CN114075141A - 阿片受体“偏向性”配体、其制备方法及其在医药上的应用 - Google Patents
阿片受体“偏向性”配体、其制备方法及其在医药上的应用 Download PDFInfo
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- CN114075141A CN114075141A CN202010841489.0A CN202010841489A CN114075141A CN 114075141 A CN114075141 A CN 114075141A CN 202010841489 A CN202010841489 A CN 202010841489A CN 114075141 A CN114075141 A CN 114075141A
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Abstract
本发明涉及阿片受体“偏向性”配体、其制备方法及其在医药上的应用。具体地,本发明化合物具有式(I)所示结构,其中各基团和取代基的定义如说明书中所述。本发明还公开了所述化合物的制备方法及其在预防和/或治疗疼痛或疼痛相关疾病方面的用途。
Description
技术领域
本发明涉及医药领域,具体地涉及阿片受体“偏向性”配体、其制备方法及其在医药上的应用,更具体地涉及一种μ型阿片受体(MOR)的小分子配体、其制备方法及其在医药上的应用。
背景技术
阿片受体药物治疗中、重度疼痛疗效显著,在治疗急性/慢性中、重度疼痛中具有不可替代的位置。然而现有的阿片受体药物(比如吗啡及其衍生物、羟考酮、芬太尼及其衍生物等)均表现出类似的严重副作用:成瘾、呼吸抑制、耐药、便秘、镇静、恶心等,极大的限制了其临床使用,而成瘾同时也带来了严重的社会问题。在过去十年中,由于滥用该类处方和非法麻醉品而导致的死亡人数急剧增加(Clin J Pain.2010 26:S10-15)。美国疾病控制与预防中心数据显示,2017年美国有创纪录的7.2万人死于阿片药物过量,较2016年增加近10%,死亡原因主要由于强效阿片受体药物过量服用引起了严重的呼吸抑制[Science.2017 358(6365):847-848;Science.2018 361(6405):831-832]。
近年来研究发现,吗啡与μ型阿片受体(MOR)结合后,不仅可以激活G蛋白信号通路,产生镇痛生理活性,同时可以激活β-arrestin通路。β-arrestin与活化的MOR结合,可导致G蛋白信号通路脱敏,促进受体内吞,并开启其它信号转导通路(Nature.2016 537(7619):185-190)。研究表明吗啡镇痛作用来自于G蛋白信号通路的激活,而便秘、呼吸抑制和耐药等多种副作用与β-arrestin通路的激活紧密相关。小鼠β-Arrestin 2基因敲除后再经吗啡给药,便秘、呼吸抑制及耐药等副作用显著降低[Science.1999 286(5449):2495-2498;J Pharmacol Exp Ther.314(3):1195-1201]。因此,选择性激活G蛋白信号通路,避免β-Arrestin 2信号通路激活的MOR“偏向性”配体,可以在发挥镇痛药效的同时,显著降低便秘、呼吸抑制和耐药等多种副作用。
2017年Cullen L.Schmid的研究[Cell.2017 171(5):1165-1175]表明,“偏向系数(Bias Factor)”是评价MOR配体“偏向性激活能力”的重要指标。作者合成了若干个“偏向系数(Bias Factor)”不等的化合物,分别测试了此类化合物动物体内镇痛作用的ED50值和呼吸抑制的ED50值,并计算了评价药物安全性的“治疗窗(Therapeutic Window)”。结果表明“偏向系数(Bias Factor)”与呼吸抑制有良好的负相关性;偏向系数(Bias Factor)越高,呼吸抑制作用越弱;相应的“治疗窗(Therapeutic Window)”越大,化合物安全性越高。
目前代表性的MOR“偏向性”配体有TRV130[J Med Chem.201356(20):8019-8031;WO2012129495]、PZM21[Nature.2016 537(7619):185-190;WO2017007695、WO2018129393]和SR17018[Cell.2017 171(5):1165-1175;WO2017161017]。TRV130是第一个μ型阿片受体的“偏向性”配体,临床已表现出与吗啡同等的镇痛效力,但由于其“偏向系数(BiasFactor)”较低[大约为3,J Med Chem.2013 56(20):8019-8031;Cell.2017 171(5):1165-1175],呼吸抑制等副作用依然存在,治疗窗口(Therapeutic window)不能满足临床需要。化合物PZM21的动物实验表明其呼吸抑制、便秘、成瘾倾向显著弱于吗啡,然而其“偏向系数(Bias Factor)”同样较低;此外,PZM21还存在代谢性质差(T1/2<1h,清除率高,暴露量低)和潜在心脏毒性问题(hERG抑制的IC50为2至4μM),成药性质差。
有鉴于此,本发明提供一类新型高“偏向系数(Bias Factor)”MOR“偏向性”激动剂配体,它们保留了优异的G蛋白通路激动活性,同时激活β-Arrestin 2信号通路能力很低,甚至不激活β-Arrestin 2信号通路,“偏向系数(Bias Factor)”与目前已有的“偏向性”激动剂相比有极大提高。另外本发明化合物代谢性质显著改善,hERG抑制活性低,成药性及动物体内镇痛活性与目前报道的化合物PZM21相比也有巨大改善。
本发明公开的MOR小分子配体,具有G蛋白信号通路“偏向性”激活的特点,可用于治疗和/或预防疼痛或疼痛相关疾病。
发明内容
本发明的目的在于提供一种具有高“偏向系数(Bias Factor)”、优异代谢性质和成药性的式(I)所示化合物及其制备方法和其在治疗和/或预防疼痛或疼痛相关疾病方面的用途。
本发明的第一方面,提供了一种式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐,
其中,Ring A选自下组:取代或未取代的C6-C10芳基、取代或未取代的含1、2或3个选自N、O或S的杂原子的4-10元杂芳基;所述取代指被选自下组的一个或多个取代基取代:氢、羟基、卤素、-B(OH)2、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基、-OC(O)R5和
G选自下组:CR7R8和NR2;
R2选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基和氰基;
R3和R4各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
R5选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和卤素;
R7和R8相同或不同,且各自独立地选自下组:H、NO2、C1-C6烷基、卤代C1-C6烷基;
n为0、1、2或3;
q为0、1、2、3或4;
Z选自下组:NR11、O、S和CR9R10;
R9、R10、R11各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和氰基;
t为0、1、2或3。
G选自下组:CHNO2和NR2;
R2选自下组:氢、C1-C6烷基、C1-C6烷氧基和氰基;
R3和R4各自独立地选自下组:氢和C1-C6烷基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
R5为氢或C1-C6烷基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基和卤素;
m为0、1、2、3、4或5;
n为0或1;
q为0、1、2、3或4;
Z选自下组:O和CH2;
t为0、1或2。
在另一优选例中,Ring A为取代的C6-C10芳基,所述取代指被选自下组的m个取代基取代:氢、羟基、卤素、-B(OH)2、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基、-OC(O)R5和m为0、1、2、3、4或5;
G选自下组:CR7R8和NR2;
R2选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基和氰基;
R3和R4各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
R5选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和卤素;
R7和R8相同或不同,且各自独立地选自下组:H、NO2、C1-C6烷基、卤代C1-C6烷基;
n为0、1、2或3;
q为0、1、2、3或4;
Z选自下组:NR11、O、S和CR9R10;
R9、R10、R11各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和氰基;
t为0、1、2或3。
在另一优选例中,Ring A为取代或未取代的含1、2或3个选自N、O或S的杂原子的4-10元杂芳基;所述取代指被选自下组的一个或多个取代基取代:氢、羟基、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基;
G选自下组:CR7R8和NR2;
R2选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基和氰基;
R3和R4各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和卤素;
R7和R8相同或不同,且各自独立地选自下组:H、NO2、C1-C6烷基、卤代C1-C6烷基;
n为0、1、2或3;
q为0、1、2、3或4;
Z选自下组:NR11、O、S和CR9R10;
R9、R10、R11各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和氰基;
t为0、1、2或3。
在另一优选例中,所述化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐选自下组:
本发明的第二方面,提供了一种药物组合物,包含药学上可接受的载体和治疗有效量的一种或多种本发明第一方面所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐。
本发明的第三方面,提供了一种本发明第一方面所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐的制备方法,所述方法选自下组:
方法1:包括步骤:
其中,Ring A、G、R3、R4、R6、Z、t、q、n如本发明第一方面所述;
M选自下组:-S-(C1-C6烷基)、-O-(C6-C10芳基);
方法二:包括步骤:
(ii-1)将式A所示化合物或其盐与式C所示化合物或其盐反应,得到式I-2所示化合物;
其中,Ring A、R2、R3、R4、R6、Z、t、q、n如本发明第一方面所述;
M选自下组:-S-(C1-C6烷基)、-O-(C6-C10芳基);
方法三:包括步骤:
(iii-1)将式D所示化合物或其盐与式E所示化合物或其盐反应,得到式I-3所示化合物;
其中,Ring A、R3、R4、R6、Z、t、q、n如本发明第一方面所述;
M为-S-(C1-C6烷基);
Q选自下组:C1-C6烷基、C1-C6烷氧基。
在另一优选例中,所述方法还包括如下步骤:
将所得产物进一步与第一物质反应,得到式(I)所示化合物;
所述第一物质选自下组:NaOH、对甲苯磺酸。
本发明的第四方面,提供了一种本发明第一方面所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐的用途,用于制备药物,所述药物用于预防和/或治疗疼痛或疼痛相关疾病。
在另一优选例中,所述疼痛或疼痛相关疾病为与MOR受体相关疼痛疾病。
在另一优选例中,所述疼痛或疼痛相关疾病为哺乳动物体内疼痛相关疾病。
在另一优选例中,所述疼痛选自下组:术后疼痛、癌症引起的疼痛、神经性疼痛、创伤性疼痛和炎症引起的疼痛。
在另一优选例中,所述癌症选自下组:实体肿瘤和非实体肿瘤。
在另一优选例中,所述癌症选自下组:肺癌、骨癌、胃癌、胰腺癌、肝癌、结肠癌、乳腺癌、子宫内膜癌、宫颈癌、皮肤癌、前列腺癌、卵巢癌、输卵管肿瘤、淋巴癌、食管癌、口腔癌和白血病。
本发明的第五方面,提供了一种预防和/或治疗疼痛或疼痛相关疾病的方法,包括步骤:将治疗有效量的本发明第一方面所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐施用于所需患者。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1是测试例5所得结果。
具体实施方式
本发明人经过长期而深入的研究,意外地制备了一种结构新颖的具有高“偏向系数(Bias Factor)”、优异代谢性质和成药性的式(I)所示化合物。在此基础上,发明人完成了本发明。
术语
在本发明中,除非特别指出,所用术语具有本领域技术人员公知的一般含义。
在本发明中,术语“卤素”指F、Cl、Br或I。
在本发明中,“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基,例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。
在本发明中,术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基,非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中,术语“C3-C6环烷基”是指在环上具有3-6个碳原子的环状烷基,非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中,术语“芳环”或“芳基”具有相同的含义,优选为“C6-C10芳基”。术语“C6-C10芳基”是指在环上不含杂原子的具有6至10个碳原子的芳香族环基,如苯基、萘基等。
在本发明中,术语“芳香杂环”或“杂芳基”具有相同的含义,指包含一个到多个杂原子的杂芳族基团。例如“C3-C10杂芳基”是指含有1~4个选自氧、硫和氮中的杂原子以及3-10个碳原子的芳香杂环。非限制性例子包括:呋喃基、噻吩基、吡啶基、吡唑基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、咪唑基、四唑基等。所述杂芳基环可以稠合于芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环。杂芳基可以是任选取代的或未取代的。
在本发明中,术语“卤代”是指被卤素取代。
在本发明中,术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基,或各实施例中所出现的取代基。除非特别说明,某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基,所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解,本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于):卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
在本发明中,术语多个指1-6个。
在本发明中,术语1-6个指1、2、3、4、5或6个。其他类似术语具有类似含义。
化合物
本发明提供了式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐,
各基团如上文所定义。
在另一优选例中,所述的化合物中,Ring A、G、R3、R4、R6、Z、t、q、n中任一个分别为实施例中所述具体化合物中所对应的基团。
在另一优选例中,所述化合物优选为实施例中所制备的化合物。
如本文所用,术语“药学上可接受的盐”指本发明化合物与酸或碱所形成的适合用作药物的盐。药学上可接受的盐包括无机盐和有机盐。一类优选的盐是本发明化合物与酸形成的盐。适合形成盐的酸包括但并不限于:盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸等无机酸;甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸等有机酸;以及脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸等氨基酸。
另一类优选的盐是本发明化合物与碱形成的盐,例如碱金属盐(例如钠盐或钾盐)、碱土金属盐(例如镁盐或钙盐)、铵盐(如低级的烷醇铵盐以及其它药学上可接受的胺盐),例如甲胺盐、乙胺盐、丙胺盐、二甲基胺盐、三甲基胺盐、二乙基胺盐、三乙基胺盐、叔丁基胺盐、乙二胺盐、羟乙胺盐、二羟乙胺盐、三羟乙胺盐,以及分别由吗啉、哌嗪、赖氨酸形成的胺盐。
制备方法
下面更具体地描述本发明式I结构化合物的制备方法,但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得,这样的组合可由本发明所属领域的技术人员容易地进行。
典型地,本发明化合物的制备工艺流程如下,其中所用原料和试剂如无特殊说明,均可通过商业途径购买。
通式(Ia)是通式(I)的胍结构化合物,其制备方法包括以下步骤:
通式(Ia-1)胺类化合物的氨基在碱性条件下依次与CS2和乙酰氯反应,得到通式(Ia-2)异硫氰酸酯化合物;通式(Ia-2)化合物与通式(Ia-3)胺类化合物的氨基反应,得到通式(Ia-4)硫脲类化合物;通式(Ia-4)化合物经碘甲烷取代后得到通式(Ia-5)的甲硫化合物;通式(Ia-5)化合物的甲硫基在碱性条件下经通式(Ia-6)胺类化合物的氨基取代,得到通式(Ia)胍结构化合物。其中,Ring A、R2、R3、R4、R6、Z、t、q、n的定义如通式(I)所述。
在另一优选例中,通式(Ib)化合物是通式(I)的氰基胍结构化合物按如下方法制备
通式(Ia-1)胺类化合物和通式(Ia-6)胺类化合物在溶剂中,依次与N-氰基羰亚胺二酯类试剂反应,得到通式(Ib)化合物。通式(Ia-1)胺类化合物和通式(Ia-6)化合物与N-氰基羰亚胺二酯类试剂的反应先后顺序可以互换。所用N-氰基羰亚胺二酯类试剂包括但不限于N-氰基羰亚胺二苯酯(CAS:79463-77-7)、N-氰基羰亚胺二甲酯(CAS:24771-25-3)、N-氰基羰亚胺二乙酯和N-氰基羰亚胺二甲硫酯(CAS:10191-60-3)。反应温度为0℃至100℃。反应可以在中性或碱性条件下进行。其中,Ring A、R3、R4、R6、Z、t、q、n的定义如通式(I)所述。
在另一优选例中,通式(Ic)化合物按如下方法制备
通式(Ia-1)胺类化合物和通式(Ia-6)胺类化合物在溶剂中,依次与1,1-(双甲硫基)-2-硝基乙烯反应,得到通式(Ic)化合物。通式(Ia-1)胺类化合物和通式(Ia-6)胺类化合物与1,1-(双甲硫基)-2-硝基乙烯的反应先后顺序可以互换。反应温度为20℃至160℃。反应可以在中性或碱性条件下进行。其中,Ring A、R3、R4、R6、Z、t、q、n的定义如通式(I)所述。
本发明制备方法中所用溶剂包括但不限于甲醇、乙醇、异丙醇、水、甲苯、四氢呋喃、乙酸乙酯、二氯甲烷、氯仿、1,4-二氧六环、DMF、乙腈、DMSO和NMP。提供碱性条件的的试剂包括常用无机碱和有机碱,所述的无机碱包括但不限于碳酸钠、碳酸钾、碳酸铯、氢氧化钠、氢氧化钾、磷酸钾;所述的有机碱包括但不限于三乙胺、N,N-二异丙基乙基胺、咪唑、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、LDA、丁基锂。
为确保各个合成步骤顺利进行,本发明所属领域的技术人员可提前使用TBS、TMS、TBDPS、Bn、THP、Tf等常见保护基对参与反应的化合物中的羟基进行保护和脱保护操作,使用Boc、Cbz、Bn、Ts、THP等常见保护基对参与反应的化合物中的NH或NH2进行保护和脱保护操作。
本发明的通式(I)表示化合物中含有一个或多个手性中心,其存在对映异构体和非对映异构体。对于对映异构体,采用一般的手性拆分方法或不对称合成方法可以得到两个对映体。对于非对映异构体,可以通过分步重结晶或者色谱分离等方法分离。
药物组合物和施用方法
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有10-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
所述的药物组合物为注射剂、囊剂、片剂、丸剂、散剂或颗粒剂。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的其他化合物(如抗肿瘤药物)联合给药。
本发明治疗方法可以单独施用,或者与其它治疗手段或者治疗药物联用。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~2000mg,优选50~1000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
与现有技术相比,本发明具有以下主要优点:
(1)本发明化合物具有优异的G蛋白通路激动活性和低的β-Arrestin 2信号通路激动活性,偏向性显著;
(2)本发明化合物具有优异的药代动力学性能,如高的血浆暴露量(AUC)、低的清除率(CL)、显著延长的半衰期(T1/2);
(3)本发明化合物具有优异的体内活性和成药性,预防和/或治疗疼痛相关疾病更加安全。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring Harbor LaboratoryPress,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
在本发明中,化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NNMR的测定是用Bruker AVANCE-400核磁仪。LCMS的测定用Waters2695液相质谱联用仪(MS型号:Micromass ZQ)。
HPLC的测定用安捷伦1100高压液相色谱仪(ZORBAX SP-C18 250x4.6mm色谱柱,Eclipse Plus-C18 250x4.6mm色谱柱)。
本发明的已知的起始原料可以采用或者按照本领域已知的方法来合成,或可购买自AcrosOrganics,Aldrich Chemical Company,J&Chem,韶远化学科技,达瑞化学品,安耐吉化学等公司。
实施例中无特殊说明,均可在氩气氛或氮气氛下进行。
微波反应使用的是CEM Discover-SP 909155型微波反应器。
实施例中无特殊说明,反应的温度为室温(20℃~35℃)。
实施例中薄层色谱法(TLC)使用的硅胶版采用的规格是0.2mm±0.03mm。纯化化合物使用的薄层层析分离纯化(prep-TLC)规格是0.4mm~0.5mm;柱层析一般使用烟台黄海硅胶200~300目硅胶为载体;采用的全自动中压快速纯化仪(Combi Flash Rf+UV-VIS),分离柱型号有:Silica Flash Column 4g、12g、25g。采用的柱层析的洗脱剂的体系和薄层色谱法的展开体系包括:A:二氯甲烷和甲醇体系;B: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,也可加入少量氨水或者醋酸等碱性或酸性试剂进行调节。
实施例中纯化最终样品化合物采用的是高压制备液相色谱仪(生产商:岛津,型号:LC-20AP),Ultimate XB-C18色谱柱(150x30mm,5μm)。流动相体系有:A:乙腈和水(含0.1%三氟乙酸)体系;B:乙腈和水(含0.1%乙酸)体系。
实施例1
2-氰基-1-(1-(1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙基)-3-(1,2,3,4-四氢萘-2-基)胍1
步骤1:(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)甲醇1a的制备
将吲唑-5-甲酸甲酯(5g,28.4mmol)溶于THF(50mL)中,室温搅拌下,加入3,4-二氢-2H-吡喃(4.77g,56.8mmol)和甲磺酸(820mg,8.5mmol),然后升温至60℃,继续搅拌2h。反应完毕,冷却至0-5℃,缓慢加入LiAlH4的THF溶液(28.4mL,28.4mmol),加料毕,继续搅拌20min。TLC检测反应完成,用EA和MeOH淬灭反应,铺硅藻土过滤,EA洗涤滤饼,滤液浓缩,柱层析(EA:PE=1:2),得到6.12g淡黄色油状物,收率:92.4%。
1H NMR(400MHz,CDCl3)δ:7.93(s,1H),7.61(s,1H),7.53(d,J=8.6Hz,1H),7.36(dd,J=8.6,1.3Hz,1H),5.69-5.66(m,1H),4.71(s,2H),3.99-3.97(m,1H),3.74-3.68(m,1H),2.57-2.49(m,2H),2.14-2.04(m,2H),1.81-1.67(m,2H).
