CN110234631A - 用于治疗高血压和/或纤维化的组合物 - Google Patents
用于治疗高血压和/或纤维化的组合物 Download PDFInfo
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- CN110234631A CN110234631A CN201780070398.8A CN201780070398A CN110234631A CN 110234631 A CN110234631 A CN 110234631A CN 201780070398 A CN201780070398 A CN 201780070398A CN 110234631 A CN110234631 A CN 110234631A
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- pharmaceutically acceptable
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Classifications
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61K31/4164—1,3-Diazoles
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Abstract
本发明涉及新型化合物及其在预防性和/或治疗性治疗高血压和/或纤维化中的用途。
Description
发明领域
本申请要求澳大利亚临时专利申请No.2016903804(2016年9月21日提交)的优先权,其内容以其整体并入本文。
本发明涉及新型化合物及其在预防性和/或治疗性治疗心血管疾病,并且尤其是治疗高血压前期、高血压和/或纤维化病症中的用途。
已经开发本发明主要用于预防性和/或治疗性治疗心血管疾病并且在下文将参考这种应用进行描述。然而,将理解本发明不局限于这种特定的使用领域。
发明背景
在本说明书通篇中的任何现有技术的讨论决不应被认为是承认这样的现有技术是广泛已知的或形成本领域公知常识的一部分。
高血压影响全世界成年人口的26%,其中在西方国家中的发病率为30-33%。由于印度和中国的西化,高血压的世界范围发病率预期到2025年达到29%。当前的研究表明少于20%的患有高血压的患者达到他们的推荐血压(BP)目标并且为了实现这些目标,>75%的患者需要利用多种抗高血压药治疗。高血压前期(轻微升高的血压)影响美国31%的成人并且如果没有被治疗,则可能会发展成高血压。
高血压和高血压前期是发展各种器官中的血管损伤中的主要因素,导致正常功能组织被伤疤组织或纤维化替代。当前的抗高血压药中的一些能够减缓功能组织被纤维化替代的进展,但都还没有显示反转已有的纤维化和恢复正常组织结构。因此对于对显著降低BP具有效力并由此利用单一药剂疗法使得更大比例的患者能够达到BP目标和/或反转已有的纤维化和/或恢复正常组织结构的药剂存在需要。
本发明的一个目的是克服或改善现有技术的缺点中的至少一个或提供有用的替代方案。
发明概述
令人惊讶地,本发明的发明人已发现,某些化合物具有血压降低和/或抗纤维化作用。这些作用可以在静脉内和/或口服剂量研究中看到。
根据一个方面,本发明提供下式的化合物:
其中:
X选自:
R1至R9独立地是C、N、O或S;
R10独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基;
Y是A、CH2-A或CH=A;
A选自任选取代的饱和、部分饱和或不饱和的5-或6-元杂环基;任选取代的C1-6烷氧基胺;任选取代的C1-6烷基胺;任选取代的C0-6烷基羧酸;任选取代的C1-6烷基羟基;任选取代的饱和或不饱和的C0-6烷基二环杂环基;和任选取代的饱和或不饱和的C1-6烷氧基二环杂环基;
Z选自:
R11独立地选自卤素、烷基、羟基、氨基和取代的氨基;
R12、R14和R15独立地是C、CH、CH2、O、N、NH或S;
R13是C、CH、CH2、N、NH、C-CF3、CH-CF3或C=O;
m是0、1、2、3、4或5;和
n是0、1、2、3或4,
或其立体异构体或药学上可接受的盐。
在一个实施方案中,R10独立地选自-CH3、-C(O)OH、-F、-NH2、-OH和-OCH3。
在一个实施方案中,R5至R9独立地是C或N。
在一个实施方案中,C0-6烷基羧酸是羧酸。
在一个实施方案中,饱和、部分饱和或不饱和的5-或6-元杂环基含有一个或多个N、S或O,任选被一个或多个氧代、C1–6烷基、氨基、羟基或卤素取代基取代。
在一个实施方案中,饱和、部分饱和或不饱和的5-或6-元杂环基选自吡咯基、吡唑基、咪唑基、***基、咪唑烷基、吡咯烷基、吡咯烷叉基、二氢吡咯基、异噁唑基、二氢噁唑基、异噁唑烷基、噁唑烷基和噁唑基,任选被一个或多个氧代、C1-6烷基、氨基、羟基或卤素取代基取代。
在一个实施方案中,C1-6烷氧基胺是氨基氧基甲基。
在一个实施方案中,C1-6烷基胺任选被一个或多个C1-6烷基、C1–6卤代烷基、羟基或卤素,优选单-、二-或三-取代的卤代烷基,最优选三氟甲烷取代。
在一个实施方案中,C1-6烷基羟基是甲基羟基或丙烷-2-醇。
在一个实施方案中,C0-6烷基二环杂环基选自吲哚基、异吲哚基、吲哚啉基(insolinyl)和异吲哚啉基,任选被一个或多个氧代,优选二氧代取代。
在一个实施方案中,C1-6烷氧基二环杂环基选自吲哚基、异吲哚基、吲哚啉基和异吲哚啉基,任选被一个或多个氧代取代,并且其中C1-6烷氧基是甲氧基或乙氧基。
在一个实施方案中,A选自:
。
在一个实施方案中,R11是选自F、Cl、Br和I的卤素。
在一个实施方案中,R11是式-NHR16的取代的氨基并且其中:
R16选自-CN、-SO2(R17)aR18和-CO(R17)aR18,
a是0或1,
R17选自-NH-和-O-,和
R18选自-H、-CH3、-CH2CH3、-CH2OH和-CH2CH2OH。
在一个实施方案中,R11是选自以下的取代的氨基:-NHSO2CH3、-NHCOH、-NHCONHCH3、-NHCONHCH2CH3、-NHSO2NHCH3、-NHSO2NHCH2CH3、-NHCOCH3、-NHCOOCH3、-NHCOOCH2CH2OH、-NHCONH2和-NHCN。
在一个实施方案中,R11是选自甲基、乙基、丙基、丁基和戊基的烷基。
在一个实施方案中,化合物选自:
。
在一个实施方案中,化合物选自:
。
根据另一个方面,本发明涉及一种药物组合物,其包含本发明的化合物和药学上可接受的赋形剂。
根据另一个方面,本发明涉及一种用于治疗性治疗受试者的高血压或高血压前期的方法,包括向所述受试者施用根据本发明的化合物。
根据另一个方面,本发明涉及一种用于治疗性治疗受试者的纤维化的方法,包括向所述受试者施用根据本发明的化合物。
