片样物质受体激动剂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不会导致呼吸抑制和便秘,并且成瘾性更低。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。
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。
综上,κ阿片样物质受体激动剂作为药物,具有药物成瘾治疗的潜力,在医药邻域具有非常好的应用前景。为了实现更好的治疗效果以满足市场需求,发明人希望开发一种更佳高效低毒的KOR激动剂。本发明提供一种含有硼酸结构片段的新的κ阿片样物质受体激动剂类化合物。经实验测试表明,此类化合物具有非常优秀的治疗效果。
发明内容
为了解决上述技术问题,本发明公开一种合成肽酰胺类化合物,该类化合物作为κ阿片样物质受体激动剂,镇痛活性更好、副作用更少。本发明还公开该合成肽酰胺类化合物在医药领域的用途。
本发明通过下述技术方案实现:
一种合成肽酰胺类化合物,其结构如通式(I)所示:
或其互变异构体、消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、同位素衍生物、溶剂合物,或其代谢物、前药或其药学上可接受的盐或酯;
其中,n为0到3中的任意整数;
R1、R2选自氢原子、烷基、烷氧基、卤代烷基、环烷基,环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、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,2,4-二甲氧基苄基和对甲氧基苄基,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,所述的杂环烷基或杂芳基含有1到3个选自N、O、S的杂原子;
R3、R4、R5、Ra、Rc、Re、Rg各自独立地选自氢原子、卤素或C1~C10烷基;
Rb、Rd、Rf、Rh各自独立地选自下列取代基:
氢原子、卤素、C1~C10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,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,所述的杂环烷基或杂芳基含有1到3个选自N、O、S的杂原子;
是可任选地取代的3元至8元杂环部分,其中Y选自C、N、O或者S;所述杂环包括芳香性杂环、非芳香性杂环、以及相应的桥环、并环和螺环;所述的芳香性杂环、非芳香性杂环,以及相应的桥环、并环和螺环,可被选自羟基、氨基、C1~C10烷基、烷氧基、烯基、炔基、酯基、酰胺基、卤素、硝基、氰基、巯基中的一个或多个取代基所取代;
W选自C1~C10烷基氨基、环烷基氨基、芳香性或非芳香性杂环基氨基、芳基氨基、芳基烷基氨基、芳香性或非芳香性杂环基烷基氨基、3~8元芳香性杂环或者非芳香性杂环、以及含有该杂环的桥环、并环或螺环;所述芳香性杂环或者非芳香性杂环、桥环、并环或螺环,含有1到3个任选自N、O、S的杂原子,并且至少含有1个N原子;
其中,W中的1个N原子与结构式中左侧的羰基直接相连,形成酰胺键;
B(OR6)2与W中的杂环上的原子直接相连,或者与该杂环的取代基上的原子相连;
B(OR6)2选自以下任一结构,且两个R6基团中的部分原子可以连接成环状取代基:
所述通式(I)中,R1连同R2、Ra和Rb中的一个或多个原子成环,形成以下任一结构:
所述通式(I)中,Rb、Rd、Rf、Rh可独立的选自C1~C10烷基或选自下列任一取代基:
所述C1~C10烷基或上述结构各自任选地被一个或者多个选自氢原子、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、(亚)磺酸酯基、(亚)磷酸酯基、硼酸(酯)基、3-10元杂环基、C1~C10环烷基、C6~C14芳基、C5~C15杂芳基的基团所取代;
A、B独立的选自NH、O、S或Se;
n1、n2、n3、n4、n5选自0到8中的任意整数。
其中,m,m1,m2,m3,m4为选自0到6中的任意整数。
优选的,本发明所述的一种多肽类衍生物,其结构如通式(II)所示:
或其互变异构体、消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、同位素衍生物、溶剂合物,或其代谢物、前药或其药学上可接受的盐或酯。
其中,W为-W1-W2-,W1为3~8元芳香性或非芳香性含氮杂环基团、或含有所述含氮杂环基团的桥环、螺环或并环基团,且N原子与羰基相连;W2选自C1~C10烷基、C1~C10烷基氨基、乙烯基或乙炔基;
或者W为-NH-W3-,且NH与羰基相连;W3选自C1~C10烷基、C3~C10环烷基、C6~C10芳基、3~8元芳香性或非芳香性杂环基团或芳基烷基、杂环基烷基。
R6的范围同上,在此不再赘述。
优选的,所述通式(II)包括但不限于以下结构的化合物,或其互变异构体、消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、同位素衍生物、溶剂合物,或其代谢物、前药或其药学上可接受的盐或酯:
化合物1:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4酰基)吡咯琳-3-基)硼酸
化合物2:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)哌啶-4-基)硼酸