MS(M+H)+:233
步骤2:5-(溴甲基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑1b的制备
将(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)甲醇(5g,21.5mmol)溶于DCM(100mL)中,N2保护后,依次分批加入Ph3P(6.21g,23.7mmol)和NBS(5.35g,23.7mmol),室温搅拌15min。反应完毕,溶剂旋干,柱层析(EA:PE=1:10),得到5.1g淡黄色固体,收率:80.3%。
MS(M+H)+:295
步骤3:2-((二苯亚甲基)氨基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)丙腈1c的制备
将二苯亚甲基氨基乙腈(1.12g,5.1mmol)溶于THF(5mL)中,N2保护后,置于-70℃条件下搅拌,缓慢滴加LDA(2.5mL,5mmol,2M的THF溶液),然后滴加5-(溴甲基)-1-(四氢-2H-吡喃-2-基)-1H-吲唑(1.0g,3.4mmol)的THF(5mL)溶液。自然升温至0℃搅拌30min。反应完毕,加入饱和氯化铵溶液(20mL)淬灭反应,EA(20mLx2)萃取,合并有机相,盐水洗涤,干燥(无水硫酸钠),过滤,浓缩,柱层析(EA:PE=1:5),得到1.04g白色固体,收率:70.6%。
1H NMR(400MHz,CDCl3)δ:7.93(s,1H),7.61-7.59(m,2H),7.48-7.32(m,8H),7.11(t,J=8.1Hz,1H),6.81(dd,J=25.5,7.0Hz,2H),5.68(dd,J=9.3,2.5Hz,1H),4.45-4.41(m,1H),4.01(d,J=11.4Hz,1H),3.76-3.70(m,1H),3.39-3.24(m,2H),2.56-2.53(m,1H),2.15-2.04(m,2H),1.78-1.65(m,3H).
MS(M+H)+:435
步骤4:(1-(1-((二苯基亚甲基)氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)乙基)环丙基)氨基甲酸叔丁酯1e的制备
取2-((二苯亚甲基)氨基)-3-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)丙腈(4g,9.21mmol)溶于干燥的THF(50mL)中,N2保护,置于-70℃条件下搅拌,加入Ti(OiPr)4(7.85g,27.6mmol),然后将乙基溴化镁(27.6mL,27.6mmol)滴加到上述-70℃的反应液中。加毕,回复至室温条件下反应1h。然后加入BF3Et2O溶液(3.9g,27.6mmol),室温搅拌1h。LCMS显示原料消失,有产物生成。加入饱和碳酸氢钠淬灭反应(150mL),EA(200mLx3)萃取,饱和氯化钠洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,得化合物1d的粗品。将以上化合物1d的粗品加入EA溶液(50mL)溶解,加入二碳酸二叔丁酯(1.52g,6.97mmol),室温下搅拌反应4h。LCMS和TLC显示原料消失,反应完毕。反应液拌硅胶,柱层析(EA:PE=1:5),得到1.2g白色固体,两步收率:23%。
MS(M+H)+:565
步骤5:(1-(1-(二甲基氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)乙基)环丙基)氨基甲酸叔丁酯1g的制备
取(1-(1-((二苯基亚甲基)氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)乙基)环丙基)氨基甲酸叔丁酯(994mg,1.76mmol),溶于甲醇(20mL),加入醋酸钾(225mg,2.3mmol),搅拌溶解,然后加入盐酸羟胺(135mg,1.94mmol),室温搅拌20min。反应毕,加入碳酸氢钠溶液(10mL)淬灭反应,EA(20mLx3)萃取,合并有机相,有机相用盐水洗涤,无水硫酸钠干燥,过滤,浓缩,得化合物1f的粗品。将以上化合物1f的粗品溶于乙腈(15mL)和水(7mL)的混合溶剂中,然后N2保护后置于冰浴条件下,依次加入37%HCHO(1.05g,8.8mmol)和NaBH(OAc)3(1.1g,5.28mmol),室温搅拌30min。LCMS显示原料消失有产物生成,加入饱和碳酸氢钠溶液(50mL)淬灭反应,DCM(40mLx3)萃取,饱和氯化钠洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(DCM:MeOH=10:1),得到550mg淡黄色油状物,两步收率:73.1%。
1H NMR(400MHz,CDCl3)δ:7.96(s,1H),7.62(s,1H),7.51(d,J=8.5Hz,1H),7.34(d,J=8.5Hz,1H),5.69(dd,J=9.5,2.5Hz,1H),5.15(s,1H),4.05-4.02(m,1H),3.77-3.72(m,1H),3.10-3.07(m,2H),2.53(s,6H),2.16-2.14(m,1H),2.09-2.01(m,2H),1.78-1.65(m,4H),1.44(s,9H),0.96-0.80(m,4H).
MS(M+H)+:429
步骤6:1-(1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙胺盐酸盐1h的制备
取(1-(1-(二甲基氨基)-2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)乙基)环丙基)氨基甲酸叔丁酯(200mg,0.47mmol)溶于DCM(2mL)中,然后加入HCl/dioxane(4N,1.2mL),并室温条件下搅拌反应1h。LCMS显示原料消失有产物生成,反应完毕后直接浓缩旋干得1-(1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙胺。
步骤7:2-氰基-1-(1-(1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙基)-3-(1,2,3,4-四氢萘-2-基)胍1的制备
取N-氰基羰亚胺二苯酯(1.62g,6.8mmol)溶于乙腈(20mL)中,然后加入1,2,3,4-四氢萘-2-胺(1g,6.8mmol)和三乙胺(1.42mL,10.2mmol)。加毕,室温条件下搅拌1h。LCMS显示原料消失,有产物生成。加水(40mL)稀释,EA萃取(30mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,加少量PE/EA(2/1,10mL)打浆,抽滤,得到苯基N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯1.57g,收率:79.6%,用于下一步。
将1-(1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙胺(88mg,0.36mmol)和苯基N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯(94mg,0.32mmol)溶于乙腈(3mL)中,加三乙胺(73mg,0.72mmol),升温至80℃反应过夜。LCMS显示有产物生成。加入水(20mL),EA萃取(15mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,柱层析(DCM:MeOH=90:10),得到38mg白色固体,经HPLC制备、冷冻干燥后得到产物为14.3mg白色固体,即化合物1。收率:9.0%。
1H NMR(400MHz,DMSO-d6)δ:12.91(s,1H),8.77(s,2H),7.96(d,J=4.4Hz,1H),7.68(d,J=6.4Hz,1H),7.43-7.28(m,3H),7.12-7.05(m,4H),4.03-3.93(m,1H),3.09-2.92(m,3H),2.89-2.80(m,3H),2.72-2.61(m,1H),2.14(s,3H),2.02-1.96(m,1H),1.91(s,3H),1.83-1.73(m,1H),0.70-0.53(m,2H),0.50-0.36(m,2H).
MS(M+H)+:442
实施例2
2-氰基-1-(1-(1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(1,2,3,4-四氢萘-2-基)胍2
步骤1:(S)-4-(3-氨基-2-((叔丁氧羰基)氨基)-3-氧代丙基)苯基三氟甲磺酸酯2a的制备
将(S)-2-氨基-3-(4-羟基苯基)丙酰胺(15g,83.2mmol)溶于DMF(150mL)中,然后冰浴下加入(Boc)2O(19.5g,91.6mmol),升温至室温,搅拌反应1h。TLC(DCM:MeOH=10:1)显示原料消失,依次向反应液中加入K2CO3(17.3g,125mmol)和PhNTf2(32.7g,91.6mmol),室温下搅拌1h。LCMS显示产物生成。反应完毕,加入水(1L)淬灭反应,EA(400mL x 3)萃取,有机相经无水硫酸钠干燥,浓缩得粗品。粗品溶于DCM(100mL),再加入PE(500mL),打浆、抽滤得到31g白色固体,收率:90.3%。
1H NMR(400MHz,DMSO-d6)δ:7.43-7.37(m,5H),7.05(brs,1H),6.89(d,J=8.9Hz,1H),4.11-4.08(m,1H),3.02-2.97(m,1H),2.79-2.67(m,1H),1.25(s,9H).
MS(M+Na)+:413
步骤2:(S)-4-(2,3-二氨基-3-氧代丙基)苯基三氟甲磺酯盐酸盐2b的制备
取(S)-4-(3-氨基-2-(叔丁氧羰基)氨基)-3-氧代丙基)苯基三氟甲磺酸酯(10g,24.25mmol)溶于THF(150mL)中,搅拌下加入HCl/dioxane(4N,100mL),室温搅拌30min。反应完毕后,直接浓缩旋干,得到粗品白色固体11g,收率:100%,直接用于下一步。
MS(M+H)+:313
步骤3:(S)-4-(3-氨基-2-(二甲基氨基)-3-氧代丙基)苯基三氟甲磺酸酯2c的制备
取(S)-4-(2,3-二氨基-3-氧代丙基)苯基三氟甲磺酸酯盐酸盐(10g,32mmol)溶于乙腈(150mL)和水(10mL)的混合溶剂中,N2保护后置于冰浴条件下,搅拌下依次加入37%HCHO(23.25mL,320mmol)和NaBH(OAc)3(18.25g,96mmol),室温搅拌过夜。LCMS显示原料消失,产物生成。加入饱和碳酸氢钠溶液(100mL)淬灭反应,DCM(40mLx3)萃取,饱和氯化钠洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(DCM:MeOH=90:10)纯化,得到4g淡黄色油状物,收率:36.7%。
1H NMR(400MHz,DMSO-d6)δ:7.39-7.36(m,4H),7.32-7.29(m,1H),7.06-6.97(m,1H),4.13-4.05(m,1H),2.97-2.84(m,2H),2.37(s,6H).
MS(M+H)+:341
步骤4:(S)-4-(2-氰基-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯2d的制备
取(S)-4-(3-氨基-2-(二甲基氨基)-3-氧代丙基)苯基三氟甲磺酸酯(500mg,1.47mmol)溶于THF(10mL)中,加入吡啶(0.59mL,7.35mmol),N2保护后置于冰浴条件下,搅拌下逐滴加入TFAA(0.41mL,2.94mmol),冰浴下搅拌1h。LCMS显示原料消失,加入饱和碳酸氢钠溶液(15mL)淬灭反应,EA(20mLx2)萃取,饱和氯化钠洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(PE:EA=80:20),得到320mg淡黄色油状物,收率:67.5%。
1H NMR(400MHz,CDCl3)δ:7.36(d,J=8.6Hz,2H),7.25(d,J=8.3Hz,2H),3.67(t,J=7.8Hz,1H),3.04(d,J=7.8Hz,2H),2.37(s,6H).
MS(M+H)+:323
步骤5:4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯2e的制备
取(S)-4-(2-氰基-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(400mg,1.24mmol)溶于干燥的THF(10mL)中,加入Ti(OiPr)4(400mg,1.39mmol),然后置于-70℃条件下搅拌,将乙基溴化镁(2.7mL,2.7mmol)逐滴加入到上述-70℃的反应液中。加毕,恢复至室温条件下反应1h。然后加入BF3Et2O溶液(0.67mL,2.48mmol),室温搅拌1h。LCMS显示原料消失,有产物生成。加入饱和碳酸氢钠淬灭反应(15mL),加入水(15mL)稀释,EA(20mLx3)萃取,饱和氯化钠洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(DCM:MeOH=91:9),得到92mg淡黄色油状物,收率:21.1%。
1H NMR(400MHz,CDCl3)δ:7.34(d,J=8.6Hz,2H),7.21(d,J=8.6Hz,2H),3.21-3.08(m,2H),2.66(s,6H),2.29-2.25(m,1H),0.92-0.77(m,2H),0.69-0.64(m,1H),0.41-0.36(m,1H).
MS(M+H)+:353
步骤6:4-(2-(1-(2-氰基-3-(1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯2f的制备
将4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(150mg,0.42mmol)和活性酯苯基N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯(123mg,0.42mmol)溶于DMSO(2mL)中,加三乙胺(42mg,0.42mmol),升温至80℃反应2h。LCMS显示有产物生成。加入水(20mL),EA萃取(15mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,柱层析(EA:PE=1:1),得到150mg黄色油状物。收率:60.9%。
MS(M+H)+:550
步骤7:2-氰基-1-(1-(1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(1,2,3,4-四氢萘-2-基)胍2的制备
取4-(2-(1-(2-氰基-3-(1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(30mg,0.055mmol)溶于THF/MeOH(2mL,1/1)和水(1滴)中,然后加入NaOH(22mg,0.55mmol)。室温搅拌反应2h。LCMS显示有产物生成,反应完毕加入NH4Cl饱和水溶液(5mL)淬灭反应,EA(10mLx2)萃取,无水硫酸钠干燥,过滤,浓缩,经HPLC制备、冷冻干燥后得到产物为5mg白色固体,即化合物2。收率:21.8%。
1H NMR(400MHz,DMSO-d6)δ:8.75(s,2H),7.25(d,J=10.5Hz,1H),7.10-7.06(m,5H),6.63(dd,J=8.3,6.2Hz,2H),4.06-4.03(m,1H),3.07-2.97(m,1H),2.89-2.60(m,5H),2.30-2.21(m,1H),2.11(s,4H),2.03-1.94(m,1H),1.89(s,2H),1.79-1.74(m,1H),0.76-0.39(m,4H).