根据另一个方面,本发明涉及一种用于预防性治疗受试者的纤维化的方法,包括向所述受试者施用根据本发明的化合物。
根据另一个方面,本发明涉及一种用于治疗性治疗受试者的高血压和纤维化的方法,包括向所述受试者施用根据本发明的化合物。
根据另一个方面,本发明涉及一种用于治疗性治疗受试者的高血压前期和纤维化的方法,包括向所述受试者施用根据本发明的化合物。
根据另一个方面,本发明涉及一种本发明的化合物,其用于治疗性治疗高血压或高血压前期。
根据另一个方面,本发明涉及一种本发明的化合物,其用于治疗性治疗纤维化。
根据另一个方面,本发明涉及一种本发明的化合物,其用于预防性治疗纤维化。
根据另一个方面,本发明涉及一种本发明的化合物,其用于治疗性治疗高血压和纤维化。
根据另一个方面,本发明涉及一种本发明的化合物,其用于治疗性治疗高血压前期和纤维化。
根据另一个方面,本发明涉及本发明的化合物用于制备药物的用途,所述药物用于治疗性治疗高血压或高血压前期。
根据另一个方面,本发明涉及本发明的化合物用于制备药物的用途,所述药物用于治疗性治疗纤维化。
根据另一个方面,本发明涉及本发明的化合物用于制备药物的用途,所述药物用于预防性治疗纤维化。
根据另一个方面,本发明涉及本发明的化合物用于制备药物的用途,所述药物用于治疗性治疗高血压和纤维化。
根据另一个方面,本发明涉及本发明的化合物用于制备药物的用途,所述药物用于治疗性治疗高血压前期和纤维化。
在一个实施方案中,纤维化是心肌纤维化。
在一个实施方案中,纤维化是肾纤维化。
在一个实施方案中,纤维化是肝纤维化。
在一个实施方案中,纤维化是肺纤维化。
除非上下文明确地另有要求,在本说明书和权利要求书通篇中,术语“包含”、“包括”等以与排他性或穷举性意义相反的包含性意义进行解释,也就是说,以“包括,但不限于”的意义进行解释。
附图简述
图1: 2-[4-苄基-1-(3-羟基苄基)-1H-咪唑-5-基]乙酰胺(VB0002)的合成。
图2: 3-(叔丁基二甲基甲硅烷基氧基)苄基异硫氰酸酯(化合物B)的合成。
图3: 3-[5-(2-羟基丙基)-4-苯基-咪唑-1-基甲基]-苯酚(VB0003)的合成。
图4: α-甲苯磺酰基苄基异腈(化合物C)的合成。
图5 3-(苄基氧基)苄基胺(化合物D)的合成。
图6: 3,3-乙二氧基-1-丁醛(化合物E)的合成。
图7: (S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酰胺(VB0005)的合成。
图8: 通过渗透微型真空泵静脉内施用含有20 pmol/kg/min的剂量的VB0002 (在20% DMSO中)或媒介物对照(20% DMSO)的2.2%盐饮食4周的SHR中的收缩压。* p<0.005 vs18周对照。
图9: 在饮用溶液中施用含有20 pmol/kg/min的剂量的VB0003 (在5%乙醇中) 、20 pmol/kg/min的剂量的VB0005 (在5%乙醇中)或媒介物对照(5%乙醇)的2.2%盐饮食4周的SHR中的收缩压。* p<0.0005 vs 18周对照。
图10: 通过渗透微型真空泵静脉内施用含有20 pmol/kg/min的剂量的VB0002(在20% DMSO中)或媒介物对照(20% DMSO)的2.2%盐饮食4周的SHR中的心肌纤维化。* p<0.005 vs 18周对照,** p<0.0005 vs 18周对照。
图11:在饮用溶液中施用含有10、100和500 pmol/kg/min的剂量的VB0003 (在5%乙醇中)或媒介物对照(5%乙醇)的 2.2%盐饮食4周的SHR中的心肌纤维化。* p<0.005 vs18周对照,** p<0.0005 vs 18周对照,# p<0.01 vs 14周对照。
图12: 在饮用溶液中施用含有100 pmol/kg/min的剂量的VB0005 (在5%乙醇中)或媒介物对照(5%乙醇)的2.2%盐饮食4周的SHR中的心肌纤维化。* p<0.001 vs 18周对照,** p<0.0005 vs 18周对照,# p<0.01 vs 14周对照。
发明详述
本发明涉及某些化合物,其在实验动物模型中在口服剂量研究中显示血压降低和抗纤维化作用。关于抗纤维化活性,本发明的化合物在防止纤维化、减慢已形成纤维化的进展和/或降低已形成纤维化的程度(反转)方面是有效的。对于可以利用本发明的化合物进行治疗的病症的范围和严重度来说,这些是重要的发现。
本发明的化合物由下式表示:
其中:
X选自:
R1至R9独立地是C、N、O或S;
R10独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基;
Y是A、CH2-A或CH=A;
A选自任选取代的饱和、部分饱和或不饱和的5-或6-元杂环基;任选取代的C1-6烷氧基胺;任选取代的C1-6烷基胺;任选取代的C0-6烷基羧酸;任选取代的C1-6烷基羟基;任选取代的饱和或不饱和的C0-6烷基二环杂环基;和任选取代的饱和或不饱和的C1-6烷氧基二环杂环基;
Z选自:
R11独立地选自卤素、烷基、羟基、氨基和取代的氨基;
R12、R14和R15独立地是C、CH、CH2、O、N、NH或S;
R13是C、CH、CH2、N、NH、C-CF3、CH-CF3或C=O;
m是0、1、2、3、4或5;和
n是0、1、2、3或4,
或其立体异构体或药学上可接受的盐。
以下化合物是本发明的化合物的具体但非限制性实例:
。
如本文使用的,术语"卤素"是指-F、-Cl、-Br或-I;术语"羟基"是指-OH;术语"氨基"是指-NH2;并且术语"取代氨基"包括-NHW,其中W选自-CN、-SO2(X)aY和-CO(X)aY,a是0或1,X选自-NH-和-O-,并且Y选自-H、-CH3、-CH2CH3、-CH2OH和-CH2CH2OH。
如本文使用的,缩写Me、Et、Ph、Ms分别表示甲基、乙基、苯基和甲磺酰基。本领域普通技术人员的有机化学家所使用的缩写的更全面列表出现在Journal of OrganicChemistry每一卷的第一期中;此列表典型地在标题为Standard List of Abbreviations的表格中呈现。所述列表中包含的缩写、以及由本领域普通技术人员的有机化学家利用的全部缩写通过引用并入本文。
本发明的化合物可以以特定几何或立体异构形式存在。本发明考虑了所有这样的化合物,包括顺式-和反式-异构体、(R)-和(S)-对映异构体、非对映异构体、(d)-异构体、(l)-异构体、其外消旋混合物、以及它们的其他混合物,如落入本发明的范围内。所有这样的异构体、以及它们的混合物意图包括在本发明中。
例如,如果本发明的化合物的特定对映异构体是所需的,则它可以通过非对称合成或通过利用手性助剂衍生化制备,其中将所得的非对映异构体混合物分离并且辅助基团裂开以提供纯的所需对映异构体。或者,非对映异构体盐可以利用适当光学活性酸或碱形成,然后拆分由此通过本领域公知的分级结晶或层析手段形成的非对映异构体,以及随后回收该纯的对映异构体。
