CN116730980A - 一种化合物及其立体异构体、或其药学上可接受盐与用途 - Google Patents
一种化合物及其立体异构体、或其药学上可接受盐与用途 Download PDFInfo
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- CN116730980A CN116730980A CN202310754737.1A CN202310754737A CN116730980A CN 116730980 A CN116730980 A CN 116730980A CN 202310754737 A CN202310754737 A CN 202310754737A CN 116730980 A CN116730980 A CN 116730980A
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
Abstract
本发明公开了一种化合物及其立体异构体、或其药学上可接受盐,化合物的结构式如下通式(Ⅰ)所示。本发明公开的化合物及其立体异构体、或其药学上可接受盐、或上述的药物组合物可作为凝血因子XIIa的抑制剂,可在避免出血风险的基础上,用于预防和治疗血栓形成,特别是由血管导管、人工心脏瓣膜和透析膜等医疗器械引发的经凝血因子XIIa介导的血栓形成。
Description
技术领域
本发明涉及药物化学技术领域,具体是一种化合物及其立体异构体、或其药学上可接受盐与用途。
背景技术
血栓,是一种遗传和环境因素相互作用与影响,具有多因素变化过程的临床综合征;其形成是指在血管腔或心腔内流动的血液变为固态凝块的过程,所形成的凝块称为血栓或栓子,具体可分为血小板血栓、红细胞血栓、纤维蛋白血栓、混合血栓等。血栓可以在体内任何部位的血管腔内形成,使血管腔发生部分或完全闭塞,导致血流淤滞或停止,从而引发血栓性疾病。其中,血栓疾病的发生与凝血异常有关。
凝血过程是指血液由液体先形成凝胶再形成凝块的一个过程,具有修复受损血管和止血的功能。凝血过程由内源性途径(intrinsic pathway)、外源性途径(extrinsicpathway)和共同路径(common pathway)组成(Norris,L.A.,Blood coagulation,BestPract Res Clin Obstet Gynaecol 2003,17(3),369-83),是通过多种酶原被顺序激活而过程不断得到加强和放大的一种连锁反应,即凝血级联反应。
内源性路径是指从因子XII激活形成XIa-VIIIa-Ca2+-PL复合物,并激活因子XI的一系列生物转化过程。当带负电的表面(例如:聚集蛋白、胶原蛋白、核酸、多磷酸盐、LPS、玻璃、硅酸盐和医疗器械材料)与因子XII接触并结合时(Naudin,C.;Burillo,E.;Blankenberg,S.;Butler,L.;Renne,T.,Factor XII contact activation.Semin ThrombHemost 2017,43,814-826),在高分子激肽原(HK)和血浆激肽释放酶(PKa)的参与下因子XII被激活为因子XIIa(Fujikawa,K.;Heimark,R.L.;Kurachi,K.;Davie,E.W.,Activationof bovine factor XII(Hageman factor)by plasma kallikrein.Biochemistry 1980,19,1322-1330.)。随后,因子XIIa将因子XI激活为因子XIa,同时,在Ca2+的存在下,因子IX被激活为因子IXa,后者与因子VIIIa结合为复合物,将因子X激活为因子Xa。最终,在共同路径中因子Xa催化凝血酶原(prothrombin)形成凝血酶(thrombin)。而凝血酶可反馈激活因子XIa,进一步形成凝血酶,放大了凝血级联反应。综上所述,凝血因子XIIa在凝血过程的内源性途径中扮演了重要角色。
凝血因子XIIa是一种丝氨酸蛋白酶,属于S1A亚家族。早在55年前凝血因子XIIa就被人们所发现,但是近十年来才揭露了其三维结构(Beringer,D.X.;Kroon-Batenburg,L.M.,The structure of the FnI-EGF-like tandem domain of coagulation factorXII solved using SIRAS.Acta Crystallogr Sect F Struct Biol Cryst Commun 2013,69,94-102;Pathak,M.;Wilmann,P.;Awford,J.;Li,C.;Hamad,B.K.;Fischer,P.M.;Dreveny,I.;Dekker,L.V.;Emsley,J.,Coagulation factor XII protease domaincrystal structure.J Thromb Haemost 2015,13,580-91)。由于凝血因子XIIa参与催化的内源性路径与血管损伤无关,因此不会影响正常的止血功能(Renne,T.;Pozgajova,M.;Gruner,S.;Schuh,K.;Pauer,H.U.;Burfeind,P.;Gailani,D.;Nieswandt,B.,Defectivethrombus formation in mice lacking coagulation factor XII.J Exp Med2005,202,271-281)。