MS(M+H)+:418
实施例3
(4-(2-(1-(2-氰基-3-(1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸3
步骤1:2-氰基-1-(1-(1-(二甲基氨基)-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙基)环丙基)-3-(1,2,3,4-四氢萘-2-基)胍3a的制备
取4-(2-(1-(2-氰基-3-(1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(150mg,0.27mmol)溶于dioxane(5mL)中,然后依次加入联硼酸频那醇酯(105mg,0.41mmol),Pd(dppf)Cl2(45mg,0.061mmol)和醋酸钾(89mg,0.91mmol),置于微波反应器中(80度,80w,1h)。反应毕,浓缩,柱层析(EA:PE=1:1)得到80mg浅棕色固体,收率:56.2%。
MS(M+H)+:528
步骤2:(4-(2-(1-(2-氰基-3-(1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸3的制备
取2-氰基-1-(1-(1-(二甲基氨基)-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙基)环丙基)-3-(1,2,3,4-四氢萘-2-基)胍(80mg,0.15mmol)溶于THF(2mL),然后加入稀HCl(1N,1mL),并室温条件下搅拌反应3h。LCMS显示大部分原料消失有产物生成,反应完毕后直接浓缩旋干,经HPLC制备、冷冻干燥后得到白色固体39mg,即化合物3。收率:58.4%。
1H NMR(400MHz,DMSO-d6)δ:8.72(s,1H),8.07(s,2H),7.70-7.60(m,2H),7.38-7.23(m,3H),7.09-7.06(m,4H),4.05-4.02(m,1H),3.07-2.96(m,1H),2.92-2.59(m,5H),2.38-2.30(m,1H),2.10(s,3H),2.01-1.95(m,1H),1.88(s,3H),1.82-1.73(m,1H),0.84-0.44(m,4H).
MS(M+H)+:446
实施例4
2-氰基-1-(1-(1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(6-氟-1,2,3,4-四氢萘-2-基)胍4
步骤1:6-氟-1,2,3,4-四氢萘-2-胺盐酸盐4a的制备
取6-氟-3,4-二氢萘-2(1H)-酮(492mg,3mmol)溶于甲醇(30mL)中,然后加入醋酸铵(2.4g,30mmol),室温搅拌30min。NaBH3CN(372mg,6mmol)分批加入,升温至60℃反应4h。LCMS显示原料消失有产物生成,加入加入水(40mL)淬灭反应,旋去甲醇,碳酸氢钠水溶液调pH至8-9,EA(30mLx5)萃取,无水硫酸钠干燥,过滤,浓缩柱层析(DCM:MeOH=10:1),得到游离态产物,加EA(5mL)和HCl(2mL),析出固体,抽滤,EA洗涤滤饼,得到360mg粉白色固体,收率:59.7%。
1H NMR(400MHz,DMSO-d6)δ:8.34(s,2H),7.20-7.09(m,1H),6.97-6.93(m,2H),3.46-3.38(m,1H),3.07(dd,J=16.0,4.9Hz,1H),2.92-2.73(m,3H),2.13-2.11(m,1H),1.80-1.70(m,1H).
MS(M+H)+:166
步骤2:4-((2S)-2-(1-(2-氰基-3-(6-氟-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)三氟甲磺酸苯酯4c的制备
取N-氰基羰亚胺二苯酯(247mg,1.04mmol)溶于乙腈(5mL)中,然后加入6-氟-1,2,3,4-四氢萘-2-胺盐酸盐(210mg,1.04mmol)和三乙胺(0.29mL,2.08mmol)。加毕,室温条件下搅拌1h。LCMS显示原料消失,有产物生成。加水(15mL)稀释,EA萃取(30mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,加少量PE/EA(1/1,10mL)打浆,抽滤,得到苯基N'-氰基-N-(6-氟-1,2,3,4-四氢萘-2-基)氨基甲酰亚胺156mg,即化合物4b,收率:69.7%,用于下一步。
将4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(248mg,0.68mmol)和苯基N'-氰基-N-(6-氟-1,2,3,4-四氢萘-2-基)氨基甲酰亚胺(187mg,0.61mmol)溶于DMSO(6mL)中,加三乙胺(75mg,0.7mmol),升温至80℃反应5h。LCMS显示有产物生成。加入水(20mL),EA萃取(15mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,柱层析(EA:PE=3:1),得到180mg黄色油状物。收率:52.1%。
MS(M+H)+:568
步骤3:2-氰基-1-(1-(-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(6-氟-1,2,3,4-四氢萘-2-基)胍4的制备
取4-(2-(1-(2-氰基-3-(6-氟-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)三氟甲磺酸苯酯(65mg,0.11mmol)溶于THF/MeOH(4mL,1/1)和水(2滴)中,然后加入NaOH(50mg,1.2mmol)。室温搅拌反应2h。LCMS显示有产物生成,反应完毕加入NH4Cl饱和水溶液(5mL)淬灭反应,EA(10mLx2)萃取,无水硫酸钠干燥,过滤,浓缩,经HPLC制备、冷冻干燥后得到产物为27mg白色固体,即化合物4。收率:56.4%。
1H NMR(400MHz,DMSO-d6)δ:9.11(s,1H),8.73(s,1H),7.30(d,J=8.4Hz,1H),7.12-7.06(m,3H),6.94-6.89(m,2H),6.64-6.60(m,2H),3.97-3.93(m,1H),3.05-2.91(m,1H),2.87-2.70(m,3H),2.69-2.56(m,2H),2.29-2.25(m,1H),2.11(s,4H),1.98-1.95(m,1H),1.91(s,2H),1.80-1.69(m,1H),0.84-0.32(m,4H).
MS(M+H)+:436
实施例5
(4-(2-(1-(2-氰基-3-(6-氟-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸5
步骤1:2-氰基-1-(1-(1-(二甲基氨基)-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙基)环丙基)-3-(6-氟-1,2,3,4-四氢萘-2-基)胍5a的制备
取4-(2-(1-(2-氰基-3-(6-氟-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)三氟甲磺酸苯酯(114mg,0.2mmol)溶于dioxane(3mL)中,然后依次加入联硼酸频那醇酯(77mg,0.3mmol),Pd(dppf)Cl2(29mg,0.04mmol)和醋酸钾(60mg,0.6mmol),N2保护,置于微波反应器中(80度,80w,1h)。反应毕,浓缩,柱层析(EA:PE=4:1)得到60mg浅棕色固体,收率:54.9%。
MS(M+H)+:546
步骤2:(4-(2-(1-(2-氰基-3-(6-氟-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸5的制备
取2-氰基-1-(1-(1-(二甲基氨基)-2-(4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙基)环丙基)-3-(6-氟-1,2,3,4-四氢萘-2-基)胍(60mg,0.11mmol)溶于THF(2mL),然后加入稀HCl(1N,1mL),并室温条件下搅拌反应3h。LCMS显示大部分原料消失有产物生成,反应完毕后直接浓缩旋干,经HPLC制备、冷冻干燥后得到产物为24mg白色固体,即化合物5。收率:47.1%。
1H NMR(400MHz,DMSO-d6)δ:8.69(s,1H),7.91-7.81(m,2H),7.68-7.54(m,2H),7.38-7.20(m,3H),7.14-7.09(m,1H),6.94-6.90(m,2H),4.08-3.96(m,1H),3.03-2.75(m,5H),2.66-2.58(m,1H),2.39-2.31(m,1H),2.12(s,3H),1.99-1.94(m,1H),1.92(s,3H),1.79-1.74(m,1H),0.83-0.40(m,4H).
MS(M+H)+:464
实施例6
1-(苯并二氢吡喃-3-基)-2-氰基-3-(1-(1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)胍6
步骤1:4-(2-(1-(3-(苯并二氢吡喃-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯6b的制备
取N-氰基羰亚胺二苯酯(277mg,1.16mmol)溶于乙腈(6mL)中,然后加入苯并二氢吡喃-3-胺盐酸盐(220mg,1.16mmol)和三乙胺(0.34mL,2.44mmol)。加毕,室温条件下搅拌1h。LCMS显示原料消失。加水(15mL)稀释,EA萃取(30mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,加少量PE/EA(1/1,10mL)打浆,抽滤,得到苯基N-苯并二氢吡喃-3-基-N'-氰基氨基甲酰亚胺酯260mg(收率:76.5%),用于下一步。
将(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(93mg,0.26mmol)和苯基N-苯并二氢吡喃-3-基-N'-氰基氨基甲酰亚胺酯(79mg,0.27mmol)溶于DMSO(3mL)中,加三乙胺(34mg,0.3mmol),升温至80℃反应5h。LCMS显示有产物生成。加入水(20mL),EA萃取(15mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,柱层析(EA:PE=3:1),得到68mg浅棕色固体。收率:46.8%。
MS(M+H)+:552
步骤2:1-(苯并二氢吡喃-3-基)-2-氰基-3-(1-(1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)胍6的制备
取4-(2-(1-(3-(苯并二氢吡喃-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(68mg,0.12mmol)溶于THF/MeOH(4mL,1/1)和水(2滴)中,然后加入NaOH(50mg,1.2mmol)。室温搅拌反应2h。LCMS显示有产物生成,反应完毕加入NH4Cl饱和水溶液(5mL)淬灭反应,EA(10mLx2)萃取,无水硫酸钠干燥,过滤,浓缩,经HPLC制备、冷冻干燥后得到产物为19mg白色固体,即化合物6。收率:37.7%。
1H NMR(400MHz,DMSO-d6)δ:9.33-8.89(m,2H),7.41(d,J=20.2Hz,1H),7.09-7.03(m,4H),6.87-6.74(m,2H),6.61-6.58(m,2H),4.15-4.04(m,3H),3.13-3.06(m,1H),2.76-2.56(m,3H),2.20-2.06(m,1H),1.96(s,4H),1.76(s,2H),0.63-0.24(m,4H).
MS(M+H)+:420
实施例7
2-氰基-1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-3-(6-氟-1,2,3,4-四氢萘-2-基)胍7
步骤1:2-(二甲基氨基)-2-(噻吩-3-基)乙腈7a的制备
将NaCN(14.9g,304mmol)溶于水(150mL),搅拌下依次加入二甲胺盐酸盐(45g,560mmol)和3-噻吩甲醛(25g,223mmol)的乙腈(150mL)溶液,室温搅拌反应过夜。TLC(PE:EA=10:1)显示原料消失,新点生成。反应完毕,加入碳酸钠水溶液调pH至碱性,EA(300mLx2)萃取,饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,浓缩,柱层析(PE:EA=10:1),得到产物33g淡黄色油状物,收率:89.1%。
1H NMR(400MHz,CDCl3)δ:7.44-7.43(m,1H),7.35(dd,J=5.0,3.0Hz,1H),7.13(dd,J=5.0,1.1Hz,1H),4.81(s,1H),2.31(s,6H).
MS(M+H)+:167
步骤2:N,N-二甲基-1-(噻吩-3-基)乙烷-1,2-二胺二盐酸盐7b的制备
取2-(二甲基氨基)-2-(噻吩-3-基)乙腈(23g,138mmol)溶于THF(200mL)中,N2保护后置于冰浴下,缓慢滴加10N BH3二甲硫醚溶液(140mL,1.4mol),加毕,升温至60℃反应过夜。LCMS显示原料消失有产物生成,反应完毕后缓慢滴加甲醇(150mL)淬灭反应,加入浓盐酸(100mL),60℃下搅拌2h。直接浓缩旋干,加少量PE/EA(1/1,30mL)打浆,抽滤,即得到白色固体21g,收率:63.6%。
1H NMR(400MHz,DMSO-d6)δ:8.47(s,2H),7.98(s,1H),7.75(dd,J=4.8,2.9Hz,1H),7.42(d,J=4.7Hz,1H),4.83-4.80(m,1H),3.80(dd,J=13.1,5.1Hz,1H),3.63-3.50(m,1H),2.59-2.57(m,6H).
MS(M+H)+:171
步骤3:苯基N'-氰基-N-(2-(二甲基氨基)-2-(噻吩-3-基)乙基)氨基甲酰亚胺7c的制备
取N-氰基羰亚胺二苯酯(454mg,1.9mmol)溶于乙腈(10mL)中,然后加入N,N-二甲基-1-(噻吩-3-基)乙烷-1,2-二胺盐酸盐(462mg,1.9mmol)和三乙胺(0.93mL,6.68mmol)。加毕,室温条件下搅拌1h。LCMS显示原料消失,有产物生成。加水(15mL)稀释,EA萃取(30mLx3),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,加少量PE/EA(1/1,10mL)打浆,抽滤,得到标题化合物427mg,收率:71.6%。
MS(M+H)+:315
步骤4:2-氰基-1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-3-(6-氟-1,2,3,4-四氢萘-2-基)胍7
由苯基N'-氰基-N-(2-(二甲基氨基)-2-(噻吩-3-基)乙基)氨基甲酰亚胺(135mg,0.43mmol)和6-氟-1,2,3,4-四氢萘-2-胺盐酸盐(86mg,0.43mmol)按照前述实施例合成,产物为87mg白色固体,即化合物7。收率:52.5%。
1H NMR(400MHz,DMSO-d6)δ:7.52(dd,J=4.8,2.9Hz,1H),7.35(d,J=2.1Hz,1H),7.14-7.07(m,1H),7.04(d,J=4.9Hz,1H),6.97-6.88(m,2H),6.68(s,1H),3.99-3.80(m,2H),3.67-3.56(m,1H),3.46-3.35(m,1H),2.94(dd,J=16.2,4.6Hz,1H),2.83-2.79(m,2H),2.62(dd,J=16.1,9.4Hz,1H),2.03(s,6H),1.94-1.88(m,1H),1.74-1.64(m,1H).
MS(M+H)+:386
实施例8
2-氰基-1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-3-(6-溴-1,2,3,4-四氢萘-2-基)胍8
步骤1:6-溴-1,2,3,4-四氢萘-2-胺盐酸盐8a的制备
取6-溴-3,4-二氢萘-2(1H)-酮(505mg,2.25mmol)溶于甲醇(30mL)中,然后加入醋酸铵(1.8g,22.5mmol),室温搅拌30min。NaBH3CN(300mg,4.5mmol)分批加入,升温至60℃反应4h。LCMS显示原料消失有产物生成,加入加入水(40mL)淬灭反应,旋去甲醇,碳酸氢钠水溶液调pH至8-9,EA(30mLx5)萃取,无水硫酸钠干燥,过滤,浓缩柱层析(DCM:MeOH=10:1),得到产物。加EA(5mL)和HCl/dioxane(4N,1mL),析出固体,抽滤,EA洗涤滤饼,得到260mg浅棕色固体,收率:44.2%。
1H NMR(400MHz,DMSO-d6)δ:8.43(s,2H),7.32(s,1H),7.30(d,J=8.1Hz,1H),7.09(d,J=8.1Hz,1H),3.47-3.38(m,1H),3.05(dd,J=16.4,4.8Hz,1H),2.92-2.72(m,3H),2.14-2.11(m,1H),1.83-1.68(m,1H).
MS(M+H)+:226
步骤2:2-氰基-1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-3-(6-溴-1,2,3,4-四氢萘-2-基)胍8的制备
由苯基N'-氰基-N-(2-(二甲基氨基)-2-(噻吩-3-基)乙基)氨基甲酰亚胺(140mg,0.44mmol)和6-溴-1,2,3,4-四氢萘-2-胺盐酸盐(116mg,0.44mmol)按照前述实施例合成,产物为92mg白色固体,即化合物8。收率:47.0%。
1H NMR(400MHz,DMSO-d6)δ:7.52(dd,J=4.8,2.9Hz,1H),7.34(d,J=2.0Hz,1H),7.30(s,1H),7.27(d,J=8.4Hz,1H),7.05-7.03(m,2H),6.97-6.88(m,2H),6.67(s,1H),3.90-3.82(m,2H),3.64-3.58(m,1H),3.44-3.40(m,1H),2.93(dd,J=16.2,4.6Hz,1H),2.81-2.77(m,2H),2.64-2.55(m,1H),2.03(s,6H),1.94-1.89(m,1H),1.73-1.65(m,1H).