通常,本发明的化合物可以通过例如在下文描述的通用反应方案中例举的方法或通过其变形,使用易于获得的起始材料、试剂和常规合成程序制备。在这些反应中,还可以利用本身是已知的但在这里没有提及的变形。
本发明还考虑了化合物的药学上可接受的盐。术语“药学上可接受的盐”包括酸和碱加成盐二者并且是指这样的盐,其保持游离碱或酸的生物学有效性和性质,并且其在生物学或其他方面不是非所需的。药学上可接受的盐利用无机或有机酸或碱形成,并且可在化合物的最终分离和纯化期间原位制备,或通过单独地使以其游离碱或酸形式的纯化的化合物与合适的有机或无机酸或碱反应,并且分离由此形成的盐而制备。
如在本发明的上下文中使用的,术语“纤维化”包括但不限于心肌纤维化、肾纤维化、肝纤维化和/或肺纤维化。
除了治疗已形成的纤维化之外,本发明的化合物可以在处于发展纤维化的风险的受试者中预防性地使用。作为处于发展纤维化的风险类别的受试者的实例是具有高血压、糖尿病、心肌炎、缺血性心脏病、Conn氏综合症、嗜铬细胞瘤、遗传性高盐饮食体质(geneticpredisposition high salt diet)和/或接受癌症化疗中使用的药物(如道诺霉素)的那些。如在本发明的上下文中使用的,术语“预防性”尤其意图涵盖用来防止或减缓在风险组中的纤维化的发展的治疗。可以给予预防性治疗的受试者可能在超声心动图上已具有早期心力衰竭的征兆。
如在本发明的上下文中使用的,术语“高血压” 表明高于约139mmHg收缩和/或高于约89mmHg舒张的成人血压。
如在本发明的上下文中使用的,术语“高血压前期”表明在约120-139mmHg收缩和/或约80-89mmHg舒张范围内的成人血压。
本发明还考虑了药物组合物,其包含本发明的化合物,连同可接受的药物赋形剂。如在本发明的上下文中使用的,术语“药学上可接受的赋形剂”是指组合物的任何药学上可接受的非活性组分。如本领域熟知的,赋形剂包括稀释剂、缓冲剂、粘合剂、润滑剂、崩解剂、着色剂、抗氧化剂/防腐剂、pH-调节剂等。赋形剂基于所需的最终形式的物理方面进行选择:例如,获得具有所需硬度和易碎性且快速可分散和易于吞咽等的片剂。在吞入后活性物质从组合物的所需释放速率在赋形剂选择方面中也起作用。药物组合物可以包括任何类型的剂型,如片剂、胶囊、粉剂、液体制剂、延迟或持续释放、贴剂、鼻烟、鼻喷雾剂等。考虑的药物组合物的物理形式和含量是可以由药物制剂领域的技术人员配制的常规制剂并且基于例如在Remington: The Science and Practiceof Pharmacy,第19版,1995;BritishPharmacopoeia 2000和类似制剂教材和手册中描述的良好建立的原则和组合物。
例如,在化合物或组合物要经口施用的情况下,它们可以配制为片剂、胶囊、颗粒剂、粉剂或糖浆;或者用于肠胃外施用的情况下,它们可以配制为注射剂(静脉内、肌肉内或皮下)、滴注制剂或栓剂。对于通过眼粘膜途径的应用,它们可以配制为滴眼液或眼膏。这些制剂可以通过常规手段制备,并且如果需要,活性成分可以与任何常规添加剂(如赋形剂、粘合剂、崩解剂、润滑剂、矫味剂、增溶剂、悬浮助剂、乳化剂或包衣剂)混合。
当本发明的化合物作为药物施用至人和动物时,它们可以以本身给予或者作为含有例如0.1至99.5%(更优选地,0.5至90%)的活性成分联合药学上可接受的载体的药物组合物给予。
应该使用的化合物的剂量和施用频率也可以容易地通过执业医师确定以产生所需响应。
尽管剂量将取决于患者的症状、年龄和体重、待治疗或预防的病症的性质和严重度、施用途径和药物形式变化,通常,0.0001mg至200mg的本发明的化合物的每日剂量对于成年人患者可以是合适的有效量,并且这可以以单次给药或分开给药施用。
要通过主题方法治疗的“患者”或“受试者”可以是指人或非人受试者。
关于治疗的方法,主题化合物的“有效量”是指当作为所需剂量方案的一部分应用时其根据用于治疗或预防的特定病症的临床可接受标准为提供益处的制剂中的治疗剂的量。
本发明现在将参考描述具体组合物和使用方法的具体但非限制性实施例更详细地进行描述。然而,应当理解具体程序、组合物和方法的详细描述仅用于例举本发明的目的而被包括。不应以任何方式理解为对以上提出的发明构思的宽泛描述的限制。
实施例
实施例 1 –化合物的合成
用于制备2-[4-苄基-1-(3-羟基苄基)-1H-咪唑-5-基]乙酰胺(VB0002)的合成路线示于图1中。由1,1′-羰基二咪唑(CDI)促进的Boc-苯基丙氨酸和丙二酸甲酯钾盐之间的缩合反应得到中间体4。然后,除去Boc基团得到化合物5,为盐酸盐。盐5与异硫氰酸酯B反应,以低收率得到环状硫脲6。在氧化条件下实现环状硫脲6向咪唑7的转化。用氨水处理咪唑7得到VB0002。
化合物B不可商购获得,并如图2中所示制备。3-氰基苯酚最初被保护为叔丁基二甲基甲硅烷基醚,随后氰基还原成相应的胺,其与硫光气反应形成化合物B。
用于制备3-[5-(2-羟基丙基)-4-苯基-咪唑-1-基甲基]-苯酚 (VB0003)的合成路线示于图3中。首先,通过α-甲苯磺酰基苄基异腈C、苄胺D和受保护的醛E的三组分偶联反应,方便地组装咪唑8。随后使用苯甲硫醚-三氟乙酸(TFA)***除去两种保护基团,得到化合物9,将其还原,得到VB0003。
如图4中所示制备化合物C。由相应的钠盐制备的4-甲苯亚磺酸参与与苯甲醛和甲酰胺的三组分反应,形成中间体,其在脱水后得到化合物C。
化合物D不可商购获得,并如图5所示制备。这是通过使用叠氮磷酸二苯酯将3-(苄基氧基)苄醇转化为相应的叠氮化物,然后还原得到苄胺D来实现的。
化合物E不可商购获得,并如图6所示制备。乙酰乙酸乙酯最初被保护为缩醛;然后将酯基还原成伯醇,随后对其进行Swern氧化以形成保护的醛E。
用于制备(S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酰胺(VB0005)的合成路线示于图7中。在标准的酰胺键形成方法中,使Fmoc-L-谷氨酸5-叔丁酯与苯胺反应,形成相应的酰胺,将其用三(2-氨基乙基)胺(TAEA)脱保护,得到化合物14。游离胺14经历与3-(苄氧基)苯基硼酸的铜介导的交联反应,得到N-芳基化产物15。随后将该化合物与溴乙酰基溴反应形成化合物16,将其转化为酮基-哌嗪17;选择性还原该化合物,得到哌嗪18。使用苯甲硫醚-TFA体系的随后的双脱保护步骤得到化合物19,使用氨水和1,1'-羰基二咪唑(CDI)对其进行氨解反应,得到VB0005。