值得注意的是,凝血因子XIIa活性与病理性血栓形成有关。缺乏凝血因子XIIa(F12–/–)的小鼠和凝血因子XIIa抑制剂给药的小鼠在中风、动脉粥样硬化和肺栓塞模型中显示出更高的存活率,并且没有表现出出血风险(Maas,C.;Renne,T.,Coagulation factorXII in thrombosis and inflammation.Blood 2018,131,1903-1909;Renne,T.;Stavrou,E.X.,Roles of factor XII in Innate Immunity.Front Immunol2019,10,2011)。类似地,凝血因子XIIa靶向抑制剂对大鼠、兔子和灵长类动物的血栓模型有效,不会引起出血风险(Xu,Y.;Cai,T.Q.;Castriota,G.;Zhou,Y.;Hoos,L.;Jochnowitz,N.;Loewrigkeit,C.;Cook,J.A.;Wickham,A.;Metzger,J.M.;et al.,Factor XIIa inhibition by Infestin-4:in vitro mode of action and in vivo antithrombotic benefit.Thromb Haemost2014,111,694-704;Barbieri,C.M.;Wang,X.;Wu,W.;Zhou,X.;Ogawa,A.M.;O'Neill,K.;Chu,D.;Castriota,G.;Seiffert,D.A.;Gutstein,D.E.;et al.,Factor XIIa as a noveltarget for thrombosis:target engagement requirement and efficacy in a rabbitmodel of microembolic signals.J Pharmacol Exp Ther 2017,360,466-475)。此外,用人类的凝血因子XIIa对缺乏凝血因子XIIa(F12–/–)的小鼠进行给药,造成了小鼠的病理性血栓形成。(Renne,T.;Pozgajova,M.;Gruner,S.;Schuh,K.;Pauer,H.U.;Burfeind,P.;Gailani,D.;Nieswandt,B.,Defective thrombus formation in mice lackingcoagulation factor XII.J Exp Med 2005,202,271-281)。此外,凝血因子XIIa不仅能介导PKa的活化进而调控PKa活化PAR2介导的神经炎症,还能介导KKS活化导致缓激肽(BK)产生。综上所述,凝血因子XIIa是一个极具潜力的,安全的,可针对多种疾病的药物靶点。
目前,已上市的新型口服抗凝剂(NOACs)靶向作用于凝血酶或因子Xa,它们包括:达比加群酯(2010年FDA批准上市)、阿哌沙班(2011年FDA批准上市)、利伐沙班(2011年FDA批准上市)、依度沙班(2015年FDA批准上市)和贝曲沙班(2017年FDA批准上市)。不同于传统口服抗凝剂(如:华法林),新型口服抗凝剂具有起效快,半衰期短,药物间相互作用少和无需监测药物抗凝强度等显著优势。但是,目前上市的新型口服抗凝剂仍然会导致出血事件的发生。由于抑制凝血因子XIIa可以避免出血风险,所以可针对凝血因子XIIa开发无出血风险的小分子抗凝剂。
此外,针对靶点凝血因子XIIa,已经发现了阻断抗体3F7,昆虫蛋白infestin-4,类肽大环FXII801等生物大分子抑制剂。
目前,已经有一些专利报道了凝血因子XIIa的小分子抑制剂。专利WO 2017123518披露了氨酰基三唑类凝血因子XIIa共价抑制剂,其可用于自身免疫性疾病的治疗。专利WO2017205296披露了氨酰基吲唑类凝血因子XIIa抑制剂,其可用于自身免疫性疾病的治疗。专利WO 2019108565披露了吡喃并吡唑类和吡唑并吡啶类凝血因子XIIa抑制剂,其可用于自身免疫性疾病的治疗。专利WO 2018093695,WO 2018093716和专利WO 2019211585披露了(S)-哌嗪-2-羧酰胺类的选择性凝血因子XIIa抑制剂,用于预防和治疗与凝血有关的疾病。专利WO2019186164披露了取代的L-脯氨酸酰胺类的选择性凝血因子XIIa抑制剂,用于用于预防和治疗与凝血有关的疾病。专利WO 2021032933披露了通式为的凝血因子XIIa抑制剂,用于治疗涉及因子XIIa抑制的疾病。专利WO 2021032934披露了通式为的凝血因子XIIa抑制剂,用于治疗涉及凝血因子XIIa抑制的疾病。专利WO 2021032935和WO 2021032938披露了通式/> 的凝血因子XIIa抑制剂,用于治疗涉及凝血因子XIIa抑制的疾病。专利WO 2021032936和2021032937披露了通式为/>的凝血因子XIIa抑制剂,用于治疗涉及凝血因子XIIa抑制的疾病。专利WO 2022175675披露了通式为/>的桥环类凝血因子抑制剂,用于治疗涉及凝血因子XIIa抑制的疾病。专利WO 2022118016披露了通式为/>的凝血因子XIIa抑制剂,用于治疗涉及凝血因子XIIa抑制的疾病。专利WO 2022248883披露了以吡咯烷-2-羧酸为骨架的凝血因子XIIa抑制剂,用于治疗涉及凝血因子XIIa抑制的疾病。可见,小分子凝血因子XIIa抑制剂对于治疗与凝血因子XIIa有关的疾病具有巨大潜力。