MS(M+H)+:446
实施例9
(R)-N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺9
步骤1:(R)-2-(((R)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙腈9a的制备
将(R)-1-(4-甲氧基苯基)乙胺盐酸盐(20g,107mmol)溶于甲醇(50mL)和水(50mL)的混合溶剂中,加入3-噻吩甲醛(10g,89.3mmol),室温搅拌15min,然后加入NaCN(4.87g,99.4mmol)的水(10mL)溶液,室温条件下搅拌反应过夜。TLC(PE:EA=10:1)显示原料大部分消失有新点生成。反应完毕后加水(170mL),搅拌15min,抽滤,滤饼用清水漂洗三次。将滤饼溶于DCM(100mL),饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩。粗品加PE/EA(10/1,200mL)打浆,抽滤,得到产物21.1g淡黄色固体,收率:86.8%。
1H NMR(400MHz,CDCl3)δ:7.45-7.42(m,1H),7.37(d,J=8.6Hz,2H),7.34(dd,J=5.0,3.0Hz,1H),7.13(dd,J=5.0,0.9Hz,1H),6.91(d,J=8.6Hz,2H),4.40(d,J=5.1Hz,1H),4.17(q,J=6.4Hz,1H),3.82(s,3H),1.81(s,1H),1.41(d,J=6.5Hz,3H).
MS(M+H)+:273
步骤2:(R)-2-(((R)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙酰胺盐酸盐9b的制备
(R)-2-(((R)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙腈(8g,29.4mmol)和碳酸钾(8.1g,58.7mmol)溶于DMSO(80mL)中,冰浴保持内温低于20℃,然后滴加H2O2(33g),加毕,撤掉冰浴,继续室温搅拌10min。LCMS显示原料消失,产物生成。加水(500mL)稀释,DCM(100mLx3)萃取,依次用亚硫酸氢钠水溶液和饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩约一半溶剂,加HCl/dioxane(4N)调pH值到1,析出固体,抽滤,得到9.2g白色固体。该产物溶于乙醇(80mL),加热至60℃搅拌5min,冷却至室温,抽滤,少量乙醇洗涤滤饼,得到产物为5.7g白色固体。收率:66.8%。
1H NMR(400MHz,DMSO-d6)δ:9.77(d,J=41.3Hz,2H),7.87(s,1H),7.66-7.59(m,3H),7.43(d,J=8.5Hz,2H),7.22(d,J=4.8Hz,1H),7.02(d,J=8.6Hz,2H),4.54(d,J=7.3Hz,1H),4.25(s,1H),3.78(s,3H),1.60(d,J=6.6Hz,3H).
MS(M+H)+:291
步骤3:(R)-2-(二甲基氨基)-2-(噻吩-3-基)乙酰胺9d的制备
取(R)-2-(((R)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙酰胺盐酸盐(3g,9.2mmol)和TFA(15mL)搅拌均匀,升温至65℃搅拌反应3h。将反应液浓缩,加水(35mL)稀释,EA萃取(30mLx2),得到的水相直接用于下一步。取上述水相,加入乙腈(30mL),室温搅拌下加入37%HCHO(3g,37mmol),室温搅拌2min,分批加入NaBH(OAc)3(6.1g,27.6mmol),室温继续搅拌30min。LCMS显示原料消失有产物生成。加入EA(40mLx3)萃取,饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(DCM:MeOH=10:1),得到1.14g无色凝胶物,两步收率:67.8%。手性HPLC分析:保留时间11.395min,手性纯度:>99%(色谱柱:Chiralpak IC,IC00CE-UE048,250mmLx4.6mm;流动相:正己烷:异丙醇=7:3(含0.1%三乙胺))。
1H NMR(400MHz,DMSO-d6)δ:7.47-7.43(m,2H),7.38(dd,J=2.8,1.2Hz,1H),7.13(dd,J=5.0,1.0Hz,1H),7.03(s,1H),3.73(s,1H),2.09(s,6H).
MS(M+H)+:185
步骤4:(R)-N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺9的制备
取(R)-2-(二甲基氨基)-2-(噻吩-3-基)乙酰胺(720mg,3.9mmol)溶于THF(10mL)中,N2保护后置于冰浴下,缓慢滴加10N BH3/THF(4mL,40mmol),加毕,升温至65℃反应过夜。LCMS显示原料消失有产物生成,反应完毕后加入甲醇(15mL)淬灭反应,加入浓盐酸(1.5mL),60℃下搅拌2h,直接浓缩旋干。粗品溶于THF(7mL),加饱和碳酸氢钠水溶液(10mL),调pH到8,然后加入(Boc)2O(853mg,3.9mmol),室温搅拌30min。加水(10mL)稀释,EA(30mLx3)萃取,饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,柱层析(DCM:MeOH=20:1),得到618mg蜡状固体,两步收率:58.5%。手性HPLC分析:保留时间4.488min,手性纯度:98.8%(色谱柱:Chiralpak IC,IC00CE-UE048,250mmLx4.6mm;流动相:正己烷:异丙醇=7:3(含0.1%三乙胺))。
上述产物(618mg,2.29mmol)溶于DCM(5mL),加HCl/dioxane(3mL,12mmol),室温搅拌1h。反应完毕,旋干溶剂。得到产物为550mg浅黄色固体,产物直接用于下一步。
MS(M+H)+:171
实施例10
(S)-N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺10
步骤1:(S)-2-(((S)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙腈10a的制备
使用(S)-1-(4-甲氧基苯基)乙胺盐酸盐(9.37g,50mmol)参照上述实施例合成,得到产物7.9g灰白色固体,收率:56.2%。
1H NMR(400MHz,CDCl3)δ:7.45-7.40(m,1H),7.37(d,J=8.6Hz,2H),7.33(dd,J=5.0,3.0Hz,1H),7.12(dd,J=5.0,1.0Hz,1H),6.91(d,J=8.6Hz,2H),4.40(d,J=6.9Hz,1H),4.16(q,J=6.4Hz,1H),3.81(s,3H),1.81(s,1H),1.40(d,J=6.5Hz,3H).
MS(M+H)+:273
步骤2:(S)-2-(((S)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙酰胺盐酸盐10b的制备
使用(S)-2-(((S)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙腈(960mg,3.53mmol)参照上述实施例合成。得到产物为840mg白色固体。收率:65.7%。
1H NMR(400MHz,DMSO-d6)δ:9.81(d,J=33.2Hz,2H),7.89(s,1H),7.67-7.58(m,3H),7.44(d,J=8.6Hz,2H),7.24(d,J=5.0Hz,1H),7.01(d,J=8.6Hz,2H),4.56(d,J=6.8Hz,1H),4.25(s,1H),3.78(s,3H),1.60(d,J=6.7Hz,3H).
MS(M+H)+:291
步骤3:(S)-2-(二甲基氨基)-2-(噻吩-3-基)乙酰胺10d的制备
使用(S)-2-(((S)-1-(4-甲氧基苯基)乙基)氨基)-2-(噻吩-3-基)乙酰胺盐酸盐(2.63g,7.2mmol)参照上述实施例合成。得到1.18g白色固体,两步收率:80.1%。手性HPLC分析:保留时间18.618min,手性纯度:>99%(色谱柱:Chiralpak IC,IC00CE-UE048,250mmLx4.6mm;流动相:正己烷:异丙醇=7:3(含0.1%三乙胺))。
1H NMR(400MHz,DMSO-d6)δ:7.48-7.43(m,2H),7.39(d,J=2.8Hz,1H),7.13(dd,J=4.9,1.0Hz,1H),7.03(s,1H),3.73(s,1H),2.10(s,6H).
MS(M+H)+:185
步骤4:(S)-N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺10的制备
使用(S)-2-(二甲基氨基)-2-(噻吩-3-基)乙酰胺(500mg,2.72mmol)参照上述实施例合成。得到470mg蜡状固体,两步收率:58.5%。手性HPLC分析:保留时间4.202min,手性纯度:97.5%(色谱柱:Chiralpak IC,IC00CE-UE048,250mmLx4.6mm;流动相:正己烷:异丙醇=7:3(含0.1%三乙胺))。
上述产物(470mg,1.74mmol)溶于DCM(4mL),加HCl/dioxane(2.5mL,10mmol),室温搅拌1h。反应完毕,旋干溶剂。得到产物为380mg浅黄色固体,产物直接用于下一步。
MS(M+H)+:171
实施例11、12
1,2,3,4-四氢萘-2-胺的拆分
将S-扁桃酸(3.64g,24mmol)溶于乙醇(65mL)中,然后加入1,2,3,4-四氢萘-2-胺(3.52g,24mmol),升温至90℃回流,重结晶2次得产物(S)-1,2,3,4-四氢萘-2-胺的S-扁桃酸盐为2.21g白色固体,收率:30.9%。[a]D 22=-90.3(c 0.2,CHCl3)(文献值为[a]D 22=-84.5(c 0.54,CHCl3))。手性HPLC分析:保留时间10.005min,手性纯度:>99%(色谱柱:Chiralpak AD-H,ADH0CE-UI049,250mmLx4.6mm;流动相体系,正己烷:乙醇=8:2(含0.1%三乙胺))。
将上述两批母液合并,旋走大部分溶剂,加水(20mL)和EA(50mL)溶解,用碳酸钾水溶液调pH到8-9,EA(40mLx2)萃取,饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,过滤,浓缩,得到2.74g褐色油状物。
将R-扁桃酸(2.83g,18.6mmol)溶于乙醇(30mL)中,然后加入1,2,3,4-四氢萘-2-胺(2.74g,18.6mmol),升温至90℃回流,补加水(1mL)至完全溶解,结晶一次得到产物为(R)-1,2,3,4-四氢萘-2-胺的R-扁桃酸盐2.9g白色固体,收率:52%。手性HPLC分析:保留时间10.323min,手性纯度:>99%(色谱柱:Chiralpak AD-H,ADH0CE-UI049,250mmLx4.6mm;流动相体系,正己烷:乙醇=8:2(含0.1%三乙胺))。
实施例13
1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-2-甲基-3-(1,2,3,4-四氢萘-2-基)胍13
步骤1:2-异硫氰基-1,2,3,4-四氢化萘13a的制备
取1,2,3,4-四氢萘-2-胺(260mg,1.77mmol)溶于干燥的THF(5mL)中,然后加入三乙胺(0.9mL,6.3mmol)。N2保护后置于0℃的冰浴下。逐滴加入CS2(0.13mL,2.1mmol)的THF(5mL)溶液,回复至室温下反应1h。TLC显示原料消失,重新把反应液置于0℃的冰浴下,并逐滴加入乙酰氯(0.15mL,2.1mmol),恢复至室温并搅拌1h。LCMS显示有产物生成,反应完毕加DCM(40mL)和水(20mL),分出有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,得到330mg黄色油状物,收率:99%。
MS(M+H)+:190
步骤2:1-甲基-3-(1,2,3,4-四氢萘-2-基)硫脲13b的制备
将2-异硫氰基-1,2,3,4-四氢化萘(500mg,2.64mmol)和甲胺盐酸盐(350mg,5.3mmol)溶于干燥的THF(15mL)中,加入三乙胺(1.5mL,10.6mmol),升温至60℃反应4h。冷却至室温,加水(25mL)稀释,DCM(30mLx3)萃取,饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,浓缩,柱层析(EA:PE=1:1)得到460mg黄色油状物,收率:78.9%。
MS(M+H)+:221
步骤3:甲基-N-甲基-N'-(1,2,3,4-四氢萘-2-基)亚胺甲酰硫酯13c的制备
取1-甲基-3-(1,2,3,4-四氢萘-2-基)硫脲(460mg,2.1mmol)溶于甲醇(30mL)中,然后N2保护后逐滴加入CH3I(300mg,2.1mmol),升温至30℃下反应1h。补加CH3I(300mg,2.1mmol),30℃下反应6h。LCMS显示原料消失有产物生成,反应完毕后,浓缩旋干。粗品溶于DCM(20mL),加饱和碳酸氢钠水溶液,调pH值为9-10,分出有机相,饱和氯化钠溶液洗涤有机相,无水硫酸钠干燥,浓缩,柱层析(DCM:MeOH=10:1)得到270mg无色油状物,收率:55.3%。
MS(M+H)+:234
步骤4:1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-2-甲基-3-(1,2,3,4-四氢萘-2-基)胍13的制备
取甲基-N-甲基-N'-(1,2,3,4-四氢萘-2-基)亚胺甲酰硫酯(124mg,0.53mmol)和N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺(96mg,0.56mmol)溶于DMF(5mL),然后加入三乙胺(0.16mL,1.12mmol)。N2保护后升温至80℃反应5h。LCMS显示有产物生成,反应完毕加饱和氯化铵溶液(15mL)淬灭反应,EA(30mLx2)萃取,再用饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,浓缩,柱层析(MeOH:DCM=1:5),得到50mg粗品,经HPLC制备、冷冻干燥得到产物为9.2mg白色固体,即化合物13。收率:5.2%。
1H NMR(400MHz,DMSO-d6)δ:7.55-7.52(m,1H),7.36(d,J=2.1Hz,1H),7.12-7.06(m,4H),7.04(d,J=5.0Hz,1H),3.89-3.66(m,4H),3.42(dd,J=14.1,5.0Hz,1H),3.04-2.90(m,1H),2.87-2.79(m,2H),2.74(d,J=1.1Hz,3H),2.03(d,J=2.0Hz,6H),1.97-1.89(m,1H),1.78-1.70(m,1H).
MS(M+H)+:357
实施例14
1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-2-甲氧基-3-(1,2,3,4-四氢萘-2-基)胍14
步骤1:1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-3-(1,2,3,4-四氢萘-2-基)硫脲的制备14a
将2-异硫氰基-1,2,3,4-四氢化萘(117mg,0.59mmol)和N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺盐酸盐(170mg,0.71mmol)溶于干燥的THF(6mL)中,加入三乙胺(0.3mL,2.13mmol),室温搅拌反应2h。加水(25mL)稀释,DCM(30mLx3)萃取,饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,浓缩,柱层析(DCM:MeOH=10:1)得到182mg淡黄色固体,收率:71.4%。
1H NMR(400MHz,CDCl3)δ:7.32(dd,J=4.6,3.0Hz,1H),7.14-7.07(m,5H),6.93(s,1H),6.46(s,1H),3.77-3.71(m,3H),3.25-3.21(m,1H),2.90(t,J=6.3Hz,2H),2.76-2.69(m,1H),2.16-2.12(m,1H),2.07(d,J=9.6Hz,6H),1.98-1.87(m,2H).
MS(M+H)+:360
步骤2:1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-2-甲氧基-3-(1,2,3,4-四氢萘-2-基)胍14的制备
取1-(2-(二甲氨基)-2-(噻吩-3-基)乙基)-3-(1,2,3,4-四氢萘-2-基)硫脲(182mg,0.51mmol)溶于甲醇(6mL)中,然后N2保护后逐滴加入CH3I(72mg,0.51mmol)的甲醇(1mL)溶液,升温至30℃下反应1h。补加CH3I(94mg,0.66mmol),30℃下反应6h。LCMS显示原料消失有产物生成,反应完毕后,浓缩旋干。Prep-TLC层析(DCM:MeOH=10:1)得到甲基-N-(2-(二甲基氨基)-2-(噻吩-3-基)乙基)-N'-(1,2,3,4-四氢萘-2-基)亚胺甲酰硫酯,即化合物14b的粗品,直接投入下一步。
取上述甲基-N-(2-(二甲基氨基)-2-(噻吩-3-基)乙基)-N'-(1,2,3,4-四氢萘-2-基)亚胺甲酰硫酯(14b)的粗品和甲氧胺盐酸盐(220mg,2.7mmol)溶于乙腈(6mL),然后加入三乙胺(0.55mL,4mmol)。N2保护后升温至80℃反应5h。LCMS显示有产物生成,反应完毕后浓缩,柱层析(MeOH:DCM=1:6),得到90mg粗品,经HPLC制备、冷冻干燥得到产物为7.3mg白色固体,即化合物14。两步收率:3.8%。
1H NMR(400MHz,DMSO-d6)δ:7.49-7.46(m,1H),7.31-7.27(m,1H),7.07-6.98(m,5H),5.39-5.31(m,1H),5.26-4.97(m,1H),4.76-3.80(m,1H),3.63-3.55(m,1H),3.44(d,J=6.3Hz,3H),3.22-3.13(m,1H),3.07-3.01(m,1H),2.77-2.70(m,2H),2.61-2.52(m,1H),1.99(d,J=10.8Hz,6H),1.71-1.51(m,2H).