化合物3:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)-2,5-二氢-1H-吡咯-3-基)硼酸
化合物4:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)-1,2,3,6-四氢吡啶-4-基)硼酸
化合物5:(2-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)乙基)硼酸
化合物6:(4-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)环己基)硼酸
化合物7:(4-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)苯基)硼酸
化合物8:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)1,2,3,6-四氢吡啶-3-基)硼酸
化合物9:(7-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)-7-氮杂螺[3.5]壬烷-2-基)硼酸
化合物10:(3-((1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)甲基)苯基)硼酸
化合物11:((1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)哌啶-4-亚基)甲基)硼酸
化合物12:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)哌啶-3-基)硼酸
本发明另一方面提供一种药物组合物,包含如通式(I)或(II)中所述的化合物或其立体异构体、溶剂合物、或其代谢物、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。
具体的,本发明提供了一种药物组合物,包括上述合成肽酰胺类化合物,以及药学上可接受的载体,赋形剂,稀释剂,辅剂,媒介物或它们的组合。
本发明另一方面提供如通式(I)或(II)中所述的化合物或其立体异构体、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯,或包含(I)或(II)中所述的化合物或其立体异构体、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯的药物组合物用于制造预防或者治疗哺乳动物的与κ阿片样物质受体相关的各种疾病或病况的药物中的应用。
本发明另一方面提供如通式(I)或(II)中所述的化合物或其立体异构体、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯,或包含(I)或(II)中所述的化合物或其立体异构体、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯的药物组合物,用于预防或者治疗哺乳动物的与κ阿片样物质受体相关的各种疾病。
本发明优选方案中,所述的κ阿片样物质受体相关的各种疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼。
本发明优选方案中,所述的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。
本发明提供一种预防或治疗κ阿片样物质受体相关的各种疾病的方法,所述方法包括给予通式(I)或(II)中所述的化合物或其立体异构体、溶剂合物、或其代谢物、前药或药学上可接受的盐或酯,或其药物组合物。所述κ阿片样物质受体相关的各种疾病选自: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,所述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中的一种或多种。
本发明所使用的物料缩写含义如下表:
本发明设计并合成得到了一系列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。
附图说明
此处所说明的附图用来提供对本发明实施例的进一步理解,构成本申请的一部分,并不构成对本发明实施例的限定。在附图中:
图1显示了目标化合物1的合成流程图;
图2显示了目标化合物6的合成流程图。
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,下面结合实施例和附图,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化合物1:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4酰基)吡咯琳-3-基)硼酸的合成
如图1所示,化合物1的合成可通过以下工艺步骤制得:
步骤一:合成中间体1-1
在室温条件下用DCM(20mL)溶胀2-CTC Resin(取代度为0.993mmol/g,2.012g),溶胀时间15min,抽掉溶剂,将4-(叔丁氧羰基氨基)-1-芴甲氧羰基哌啶-4-羧酸(1.118g,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,直接将树脂往下一步投反应。
步骤二:合成中间体1-2