发明内容
本发明要解决的技术问题是提供一种化合物及其立体异构体、或其药学上可接受盐与用途。
本发明的技术方案为:
一种化合物及其立体异构体、或其药学上可接受盐,所述的化合物的结构式如下通式(Ⅰ)所示:
式(1)中,R1选自氢、氘、卤素、Cl-3烷基、Cl-3卤代烷基和Cl-3烷氧基;R2选自未取代的单环烷基、环上有取代基的单环烷基、未取代的苯基、苯环上有取代基的苯基、杂芳基、双环系统和烷胺基叉链系统;
其中,所述的未取代的单环烷基选自环丙烷、环丁烷、环戊烷、环己烷、环庚烷和环辛烷;
所述的环上有取代基的单环烷基选自环上有取代基的环丙烷、环上有取代基的环丁烷、环上有取代基的环戊烷、环上有取代基的环己烷、环上有取代基的环庚烷和环上有取代基的环辛烷;其中,环上的取代基选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基和氰基;当环上的取代基为一个时,单取代基取代于环烷基的任意亚甲基上;当环上的取代基为多个时,多个取代基分别取代于环烷基不同位置的亚甲基上;
所述的杂芳基选自咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、哒嗪基和吡嗪基;
所述的双环系统选自萘基、1,2,3,4-四氢萘基、2,3-二氢苯并[b][1,4]二噁烷基、吲哚基、异吲哚基、羟吲哚基、四氢吲哚基、二氢吲哚基、异二氢吲哚基、四氢喹啉基、四氢异喹啉基、3,4-二氢-1H-异色烯基、3,4-二氢-2H-色烯基、苯并呋喃基、二氢苯并呋喃基、四氢苯并呋喃基、苯并噻吩基、四氢苯并噻吩基、吲唑基、四氢吲唑基、2,3-二氢-1H-茚基、萘基和异色满基;
所述的烷胺基叉链系统选自下式(Ⅱ-1)-(Ⅱ-9):
(Ⅱ-1)-(Ⅱ-9)中,表示此处手性C原子上的C-N键内翻。
所述的苯环上有取代基的苯基其结构式为下式(Ⅲ):
式(Ⅲ)中,取代基R3-R7均选自氢、氘、卤素、C1-4烷基、C1-4氘代烷基、二氟甲基、三氟甲基、C1-3烷氧基、二氟甲氧基、三氟甲氧基、C1-3烷硫基、羟基、氨基、氰基和硝基;为取代基的连接点位。
一种药物组合物,包括所述的化合物及其立体异构体、或其药学上可接受盐。
所述的化合物及其立体异构体、或其药学上可接受盐或所述的药物组合物在制备一种用于抑制凝血因子XIIa的药物的用途。
所述的抑制凝血因子XIIa的药物是通过抑制凝血因子XIIa,用于预防和治疗与血液增稠、凝血或血凝块形成有关的疾病。
本发明的化合物及其立体异构体、或其药学上可接受盐、或上述的药物组合物可以用于治疗和/或预防选自以下的疾病或作为联合疗法用于治疗和/或预防选自以下的疾病:血栓形成;深静脉血栓形成;复杂的左侧消融(肺静脉隔离;VT消融);再灌注损伤,也称为缺血再灌注损伤;经导管主动脉瓣置换(TAVR),也称为经导管主动脉瓣植入(TAVI);脊髓或硬膜外麻醉;腰椎诊断穿刺;胸外科手术;腹部外科手术;大型骨科手术;肝活检;经尿道前列腺切除术;肾脏活检;肾功能不全;肝病;内窥镜活检;前列腺或膀胱活检;用于室上性心动过速的电生理研究或射频导管消融(包括经由单次经中隔穿刺术进行左侧消融);血管造影;起搏器或植入式心脏复律除颤器(ICD)植入(除非复杂的解剖学背景,例如先天性心脏病);机械瓣膜植入;假体瓣膜植入;心肌梗塞;心绞痛(包括不稳定型心绞痛);血管成形术或主动脉冠状动脉分流术后的再闭塞和再狭窄;中风;心房颤动以降低它们的中风风险的患者;患有心房颤动和慢性肾脏疾病的患者;短暂性脑缺血发作;周围动脉阻塞性病症;深静脉血栓形成;肺栓塞;深静脉微血管疾病;需要体外膜氧合(ECMO)的患者;需要体外循环如冠状动脉旁路移植术(CABG)的患者;弥散性血管内凝血(DIC)动脉粥样硬化;关节炎;癌症患者中的血栓形成;沉默性脑缺血;中风;神经创伤性病症;神经炎性病症;包括与人造表面接触的医疗程序,医疗程序包括肾透析;抑制凝血因子XIIa可能有益的其它疾病诸如阿尔茨海默氏病、血管性痴呆、黄斑变性、糖尿病性视网膜病变、糖尿病性黄斑水肿、脑卒中脑水肿,水肿的其它起因、遗传性血管性水肿或获得性血管性水肿。
本发明的化合物及其立体异构体、或其药学上可接受盐、或上述的药物组合物可用于避免或减轻现有抗凝疗法的副作用,现有抗凝疗法任选自华法林,达比加群酯、阿哌沙班、利伐沙班、依度沙班和贝曲沙班。
本发明的优点:
本发明公开的化合物及其立体异构体、或其药学上可接受盐、或上述的药物组合物可作为凝血因子XIIa的抑制剂,可在避免出血风险的基础上,用于预防和治疗血栓形成,特别是由血管导管、人工心脏瓣膜和透析膜等医疗器械引发的经凝血因子XIIa介导的血栓形成。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
化合物的制备可涉及各种化学基团的保护和脱保护。本领域技术人员可以容易地确定对保护和脱保护的需求以及对合适的保护基的选择。用于该目的合适基团已在化学领域的标准教科书中有讨论,例如由T.W.Greene和P.G.M.Wuts出版的Protective Groups inOrganic Synthesis(John Wiley&Sons,纽约,1999年)、in Protecting Group Chemistry(第1版,牛津大学出版社,2000年)、以及March出版的Advanced Organic chemistry:Reactions,Mechanisms,and Structure(第5版,Wiley-Interscience Publication,2001年)。