MS(M+H)+:373
实施例15
2-氰基-1-((S)-2-(二甲基氨基)-2-(噻吩-3-基)乙基)-3-(6-氟苯并二氢吡喃-3-基)胍15
步骤1:6-氟-2H-色烯-3-羧酸叔丁酯15a的制备
将5-氟水杨醛(5g,35.71mmol)加入N-甲基吡咯烷酮(25mL)搅拌溶解。加入无水K2CO3(7.4g,53.57mmol),丙烯酸叔丁酯(6.9g,53.57mmol)。升温至150℃,搅拌3h。TLC监控(EA:PE=1:10),反应完毕。降温至室温,加入水(150mL),EA(150mL)萃取二次。有机层饱和盐水洗涤一次,无水硫酸钠干燥。然后过柱分离(EA:PE=1:20),得到3.66g蜡状固体。收率:38.2%。
1H NMR(400MHz,CDCl3)δ7.26(s,1H),6.90(td,J=8.5,3.0Hz,1H),6.84(dd,J=8.2,2.9Hz,1H),6.78(dd,J=8.8,4.5Hz,1H),4.92(d,J=1.0Hz,2H),1.52(s,9H).
步骤2:6-氟色满-3-羧酸叔丁酯15b的制备
将6-氟-2H-色烯-3-羧酸叔丁酯(3.66g,14.64mmol)加入甲醇(40mL)中搅拌溶解,然后加入水(1.5mL),10%钯碳(732mg,含水50%)。常压加氢,室温搅拌过夜,约16h。TLC监控(EA:PE=1:10),反应完毕。抽滤回收钯碳,滤液浓缩,然后加入DCM,无水硫酸钠干燥,抽滤,滤液浓缩后加入PE(30mL)打浆搅拌30min,抽滤,抽干后得到白色固体3.66g。收率:99.2%。
步骤3:6-氟色满-3-羧酸15c的制备
6-氟色满-3-羧酸叔丁酯(3.66g,14.52mmol),加入二氯甲烷(30mL),搅拌溶解,加入三氟乙酸(10mL)。室温搅拌2小时。TLC监控原料消失(石油醚:乙酸乙酯10:1)。反应液倒入(100mL)水中,二氯甲烷(30mL)萃取三次。有机层饱和食盐水洗涤一次。无水硫酸钠干燥。浓缩后加入石油醚(20mL)打浆搅拌30分钟。抽滤,抽干。得到白色固体2.53g。收率:88.8%。
MS(M+H)+:197.
步骤4:(6-氟色满)-3-氨基甲酸叔丁酯15d的制备
将6-氟色满-3-羧酸(2g,10.20mmol),加入叔丁醇(30mL)室温搅拌溶解,加入DPPA(3.37g,12.24mmol),然后加入三乙胺(2.2mL,15.30mmol)。升温至85℃搅拌回流过夜,约20h。TLC和LC-MS监控,反应完毕。浓缩后过柱分离(EA:PE=1:20)。得到白色固体1.15g收率:42%。
1H NMR(400MHz,CDCl3)δ6.87-6.80(m,1H),6.80-6.76(m,1H),6.76-6.70(m,1H),4.97-4.75(m,1H),4.22-4.12(m,1H),4.12-4.03(m,2H),3.08(dd,J=16.8,5.1Hz,1H),2.72(d,J=16.8Hz,1H),1.44(s,9H).
MS(M+H)+:268.
步骤5:6-氟苯并二氢吡喃-3-胺盐酸盐15e的制备
将(6-氟色满)-3-氨基甲酸叔丁酯(1.246g,4.7mmol),加入DCM(10mL)搅拌溶解,加入4N HCl乙醇溶液(5mL)。室温搅拌1~2h,TLC、LC-MS监控,反应结束。浓缩后得到类白色固体954mg,收率100%。
MS(M+H)+:168.
步骤6:苯基N'-氰基-N-(6-氟色满-3-基)氨基甲酰亚胺酯15f的制备
将6-氟苯并二氢吡喃-3-胺盐酸盐(300mg,1.47mmol),加入乙腈(6mL)室温搅拌,加入N-氰基羰亚胺二苯酯(357mg,1.47mmol),三乙胺(0.65mL,4.5mmol),室温搅拌1.5h。TLC、LC-MS监控,反应结束。加入水(20mL),EA(20mL)萃取三次。有机层饱和盐水洗涤一次,无水硫酸钠干燥后,浓缩。加入PE(10mL)打浆搅拌30min。抽滤,抽干得到407mg白色固体。收率:89%。
MS(M+H)+:312.
步骤7:2-氰基-1-((S)-2-(二甲基氨基)-2-(噻吩-3-基)乙基)-3-(6-氟苯并二氢吡喃-3-基)胍15的制备
将(S)-N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺二盐酸盐(120mg,0.494mmol)加入N,N-二甲基甲酰胺(3mL)室温搅拌,然后加入苯基N'-氰基-N-(7-氟色满-3-基)氨基甲酰亚胺酯(154mg,0.494mmol),三乙胺(0.35mL,2.47mmol)。油浴中80℃搅拌3h。反应完毕,降温至室温后,加入水(20mL),EA(10mL)萃取三次,有机层饱和盐水洗涤一次,无水硫酸钠干燥,浓缩,过柱(MeOH:DCM=1:20)。得到167mg淡黄色粘稠液体。经HPLC制备、冷冻干燥得到70mg白色固体,即化合物15,收率:36.6%。
1H NMR(400MHz,DMSO-d6)δ8.07(brs,1H),7.54-7.47(m,1H),7.34-7.25(m,1H),7.04-6.87(m,4H),6.84-6.76(m,1H),4.18-4.03(m,2H),4.00-3.88(m,1H),3.76(td,J=8.3,4.4Hz,1H),3.67-3.54(m,1H),3.02(dd,J=16.8,5.2Hz,1H),2.83-2.69(m,1H),1.94(d,J=7.0Hz,6H),1.86(d,J=7.8Hz,1H).
MS(M+H)+:388.
实施例16
4-(2-(二甲基氨基)-2-(1-((2-硝基-1-((1,2,3,4-四氢萘-2-基)氨基)乙烯基)氨基)环丙基)乙基)苯酚16
步骤1:4-(2-(二甲基氨基)-2-(1-((1-(甲硫基)-2-硝基乙烯基)氨基)环丙基)乙基)苯基三氟甲磺酸16a的制备
将1,1-(双甲硫基)-2-硝基乙烯(240mg,1.46mmol)和4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(342mg,0.97mmol)溶于乙醇(10mL),升温至80℃反应16h。冷却至室温,浓缩,柱层析(DCM/MeOH=15/1),得到产物为90mg淡黄色油状物,收率:20%。
MS(M+H)+:470
步骤2:4-(2-(二甲基氨基)-2-(1-((2-硝基-1-((1,2,3,4-四氢萘-2-基)氨基)乙烯基)氨基)环丙基)乙基)苯基三氟甲磺酸酯16b的制备
将4-(2-(二甲基氨基)-2-(1-((1-(甲硫基)-2-硝基乙烯基)氨基)环丙基)乙基)苯基三氟甲磺酸酯(90mg,0.19mmol)和1,2,3,4-四氢萘-2-胺(56mg,0.38mmol)溶于乙醇(10mL),加入三乙胺(77mg,0.76mmol),然后升温至80℃反应48h。冷却至室温,浓缩,制备TLC分离(DCM/MeOH=15/1),得到产物26mg淡黄色油状物,收率:24%。
MS(M+H)+:569
步骤3:4-(2-(二甲基氨基)-2-(1-((2-硝基-1-((1,2,3,4-四氢萘-2-基)氨基)乙烯基)氨基)环丙基)乙基)苯酚16的制备
4-(2-(二甲基氨基)-2-(1-((2-硝基-1-((1,2,3,4-四氢萘-2-基)氨基)乙烯基)氨基)环丙基)乙基)苯基三氟甲磺酸酯(30mg,0.053mmol)溶于THF/MeOH(4mL,1/1)和水(2滴)中,然后加入NaOH(21mg,0.53mmol)。室温搅拌反应2h。LCMS显示有产物生成,反应完毕加入NH4Cl饱和水溶液(10mL)淬灭反应,EA(15mLx2)萃取,无水硫酸钠干燥,过滤,浓缩,经HPLC制备、冷冻干燥后得到产物为7.8mg白色固体,即化合物16。收率:34%。
1H NMR(400MHz,DMSO-d6)δ:9.96(d,J=14.0Hz,1H),9.22(s,1H),7.10(s,4H),7.01(t,J=7.7Hz,2H),6.69-6.61(m,3H),3.94-3.87(m,1H),3.12-3.01(m,2H),2.91-2.82(m,3H),2.72-2.59(m,2H),2.25-2.23(m,1H),2.15(s,3H),2.08-2.01(m,1H),1.80(s,3H),0.89-0.74(m,2H),0.48-43(m,1H),0.30-0.25(m,1H).
MS(M+H)+:437
实施例17
2-氰基-1-((S)-2-(二甲基氨基)-2-(噻吩-3-基)乙基)-3-(6-氟-1,2,3,4-四氢萘吡啶-2-基)胍单一构型17
步骤1:6-氟-1,2,3,4-四氢萘-2-胺的手性拆分
将S-扁桃酸(925mg,6.08mmol)溶于乙醇(3mL)中,然后加入6-氟-1,2,3,4-四氢萘-2-胺(1g,6.08mmol),逐步升温至85℃回流,补加乙醇(2mL)至完全溶解,重结晶六次得产物为330mg。收率:10%。
手性HPLC分析:保留时间27.397min,手性纯度:>99%(色谱柱:Chiralpak AD-H,ADH0CE-UI049,250mmLx4.6mm;流动相体系,正己烷:异丙醇=92:8(含0.1%TFA)。
步骤2:苯基N'-氰基-N-(6-氟-1,2,3,4-四氢萘-2-基)氨基甲酰亚胺(JH-82-16-S)17b的制备
取6-氟1,2,3,4-四氢萘-2-胺(S-扁桃酸拆分)(228mg,0.72mmol)溶于加碳酸钾水溶液(15mL,25%)和NaOH(2N,1mL),DCM(20mLx2)萃取,无水硫酸钠干燥,过滤,浓缩,得到126mg无色油状物。
上述无色油状物(126mg,0.72mmol)溶于乙腈(5mL),加入N-氰基羰亚胺二苯酯(180mg,0.75mmol)和三乙胺(0.21mL,1.5mmol)。加毕,室温条件下搅拌2h。LCMS显示原料消失,有产物生成。加水(20mL)稀释,EA萃取(20mLx3),饱和氯化钠溶液洗涤合并的有机相,无水硫酸钠干燥,浓缩,Flash柱分离(PE/EA=2/1),得到160mg活性酯(收率:70%),用于下一步。
MS(M+H)+:310
步骤3:2-氰基-1-((S)-2-(二甲基氨基)-2-(噻吩-3-基)乙基)-3-(6-氟-1,2,3,4-四氢萘吡啶-2-基)胍17的制备
将(S)-N1,N1二甲基-1-(噻吩-3-基)乙烷-1,2-二胺盐酸盐(63mg,0.26mmol)和(S)-苯基N'-氰基-N-(6-氟-1,2,3,4-四氢萘-2-基)氨基甲酰亚胺(65mg,0.21mmol)溶于DMF(2mL)中,加三乙胺(104mg,1.03mmol),升温至80℃反应3h。LCMS显示原料消失有产物生成。加入氯化铵水溶液(10mL)和水(10mL),EA萃取(15mLx3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,经HPLC制备、冷冻干燥后得到产物为30mg乳白色固体,即化合物17。收率:30%。
1H NMR(400MHz,DMSO-d6)δ:7.51(dd,J=4.8,2.9Hz,1H),7.33(d,J=2.0Hz,1H),7.09(dd,J=8.9,6.2Hz,1H),7.03(d,J=4.6Hz,1H),6.93-6.89(m,2H),6.70(s,1H),3.90(s,1H),3.82(dd,J=8.8,5.2Hz,1H),3.63-3.56(m,1H),3.41-3.35(m,2H),2.93(dd,J=16.1,4.1Hz,1H),2.83-2.77(m,2H),2.60(dd,J=16.0,9.5Hz,1H),2.01(s,6H),1.91-1.85(m,1H),1.72-1.62(m,1H).
MS(M+H)+:386
实施例18
2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-((R)-1,2,3,4-四氢萘-2-基)胍18
步骤1:4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯的拆分
4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯5.6g甲醇溶解,手性柱拆分,拆分条件:仪器:SHIMADZU LC-20;色谱柱:S-Chiral C,7μm,20*250mm;流动相:正己烷/乙醇/三乙胺90/10/0.1;流速:25mL/min;柱温:20℃;检测波长:220nm。得(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯2.4g(保留时间5.1min,ee%>95%)和(R)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯1.0g(保留时间7.8min,ee%>95%);
步骤2:4-((S)-2-(1-(2-氰基-3-((R)-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯18b的制备
将(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(200mg,0.57mmol)加入2.5mL搅拌溶解,加入单一构型的苯基(R)-N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯(164mg,0.57mmol),加入TEA(230mg,2.28mmol),80℃保温搅拌3h。TLC,LC-MS监控反应,反应结束。加入水(20mL),DCM萃取三次,饱和盐水洗涤两次,无水Na2SO4干燥,硅胶柱纯化。EA:PE 30%。得到淡黄色固体228mg,收率:72.9%。
MS(M+H+):550。
步骤3:2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-((R)-1,2,3,4-四氢萘-2-基)胍18的合成
将4-((S)-2-(1-(2-氰基-3-((R)-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(114mg,0.21mmol)加入THF(2.5mL)搅拌溶解,加入NaOH(83mg,2.1mmol),水(0.4mL),甲醇(2.5mL)室温搅拌2h,TLC,LC-MS监控反应完毕。加入饱和NH4Cl溶液50mL,EA萃取三次,饱和盐水洗涤一次,无水Na2SO4干燥,浓缩。经HPLC制备、冷冻干燥后得到产物为白色固体47mg,即化合物18。HPLC:98.00%。
1H NMR(400MHz,DMSO-d6)δ8.81(s,1H),7.30(s,1H),7.11-6.97(m,6H),6.63(d,J=8.3Hz,2H),4.11(s,1H),3.05(dd,J=16.5,4.7Hz,1H),2.86(dd,J=15.3,8.7Hz,2H),2.79-2.59(m,4H),2.25-2.13(m,1H),1.89(s,6H),1.82-1.75(m,1H),0.84-0.76(m,1H),0.70-0.62(m,1H),0.61-0.53(m,1H),0.49-0.40(m,1H).
MS(M+H+):418.
实施例19
2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍19
由(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯和苯基(S)-N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯按照上述实施例方法合成。
1H NMR(400MHz,DMSO-d6)δ8.76(s,1H),7.27(s,1H),7.14-7.05(m,6H),6.64(d,J=8.4Hz,2H),3.98(s,1H),3.02(dd,J=16.3,4.7Hz,1H),2.87-2.75(m,3H),2.71-2.61(m,2H),2.28(s,1H),2.11(s,6H),2.04-1.96(m,1H),1.83-1.72(m,1H),0.76-0.60(m,2H),0.53-0.39(m,2H).
MS(M+H+):418.
实施例20
(4-((S)-2-(1-(2-氰基-3-((S)-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸20
由(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯和苯基(S)-N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯按照前述实施例的方法合成。
1H NMR(400MHz,DMSO-d6)δ:7.97(s,1H),7.66(d,J=7.8Hz,2H),7.33(s,1H),7.28(d,J=7.9Hz,2H),7.08-7.06(m,5H),3.96(s,1H),3.00(dd,J=16.2,4.6Hz,1H),2.93-2.72(m,4H),2.64(dd,J=16.3,7.5Hz,1H),2.40-2.35(m,1H),2.10(s,6H),2.01-1.95(m,1H),1.79-1.73(m,1H),0.77-0.58(m,2H),0.48-0.40(m,2H).