向步骤一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-Lys(Boc)-OH(1.820g,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。
步骤三:合成中间体1-3
向步骤二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,抽干直接用于下一步反应。
步骤四:合成中间体1-4
向步骤三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。
步骤五:合成中间体1-5
向步骤四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Boc-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。
步骤六:合成中间体1
在室温条件下将1-5(4.20g)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中间体1(2.103g,纯度92.3%)。
ESI-MS(m/z):980.6(M+H+)
步骤七:合成中间体2
将TFA(2mL)滴加到1-N-叔丁氧羰基吡咯-3-硼酸频哪醇酯(0.350g,1.1mmol)的DCM(4mL)溶液中,室温搅拌0.5h。TLC显示反应完毕,减压下浓缩得到透明油状物(中间体2的三氟醋酸盐),直接用于下一步反应。
步骤八:合成中间体3
将中间体1(0.980g,1.0mmol),HOBT(0.203g,1.5mmol),HBTU(0.569g,1.58mmol),DIEA(0.388g,3.0mmol)的DCM(20mL)溶液于室温下搅拌0.5h,然后加入上述中间体2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450mg目标化合物3,纯度93.5%。
ESI-MS(m/z):1159.7(M+H+)
步骤九:合成化合物1
将TFA(5mL)滴加到中间体3的DCM(10mL)溶液中,室温搅拌1h。浓缩干后的粗品经Prep-HPLC纯化,得到213mg目标化合物1的三氟醋酸盐,纯度为98%。
ESI-MS(m/z):777.5(M+H+)
1H NMR(400MHz,DMSO-d6+D2O):δ7.47–6.86(m,10H),4.80–4.50(m,2H),4.27(d,J=33.7Hz,2H),3.59(s,3H),3.32(d,J=53.1Hz,4H),3.06–2.83(m,3H),2.81–2.64(m,3H),2.42–1.69(m,6H),1.67–1.09(m,11H),0.89-0.83(m,6H).
实施例2化合物2:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)哌啶-4-基)硼酸硼酸的合成
化合物2的制备如实施例1所述。所不同的是硼酸酯原料使用的是1-N-叔丁氧羰基哌啶-4-硼酸频哪醇酯。
ESI-MS(m/z):791.5(M+H+);
1H NMR(400MHz,DMSO-d6+D2O):δ7.35–7.11(m,10H),4.61-4.58(m,2H),4.16(d,J=130.5Hz,3H),3.41(d,J=11.4Hz,1H),3.06-2.90(m,5H),2.86–2.64(m,4H),
2.44-2.31(m,1H),2.29-1.91(m,2H),1.82(d,J=14.2Hz,2H),1.76–0.93(m,16H),0.88-0.83(m,6H).
实施例3化合物3:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)-2,5-二氢-1H-吡咯-3-基)硼酸的合成
化合物3的制备如实施例1所述。所不同的是硼酸酯原料使用的是1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯。
ESI-MS(m/z):775.5(M+H+)
1H NMR(400MHz,DMSO)δ8.79-8.77(m,1H),8.51(s,2H),8.33-8.29(m,1H),8.03(s,3H),7.78-7.71(m,4H),δ7.34–7.14(m,10H),6.33(s,1H),4.73–4.55(m,2H),
4.37-4.27(m,2H),4.25–3.94(m,3H),3.64–3.33(m,3H),3.12-2.89(m,4H),2.83–2.68(m,3H),2.17-2.06(m,3H),1.89-1.77(m,2H),1.66–1.21(m,9H),0.89-0.85(m,6H).
实施例4化合物4:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)-1,2,3,6-四氢吡啶-4-基)硼酸的合成
化合物4的制备如实施例1所述。所不同的是硼酸酯原料使用的是N-Boc-1,2,5,6-四氢吡啶-4-硼酸频哪醇酯。
ESI-MS(m/z):789.5(M+H+)
1H NMR(400MHz,DMSO-d6)δ7.34–7.14(m,10H),6.33(s,1H),4.75–4.55(m,2H),4.50-4.23(m,2H),4.23–3.88(m,4H),3.63–3.33(m,3H),3.12-2.89(m,4H),2.83–2.69(m,3H),2.44–1.96(m,4H),1.89-1.77(m,2H),1.66–1.21(m,9H),0.89-0.85(m,6H).