所有实施例所使用的溶剂和原料均可市售获得,并且无需进一步纯化即可使用。所有氘代溶剂通常含有0.03%至0.05%(v/v)的四甲基硅烷,用作参比信号(对于1H设置为d 0.00)。
薄层色谱(TLC)检测在购自南京全隆生物技术有限公司的G型薄层层析硅胶板上进行,并通常利用紫外线观察斑点。在某些情况下,还使用了其他可视化方法。在这些情况下,TLC板是用碘(将约1g的碘加入10g硅胶中并充分混合生成)显影以显示化合物。柱层析色谱所采用的是200-300目的硅胶。玻璃仪器购自欣维尔。所有实施例中所用流动相和展开剂的溶液选自石油醚(PE)和乙酸乙酯(EA)的混合溶剂,石油醚(PE)、乙酸乙酯(EA)和三乙胺(Et3N)组成的混合溶剂,二氯甲烷(DCM)和甲醇(MeOH)的混合溶剂、以及二氯甲烷(DCM)、甲醇(MeOH)和三乙胺(Et3N)组成的混合溶剂,上述混合溶剂中各组分按体积比混合。
分析及鉴定方法
1H-NMR:采用美国安捷伦公司600MHz的超导核磁共振波谱仪(VNMRS600)对化合物进行检测,所得图谱参考TMS(0.0ppm)、DMSO-d6(2.50ppm)、CDCl3(7.26ppm)报告化学位移(δ-值),单位为百万分率(ppm)。偶合常数(J)以赫兹(Hz)为单位,光谱分裂图样指定为单峰(s)、双重峰(d)、三重峰(t)、四重峰(q)、多重峰或更多重叠信号(m)、宽信号(br);溶剂在括号中给出。
MS:采用美国沃特世公司的飞行时间质谱仪对化合物进行检测。该质谱仪电离源为ESI,质量范围m/z在100-2000之间,检测器分辨率达到小数点后四位,给出的测定数据为[M+H]+质核比(m/z)。
术语解释:
“烷基”是指直链或支链的烃链;例如,“C1-3烷基”是指含有1、2或3个碳原子的直链或支链烃链,例如甲基、乙基、正丙基、异丙基等。
“烷氧基”是指通过氧与分子连接的烷基。
“烷硫基”是指通过硫与分子连接的烷基。
“卤代烷基”是指被一个或多个卤素取代的烷基,其中烷基如上所定义。
“卤代烷氧基”指被一个或多个卤素取代的烷氧基,其中烷氧基如上所定义。
“羟烷基”指被羟基取代的烷基,其中烷基如上所定义。
“亚烷基”是指烷基的一个氢原子进一步被取代,例如:“亚甲基”指-CH2-、“亚乙基”指-(CH2)2-、“亚丙基”指-(CH2)3-、“亚丁基”指-(CH2)4-。
“烯基”是指由至少由两个碳原子和至少一个碳-碳双键组成的如上定义的烷基,例如乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基。
“炔基”是指含有至少一个三键的支链或直链烃链;例如:“C2-6炔基”是指含有至少一个三键并具有2、3、4、5或6个碳原子的支链或直链烃链;三键可以在烃链的任何可能位置上;例如,“C2-6炔基”是乙炔基、丙炔基、丁炔基、戊炔基或己炔基。
“单环烷基”是指饱和或部分不饱和单环环状烃取代基,单环烷基环包含3至20个碳原子。
“芳基”是指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团。
“杂芳基”是指包含1至4个杂原子、5至14个环原子的杂芳族体系,其中杂原子选自氧、硫和氮。
缩略语解释:
EDCI:1-乙基-(3-二甲基氨基丙基)碳化二亚胺盐酸盐;
CMPI:碘代2-氯-1-甲基吡啶;
POCl3:三氯氧磷;
SOCl2:氯化亚砜;
NaBH(OAc)3:三乙酰基硼氢化钠;
HCl:盐酸;
AcOH:冰醋酸;
NaOH:氢氧化钠;
LiOH·H2O:氢氧化锂一水合物;
K2CO3:碳酸钾;
Et3N:三乙胺;
DIPEA:N,N-二异丙基乙胺;
Py:吡啶;
DAMP:4-二甲氨基吡啶;
NaHCO3:碳酸氢钠;
Na2SO4:硫酸钠;
DCM:二氯甲烷;
DCE:1,2-二氯乙烷;
DMF:N,N-二甲基甲酰胺;
2-MeTHF:2-甲基四氢呋喃;
H2O:水;
THF:四氢呋喃;
EA:乙酸乙酯;
PE:石油醚;
MeOH:甲醇;
EtOH:乙醇;
DMSO:二甲基亚砜;
CDCl3:氘代氯仿;
N2:氮气;
MS:质谱;
1H-NMR:核磁共振氢谱;
TLC:薄层色谱;
Rf(比移值):指薄层色谱法中原点到斑点中心的距离与原点到溶剂前沿的距离的比值;
min:分钟;
h:小时。
一种化合物及其立体异构体、或其药学上可接受盐,化合物的结构式如下通式(Ⅰ)所示:
化合物的合成通式见下式:
四种中间体的合成方法:
一、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺的合成,化学方程式为:
向100mL耐压瓶中加入研磨均匀的2-吡啶甲酸(2.02g、16.25mmol)和1,2,3-三氨基胍盐酸盐(3.59g、32.47mmol),升温至190℃反应5-6h,冷却至室温后加入水,在冰浴下滴加2M的NaOH调pH值至7-8,搅拌30min,过滤,收集滤渣,干燥得1.51g的棕色固体,即3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(收率:58%);TLC监测反应情况(DCM:MeOH:Et3N=10:1:0.25,Rf=0.26);MS m/z(ESI):162.1782[M+H]+。
二、(R)-3-环己基-2-(环己基氨基)丙酸的合成,化学方程式为:
(1)、将(R)-2-氨基-3-环己基丙酸(5.00g、29.20mmol)置于250mL单颈圆底烧瓶中,加入50mL的MeOH,随后,在冰浴条件下滴加SOCl2(5.21g、43.79mmol),搅拌5min后升温至60℃回流搅拌过夜,期间TLC监测反应情况(EA,Rf=0.68(碘显));然后旋蒸除去溶剂,向浓缩液中加入50mL的EA,搅拌,并滴加饱和NaHCO3水溶液至无气泡产生;滴毕,萃取,收集有机相,水相再用50mL的EA萃取2次,收集有机相,加入无水Na2SO4,过滤,旋蒸除去EA,干燥,得4.90g的淡黄色透明油状物,即(R)-2-氨基-3-环己基丙酸甲酯(收率:91%),无需进一步纯化即可用于下一步反应;
(2)、将(R)-2-氨基-3-环己基丙酸甲酯(4.90g,、26.45mmol)和环己酮(3.44g、35.05mmol)置于250mL的单颈圆底烧瓶中,加入40mL的DCE,随后再加入AcOH(2.10g、35.00mmol),并在N2氛围下搅拌30min,然后缓慢加入NaBH(OAc)3(11.43g,53.93mmol),再在N2氛围和室温下搅拌10h,期间TLC监测反应情况(PE:EA=20:1,Rf=0.58);然后旋蒸除去溶剂,向浓缩液中加入40mL的饱和NaHCO3水溶液,用120mL的EA萃取3次,收集有机相,加入无水Na2SO4,过滤,旋蒸除去EA,得粗产物,粗产物经柱层析(PE),得6.06g的无色透明油状物,即(R)-3-环己基-2-(环己基氨基)丙酸甲酯(收率:86%);
(3)、将(R)-3-环己基-2-(环己基氨基)丙酸甲酯(6.06g、22.66mmol)加入到200mL的单颈圆底烧瓶中,加入THF(30mL)搅拌2min,随后,在室温下滴加30mL的LiOH·H2O(5.71g,、0.14mol)水溶液,滴毕,在50℃下剧烈搅拌12h,然后旋蒸除去反应液中的THF,室温下,向反应液中滴加6M的HCl,pH值接近7时,停止滴加,过滤,收集滤渣,用水洗涤,干燥,得5.05g的白色固体,即(R)-3-环己基-2-(环己基氨基)丙酸(收率:88%),无需进一步纯化即可进行下一步反应;MS m/z(ESI):254.2115[M+H]+。
三、环己基-D-苯丙氨酸的合成,化学方程式为:
(1)、将D-苯丙氨酸(5.00g、23.18mmol)置于250mL的单颈圆底烧瓶中,加入45mL的MeOH;随后,在冰浴条件下滴加SOCl2(4.14g,43.79mmol),搅拌5min后,升温至60℃,回流搅拌过夜,期间TLC监测反应情况(EA、Rf=0.61(碘显)),;然后旋蒸除去溶剂,向浓缩液中加入50mL的EA,搅拌,并滴加饱和NaHCO3水溶液至无气泡产生,滴毕,萃取,收集有机相,水相再用50mL的EA萃取2次,收集有机相,加入无水Na2SO4,过滤,旋蒸除去EA,干燥,得3.28g的淡黄色透明油状物,即D-苯丙氨酸甲酯(收率:79%),无需进一步纯化即可用于下一步反应;
(2)、将D-苯丙氨酸甲酯(3.28g、19.86mmol)和环己酮(2.53g,25.78mmol)置于250mL的单颈圆底烧瓶中,加入50mL的DCE,随后再加入AcOH(1.55g、25.83mmol),并在N2氛围下搅拌30min,然后缓慢加入NaBH(OAc)3(8.42g、39.73mmol),在N2氛围和室温下搅拌10h,期间TLC监测反应情况(PE:EA=20:1,Rf=0.51);然后旋蒸除去溶剂,向浓缩液中加入50mL的饱和NaHCO3水溶液,用150mL的EA萃取3次,收集有机相,加入无水Na2SO4,过滤,旋蒸除去EA,得粗产物,粗产物经柱层析(PE),得2.43g的无色透明油状物,即环己基-D-苯丙氨酸甲酯(收率:47%);
(3)、将环己基-D-苯丙氨酸甲酯(2.43g、9.82mmol)加入到200mL的单颈圆底烧瓶中,加入THF(15mL)搅拌2min,随后,在室温下滴加15mL的LiOH·H2O(2.47g、58.87mmol)水溶液,滴毕,在50℃下,剧烈搅拌12h;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加6M的HCl,pH值接近7时,停止滴加,然后过滤,收集滤渣,用水洗涤,干燥,得2.20g的白色固体,即环己基-D-苯丙氨酸(收率:91%),无需进一步纯化即可进行下一步反应;MS m/z(ESI):248.1628[M+H]+。
四、环戊基-D-亮氨酸的合成,化学方程式为:
(1)、将D-亮氨酸甲酯盐酸盐(5.00g、27.52mmol)和环戊酮(3.00g、35.66mmol)置于250mL的单颈圆底烧瓶中,加入80mL的DCE,随后再加入AcOH(2.15g、35.83mmol)并在N2氛围下搅拌30min,然后缓慢加入NaBH(OAc)3(11.67g、55.06mmol),在N2氛围和室温下搅拌10h,TLC监测反应情况(PE:EA=20:1,Rf=0.72);然后旋蒸除去溶剂,向浓缩液中加入80mL的饱和NaHCO3水溶液,用240mL的EA萃取3次,收集有机相,加入无水Na2SO4,过滤,旋蒸除去EA,得粗产物,粗产物经柱层析(PE),得4.12g的无色透明油状物,即环己基-D-苯丙氨酸甲酯(收率:70%);
(2)、将环戊基-D-亮氨酸甲酯(4.12g、19.31mmol)加入到200mL的单颈圆底烧瓶中,加入20mL的THF搅拌2min;随后,在室温下滴加20mL的LiOH·H2O(4.86g、0.12mol)水溶液,滴毕,在50℃下,剧烈搅拌12h;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加6M的HCl,pH值接近7时,停止滴加,然后过滤,收集滤渣,用水洗涤,干燥,得3.12g的白色固体,即环己基-D-苯丙氨酸(收率:81%),无需进一步纯化即可进行下一步反应;MS m/z(ESI):200.1645[M+H]+。