叔丁氧基羰基氨基)-3-氧代-5-苯基戊酸甲酯(4)。将氯化镁(6.96 g, 73.0mmol)和丙二酸甲酯钾盐(17.66 g, 113.2 mmol)的悬浮液在THF (280 mL)中在50 ℃在氮气氛下搅拌6 h。在氮气下和在0 ℃向在单独的烧瓶中的N-(叔丁氧基羰基)-L-苯基丙氨酸(20.0 g, 75.4mmol)于THF (200 mL)中的溶液中分批加入1,1′-羰基二咪唑(18.34 g,113.1 mmol)并将反应在环境温度下搅拌2 h,然后加入冷却的丙二酸酯悬浮液中。然后将反应混合物在室温下搅拌17 h。在真空中除去大部分THF。向残余物中加入饱和硫酸氢钾(300 mL)和乙酸乙酯(300 mL)。分离各层,然后将水层用乙酸乙酯再萃取两次。将合并的有机层用饱和碳酸氢钠(2x300 mL)和盐水(300 mL)洗涤,干燥并真空浓缩,得到4-(叔丁氧基羰基氨基)-3-氧代-5-苯基戊酸甲酯(22.22 g, 92%),为浅色粘稠油状物,其固化。
C17H23NO5的HRMS计算值 321.1576, 实测值321.1555。
氨基-3-氧代-5-苯基戊酸甲酯盐酸盐(5)。将4-(叔丁氧基羰基氨基)-3-氧代-5-苯基戊酸甲酯(22.20 g, 69.2 mmol)与用氯化氢饱和的乙酸乙酯搅拌2天。过滤收集所得固体,用***洗涤并在空气中干燥,得到4-氨基-3-氧代-5-苯基戊酸甲酯盐酸盐(16.25 g,92%),为不稳定的奶油色固体。
苄基-3-[3-(叔丁基二甲基甲硅烷基氧基)苄基]-2-硫代-2,3-二氢-1H-咪唑-4-基}乙酸甲酯(6)。将4-氨基-3-氧代-5-苯基戊酸甲酯盐酸盐(7.15 g, 27.9 mmol)、3-(叔丁基二甲基甲硅烷基氧基)苄基异硫氰酸酯(9.34 g, 33.5 mmol)、三乙基胺(5.8 mL,41.9 mmol)和4-甲苯磺酸吡啶鎓(0.70 g, 2.8 mmol)于甲苯(100 mL)中的混合物在温和回流下在氮气下加热5 h。将反应混合物冷却至室温,然后在水(150 mL)和乙酸乙酯(150mL)之间分配。分离各层并将水层用乙酸乙酯再萃取两次。将合并的有机层用水(2x150 mL)洗涤,干燥并真空浓缩,得到黄褐色油状物。将粗物质溶解于***,播晶种并使其结晶20 h。过滤收集2-{5-苄基-3-[3-(叔丁基二甲基甲硅烷基氧基)苄基)]-2-硫代-2,3-二氢-1H-咪唑-4-基}乙酸甲酯(2.14 g, 13%),为奶油色针状物; mp 154.0-156.0 ℃。
C26H34N2O3SSi的HRMS计算值482.2054, 实测值482.2039。
苄基-1-[3-(叔丁基二甲基甲硅烷基氧基)苄基]-1H-咪唑-5-基}乙酸甲酯(7)。在氮气下向2-{5-苄基-3-[3-(叔丁基二甲基甲硅烷基氧基)苄基]-2-硫代-2,3-二氢-1H-咪唑-4-基}乙酸甲酯(1.00 g, 2.1 mmol)于乙酸(3.4 mL)中的悬浮液中缓慢加入30%过氧化氢(941 µL)。10分钟后,将反应溶液在冰浴中冷却,然后用10% 碳酸钠(20 mL)淬灭。用1M氢氧化钠将pH调节至9-10,然后用乙酸乙酯(3x20 mL)萃取,干燥并真空浓缩,得到2-{4-苄基-1-[3-(叔丁基二甲基甲硅烷基氧基)苄基]-1H-咪唑-5-基}乙酸甲酯(0.86 g, 91%),为黄褐色油状物。
C26H34N2O3Si的HRMS计算值 450.2333, 实测值450.2323。
苄基-1-(3-羟基苄基)-1H-咪唑-5-基]乙酰胺(VB0002)。向2-{4-苄基-1-[3-(叔丁基二甲基甲硅烷基氧基)苄基]-1H-咪唑-5-基}乙酸甲酯(0.86 g, 1.9 mmol) 于甲醇(2mL)中的溶液中加入25%氨水溶液。将烧瓶塞住,并将反应混合物在室温下搅拌3天。加入更多的甲醇和***并将反应混合物搅拌2 h。过滤收集细沉淀物,用***充分洗涤, 然后空气干燥,得到2-[4-苄基-1-(3-羟基苄基)-1H-咪唑-5-基]乙酰胺(0.193 g, 32%),为无色固体; mp 249 ℃ (dec.)。
C19H19N3O2的HRMS计算值 321.1477, 实测值321.1470。
叔丁基二甲基甲硅烷基氧基)苄腈。在氮气下和在0 ℃向3-氰基苯酚 (10.34 g,86.8 mmol)和咪唑(14.77 g, 217 mmol)于DMF (100 mL)中的搅拌的溶液中历经5 min分批加入叔丁基二甲基甲硅烷基氯(13.74 g, 91 mmol)。使反应温热至环境温度并搅拌另外2 h。将反应混合物转移至分液漏斗并在***(150 mL)和水(150 mL)之间分配。分离各层并将水层用***再萃取两次。将合并的有机萃取物用水(2x100mL)洗涤,干燥并浓缩,得到3-(叔丁基二甲基甲硅烷基氧基)苄腈(20.38 g, 定量),为浅黄色油状物。
C13H19NOSi的HRMS计算值 233.1236,实测值233.1227。
叔丁基二甲基甲硅烷基氧基)苄基胺。将氢化铝锂(4.97 g, 131 mmol)和***(400 mL)的混合物在回流下加热1 h,然后冷却至环境温度。逐滴加入3-(叔丁基二甲基甲硅烷基氧基)苄腈(15.25 g, 65.5 mmol)在***(50 mL)中的溶液,以保持温和的回流。然后将反应在回流下加热3 h,然后在冰浴中冷却。小心地逐滴加入水(5 mL),然后加入15%氢氧化钠溶液(5 mL),然后加入水(15 mL)。滤出固体并用***彻底洗涤。将滤液用水洗涤,干燥并真空浓缩,得到浅黄色油状物(14.68 g, 95%)。将粗物质预吸附在硅藻土上,然后通过DCVC层析分离,用PE中的乙酸乙酯梯度(5%-100%乙酸乙酯)洗脱,得到3-(叔丁基二甲基甲硅烷基氧基)苄基胺(11.85 g, 77%),为浅黄色油状物。
C13H23NOSi 的HRMS计算值237.1543, 实测值237.1545。
叔丁基二甲基甲硅烷基氧基)苄基异硫氰酸酯(B)。将3-(叔丁基二甲基甲硅烷基氧基)苄基胺(13.0 g, 54.8 mmol)、碳酸钙(5.65 g, 56.4 mmol)、硫光气(8.5 mL, 111mmol)、水(41 mL)和氯仿(356 mL)的混合物在带塞的烧瓶中在室温剧烈搅拌20 h。将反应混合物用水(2 x 250 mL)洗涤,干燥并真空浓缩,得到3-(叔丁基二甲基甲硅烷基氧基)苄基异硫氰酸酯(14.29 g, 93%),为浅黄褐色油状物。
C14H21NOSi 的HRMS计算值279.1108, 实测值279.1105。
苄基氧基苄基)-5-(2-甲基-1,3-二氧戊环-2-基-甲基)-4-苯基-1H-咪唑(8)。向3,3-乙二氧基-1-丁醛(1.37g, 10.5 mmol)于干燥的甲醇(60 mL)中的溶液中加入3-苄基氧基苄基胺(2.10 g, 10.5 mmol)并将澄清溶液在25 ℃搅拌90 min。加入α-甲苯磺酰基苄基异腈(2.86 g, 10.5 mmol),随后加入三乙基胺(2.93 mL, 21.1 mmol),并将反应混合物搅拌并在65 ℃加热4 h。然后除去溶剂并将残余物溶解于乙酸乙酯(50 mL),用水(50 mL)洗涤,干燥并将溶剂在真空中除去。通过柱层析法纯化残余物(使用20-80% 乙酸乙酯/PE梯度洗脱),得到1-(3-苄基氧基苄基)-5-(2-甲基-[1,3]-二氧戊环-2-基-甲基)-4-苯基-1H-咪唑(2.05 g, 44%),为粘稠的浅橙色油状物。