MS(M+H)+:446
实施例21
(4-((S)-2-(1-(3-((R)-色满-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸21
步骤1:4-((S)-2-(1-(3-((R)-色满-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯的21a制备
将(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(100mg,0.28mmol)和(R)-苯基N-苯并二氢吡喃-3-基-N'-氰基氨基甲酰亚胺酯(105mg,0.36mmol)((R)-苯并二氢吡喃-3-胺按照实施例6制备)溶于DMSO(2.5mL),加入加入三乙胺(59mg,0.59mmol),然后升温至80℃反应4h。冷却至室温,加入氯化铵水溶液(15mL),EA萃取(15mLx3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,柱层析(EA:PE=2:1),得到110mg无色凝胶状物。收率:70%。
MS(M+H)+:552
步骤2:1-((R)-苯并二氢吡喃-3-基)-2-氰基-3-(1-((S)-1-(二甲基氨基)-2-(4-(4,4,5,5-四甲基5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙基)环丙基)胍21b的制备
取4-((S)-2-(1-(3-((R)-色满-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(110mg,0.20mmol)溶于dioxane(3mL)中,然后依次加入联硼酸频那醇酯(76mg,0.30mmol),Pd(dppf)Cl2(30mg,0.04mmol)和醋酸钾(60mg,0.6mmol),置于微波反应器中(80度,100w,1h)。反应毕,浓缩,柱层析(EA:PE=2:1)得到90mg灰白色固体,收率:85%。
MS(M+H)+:530
步骤3:(4-((S)-2-(1-(3-((R)-色满-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸21的制备
取1-((R)-苯并二氢吡喃-3-基)-2-氰基-3-(1-((S)-1-(二甲基氨基)-2-(4-(4,4,5,5-四甲基5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)苯基)乙基)环丙基)胍(90mg,0.17mmol)溶于THF(2mL),然后加入稀HCl(2N,1mL),并室温条件下搅拌反应3h。LCMS显示大部分原料消失有产物生成,反应完毕后直接浓缩旋干,经HPLC制备、冷冻干燥后得到产物为43mg白色固体,即化合物21。收率:56%。
1H NMR(400MHz,DMSO-d6)δ:9.21(s,1H),8.04(s,2H),7.66(d,J=7.8Hz,2H),7.48(s,1H),7.27(d,J=7.8Hz,2H),7.09(t,J=7.7Hz,2H),6.85(t,J=7.4Hz,1H),6.79(d,J=8.0Hz,1H),4.18-4.12(m,J=11.7Hz,3H),3.11(dd,J=16.5,4.2Hz,1H),2.87(dd,J=14.4,7.2Hz,1H),2.79-2.64(m,2H),2.28(s,1H),1.98(s,6H),0.62-0.57(m,1H),0.53-0.49(m,1H),0.41-0.36(m,1H),0.34-0.29(m,1H).
MS(M+H)+:448
实施例22
(4-((S)-2-(1-(3-((S)-色满-3-基)-2-氰基胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸22
使用(S)-苯基N-苯并二氢吡喃-3-基-N'-氰基氨基甲酰亚胺酯为起始原料按照上述实施例制备。
1H NMR(400MHz,DMSO-d6)δ:8.93(s,1H),8.11(s,1H),7.61(d,J=8.2Hz,1H),7.51(s,1H),7.24(d,J=8.2Hz,1H),7.16(d,J=7.6Hz,1H),7.09-7.04(m,2H),6.83(t,J=7.4Hz,1H),6.78(d,J=8.0Hz,1H),4.22-4.01(m,3H),3.10(dd,J=16.7,4.6Hz,1H),2.86-2.63(m,3H),2.22(s,1H),1.78(d,J=7.1Hz,6H),0.75-0.53(m,3H),0.43-0.33(m,1H).
MS(M+H)+:448
实施例23
2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(5-氟苯并二氢吡喃-3-基)胍23
步骤1:苯基N'-氰基-N-(5-氟色满-3-基)氨基甲酰亚胺23d的制备
使用2-氟-6-羟基苯甲醛为起始原料按前述实施例15e方法合成
MS(M+H)+:312
步骤2:4-((2S)-2-(1-(2-氰基-3-(5-氟色满-3-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯23e的制备
将(S)-4-(2-(1-氨基环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(103mg,0.29mmol)和苯基N'-氰基-N-(5-氟色满-3-基)氨基甲酰亚胺(100mg,0.37mmol)溶于DMSO(2mL),加入加入三乙胺(65mg,0.64mmol),然后升温至80℃反应3h。冷却至室温,加入氯化铵水溶液(15mL),EA萃取(15mLx3),合并有机相,饱和氯化钠溶液洗涤,无水硫酸钠干燥,浓缩,柱层析(EA:PE=2:1),得到90mg黄色油状物。收率:54%。
MS(M+H)+:570
步骤3:2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(5-氟苯并二氢吡喃-3-基)胍23的制备
取4-((2S)-2-(1-((E)-2-氰基-3-(5-氟色满-3-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基三氟甲磺酸酯(90mg,0.16mmol)溶于THF/MeOH(4mL,1/1)和水(2滴)中,然后加入NaOH(64mg,1.6mmol)。室温搅拌反应2h。反应完毕,加入NH4Cl饱和水溶液(5mL)淬灭反应,EA(10mLx2)萃取,无水硫酸钠干燥,过滤,浓缩,经HPLC制备、冷冻干燥后得到产物为47mg白色固体。收率:68.1%。
1H NMR(400MHz,DMSO-d6)δ:9.34(s,1H),8.99(s,1H),7.49(d,J=20.9Hz,1H),7.14(dd,J=15.4,7.9Hz,1H),7.08-7.05(m,2H),6.76-6.72(m,1H),6.71-6.66(m,1H),6.64-6.60(m,2H),4.125-4.15(m,2H),4.11(t,J=11.4Hz,1H),2.99(dt,J=16.6,4.5Hz,1H),2.80-2.68(m,2H),2.66-2.59(m,1H),2.22-2.12(m,1H),2.00(s,3H),1.80(s,3H),0.71-0.58(m,2H),0.55-0.28(m,2H).
MS(M+H)+:438
实施例24
2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟基苯基)乙基)环丙基)-3-(8-氟苯并二氢吡喃-3-基)胍24
使用3-氟-2-羟基苯甲醛为起始原料按照前述实施例23合成。
1H NMR(400MHz,DMSO-d6)δ9.40-8.93(m,2H),7.48(d,J=23.8Hz,1H),7.10-7.05(m,,2H),7.05-7.00(m,1H),6.96-6.92(m,1H),6.87-6.80(m,1H),6.50-6.59(m,2H),4.29-4.21(m,2H),4.20-4.09(m,1H),3.21-3.08(m,1H),2.82-2.68(m,2H),2.67-2.58(m,1H),2.22-2.10(m,1H),1.99(s,3H),1.79(s,3H),0.72-0.26(m,4H).
MS(M+H)+:438
实施例25
2-氰基-1-(3-((二甲氨基)(噻吩-3-基)甲基)戊烷-3-基)-3-(1,2,3,4-四氢萘-2-基)胍25
步骤1:2-乙基N1,N1二甲基-1-(噻吩-3-基)丁烷-1,2-二胺(JH-77-16)25a的制备
取2-(二甲基氨基)-2-(噻吩-3-基)乙腈(513mg,3.1mmol)溶于干燥的THF(10mL)中,置于-70℃条件下搅拌,滴加Ti(OiPr)4(1.08g,3.72mmol),然后将乙基溴化镁(13mL,13mmol)滴加到上述-70℃的反应液中。加毕,恢复至室温条件下反应2h。然后冰浴下滴加水(3mL)淬灭反应,加EA(20mL)稀释,用HCl(1N)调pH到1-2,静置分层,分出的水相用NaOH(5N)调pH到10-11,EA(20mLx3)萃取,无水硫酸钠干燥,过滤,浓缩。粗品拌硅胶,柱层析(MeOH:DCM=1:15),得到产物为170mg浅黄色固体,收率:24.3%。
MS(M+H)+:227
步骤2:2-氰基-1-(3-((二甲氨基)(噻吩-3-基)甲基)戊烷-3-基)-3-(1,2,3,4-四氢萘-2-基)胍25的制备
2-乙基N1,N1二甲基-1-(噻吩-3-基)丁烷-1,2-二胺和苯基-N'-氰基-N-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯按照前述实施例方法合成。
1H NMR(400MHz,DMSO-d6)δ:7.44(dd,J=7.2,4.0Hz,1H),7.31(s,1H),7.14-7.12(m,1H),7.08-7.04(m,4H),6.59(s,1H),5.24(d,J=4.6Hz,1H),3.87-3.80(m,1H),3.75(d,J=9.6Hz,1H),2.96(dd,J=16.4,4.5Hz,1H),2.84-2.73(m,2H),2.57-2.53(m,1H),2.06(s,3H),2.02(s,3H),1.94-1.91(m,1H),1.81-1.76(m,2H),1.69-1.60(m,2H),1.50-1.41(m,1H),0.77-0.68(m,6H).
MS(M+H)+:424
实施例26
(4-((S)-2-(1-(2-氰基-3-((S)-1,2,3,4-四氢-萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸对甲苯磺酸盐的制备
将(4-((S)-2-(1-(2-氰基-3-((S)-1,2,3,4-四氢-萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸(6.7mg,0.015mmol)溶于DCM(1mL),加入对甲苯磺酸(2.85mg,0.015mmol)的THF(0.6mL)溶液,搅拌1h。旋蒸浓缩溶剂,加入EA(0.3mL),正己烷(3mL)打浆。得到9.1mg白色固体,即化合物26。收率:98.3%。
1H NMR(400MHz,DMSO-d6)δ:9.06(s,1H),8.02(s,2H),7.76(d,J=7.6Hz,2H),7.45(d,J=8.0Hz,2H),7.34(d,J=7.7Hz,2H),7.28(s,1H),7.10-7.07(m,6H),4.05-3.95(m,1H),3.55-3.49(m,1H),3.16-3.04(m,2H),3.00-2.70(m,10H),2.27(s,3H),2.03-1.94(m,1H),1.85-1.75(m,1H),1.20-1.12(m,1H),1.02-0.97(m,1H),0.89-0.81(m,1H),0.79-0.72(m,1H).
实施例27
(4-((S)-2-(1-((2-氰基-3-((S)-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸酯二钠盐的制备
将(4-((S)-2-(1-(2-氰基-3-((S)-1,2,3,4-四氢-萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基)硼酸(16.3mg,0.036mmol)置于茄形瓶中,加水(3mL),然后加入NaOH水溶液(0.2mmol/mL,0.36mL)搅拌1h。旋蒸浓缩溶剂,加入EA(0.3mL),正己烷(3mL)打浆,得到17.2mg白色固体,即化合物27。收率:96%。
1H NMR(400MHz,DMSO-d6)δ:7.80-7.65(m,2H),7.53(d,J=6.9Hz,1H),7.30-7.20(s,1H),7.06-6.94(m,7H),3.98-3.75(m,2H),2.85-2.73(m,5H),2.28-2.06(m,8H),2.01-1.93(m,1H),0.65-0.35(m,4H).
实施例28
4-((S)-2-(1-(2-氰基-3-((S)-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(二甲基氨基)乙基)苯基乙酸酯
将2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟苯基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍(43)(50mg,0.12mmol)溶于DCM(0.5mL),加入吡啶(20mg,0.24mmol)。然后加入乙酸酐(12mg,0.12mmol),室温搅拌反应1h。补加乙酸酐(8mg,0.08mmol),继续搅拌2h。反应毕,加水(10mL)淬灭,用EA萃取(20mLx3),合并有机相,饱和氯化胺溶液(20mL)洗涤一次,饱和碳酸氢钠钠溶液(20mL)洗涤一次,饱和氯化钠溶液(20mL)洗涤一次,无水硫酸钠干燥,浓缩,制备TLC板分离(MeOH:DCM=1:20),得到50mg淡黄色固体。收率:90%。再次制备得到产物为27mg白色固体,即化合物28。收率:49.0%。
1H NMR(400MHz,DMSO-d6)δ:8.63(s,1H),7.34(d,J=8.2Hz,3H),7.06(s,4H),6.98(d,J=8.0Hz,2H),3.96(s,1H),3.04-2.95(m,1H),2.92-2.79(m,3H),2.75(dd,J=14.3,6.5Hz,1H),2.63(dd,J=16.2,7.5Hz,1H),2.34(s,1H),2.21(s,3H),2.10(s,6H),2.01-1.94(m,1H),1.78-1.73(m,1H),0.71-0.63(m,2H),0.45-0.40(m,2H).
MS(M+H)+:460。
实施例29
4-((S)-2-(1-(2-氰基-3-((S)-1,2,3,4-四氢萘-2-基)胍基)环丙基)-2-(磷酸二甲基氨基)乙基)苯基二氢
将2-氰基-1-(1-((S)-1-(二甲基氨基)-2-(4-羟苯基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍(43)(112mg,0.27mmol)溶于DCM(3mL),加入三乙胺(55mg,0.54mmol)。然后加入氧氯化磷(60mg,0.41mmol),室温搅拌反应1h。加入NaHCO3水溶液(3mL),室温搅拌40min。然后用HCl(1N)调pH值约3-4,室温搅拌2h。然后将低沸点溶剂旋走,剩余母液直接制备HPLC分离。得到产物为20mg白色固体,即化合物29。收率:15.5%。
1H NMR(400MHz,DMSO-d6)δ:7.50(s,1H),7.21(d,J=8.0Hz,2H),7.06-7.02(m,5H),4.00(s,1H),2.98-2.82(m,5H),2.74-2.70(m,1H),2.48(s,6H),2.31-2.28(m,1H),2.01-1.96(m,1H),1.78-1.70(m,1H),0.95-0.55(m,4H).
MS(M+H)+:498。
实施例30
2-氰基-1-(1-((1S)-1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍的制备
步骤1:(1-((1S)-1-氨基-2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)乙基)环丙基)氨基甲酸叔丁酯(30a)的制备
将1-(1-氨基-2-(1-(四氢-2H-吡喃-2-基)-1H-吲唑-5-基)乙基)环丙基)氨基甲酸叔丁酯(2.9g,7.24mmol)(5f)溶于20mL EtOH:MeCN=1:9的混合溶剂中,室温搅拌下,向该溶液中缓慢滴加L-(-)-二对甲氧基苯甲酰酒石酸的EtOH:MeCN=1:9的混合溶液。室温搅拌20分钟,产生大量白色固体,将反应升温至80℃继续搅拌30分钟。30分内将该悬浊液降温至室温,过滤后干燥得白色固体。将该白色固体使用20mL EtOH:MeCN=1:9的混合溶剂按上述操作重结晶两次,得白色固体1.8g。将白色固体置于单口瓶中,加入30mL二氯甲烷,缓慢加入1N的NaOH水溶液调pH=8~9。水相使用DCM进行萃取,合并有机相,使用饱和食盐水洗涤,无水硫酸钠干燥后浓缩,得白色固体800mg,产率28%,ee%=93%,(CHIRALPAK AD-H,(正己烷:乙醇=4:1)+0.1%TEA,1mL/min)。
MS(M+H)+:401。
步骤2:2-氰基-1-(1-((1S)-1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍(30)的制备
30a到30的合成方法同实施例1路线。
1H NMR(400MHz,DMSO-d6)δ12.90(s,1H),8.69(s,1H),7.94(s,1H),7.68(s,1H),7.40(d,J=8.5Hz,1H),7.35(s,1H),7.29(d,J=8.6Hz,1H),7.06(s,4H),3.96(s,1H),3.05-2.90(m,2H),2.90-2.74(m,3H),2.63(dd,J=16.3,7.5Hz,1H),2.39(s,1H),2.12(s,6H),2.03-1.92(m,1H),1.87(s,1H),1.82-1.70(m,1H),0.78-0.56(m,2H),0.47-0.33(m,2H).
MS(M+H)+:442。
实施例31
2-氰基-1-(1-(1-((S)-1-(二甲基氨基)-2-(1H-吲哚-5-基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍
步骤1:5-甲酰基-1H-吲哚-1-羧酸叔丁酯(31a)的合成
将5-吲哚甲醛(4.42g,30.5mmol)溶解于DCM(70mL)中,加入DMAP(370mg,0.3mmol),加入(Boc)2O(7.0g,32mmol)室温搅拌1h,TLC监控(PE:EA=3:1)原料点消失,反应完毕。补加DCM(50mL),0.5N盐酸洗涤(50mL*1),饱和NaHCO3溶液洗涤(50mL*1),无水硫酸钠干燥,浓缩得到粗品8.4g。收率:100%。
MS(M+H)+:246
步骤2:5-(羟甲基)-1H-吲哚-1-甲酸叔丁酯(31b)的合成
将5-甲酰基-1H-吲哚-1-羧酸叔丁酯(8.2g,33.47mmol)加入THF(50mL)中搅拌溶解,然后加入MeOH(20mL),氮气保护下冰水浴降温至0~5℃,,分5批加入NaBH4(400mg,10.52mmol),加完后撤去冰浴,室温环境搅拌1h,TLC监控(PE:EA=3:1)原料点消失,反应完毕。滴加饱和NH4Cl水溶液(50mL),然后加入水(20mL),室温搅拌5~10min,EA萃取(70mL*3)饱和盐水洗涤(50mL*1),无水硫酸钠干燥,柱层析(PE:EA=3:1)纯化,得到无色油状液体7.24g,收率:85.4%。
MS(M+H)+:248
1H NMR(400MHz,CDCl3)δ8.11(d,J=7.7Hz,1H),7.63-7.51(m,2H),7.30(d,J=8.4Hz,1H),6.55(d,J=2.9Hz,1H),4.76(s,2H),1.67(s,9H).