实施例5化合物5:(2-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)乙基)硼酸的合成
化合物5的制备如实施例1所述。所不同的是硼酸酯原料使用的是2-(Boc-氨基)乙基硼酸频哪醇酯。
ESI-MS(m/z):751.5(M+H+)
1H NMR(400MHz,DMSO-d6+D2O):δ7.38–7.08(m,10H),4.77–4.53(m,2H),4.31(s,1H),3.97(d,J=5.3Hz,1H),3.80–3.35(m,3H),3.27–2.88(m,6H),2.83
–2.65(m,3H),2.17–1.95(m,2H),1.75(s,2H),1.66–1.36(m,7H),1.28(d,J=7.8Hz,2H),0.89-0.82(m,8H).
实施例6化合物6:(4-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)环己基)硼酸的合成
步骤一:合成中间体4-1
室温条件下将DIC(0.133g,1.05mmol),DMAP(0.012g,0.1mmol),N-羟基邻苯二甲酰亚胺(0.202g,1.2mmol)加入到4-(叔丁氧羰基氨基)环己烷羧酸(0.243g,1.0mmol)的DCM(8mL)溶液中,室温搅拌2h。反应液用20mL DCM稀释后,用1N HCl和水各洗涤2次,经无水硫酸钠干燥后过滤、浓缩,得到白色固体4-1(0.545g),直接用于下一步反应。
ESI-MS(m/z):389.2(M+H+)
步骤二:合成中间体4-2
反应瓶A:0℃,氮气保护下,将MeLi(1.6M,2mL,3eq)缓慢滴加到联硼酸频哪醇酯(0.838g,3.3mmol)的无水THF(4mL)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4-1(0.189g)和溴化镁乙醚络合物(0.258g,1.0eq)溶于无水THF(4mL)中,再加入六水合氯化镍(0.024g,0.1eq),4,4’-二甲氧基-2,2’-联吡啶(0.028g,0.13eq)和无水THF(4mL),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。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0.750g粗品;经柱层析纯化得透明油状物0.150g。
ESI-MS(m/z):326.2(M+H+)
步骤三:合成中间体4
将4-2(0.047g,0.145mmol)溶解于DCM(2mL)中,加入TFA(1mL),室温搅拌0.5h。浓缩干后得到透明油状物(中间体4的三氟醋酸盐),直接用于下一步反应。
ESI-MS(m/z):226.2(M+H+)
步骤四:合成中间体5
将中间体1(0.100g,0.132mmol),HOBT(0.027g,0.198mmol),HBTU(0.75g,0.198mmol),DIEA(0.055g,0.396mmol)的DCM(7mL)溶液于室温下搅拌0.5h,然后加入上述中间体2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30mg化合物5。
ESI-MS(m/z):1187.7(M+H+)
步骤五:合成化合物6
将TFA(2mL)滴加到化合物5的DCM(4mL)溶液中,室温搅拌1h。浓缩干后的粗品经Prep-HPLC纯化,得到11mg化合物6的三氟醋酸盐,纯度为98%。
ESI-MS(m/z):805.5(M+H+)
1H NMR(400MHz,MeOD)δ7.39–7.24(m,10H),4.88-4.73(m,1H),4.44-4.40m,2H),4.11-4.10(m,2H),3.83-3.81(m,1H),3.76–3.59(m,1H),3.59–3.43(m,1H),3.31–3.06(m,3H),3.04–2.89(m,4H),2.49-2.25(m,2H),1.96-1.91(m,3H),1.84–1.61(m,10H),1.57-1.44(m,3H),1.36–1.22(m,2H),1.02-0.96(m,6H).
实施例7化合物7:(4-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)苯基)硼酸的合成
化合物7的制备如实施例1所述。所不同的是硼酸酯原料使用的是4-氨基苯硼酸频哪醇酯。
ESI-MS(m/z):799.3(M+H+)
1H NMR(400MHz,DMSO-d6+D2O):δ7.90-7.65(m,4H),7.35–7.10(m,10H),4.51-4.48(m,2H),4.12(d,J=130.5Hz,3H),3.33(d,J=11.2Hz,1H),3.00-2.29(m,5H),2.85–2.60(m,4H),2.44-2.32(m,1H),2.27-1.92(m,2H),1.80(d,J=14.1Hz,2H),1.73–0.90(m,16H),0.88-0.83(m,6H).