C28H28N2O3 的HRMS计算值440.2094, 实测值440.2075。
羟基苄基)-5-苯基-3H-咪唑-4-基]-丙烷-2-酮(9)。向1-(3-苄基氧基苄基)-5-(2-甲基-[1,3]-二氧戊环-2-基-甲基)-4-苯基-1H-咪唑(1.12 g, 2.54 mmol)于TFA (5mL)中的搅拌的溶液中加入苯甲硫醚(598 µL, 5.09 mmol)并使反应在25 ℃搅拌15 h。然后将反应混合物冷却至0 ℃,并缓慢加入水(30 mL),随后加入乙酸乙酯(50 mL)。将混合物转移至分液漏斗并除去水层。将有机相用水(2x50 mL)洗涤,干燥并将溶剂在真空中除去。然后将残余物通过小硅胶塞(90% 乙酸乙酯/PE),减压除去溶剂,并从氯仿/PE重结晶,得到1-[3-(3-羟基苄基)-5-苯基-3H-咪唑-4-基]-丙烷-2-酮(419 mg, 54%),为白色固体; mp173.7-175.5 ℃。
C19H18N2O2 的HRMS计算值306.1363 , 实测值306.1365。
羟基丙基)-4-苯基-咪唑-1-基甲基]-苯酚 (VB0003)。向1-[3-(3-羟基苄基)-5-苯基-3H-咪唑-4-基]丙烷-2-酮(419 mg, 1.37 mmol)于干燥的甲醇(50 mL)中的冰冷的溶液中加入硼氢化钠(155 mg, 4.10 mmol)并使混合物在25 ℃搅拌15 h。然后加入丙酮(20mL)并将反应混合物搅拌另外2h。然后在真空中除去溶剂; 将残余物溶解于乙酸乙酯(50mL),用水(50 mL)洗涤并将有机相干燥并减压除去溶剂。将所得固体从甲醇重结晶,收集并用冷乙腈(4x)洗涤,得到3-[5-(2-羟基丙基)-4-苯基-咪唑-1-基甲基]-苯酚(210 mg,50%),为白色固体; mp 193-194 ℃。
C19H20N2O2 的HRMS计算值308.1519, 实测值308.1517。HPLC 纯度 = 98%。
甲苯亚磺酸。向500 mL Erlenmeyer烧瓶中加入4-甲苯亚磺酸钠盐四水合物(26.82 g, 0.11 mol)和水(134 mL)并搅拌30 min直至所有固体溶解。将叔丁基甲基醚(134 mL)加入至搅拌的溶液,然后历经5 min缓慢加入32% HCl (12.2 mL, 0.11 mol)。将反应搅拌30 min并转移至分液漏斗中,并将有机相分离并用甲苯(134mL)稀释。将溶剂在旋转蒸发器上浓缩至约50 mL,然后加入庚烷(40mL),得到固体,其使用布氏漏斗收集。随后用庚烷(50mL)洗涤并在真空下干燥,得到4-甲苯亚磺酸(15.48g,93%),为白色固体。
N-(α-甲苯磺酰基苄基)甲酰胺。向装有回流冷凝器的500mL三颈烧瓶中加入乙腈(35mL)、甲苯(35mL)、苯甲醛(6.74mL,66mmol)、甲酰胺(6.57mL,166mmol)和TMSCI(9.18mL, 72 mmol)。将反应混合物在50℃(内部温度)加热4小时后,在搅拌下加入4-甲苯亚磺酸(15.48g,99mmol)。在1小时内形成固体,每30分钟用特氟隆搅拌棒搅拌反应4小时。然后使反应冷却至室温,加入叔丁基甲基醚(35mL)并继续搅拌5分钟,然后加入水(170mL)。在布氏漏斗上收集固体,用叔丁基甲基醚(2×50mL)洗涤并真空干燥,得到N-(α-甲苯磺酰基苄基)甲酰胺 (16.73 g, 82%)。
α-甲苯磺酰基苄基异腈(C)。向装有温度计的500mL三颈烧瓶中加入N-(α-甲苯磺酰基苄基)甲酰胺(16.73 g, 57.8 mmol)和干燥的THF (120 mL)。通过注射器加入磷酰氯(10.78mL,116.0mmol),并将得到的溶液在25℃下搅拌5分钟。用冰/盐浴将溶液冷却至约0℃后,通过滴液漏斗历经45分钟加入三乙胺(48.4mL,347.0mmol),同时保持内部温度低于10℃。加完三乙胺后,将反应在5-10℃(冰浴)下搅拌45分钟。向反应中加入乙酸乙酯(85mL),然后加入水(85mL),将混合物搅拌5分钟,在将混合物转移到分液漏斗中后,除去水层。将有机相用水(2x85mL)、饱和碳酸氢钠溶液(85mL)、盐水(50mL)洗涤,并在减压下浓缩直至残留浆液。将残余物用正丙醇(85mL)稀释并浓缩至其原始体积的一半。将沉淀物冷却至0℃,保持15分钟,在布氏漏斗上收集,用正丙醇(2×50mL)洗涤并真空干燥。 这样得到α-甲苯磺酰基苄基异腈(7.47 g, 48%),为米色固体。
苄基氧基)苄基叠氮化物。在0 ℃在氩气氛下向3-苄基氧基苄基醇(5.0 g, 23.3mmol)和叠氮磷酸二苯酯(6.03 mL, 28.0 mmol)于干燥的甲苯(40 mL)中的搅拌的溶液中加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(3.83 mL, 25.6 mmol)。使所得混合物温热至环境温度,并搅拌18 h。将反应混合物用水(2x)和5%HCl溶液(1x)洗涤,然后干燥并减压浓缩。将粗物质通过短的二氧化硅柱过滤,用4/96乙酸乙酯/戊烷洗脱,得到3-(苄基氧基)苄基叠氮化物(5.28 g, 95%),为透明无色油状物。
苄基氧基)苄基胺(D)。将3-(苄基氧基)苄基叠氮化物(1.0 g, 4.2 mmol)溶解于无水THF (20 mL)并将溶液冷却至-70 ℃. 在氩气氛下逐滴加入固体氢化铝锂(238 mg,6.3 mmol)在THF (6 mL)中的溶液。添加后,使反应温热至0 ℃并搅拌1 h。小心地用水淬灭反应,然后加入1.0 M罗谢尔盐并用***(3x)萃取。将合并的有机萃取物用盐水(1x)洗涤,然后干燥并浓缩,得到3-(苄基氧基)苄基胺(787 mg, 88%),为透明的浅黄色油状物。不需要进一步纯化。
乙二氧基丁酸乙酯。将乙酰乙酸乙酯(9.72 mL, 76.84 mmol)、乙二醇(7.50 mL,134.50 mmol)和对甲苯磺酸(15 mg, 0.08 mmol)于苯(125 mL)中的混合物在Dean-Stark条件下在回流下加热24 h。使反应混合物冷却,然后用5% NaHCO3溶液(1x)和水(2x)洗涤,干燥并浓缩,得到3,3-乙二氧基-丁酸乙酯(11.67 g, 87%),为透明的无色油状物。不需要进一步纯化。
乙二氧基-1-丁醇。在-10 ℃在氩气氛下将3,3-乙二氧基丁酸乙酯(5.0 g, 28.70mmol)于无水THF (10 mL)中的溶液逐滴加入至氢化铝锂(1.10 g, 28.70 mmol)于THF (50mL)中的悬浮液中。将反应在0 ℃搅拌1.5 h,然后用1.0 M罗谢尔盐溶液(75 mL)淬灭。将混合物用***(3x)萃取,然后将合并的有机萃取物用盐水(1x)洗涤,然后干燥并浓缩,得到3,3-乙二氧基-1-丁醇(3.43 g, 90%),为透明的浅黄色液体。不需要进一步纯化。