步骤3:5-(溴甲基)-1H-吲哚-1-甲酸叔丁酯(31c)的合成
将5-(羟甲基)-1H-吲哚-1-甲酸叔丁酯(4.3g,17.4mmol)按照实施例1b方法制备,得到5.144g淡黄色粘稠液体,收率:95.6%。
步骤4:5-(2-氰基-2-(((二苯基亚甲基)氨基)乙基)-1H-吲哚-1-甲酸叔丁酯(31d)的合成
5-(溴甲基)-1H-吲哚-1-甲酸叔丁酯按照实施例1c方法制备,收率:99%。
MS(M+H)+:450
1H NMR(400MHz,CDCl3)δ8.00(d,J=8.1Hz,1H),7.65-7.58(m,2H),7.55(d,J=3.4Hz,1H),7.46-7.30(m,6H),7.26(d,J=4.2Hz,1H),7.01(dd,J=8.5,1.4Hz,1H),6.81(d,J=6.9Hz,2H),6.46(d,J=3.6Hz,1H),4.44(dd,J=7.9,6.2Hz,1H),3.31(ddd,J=21.4,13.5,7.1Hz,2H),1.65(s,9H).
步骤5:5-(2-(1-(氨基环丙基)-2-)(((二苯基亚甲基)氨基)乙基)-1H-吲哚-1-甲酸叔丁酯(31e)
5-(2-氰基-2-(((二苯基亚甲基)氨基)乙基)-1H-吲哚-1-甲酸叔丁酯(5.9g,13.14mmol)按照实施例1d方法制备,得到3.6g,收率:57.2%。
MS(M+H)+:480
步骤6:5-(2-(1-(1-((叔丁氧基羰基)氨基)环丙基)-2-((二苯基亚甲基)氨基)乙基)-1H-吲哚-1-甲酸叔丁基酯(31f)的合成
5-(2-(1-(氨基环丙基)-2-)(((二苯基亚甲基)氨基)乙基)-1H-吲哚-1-甲酸叔丁酯(3.6g,7.5mmol)按照实施例1e方法制备,得到2.066g,收率:47.5%。
MS(M+H)+:580
1H NMR(400MHz,CDCl3)δ7.90(d,J=7.4Hz,1H),7.53(d,J=8.5Hz,3H),7.42-7.14(m,6H),7.06(d,J=7.0Hz,2H),6.92(d,J=8.4Hz,1H),6.39(d,J=3.5Hz,1H),6.24(s,1H),3.26(s,1H),3.18(d,J=12.9Hz,1H),3.07-2.95(m,1H),1.65(s,9H),1.41(s,9H),1.05(s,1H),0.70(d,J=10.9Hz,3H).
步骤7:5-(2-氨基-2-(1-(((叔丁氧基羰基)氨基)环丙基)乙基)-1H-吲哚-1-甲酸叔丁酯(31g)的合成
5-(2-(1-(1-((叔丁氧基羰基)氨基)环丙基)-2-((二苯基亚甲基)氨基)乙基)-1H-吲哚-1-甲酸叔丁基酯(2.06g,3.56mmol)按照实施例1f合成方法制备,得到1.55g类白色固体。收率:100%。
MS(M+H)+:416
步骤8:(S)-5-(2-氨基-2-(1-(((叔丁氧基羰基)氨基)环丙基)乙基)-1H-吲哚-1-甲酸叔丁酯(31h)
5-(2-氨基-2-(1-(((叔丁氧基羰基)氨基)环丙基)乙基)-1H-吲哚-1-甲酸叔丁酯(1.5g,3.6mmol)按照实施例30a的方法拆分,得到得到480mg白色固体(S)-5-(2-氨基-2-(1-(((叔丁氧基羰基)氨基)环丙基)乙基)-1H-吲哚-1-甲酸叔丁酯的L-(-)-二对甲氧基苯甲酰酒石酸盐。收率:40.2%,ee.:99%.
手性HPLC分析条件:
仪器:Agilent 1100
色谱柱:CHIRALPAK IC,4.6mm*250mm,5.0μm,
流动相:(正己烷:乙醇=4:1)+0.1%TEA等度洗脱
流速:1mL/min
检测波长:220nm
步骤9:(S)-5-(2-(1-(((叔丁氧基羰基)氨基)环丙基)-2-(二甲基氨基)乙基)-1H-吲哚-1-甲酸叔丁酯(31i)的合成
将(S)-5-(2-氨基-2-(1-(((叔丁氧基羰基)氨基)环丙基)乙基)-1H-吲哚-1-甲酸叔丁酯L-(-)-二对甲氧基苯甲酰酒石酸盐(400mg,0.48mmol)中加入10%K2CO3水溶液(20mL)搅拌,加入EA(10mL)搅拌至固体溶解,分层,水层EA萃取(20mL*2),合并EA层,饱和盐水洗涤(20mL*1),无水硫酸钠干燥,浓缩,得到无色粘稠液体200mg。将该粘稠液体中加入MeCN(2mL),水(1mL),37%甲醛溶液(190mg,2.4mmol)室温搅拌,加入NaBH(OAc)3(306mg,1.44mmol)室温搅拌10min,TLC监控(DCM:MeOH=10:1)反应完毕。滴入饱和NaHCO3溶液(15mL)EA萃取(15mL*3),饱和盐水洗涤(20mL*1),无水硫酸钠干燥,浓缩,得到淡黄色粘稠液体210mg,收率:98.3%。
MS(M+H)+:444
步骤10:(S)-1-(1-(二甲基氨基)-2-(1H-吲哚-5-基)乙基)环丙胺(31j)的合成
将(S)-5-(2-(1-(((叔丁氧基羰基)氨基)环丙基)-2-(二甲基氨基)乙基)-1H-吲哚-1-甲酸叔丁酯(180mg,0.41mmol)溶解于DCM(2mL)中,室温搅拌下加入TFA(1mL),室温搅拌2.5h,LC-MS监控,反应完毕。加入冰水(15mL),DCM萃取(10mL*1),水层20%K2CO3调pH≈12,加入氯化钠至饱和,THF萃取(10mL*5),无水硫酸钠干燥过夜,抽滤,滤液浓缩得到黄色粘稠状物104mg粗品。
MS(M+H)+:244
步骤11:2-氰基-1-(1-(1-((S)-1-(二甲基氨基)-2-(1H-吲哚-5-基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍(31)
(S)-1-(1-(二甲基氨基)-2-(1H-吲哚-5-基)乙基)环丙胺(63j)(100mg,0.41mmol)按照实施例1的制备方法,得到白色固体30mg,即化合物31,收率:16.6%。
MS(M+H)+:441
1H NMR(400MHz,DMSO-d6)δ10.91(s,1H),8.78(s,1H),7.44(s,1H),7.33-7.19(m,3H),7.12-6.95(m,5H),6.30(s,1H),3.96(s,1H),3.03-2.90(m,2H),2.87-2.76(m,3H),2.62(dd,J=16.3,7.4Hz,1H),2.39(s,1H),2.11(s,6H),1.97(s,1H),1.75(dd,J=12.7,7.4Hz,1H),0.72(s,1H),0.61(d,J=4.7Hz,1H),0.42(d,J=8.5Hz,2H).
实施例32
2-氰基-1-(1-(1-(二甲基氨基)-2-(3,5-二氯-4-羟基苯基)乙基)环丙基)-3-(S)-1,2,3,4-四氢萘-2-基)胍
步骤1:4-(叔丁基二甲基硅氧基)-3,5-二氯-苯甲酸甲酯32c的制备
将4-羟基-3,5-二氯-苯甲酸甲酯(5g,22.6mmol)溶于DCM(50mL)中,降温至0℃,加入咪唑(3.85g,56.5mmol)并搅拌5分钟,随后加入叔丁基二甲基氯硅烷(4.69g,31.1mmol)。室温搅拌2小时,TLC检测反应完全,加入水(50mL)淬灭反应,并搅拌5分钟。分离有机相,并使用DCM进行萃取,合并有机相,依次使用水和饱和食盐水洗涤,无水硫酸钠干燥。浓缩后,使用硅胶短柱过滤,EA:PE=1:10混合溶液(250mL)淋洗,滤液浓缩后得到8.3g黄色油状粗产品,粗产品未经进一步纯化,直接用于下步反应。
将4-(叔丁基二甲基硅氧基)-3,5-二氯-苯甲酸甲酯粗产品溶于无水THF(80mL)中,降温至0℃,缓慢滴加四氢铝锂的THF溶液(9.0mL,2.5M,22.6mmol),滴加完全升至室温反应30分钟。TLC检测反应完全,将反应体系降到0℃,缓慢加入十水合硫酸钠固体至不产生气泡,随后加入EA(50mL)和水(100mL),搅拌10分钟。分离有机相,水相用EA萃取两次,合并有机相,分别用水和饱和食盐水洗涤,无水硫酸钠干燥。过滤浓缩后,得7.62g黄色油状粗产品,粗产品未经分离直接用于下一步反应。
将1-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)甲醇粗产品溶于DCM(80mL)中,N2保护后,依次分批加入Ph3P(7.40g,28.2mmol)和NBS(5.02g,28.2mmol),室温搅拌一小时。TLC检测反应完全,旋干溶剂,柱层析分离(100%PE),得到5.95g淡黄色液体,三步收率:71%。
1H NMR(400MHz,CDCl3)δ:7.29(s,2H),4.36(s,3H),1.05(s,9H),0.29(s,6H).
步骤2:2-((二苯亚甲基)氨基)-3-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)丙腈32d的制备
将二苯亚甲基氨基乙腈(3.23g,14.7mmol)溶于THF(40mL)中,N2保护后,置于-78℃条件下搅拌,缓慢滴加LDA(15.4mL,7.7mmol,2.0M in THF),随后缓慢滴加(4-(溴甲基)-2,6-二氯苯氧基)叔丁基二甲基硅烷(5.71g,15.4mmol)的THF(20mL)溶液,自然升温至0℃搅拌1小时。TLC检测反应完全,加入饱和氯化铵溶液(50mL)淬灭反应。分离有机相,水相用EA萃取两次,合并有机相,分别用水和饱和食盐水洗涤,无水硫酸钠干燥。过滤浓缩后,柱层析分离(EA:PE=1:5),得到4.6g白色固体,收率:58.6%。
1H NMR(400MHz,CDCl3)δ:7.58(d,J=7.5Hz,2H),7.55-7.40(m,4H),7.35(t,J=7.4Hz,2H),6.99(s,2H),6.91(s,2H),4.36(t,J=6.8Hz,1H),3.11(d,J=6.8Hz,2H),1.02(s,9H),0.25(d,J=3.0Hz,6H).
MS(M+H)+:509.
步骤3:(1-(1-((二苯基亚甲基)氨基)-2-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)-乙基)环丙基)氨基甲酸叔丁酯32f的制备
将2-((二苯亚甲基)氨基)-3-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)丙腈(4.4g,8.63mmol)溶于干燥的THF(20mL)中,N2保护下,降温至-78℃。向反应液中缓慢加入Ti(OiPr)4(2.70g,9.51mmol),随后缓慢滴加乙基溴化镁(19mL,19mmol,1.0M in THF)。加毕,反应体系回复至室温搅拌1小时。将反应体系降温至0℃,加入BF3Et2O(2.45g,17.2mmol),恢复至室温搅拌1小时。LCMS显示原料反应完全,有产物生成,加入饱和碳酸氢钠溶液淬灭反应(50mL)。分离有机相,水相用EA萃取两次,合并有机相,分别用水和饱和食盐水洗涤,无水硫酸钠干燥。过滤浓缩后,得黄色油状32e的粗产品。将32e的粗产品溶于乙醇(30mL)中,加入二碳酸二叔丁酯(2.2g,10.1mmol),搅拌过夜。TLC检测反应完全。旋干溶剂后,柱层析分离(EA:PE=1:20),得到1.4g淡黄色固体,两步收率:25.3%。
1H NMR(400MHz,CDCl3)δ:7.53(d,J=7.4Hz,2H),7.38-7.25(m,6H),6.85(s,2H),6.47(s,2H),5.17(s,1H),3.19(s,1H),3.05-2.90(m,1H),2.89–2.75(m,1H),1.45(s,9H),1.03(s,10H),0.71(s,3H),0.25(s,3H),0.23(s,3H).
MS(M+H)+:639.
步骤4:(1-(1-(二甲基氨基)-2-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)乙基)环丙基)氨基甲酸叔丁酯32h的制备
将(1-(1-((二苯基亚甲基)氨基)-2-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)-乙基)环丙基)氨基甲酸叔丁酯(1.4g,2.19mmol)溶于甲醇(10mL)中,依次向反应液中加入醋酸钾(279mg,2.85mmol)和盐酸羟胺(160mg,2.30mmol),室温条件下搅拌20分钟。TLC检测反应完全,加入碳酸氢钠溶液(10mL)淬灭反应,使用EA(20mLx3)进行萃取,合并有机相,有机相用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩后得32g的粗产品。将32g的粗产品溶于乙腈(10mL)和水(5mL)的混合溶剂中,降温至0℃,向反应液中依次加入37%甲醛水溶液(888mg,11.0mmol)和NaBH(OAc)3(1.4g,6.57mmol),室温搅拌30分钟。LCMS显示原料消失,有产物生成,向反应液中加入饱和碳酸氢钠溶液(20mL)淬灭反应,使用DCM(10mLx2)进行萃取,合并有机相,使用饱和食盐水洗涤,无水硫酸钠干燥。过滤浓缩后,柱层析分离(DCM:MeOH=10:1),得到882mg淡黄色油状物,两步收率:80%。
1H NMR(400MHz,CDCl3)δ:7.17(s,2H),5.10–4.90(m,2H),2.81(s,2H),2.45(s,6H),1.53–1.42(m,12H),1.04(s,6H),0.91(s,2H),0.77(s,1H),0.47(s,1H),0.27(s,6H).
MS(M+H)+:503.
步骤5:1-(1-(二甲基氨基)-2-(4-羟基-3,5-二氯-苯基)乙基)环丙胺盐酸盐32i的制备
将(1-(1-(二甲基氨基)-2-(4-(叔丁基二甲基硅氧基)-3,5-二氯-苯基)乙基)环丙基)氨基甲酸叔丁酯(480mg,0.953mmol)溶于DCM(3mL)中,向反应液中加入盐酸的二氧六环溶液(4N,3mL),室温下搅拌1小时。LCMS显示原料反应完毕,有产物生成,旋干溶剂得1-(1-(二甲基氨基)-2-(4-羟基-3,5-二氯-苯基)乙基)环丙胺。
MS(M+H)+:403.
步骤6:2-氰基-1-(1-(1-(二甲基氨基)-2-(4-羟基-3,5-二氯-苯基)乙基)环丙基)-3-(S-1,2,3,4-四氢萘-2-基)胍32的制备
将1-(1-(二甲基氨基)-2-(4-羟基-3,5-二氯-苯基)乙基)环丙胺(160mg,0.396mmol)和苯基N'-氰基-N-(S)-(1,2,3,4-四氢萘-2-基)氨基甲酰亚胺酯(127mg,0.436mmol)溶于DMSO(2.5mL)中,向反应液中加入三乙胺(80mg,0.792mmol),并升温至80℃反应2小时。LCMS检测显示有产物生成,加入饱和氯化铵溶液(25mL)淬灭反应(25mL),水相使用DCM萃取(15mLx3),合并有机相,使用饱和食盐水洗涤,无水硫酸钠干燥。过滤浓缩后柱层析分离(EA:PE=1:1),得到84mg白色固体,经HPLC制备、冷冻干燥后得到34mg白色固体,即化合物32。收率:14.3%。
1H NMR(400MHz,DMSO-d6)δ:8.62(d,J=31.5Hz,1H),7.39(d,J=11.9Hz,1H),7.33(d,J=4.5Hz,2H),7.07(s,4H),4.02(d,J=52.7Hz,2H),3.07–2.93(m,2H),2.88–2.57(m,4H),2.23(d,J=37.4Hz,1H),2.11(s,3H),1.87(s,3H),1.77(d,J=6.6Hz,2H),0.79(s,1H),0.72–0.59(m,1H),0.54(s,1H),0.40(s,1H).
MS(M+H)+:486.