实施例8化合物8:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)1,2,3,6-四氢吡啶-3-基)硼酸的合成
化合物8的制备如实施例1所述。所不同的是硼酸酯原料使用的是1-叔丁氧羰基-3,6-二氢-2H-吡啶-5-硼酸频哪醇酯。
ESI-MS(m/z):789.5(M+H+)
1H NMR(400MHz,DMSO)δ8.86–8.72(m,1H),8.49(s,3H),8.03(s,3H),7.80(s,4H),7.37–7.19(m,10H),6.55(s,1H),4.76–4.61(m,2H),4.46–3.91(m,10H),3.54–3.35(m,2H),3.19–2.91(m,4H),2.83–2.75(m,2H),2.31-2.16(m,2H),1.97–1.76(m,2H),1.70–1.50(m,5H),1.50–1.42(m,2H),1.39–1.26(m,2H),0.96–0.78(m,6H).
实施例9化合物9:(7-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)-7-氮杂螺[3.5]壬烷-2-基)硼酸的合成
化合物9的制备如实施例6所述。所不同的是羧酸原料使用的是7-(叔丁氧羰基)-7-氮杂螺[3.5]壬烷-2-羧酸。
ESI-MS(m/z):831.3(M+H+)
1H NMR(400MHz,DMSO-d6+D2O):δ7.90-7.65(m,4H),7.35–7.10(m,10H),4.51-4.48(m,2H),4.12(d,J=130.5Hz,3H),3.33(d,J=11.2Hz,1H),3.00-2.29(m,5H),2.85–2.60(m,4H),2.44-2.32(m,1H),2.27-1.92(m,2H),1.80(d,J=14.1Hz,2H),1.73–0.90(m,16H),1.66-1.54(m,4H),0.88-0.83(m,6H).
实施例10化合物10:(3-((1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰胺基)甲基)苯基)硼酸的合成
化合物10的制备如实施例1所述。所不同的是硼酸酯原料使用的是3-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)苄基氨基甲酸叔丁酯。
ESI-MS(m/z):813.5(M+H+)
1H NMR(400MHz,DMSO+D2O)δ9.05–8.70(m,2H),8.60–8.43(m,3H),8.20-8.01(M,5H),7.69(s,2H),7.37–7.17(m,12H),4.77–4.60(m,2H),4.46–4.12(m,4H),4.07–3.99(m,1H),3.802-3.79(m,2H),3.12-3.05(m,3H),2.95-2.90(m,1H),2.86–2.70(m,3H),2.20-2.12(m,2H),1.84-1.81(m,2H),1.71–1.42(m,7H),1.38–1.26(m,2H),0.96–0.79(m,6H).
实施例11化合物11:((1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)哌啶-4-亚基)甲基)硼酸的合成
化合物11的制备如实施例1所述。所不同的是硼酸酯原料使用的是4-[(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)亚甲基]哌啶-1-甲酸叔丁酯。
ESI-MS(m/z):803.5(M+H+)
1H NMR(400MHz,DMSO+D2O)8.83–8.70(m,1H),8.51(s,2H),8.42–8.30(m,1H),8.25(s,1H),8.02(s,3H),7.74(s,4H),7.36–7.12(m,10H),5.12(s,1H),4.77–4.56(m,2H),4.43–4.24(m,2H),4.21–3.90(m,2H),3.64–3.33(m,5H),3.16–2.85(m,4H),2.84–2.65(m,3H),2.38–2.00(m,4H),1.97–1.77(m,2H),1.66–1.22(m,9H),0.96–0.73(m,6H).