实施例1
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-4-氯苯甲酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-4-氯苯甲酰胺的结构式为:
(1)、4-(4-氯苯甲酰氨基)苯甲酸甲酯的合成,化学方程式为:
首先将4-氯苯甲酸(502mg、3.21mmol)和4-氨基苯甲酸甲酯(533mg、3.53mmol)加入单颈圆底烧瓶中,再加入12mL的无水DCM溶解,然后在冰浴条件下加入Py(1.51g、19.11mmol),搅拌5min后,缓慢滴加POCl3(730mg、4.77mmol),保持冰浴条件反应20min,期间TLC监测反应情况(PE:EA=4:1,Rf=0.52);反应完全后,加入1M的HCl(12mL)进行淬灭反应;然后将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相,然后,向水相中分别加入10mL的DCM萃取2次,收集有机相,再将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后,得到粗产物;粗产物经过柱层析纯化(PE:EA=8:1,PE:EA=4:1),得到431mg的白色固体,即4-(4-氯苯甲酰氨基)苯甲酸甲酯(收率:47%);
(2)、4-(4-氯苯甲酰氨基)苯甲酸的合成,化学方程式为:
将4-(4-氯苯甲酰氨基)苯甲酸甲酯(432mg、1.49mmol)加入到100mL的单颈圆底烧瓶中,再加入5mL的THF,进行2min的搅拌溶解;随后,在室温下滴加5mL的LiOH·H2O(321mg、7.65mmol)水溶液,滴毕,在室温下剧烈搅拌12h;然后旋蒸除去反应液中的THF,然后在室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时,停止滴加,然后过滤,收集滤渣,用水洗涤,干燥,得330mg的白色固体,即4-(4-氯苯甲酰氨基)苯甲酸粗产物(收率:81%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-4-氯苯甲酰胺的合成,化学方程式为:
将4-(4-氯苯甲酰氨基)苯甲酸粗品(202mg、0.73mmol)、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(121mg、0.75mmol)、EDCI(279mg、1.46mmol)和DMAP(178mg、1.46mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,然后在冰浴条件下,加入4mL的无水DMF搅拌1h,再升温至室温,搅拌2h,期间TLC监测反应情况(DCM:MeOH=5:1,Rf=0.67);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加;然后过滤,收集滤渣,用水洗涤,再分别用EA(6mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得123mg的白色固体,即N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-4-氯苯甲酰胺(收率:22%);MS m/z(ESI):419.1023[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.72(s,1H),8.68(d,J=3.0Hz,1H),8.25(d,J=8.6Hz,2H),8.06–8.02(m,2H),8.01(s,1H),7.99(d,J=8.6Hz,2H),7.93(t,J=7.7Hz,1H),7.85(s,2H),7.64(d,J=8.3Hz,2H),7.51–7.46(m,1H)。
实施例2
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3,5-二甲基苯甲酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3,5-二甲基苯甲酰胺的结构式为:
(1)、4-(3,5-二甲基苯甲酰氨基)苯甲酸甲酯的合成,化学方程式为:
将3,5-二甲基苯甲酸(501mg、3.34mmol)和4-氨基苯甲酸甲酯(502mg、3.32mmol)加入到单颈圆底烧瓶中,再加入10mL的无水DCM溶解,然后在冰浴条件下加入Py(1.58g、20.00mmol),搅拌5min后,缓慢滴加POCl3(759mg,4.97mmol),保持冰浴条件反应25min,期间TLC监测反应情况(PE:EA:Et3N=4:1:0.15,Rf=0.48);反应完全后加入1M的HCl(10mL)进行淬灭反应;然后将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相,然后,向水相中分别加入10mL的DCM萃取2次,收集有机相,再将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后,得到粗产物;粗产物经过柱层析纯化(PE:EA:Et3N=20:1:0.5,PE:EA:Et3N=10:1:0.25),得到375mg的白色固体,即4-(3,5-二甲基苯甲酰氨基)苯甲酸甲酯(收率:40%);