实施例33:
2-氰基-1-(1-(1-(二甲基氨基)-2-(4-羟基-3,5-二甲基苯基)乙基)环丙基)-3-(S)-1,2,3,4-四氢萘-2-基)胍
使用(4-(溴甲基)-2,6-二甲基苯氧基)叔丁基二甲基硅烷为起始原料按照前述实施例32路线合成。
1H NMR(400MHz,DMSO-d6)δ:8.79(d,J=25.7Hz,1H),7.26(d,J=10.0Hz,1H),7.09(s,4H),6.82(d,J=7.2Hz,2H),4.04(d,J=52.3Hz,1H),3.03(t,J=12.3Hz,1H),2.84(s,2H),2.78–2.55(m,4H),2.27(d,J=37.0Hz,2H),2.11(s,9H),1.89(s,3H),1.78(d,J=6.8Hz,1H),0.88–0.61(m,2H),0.48(d,J=29.1Hz,2H).
MS(M+H)+:446.
实施例34:
(S)-2-氰基-1-(2,3-二氢-1H-茚满-2-基)-3-(1-(1-(1-二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙基)胍的合成
(S)-1-(1-(二甲基氨基)-2-(1H-吲唑-5-基)乙基)环丙胺(100mg,0.41mmol)与苯基N'-氰基-N-(2,3-二氢-1H-茚满-2-基)氨基甲酸酯(102mg,0.37mmol)按照前述实施例1制备,得到白色固体:40mg。经制备液相纯化,得到白色固体:12mg,收率:7%。
1H NMR(400MHz,DMSO-d6)δ12.92(s,1H),9.16(s,1H),7.95(s,1H),7.67(s,1H),7.43-7.36(m,2H),7.29(s,1H),7.27-7.24(m,2H),7.17-7.13(m,2H),4.45-4.36(m,1H),3.27-3.16(m,2H),2.98-2.90(m,1H),2.86-2.81(m,1H),2.80-2.71(m,2H),2.37(s,1H),1.89(s,6H),0.81-0.74(m,1H),0.69-0.61(m,1H),0.55-0.48(m,1H),0.47-0.38(m,1H).
MS(M+H)+:428.
实施例35:
2-氰基-1-(1-(1-(二甲胺基)-2-(4-羟基-3-(三氟甲基)苯基)-1-(二甲胺基)乙基)环丙基)-3-((S)-1,2,3,4-四氢萘-2-基)胍
使用(4-(溴甲基)-2-(三氟甲基)苯氧基)叔丁基二甲基硅烷为起始原料按照前实施例32路线合成。
1H NMR(400MHz,DMSO-d6)δ8.65(d,J=31.9Hz,2H),7.43-7.31(m,3H),7.07(s,3H),6.88(s,1H),4.03(d,J=51.7Hz,1H),2.99(d,J=13.5Hz,1H),2.82(s,3H),2.75-2.60(m,2H),2.26(d,J=37.9Hz,1H),2.10(s,3H),1.96(s,1H),1.87(s,3H),1.77(d,J=6.3Hz,1H),0.81(s,1H),0.74-0.50(m,2H),0.42(s,1H).
MS(M+H)+:486
生物学评价
测试例1:MOR cAMP激动活性筛选实验
1.1实验目的
本实验是为了测试化合物对MOR的激动作用,根据EC50和Emax的大小评价化合物的体外活性。
1.2实验方法
受化合物激活的MOR可调节细胞内cAMP的水平。利用HTRF(均相时间分辨荧光,Homogeneous Time-Resolved Fluorescence)技术,以Cisbio公司的cAMP检测试剂盒可检测受化合物刺激后hMOR细胞内的cAMP水平。该cAMP检测试剂盒的检测原理基于竞争法,试剂盒中有Eu标记的cAMP抗体和d2标记的cAMP,抗体可以识别cAMP,使Eu和d2接近。Eu受到激发后,其能量可共振转移到d2上,产生信号。当细胞中有cAMP产生时,其与d2标记的cAMP竞争结合抗体结合位点,使后者与Eu的距离增大,不能产生能量转移,从而信号下降。根据实验的信号数据,可以分析受试化合物对hMOR的cAMP激动作用
1.3实验材料
1.4实验步骤
化合物配制
化合物样品先用DMSO溶解至30mM的保存浓度。在384孔LDV板(Labcyte#LP-0200)上配制样品稀释序列,稀释起始首浓度点均为2mM,3.162倍梯度稀释,总计11个浓度点;使用Echo机器将样品稀释序列转移至384孔实验板(Corning,#3824),对应每孔转移50nL;使用Echo机器向384孔实验板的相应位置转移50nL的阳性对照或阴性对照。
化合物对MOR激动作用实验
配制实验所需的实验缓冲液(Assay Buffer:1x HBSS(+/+),含20mM HEPES)以及刺激剂缓冲液(Stimulation Buffer:3μM NKH477,200μM IBMX溶于实验缓冲液)。向384孔实验板(孔内已有50nL化合物)各孔加入5μL刺激剂缓冲液,之后再加入5μL细胞悬浮液(用实验缓冲液悬浮),细胞数为10000个/孔;将实验板置于5%二氧化碳,37摄氏度恒温孵箱内孵育40分钟。在孵育期间可配制cAMP标准浓度曲线实验板,首浓度点2848nM,4倍梯度稀释,总计16个检测浓度,各浓度点设3个重复。待孵育完成后,向测试样品实验板及cAMP标准浓度曲线实验板加入cAMP检测试剂(Cisbio#62AM4PEJ):先加入5μL/孔D2 reagent试剂,再加入5μL/孔Cryptate reagent试剂。之后实验板于室温静置,60分钟后在Envision上读数。
测试例2:MORβ-arrestin激动活性筛选实验
2.1实验目的
本实验是为了测试化合物对MORβ-arrestin的激动作用,根据EC50和Emax的大小评价化合物的体外活性
2.2实验方法
本实验采用的细胞所表达的μ-阿片受体(MOR)和β-arrestin上分别标记有β-半乳糖苷酶的部分氨基酸片段,当MOR受体被化合物激活并募集β-arrestin,两者所带有的β-半乳糖苷酶的氨基酸片段能够组成完整有活性的β-半乳糖苷酶,因此可以通过检测β-半乳糖苷酶水解底物产生的荧光强度来评价化合物对MORβ-arrestin的激动作用。
2.3实验材料
2.4实验步骤
化合物配制
化合物样品用DMSO溶解至30mM的保存浓度;在384孔LDV板(Labcyte#LP-0200)上配制样品稀释序列,稀释起始浓度点均为2mM,3.162倍梯度稀释,总计11个浓度点;使用Echo机器将样品稀释序列转移至384孔实验板(PerkinElmer,#6007680),对应每孔转移100nL;使用Echo机器向384孔实验板的相应位置转移100nL的阳性对照或阴性对照。
化合物对MORβ-arrestin激动作用实验
配制实验所需的检测试剂(Path Hunter Detection Reagent),配制方法参照Path Hunter试剂盒说明,Galacton Star:Emerald II:PathHunter Cell Assay Buffer=1:5:19。用DPBS溶液悬浮细胞,并向384孔实验板(孔内已有100nL化合物)各孔加入20μLMOR beta-arrestin细胞悬浮液,细胞数为7500个/孔,室温避光孵育2小时。之后向384孔实验板加入6μL/孔的检测试剂,室温避光孵育1小时。孵育结束后,在Envision上读数。
测试例1和测试例2结果:以上两个测试读取的数据用软件处理并计算EC50、Emax%值;Emax%为化合物激活cAMP和β-arrestin信号通路的最大效应(以DAMGO为100%);“偏向系数(Bias Factor)”的计算按照参考文献Cell.2017171(5):1165-1175提供的公式进行计算。
表1
结论:本发明提供的化合物保留了优异的G蛋白通路激动活性,同时β-Arrestin 2信号通路激动活性低,“偏向系数(Bias Factor)”与经典MOR偏向性配体PZM21和TRV130相比大幅提高1-3个数量级。
测试例3:本发明化合物小鼠体内药代动力学实验
实验方法:健康雄性C57小鼠,随机分组,每组3只,静脉注射给予被试化合物,给药剂量为10mg/kg。各受试化合物溶解于生理盐水中配成一定浓度溶液给药。给药前1天禁食不禁水12-14h,给药后4h给食。每只动物每次通过眼眶取0.030mL血液,EDTAK2抗凝,采集时间点为给予受试物后5min,15min,30min,1h,2h,4h,6h,8h,24h。血液样本采集后置于冰上,并于30分钟之内离心分离血浆(离心条件:5000转/分钟,10分钟,4℃)。分析前存放于–80℃。
测试例3结果:见下表2。
表2
结论:本发明提供的化合物代谢特征优异。与对照PZM21相比,血浆暴露量(AUC)大幅提高,清除率(CL)数值降低了3-10倍,半衰期(T1/2)延长。
测试例4:本发明化合物hERG钾通道抑制实验
4.1、实验目的
应用全自动膜片钳在转染hERG钾通道的稳定细胞株上测试本发明化合物对hERG钾电流的阻断作用。
4.2、实验方法
4.2.1、细胞准备
CHO-hERG细胞培养于175cm2培养瓶中,待细胞密度生长到60-80%,移走培养液,用7ml PBS(Phosphate Buffered Saline磷酸盐缓冲液)洗一遍,然后加入3ml Detachin消化。
待消化完全后加入7ml培养液中和,然后离心,移除上清液,再加入5ml培养液重悬,以确保细胞密度为2-5×106/ml。
4.2.2、溶液配制
4.2.3电生理记录过程
单细胞高阻抗封接和全细胞模式形成过程全部有Qpatch仪器自动完成,在获得记录模式后,细胞钳制在-80毫伏,在给予一个5秒的+40毫伏去极化刺激前,先给予一个50毫秒的-50毫伏前置电压,然后复极化到-50毫伏维持5秒,再回到-80毫伏。每15秒施加此电压刺激,记录2min后给予细胞外液记录5min,然后开始给药过程,化合物浓度从最低测试浓度开始,每个测试浓度给予2.5min,连续给完所有浓度后,给予阳性对照化合物3μMCisapride。每个浓度至少测试3个细胞(n≥3)。
4.2.4、化合物准备
将20mM的化合物母液用细胞外液进行稀释,取5μL 20mM的化合物母液加入2495μL细胞外液,500倍稀释至40μM,然后在含0.2%DMSO的细胞外液中依次进行3倍连续稀释得到需要测试的最终浓度。
最高测试浓度为40μM,依次分别为40,13.33,4.44,1.48,0.49,0.16μM共6个浓度。
最终测试浓度中的DMSO含量不超过0.2%,此浓度的DMSO对hERG钾通道没有影响。
4.3、数据分析
实验数据由XLFit软件进行分析。
4.4、实验结果
化合物 | 17 | 22 | PZM21 | Cispride |
IC<sub>50</sub>(μM) | 9.4 | 21.4 | 2-4 | 0.043 |
结论:本发明提供的化合物hERG钾通道抑制活性显著低于PZM21报道的文献值[IC50为2至4μM,Nature.2016 537(7619):185-190],具有更低的心脏毒性风险。
测试例5:本发明化合物体内镇痛实验(Hot Plate热板实验)
5.1化合物及动物
吗啡用0.9%生理盐水稀释,其它测试化合物使用5%DMSO和5%Solutol HS-15配制,再用0.9%生理盐水稀释。实验动物选用18–25g的成年雄性Swiss小鼠,采用皮下给药方式。
5.2实验方法
实验方法参考文献Journal of Ethnopharmacology 196:151-159,采用YLS-6B智能热板镇痛仪(山东省医学科学院装置站,山东,中国)测量热板对热刺激反应的疼痛反射。热板表面加热至恒温50±0.1℃,由内置数字温度计测量,精度为0.1℃。在实验过程中,将小鼠放在热板上,热板周围有一个透明的丙烯酸笼子,启动计时器上的开始/停止按钮。研究人员测量后爪舔或跳(先出现的动作)的延迟期(Paw Lick Latency)。
5.3实验结果
如图1所示,与空白对照组(Vehicle)相比,同等剂量下,实施例化合物30(代号为JH-77-14-SS)、实施例化合物19(代号为JH-75-45-AB)在注射0.5h后显著延长了小鼠后爪舔跳的延迟期(Paw Lick Latency),最大延长幅度分别达到99.0%、60.8%,均显著高于阳性对照PZM21(代号为JH-28-234)的42.9%。另外,实施例化合物30(代号为JH-77-14-SS)还表现出比吗啡更长的镇痛时间。
结论:在小鼠热板实验(Hot Plate)中,本发明提供的化合物镇痛效果优于PZM21。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
1.一种式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐,
其中,Ring A选自下组:取代或未取代的C6-C10芳基、取代或未取代的含1、2或3个选自N、O或S的杂原子的4-10元杂芳基;所述取代指被选自下组的一个或多个取代基取代:氢、羟基、卤素、-B(OH)2、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基、-OC(O)R5和
G选自下组:CR7R8和NR2;
R2选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基和氰基;
R3和R4各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
R5选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和卤素;
R7和R8相同或不同,且各自独立地选自下组:H、NO2、C1-C6烷基、卤代C1-C6烷基;
n为0、1、2或3;
q为0、1、2、3或4;
Z选自下组:NR11、O、S和CR9R10;
R9、R10、R11各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和氰基;
t为0、1、2或3。
G选自下组:CHNO2和NR2;
R2选自下组:氢、C1-C6烷基、C1-C6烷氧基和氰基;
R3和R4各自独立地选自下组:氢和C1-C6烷基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
R5为氢或C1-C6烷基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基和卤素;
m为0、1、2、3、4或5;
n为0或1;
q为0、1、2、3或4;
Z选自下组:O和CH2;
t为0、1或2。
3.如权利要求1所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐,其特征在于,
Ring A为取代的C6-C10芳基,所述取代指被选自下组的m个取代基取代:氢、羟基、卤素、-B(OH)2、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基、-OC(O)R5和m为0、1、2、3、4或5;
G选自下组:CR7R8和NR2;
R2选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基和氰基;
R3和R4各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
R5选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和卤素;
R7和R8相同或不同,且各自独立地选自下组:H、NO2、C1-C6烷基、卤代C1-C6烷基;
n为0、1、2或3;
q为0、1、2、3或4;
Z选自下组:NR11、O、S和CR9R10;
R9、R10、R11各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和氰基;
t为0、1、2或3。
4.如权利要求1所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐,其特征在于,
Ring A为取代或未取代的含1、2或3个选自N、O或S的杂原子的4-10元杂芳基;所述取代指被选自下组的一个或多个取代基取代:氢、羟基、卤素、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基;
G选自下组:CR7R8和NR2;
R2选自下组:H、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基和氰基;
R3和R4各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基,或R3和R4与它们连接的碳原子关环形成3-6元环烷基;
各R6相同或不同,且各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和卤素;
R7和R8相同或不同,且各自独立地选自下组:H、NO2、C1-C6烷基、卤代C1-C6烷基;
n为0、1、2或3;
q为0、1、2、3或4;
Z选自下组:NR11、O、S和CR9R10;
R9、R10、R11各自独立地选自下组:氢、C1-C6烷基、C1-C6烷氧基、C3-C6环烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、卤代C3-C6环烷氧基和氰基;
t为0、1、2或3。
7.一种药物组合物,其特征在于,包含药学上可接受的载体和治疗有效量的一种或多种权利要求1所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐。
8.一种权利要求1所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐的制备方法,其特征在于,所述方法选自下组:
方法1:包括步骤:
其中,Ring A、G、R3、R4、R6、Z、t、q、n如权利要求1所述;
M选自下组:-S-(C1-C6烷基)、-O-(C6-C10芳基);
方法二:包括步骤:
(ii-1)将式A所示化合物或其盐与式C所示化合物或其盐反应,得到式I-2所示化合物;
其中,Ring A、R2、R3、R4、R6、Z、t、q、n如权利要求1所述;
M选自下组:-S-(C1-C6烷基)、-O-(C6-C10芳基);
方法三:包括步骤:
(iii-1)将式D所示化合物或其盐与式E所示化合物或其盐反应,得到式I-3所示化合物;
其中,Ring A、R3、R4、R6、Z、t、q、n如权利要求1所述;
M为-S-(C1-C6烷基);
Q选自下组:C1-C6烷基、C1-C6烷氧基。
9.一种权利要求1所述的式(I)所示的化合物或其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体、或其混合物形式、或其药学上可接受的盐的用途,其特征在于,用于制备药物,所述药物用于预防和/或治疗疼痛或疼痛相关疾病。
10.如权利要求9所述的用途,其特征在于,所述疼痛或疼痛相关疾病为与MOR受体相关疼痛疾病。
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