实施例12化合物12:(1-(1-(D-Phe-D-Phe-D-Leu-D-Lys)-4-氨基哌啶-4-酰基)哌啶-3-基)硼酸的合成
化合物12的制备如实施例1所述。所不同的是硼酸酯原料使用的是1-N-叔丁氧羰基哌啶-3-硼酸频哪醇酯。
ESI-MS(m/z):791.5(M+H+)
1H NMR(400MHz,DMSO)δ8.85–8.71(m,1H),8.56–8.36(m,3H),8.34–8.25(m,1H),8.23–8.13(m,1H),8.03(s,3H),7.88–7.55(m,4H),7.37–7.16(m,10H),4.77–4.57(m,2H),4.46–4.16(m,2H),4.12–3.84(m,3H),3.51–3.30(m,1H),3.18–2.86(m,5H),2.83–2.56(m,4H),2.41–1.98(m,2H),1.94–1.71(m,3H),1.69–1.06(m,12H),0.92–0.84(m,6H).
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(5X105 cell/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1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1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2所示,受试化合物对五种常见的P450酶亚型的IC50均大于50uM。
表2化合物的细胞色素P 450 CYP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3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)
1.一种合成肽酰胺类化合物,其特征在于,具有如通式(I)所示的结构:
或其互变异构体、消旋体、外消旋体、对映异构体、非对映异构体或其混合物形式、同位素衍生物、溶剂合物,或其代谢物、前药或其药学上可接受的盐或酯;
其中,n为0到3中的任意整数;
R1、R2选自氢原子、烷基、烷氧基、卤代烷基、环烷基、环烷基烷基、杂环烷基、杂环烷基烷基、芳基、芳基烷基、杂芳基、杂芳基烷基、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、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,2,4-二甲氧基苄基和对甲氧基苄基,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、杂芳基烷基可任选的被选自烷基、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,所述的杂环烷基或杂芳基含有1到3个选自N、O、S的杂原子;
R3、R4、R5、Ra、Rc、Re、Rg各自独立地选自氢原子、卤素或C1~C10烷基;
Rb、Rd、Rf、Rh各自独立地选自下列基团:
氢原子、卤素、C1~C10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、脒基或脲基,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)磺酸酯基、(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,所述的杂环烷基或杂芳基含有1到3个选自N、O、S的杂原子;
是可任选地取代的3元至8元杂环基团,其中Y选自C、N、O或者S;所述杂环基团选自芳香性杂环、非芳香性杂环、或含有该杂环的桥环、并环或螺环;所述的芳香性杂环、非芳香性杂环,桥环、并环或螺环,可任选的被选自羟基、氨基、C1~C10烷基、烷氧基、烯基、炔基、酯基、酰胺基、卤素、硝基、氰基、巯基中的一个或多个取代基所取代;
W选自C1~C10烷基氨基、环烷基氨基、芳香性或非芳香性杂环基氨基、芳基氨基、芳基烷基氨基、芳香性或非芳香性杂环基烷基氨基、3~8元芳香性杂环或者非芳香性杂环、以及含有该杂环的桥环、并环或螺环;所述芳香性杂环或者非芳香性杂环、桥环、并环或螺环,含有1到3个任选自N、O、S的杂原子,并且至少含有1个N原子;
其中,W中的1个N原子与结构式中左侧的羰基直接相连,形成酰胺键;
B(OR6)2与W中的杂环上的原子直接相连,或者与该杂环的取代基上的原子相连;
B(OR6)2选自以下任一结构,且两个R6基团中的部分原子可以连接成环状取代基:
7.一种药物组合物,包括权利要求1~6任意一项所述的合成肽酰胺类化合物,以及药学上可接受的载体,赋形剂,稀释剂,辅剂,媒介物或它们的组合。
8.如权利要求1-6中任一项所述的一种合成肽酰胺类化合物或权利要求7所述的药物组合物在医药领域的应用。
9.根据权利要求8所述的应用,其特征在于,所述应用为预防或者治疗哺乳动物的与κ阿片样物质受体相关的疾病。
10.根据权利要求9所述的应用,其特征在于,所述的κ阿片样物质受体相关的疾病选自疼痛、炎症、瘙痒、水肿、低钠血症、低钾血症、肠梗阻、咳嗽和青光眼;所述的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、癌症疼痛和胃肠道紊乱相关的疼痛中的一种或多种。
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