乙二氧基-1-丁醛(E)。向滴液漏斗中加入干燥的DMSO (4.42 mL, 62.3 mmol)和干燥的二氯甲烷(25 mL)。在-78 ℃将该溶液历经10分钟的时间逐滴加入到搅拌的草酰氯(2.64 mL, 31.14 mmol)于干燥的二氯甲烷(75 mL)中的搅拌的溶液中。10 min后,历经10分钟的时间逐滴加入2-(2-甲基-1,3-二氧戊环-2-基)乙醇(3.43 g, 26.0 mmol)于干燥的二氯甲烷(25 mL)中的溶液(通过滴液漏斗)。将所得溶液在-78 ℃搅拌15 min,然后通过注射器逐滴加入三乙基胺(14.47 mL, 103.8 mmol)。移去冷却浴并使反应混合物搅拌另外30min。然后加入水(70 mL),继续搅拌另外10 min。将有机相分离,并将水相用二氯甲烷(70mL)洗涤。将合并的有机相用水(4x70 mL)洗涤,干燥并将溶剂在真空中除去。通过小硅胶塞(二氯甲烷)过滤纯化残余物,得到2-(2-甲基-[1,3]-二氧戊环-2-基)乙醛(1.40 g, 42%),为浅黄色油状物。
S氨基-5-氧代-5-苯基氨基)戊酸叔丁酯(14)。向(S)-2-(9H-芴-9-基甲氧基羰基氨基)-5-叔丁氧基-5-氧代-戊酸(25.3 g, 57 mmol)于DMF (150 mL)中的搅拌的溶液中加入N-(3-二甲基氨基丙基)-N′-乙基碳二亚胺(12.08 g, 63 mmol)、1-羟基苯并***水合物(8.51 g, 63 mmol)和苯胺(5.2 mL, 57 mmol),并使反应混合物在环境温度搅拌2天。加入水(300 mL),然后加入乙酸乙酯(300 mL)。将混合物转移至分液漏斗并分离各层。将水层用乙酸乙酯再萃取两次。将合并的有机层用水(2x300 mL)洗涤,干燥并真空除去溶剂,得到粗品(S)-4-(9H-芴-9-基甲氧基羰基氨基)-5-氧代-5-(苯基氨基)戊酸叔丁酯,为黄色油状物。它在未经纯化的情况下用于下一步骤。向粗品(S)-4-(9H-芴-9-基甲氧基羰基氨基)-5-氧代-5-(苯基氨基)戊酸叔丁酯于二氯甲烷(300 mL)中的搅拌的溶液中加入三(2-氨基乙基)胺(40 mL, 267 mmol)并将反应混合物在环境温度下搅拌1-2 h。然后将反应混合物用pH 5.5 磷酸盐缓冲液(2x200 mL)洗涤,然后用水(200 mL)洗涤,干燥并真空除去溶剂。将残余物溶解于二氯甲烷,过滤除去不溶的副产物。将溶液预吸附在硅藻土上,然后进行层析分离(DCVC),用PE中的氯仿梯度洗脱,然后用氯仿中的乙酸乙酯梯度洗脱。合并相同的级分,得到(S)-(4-氨基-5-氧代-5-苯基氨基)戊酸叔丁酯(10.85 g, 68%),为浅黄色油状物。
C15H22N2O3 的HRMS计算值278.1625, 实测值278.1612。
S-苄基氧基)苯基氨基]-5-氧代-5-(苯基氨基)戊酸叔丁酯(15)。在氮气下将3-(苄基氧基)苯基硼酸(7.05 g, 30.0 mmol)于甲苯中(150 mL)中的溶液共沸回流2.5 h,形成2,4,6-三(3-苄基氧基)苯基)-1,3,5,2,4,6-三氧杂三硼杂环己烷。真空除去甲苯,并在环境温度向残余物中加入(S)-(4-氨基-5-氧代-5-苯基氨基)戊酸叔丁酯(4.30 g, 15.5mmol)于二氯甲烷(100 mL)、吡啶(2.5 mL, 30.9 mmol)和无水乙酸铜(II)(4.64 g, 23.2mmol)中的溶液。将反应混合物对空气开放并使其在环境温度搅拌2天。然后将反应混合物倒在填充有硅胶并且顶部有一层硅藻土的短柱上。用氯仿洗脱粗产物,合并含有粗产物的各级分。将粗物质预吸附在硅藻土上,然后通过硅胶DCVC纯化,用氯仿在PE中的梯度(60-100%氯仿)洗脱,得到(S)-4-[(3-苄基氧基)苯基氨基]-5-氧代-5-(苯基氨基)戊酸叔丁酯(3.35 g, 50%),为浅黄褐色油状物。
C28H32N2O4 的HRMS计算值460.2357, 实测值460.2341。
S-N苄基氧基)苯基-2-溴乙酰胺基]-5-氧代-5-(苯基氨基)戊酸叔丁酯(16)。在氮气下和在-30oC向(S)-4-(3-苄基氧基苯基氨基)-5-氧代-5-(苯基氨基)戊酸叔丁酯(4.05g, 8.80 mmol)于二氯甲烷(80 mL)中的搅拌的溶液中依次加入三乙基胺(1.22 mL, 8.80mmol)、N,N-二甲基氨基吡啶(20 mg)和溴乙酰溴(941 μL, 10.80 mmol)。使反应混合物温热至环境温度,然后搅拌30 min。将反应混合物转移至分液漏斗,用10%柠檬酸(50 mL)和盐水(2 x 50 mL)洗涤,干燥并真空除去溶剂。将残余物预吸附在硅藻土上,然后通过硅胶DCVC纯化成(S)-4-[N-(3-苄基氧基)苯基-2-溴乙酰胺基]-5-氧代-5-(苯基氨基)戊酸叔丁酯(4.28 g, 83%),为浅黄色油状物。
C30H33BrN2O5 的HRMS计算值580.1567, 实测值580.1547。
S-苄基氧基)苯基-3,6-二氧代-4-苯基哌嗪-2-基]丙酸叔丁酯(17)。在氮气和在冰浴中冷却下向(S)-4-[N-(3-苄基氧基)苯基-2-溴乙酰胺基]-5-氧代-5-(苯基氨基)戊酸叔丁酯(4.15 g, 7.15 mmol)于DMF (70 mL)中的搅拌的溶液中加入碳酸铯(2.33 g, 7.15mmol)。使反应混合物温热至环境温度并搅拌4 h。将混合物在冰浴中冷却并加入水(100mL),随后加入乙酸乙酯(100 mL)。将混合物转移至分液漏斗并分离各层。将水相用乙酸乙酯再萃取两次。将合并的有机层用10%柠檬酸(100 mL)、饱和碳酸氢钠(100 mL)和盐水(100mL)洗涤,干燥并真空除去溶剂。将残余物预吸附在硅藻土上,然后通过硅胶DCVC纯化。合并相同的级分,然后用***研磨,得到(S)-3-[1-(3-苄基氧基)苯基-3,6-二氧代-4-苯基哌嗪-2-基]丙酸叔丁酯(4.18 g, 59%),为无色固体; mp 141.6-143.6oC。
C31H32N2O5 的HRMS计算值500.2306, 实测值500.2294。
S-苄基氧基)苯基-4-苯基哌嗪-2-基]丙酸叔丁酯(18)。在氮气下向(S)-3-[1-(3-苄基氧基)苯基-3,6-二氧代-4-苯基哌嗪-2-基]丙酸叔丁酯(2.97 g, 5.95 mmol)于无水THF (40 mL)中的搅拌的溶液中加入硼烷-甲基硫醚络合物(7.14 mL, 14.30 mmol, 2M于THF中的溶液)并使反应在环境温度搅拌20 h。然后将反应混合物在冰浴中冷却,并逐滴加入甲醇(2 mL)于THF (8 mL)中的溶液。真空除去溶剂,然后加入更多的甲醇(10 mL)。真空除去溶剂,并再一次重复该过程。将残余物预吸附在硅藻土上,然后通过硅胶(DCVC)纯化,用PE中的乙酸乙酯梯度(2%-7% 乙酸乙酯)洗脱,得到(S)-3-[1-(3-苄基氧基)苯基-4-苯基哌嗪-2-基]丙酸叔丁酯(2.08 g, 74%),为浅黄色油状物。
C30H36N2O3 的HRMS计算值472.2720, 实测值472.2710。
(S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酸(19)。向(S)-3-[1-(3-苄基氧基)苯基-4-苯基哌嗪-2-基]丙酸叔丁酯(0.82 g, 1.75 mmol)于三氟乙酸(3.5 mL)中的搅拌的溶液中加入苯甲硫醚(620 μL, 5.22 mmol)并使反应在环境温度搅拌3天。然后将反应混合物冷却至0 ℃,并缓慢加入水(10 mL),随后加入EtOAc (15 mL)。将混合物转移至分液漏斗,分离各层并将水相用EtOAc再萃取两次,干燥并真空除去溶剂。将深黄褐色油状物预吸附在硅藻土上,然后进行层析分离(DCVC),用氯仿中的甲醇梯度(0-5% MeOH)洗脱,得到(S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酸(418 mg, 70%),为黄褐色泡沫。
C19H22N2O3的HRMS计算值326.1625, 实测值326.1620。
从该反应也得到(S)-3-[1-(3-苄基氧基)苯基-4-苯基哌嗪-2-基]丙酸(230 mg,30%)并分离为浅黄褐色泡沫。
C26H28N2O3的HRMS计算值416.2094, 实测值416.2091。
(S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酰胺(VB0005)。向(S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酸(0.76 g, 2.32 mmol)于THF (20 mL)中的搅拌的溶液中加入1,1′-羰基二咪唑(0.94 g, 5.80 mmol)并将反应搅拌2 h。加入氨水溶液(25%) (20mL)并将反应搅拌另外3 h。将反应混合物转移至分液漏斗并分离各层。然后将水相用乙酸乙酯(2x20 mL)萃取。将合并的有机层用盐水(20 mL)洗涤,干燥并真空浓缩。将粗残余物通过短的florsil柱,用在PE中的EtOAc梯度(50-100%乙酸乙酯)洗脱。合并相同的级分,溶解于二氯甲烷(20 mL)并用水(3x20 mL)洗涤。从湿二氯甲烷中结晶出固体。加入石油醚40–60℃并将混合物放置1 h。过滤收集所得固体,得到外消旋产物(100 mg, 13%)。将滤液浓缩至干,得到(S)-3-[1-(3-羟基)苯基-4-苯基哌嗪-2-基]丙酰胺(185 mg, 21%),为浅黄褐色泡沫。
C19H23N3O2的HRMS计算值325.1790, 实测值325.1776。[α]D = -13.5° (CHCl3, c =0.005)。
3-[5-(2-羟基丙基)-4-苯基-咪唑-1-基甲基]苯酚盐酸盐(20)。使3-[5-(2-羟基丙基)-4-苯基-咪唑-1-基甲基]苯酚(14 mg, 0.05 mmol)、浓盐酸(3.6 µL, 0.05 mmol)和甲醇(1 mL)的溶液在环境温度搅拌20 min。然后在真空中除去溶剂;然后将残余物溶解于***(2 mL),减压除去溶剂并重复程序。将所得白色泡沫在真空中在35 ℃干燥,溶解于水(10 mL),通过玻璃纤维纸塞过滤并冷冻干燥,得到3-[5-(2-羟基丙基)-4-苯基-咪唑-1-基甲基]苯酚盐酸盐,为蓬松的白色固体; mp 84-88 ℃。
基于上述信息、可商购获得的试剂和有机化学和化合物合成领域的常规知识,本领域技术人员将容易明白用于制备本发明其它化合物的合成方案、方法和试剂。
实施例2 –体内实验
将基于2.2%盐饮食(Glenn Forrest Stockfeeders, WA)的十四周龄自发性高血压大鼠(SHR;Australian Animal Resources Centre, WA)随机分配到以下治疗组:14周对照或VB0002输注(20 pmol/kg/min 在20% DMSO中)或媒介物对照输注(20% DMSO)达4周。VB0002和媒介物对照输注通过Alzet渗透微型真空泵进行,其在14周时在全身麻醉(异氟烷3%在氧气中)下***。
将基于2.2%盐饮食的十四周龄自发性高血压大鼠也随机分配到以下治疗组:14-周对照或VB0003施用(10、100或500 pmol/kg/min 在5%乙醇中)、VB0005施用(100 pmol/kg/min 在5%乙醇中)或饮用溶液(5%乙醇)施用达4周。
使用在氧气中递送的异氟烷(3%)对14周对照组进行麻醉,然后采集血液并收集心脏和肾脏用于纤维化的定量。将剩余的组称重并通过尾套体积描记法(ADIInstruments)每周两次测量血压,再持续4周。4周治疗后,将大鼠麻醉并按照14周对照组收集样品。结果是每组n = 5只大鼠的平均值+标准差。
为了定量纤维化,将<3mm厚的组织切片在10%缓冲的***中固定24小时,处理并包埋在石蜡中。使用Masson's Trichrome染色3μm横切面。从横切面(在2个水平中的每个水平处5个)放大40倍的最小20个随机视野被数字化。使用Image-Pro Plus V.5(MediaCybernetics,Bethesda,MD,USA)将纤维化程度确定为每个数字化图像的视野面积的百分比,然后取平均值以确定每只大鼠的纤维化水平。
与18周对照相比,用VB0002、VB0003和VB0005处理的大鼠中的收缩压降低(图8和9),表明这些化合物可有效降低血压。
与14周对照和18周对照相比,用20 pmol/kg/min的VB0002处理的大鼠中的心肌纤维化减少(图10),表明该化合物减少心肌纤维化的发展并逆转已形成的心肌纤维化。
与18周对照相比,用10、100和500 pmol/kg/min的VB0003处理的大鼠中的心肌纤维化减少(图11),表明这些化合物减少心肌纤维化的发展。与14周对照相比,用100和500pmol/kg/min的VB0003处理的大鼠中的心肌纤维化减少(图11),表明这些剂量的化合物逆转已形成的心肌纤维化。
与14周对照和18周对照相比,用100 pmol/kg/min的VB0005处理的大鼠中的心肌纤维化减少(图10),表明该化合物减少心肌纤维化的发展并逆转已形成的心肌纤维化(图12)。
Claims (25)
1.下式的化合物:
其中:
X选自:
R1至R9独立地是C、N、O或S;
R10独立地选自C1-6烷基、卤素、C0-6烷基羧酸、氨基、羟基和C1-6烷氧基;
Y是A、CH2-A或CH=A;
A选自任选取代的饱和、部分饱和或不饱和的5-或6-元杂环基;任选取代的C1-6烷氧基胺;任选取代的C1-6烷基胺;任选取代的C0-6烷基羧酸;任选取代的C1-6烷基羟基;任选取代的饱和或不饱和的C0-6烷基二环杂环基;和任选取代的饱和或不饱和的C1-6烷氧基二环杂环基;
Z选自:
R11独立地选自卤素、烷基、羟基、氨基和取代的氨基;
R12、R14和R15独立地是C、CH、CH2、O、N、NH或S;
R13是C、CH、CH2、N、NH、C-CF3、CH-CF3或C=O;
m是0、1、2、3、4或5;和
n是0、1、2、3或4,
或其立体异构体或药学上可接受的盐。
2.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中R10独立地选自-CH3、-C(O)OH、-F、-NH2、-OH和-OCH3。
3.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中R5至R9独立地是C或N。
4.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中C0-6烷基羧酸是羧酸。
5.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中饱和、部分饱和或不饱和的5-或6-元杂环基含有一个或多个N、S或O,任选被一个或多个氧代、C1–6烷基、氨基、羟基或卤素取代基取代。
6.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中饱和、部分饱和或不饱和的5-或6-元杂环基选自吡咯基、吡唑基、咪唑基、***基、咪唑烷基、吡咯烷基、吡咯烷叉基、二氢吡咯基、异噁唑基、二氢噁唑基、异噁唑烷基、噁唑烷基和噁唑基,任选被一个或多个氧代、C1-6烷基、氨基、羟基或卤素取代基取代。
7.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中C1-6烷氧基胺是氨基氧基甲基。
8.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中C1-6烷基胺任选被一个或多个C1-6烷基、C1–6卤代烷基、羟基或卤素,优选单-、二-或三-取代的卤代烷基,最优选三氟甲烷取代。
9.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中C1-6烷基羟基是甲基羟基或丙烷-2-醇。
10.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中C0-6烷基二环杂环基选自吲哚基、异吲哚基、吲哚啉基和异吲哚啉基,任选被一个或多个氧代,优选二氧代取代。
11.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中C1-6烷氧基二环杂环基选自吲哚基、异吲哚基、吲哚啉基和异吲哚啉基,任选被一个或多个氧代取代,并且其中C1-6烷氧基是甲氧基或乙氧基。
12.根据权利要求1的化合物或其立体异构体或药学上可接受的盐, 其中A选自:
。
13.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中R11是选自F、Cl、Br和I的卤素。
14.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中R11是式-NHR16的取代的氨基并且其中:
R16选自-CN、-SO2(R17)aR18和-CO(R17)aR18,
a是0或1,
R17选自-NH-和-O-,和
R18选自-H、-CH3、-CH2CH3、-CH2OH和-CH2CH2OH。
15.根据权利要求1的化合物或其立体异构体或药学上可接受的盐, 其中R11是选自以下的取代的氨基:-NHSO2CH3、-NHCOH、-NHCONHCH3、-NHCONHCH2CH3、-NHSO2NHCH3、-NHSO2NHCH2CH3、-NHCOCH3、-NHCOOCH3、-NHCOOCH2CH2OH、-NHCONH2和-NHCN。
16.根据权利要求1的化合物或其立体异构体或药学上可接受的盐, 其中R11是选自甲基、乙基、丙基、丁基和戊基的烷基。
17.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中化合物选自:
。
18.根据权利要求1的化合物或其立体异构体或药学上可接受的盐,其中化合物选自:
。
19.一种药物组合物,其包含根据权利要求1-18中任一项的化合物或其立体异构体或药学上可接受的盐和药学上可接受的赋形剂。
20.一种用于治疗性治疗受试者的高血压或高血压前期的方法,包括向所述受试者施用根据权利要求1-18中任一项的化合物或其立体异构体或药学上可接受的盐或根据权利要求19的组合物。
21.一种用于预防性治疗受试者的纤维化的方法,包括向所述受试者施用根据权利要求1-18中任一项的化合物或其立体异构体或药学上可接受的盐或根据权利要求19的组合物。
22.一种用于治疗性治疗受试者的纤维化的方法,包括向所述受试者施用根据权利要求1-18中任一项的化合物或其立体异构体或药学上可接受的盐或根据权利要求19的组合物。
23.一种用于治疗性治疗受试者的高血压和纤维化的方法,包括向所述受试者施用根据权利要求1-18中任一项的化合物或其立体异构体或药学上可接受的盐或根据权利要求19的组合物。
24.一种用于治疗受试者的高血压前期和纤维化方法,包括向所述受试者施用根据权利要求1-18中任一项的化合物或其立体异构体或药学上可接受的盐或根据权利要求19的组合物。
25.根据权利要求21-24中任一项的方法,其中所述纤维化选自心肌纤维化、肾纤维化、肝纤维化和肺纤维化。
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WO2018053588A1 (en) | 2018-03-29 |
US11834417B2 (en) | 2023-12-05 |
KR102640385B1 (ko) | 2024-02-23 |
CA3223869A1 (en) | 2018-03-29 |
ES2890924T3 (es) | 2022-01-25 |
US11053202B2 (en) | 2021-07-06 |
JP2019532932A (ja) | 2019-11-14 |
EP3640243A1 (en) | 2020-04-22 |
CA3037222C (en) | 2024-02-13 |
IL265242A (en) | 2019-05-30 |
RU2752088C1 (ru) | 2021-07-22 |
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