(2)、4-(3,5-二甲基苯甲酰氨基)苯甲酸的合成,化学方程式为:
将4-(3,5-二甲基苯甲酰氨基)苯甲酸甲酯(370mg、1.31mmol)加入到100mL的单颈圆底烧瓶中,加入10mL的THF搅拌2min,溶解;随后,在室温下滴加10mL的LiOH·H2O(271mg,6.46mmol)水溶液,滴毕,在室温下剧烈搅拌过夜;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时,停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得302mg的白色固体,即4-(3,5-二甲基苯甲酰氨基)苯甲酸粗产物(收率:86%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3,5-二甲基苯甲酰胺的合成,化学方程式为:
将4-(3,5-二甲基苯甲酰氨基)苯甲酸粗品(199mg、0.74mmol)、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(121mg、0.75mmol)、EDCI(280mg,1.47mmol)和DMAP(178mg、1.46mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,然后在冰浴条件下,加入无水DMF(4mL)搅拌1h,再升温至室温下搅拌2h,期间TLC监测反应情况(DCM:MeOH=10:1,Rf=0.66);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加;然后过滤,收集滤渣,用水洗涤,并分别用EA(5mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得180mg的淡黄色固体,即N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3,5-二甲基苯甲酰胺(收率:59%);MS m/z(ESI):413.1714[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.59(s,1H),8.68(d,J=4.7Hz,1H),8.24(d,J=8.4Hz,2H),8.04(d,J=7.9Hz,1H),8.00(d,J=8.5Hz,2H),7.93(t,J=7.8Hz,1H),7.86(s,2H),7.59(s,2H),7.50–7.46(m,1H),7.24(s,1H),2.36(s,6H)。
实施例3
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-5,6,7,8-四氢萘-1-甲酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-5,6,7,8-四氢萘-1-甲酰胺的结构式为:
(1)、4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸甲酯的合成,化学方程式为:
将5,6,7,8-四氢萘-1-甲酸(500mg、2.84mmol)和4-氨基苯甲酸甲酯(430mg、2.84mmol)加入到单颈圆底烧瓶中,再加入无水DCM(12mL)溶解,然后在冰浴条件下加入Py(1.34g、16.96mmol),搅拌5min后,缓慢滴加POCl3(651mg、4.25mmol),保持冰浴条件反应25min,期间TLC监测反应情况(PE/EA=6:1,Rf=0.51);反应完全后,加入1M的HCl(10mL)进行淬灭反应,再将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相,然后向水相中分别加入10mL的DCM萃取2次,收集有机相,并将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后,得到粗产物;粗产物经过柱层析纯化(PE:EA=40:1,PE/EA=10:1),得到174mg的白色固体,即4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸甲酯(收率:20%);
(2)、4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸的合成,化学方程式为:
将4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸甲酯(120mg、0.39mmol)加入到100mL的单颈圆底烧瓶中,加入THF(10mL)搅拌2min溶解;随后,在室温下,滴加10mL的LiOH·H2O(81mg、1.93mmol)水溶液,滴毕,在室温下剧烈搅拌过夜;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时,停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得86mg的白色固体,即4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸粗产物(收率:59%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-5,6,7,8-四氢萘-1-甲酰胺的合成,化学方程式为:
将4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸(86mg,0.29mmol)粗产物、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(47mg、0.29mmol)、EDCI(11mg、0.06mmol)和DMAP(71mg、0.58mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,然后在冰浴条件下加入无水DMF(3mL)搅拌1h,再升温至室温,搅拌2h,期间TLC监测反应情况(DCM:MeOH=10:1,Rf=0.85);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,再过滤,
收集滤渣,用水洗涤;然后分别用EA(5mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得45mg的淡黄色固体,即N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-5,6,7,8-四氢萘-1-甲酰胺(收率:35%);MS m/z(ESI):439.1867[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.72(s,1H),8.68(d,J=4.7Hz,1H),8.22(d,J=8.5Hz,2H),8.04(d,J=7.9Hz,1H),7.94(d,J=8.7Hz,3H),7.84(s,2H),7.50–7.46(m,1H),7.27(t,J=4.4Hz,1H),7.21(d,J=4.5Hz,2H),2.80(s,4H),1.74(s,4H)。
实施例4
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-1-萘酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-1-萘酰胺的结构式为:
(1)、4-(1-萘酰胺)苯甲酸甲酯的合成,化学方程式为:
将1-萘甲酸(502mg、2.92mmol)和4-氨基苯甲酸甲酯(439mg、2.90mmol)加入到单颈圆底烧瓶中,再加入无水DCM(10mL)溶解;然后在冰浴条件下,加入Py(1.38g、17.47mmol),搅拌5min后,缓慢滴加POCl3(671mg、4.39mmol),保持冰浴条件反应25min,期间TLC监测反应情况(PE/EA=6:1,Rf=0.58);反应完全后,加入1M的HCl(10mL)进行淬灭反应;然后将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相;然后向水相中分别加入10mL的DCM萃取2次,收集有机相;再将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后得到粗产物;粗产物经过柱层析纯化(PE/EA=20:1,PE/EA=10:1,PE/EA=4:1),得到290mg的白色固体,即4-(5,6,7,8-四氢萘-1-甲酰胺基)苯甲酸甲酯(收率:33%);
(2)、4-(1-萘酰胺)苯甲酸的合成,化学方程式为:
将4-(1-萘酰胺)苯甲酸甲酯(590mg、1.93mmol)加入到100mL的单颈圆底烧瓶中,再加入THF(10mL)搅拌2min,溶解;随后,在室温下滴加10mL的LiOH·H2O(406mg、9.68mmol)水溶液,滴毕,在室温下剧烈搅拌过夜;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得510mg的白色固体,即4-(1-萘酰胺)苯甲酸粗产物(收率:91%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-1-萘酰胺的合成,化学方程式为:
将4-(1-萘酰胺)苯甲酸(198mg、0.68mmol)、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(111mg、0.69mmol)、EDCI(259mg、1.36mmol)和DMAP(171mg、1.40mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,然后在冰浴条件下,加入无水DMF(3.5mL)搅拌1h,再升温至室温搅拌2h,期间TLC监测反应情况(DCM/MeOH=10:1,Rf=0.63);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤;然后分别用EA(5mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得150mg的白色固体,即N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-1-萘酰胺(收率:35%);MS m/z(ESI):435.1558[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):11.04(s,1H),8.69(d,J=4.7Hz,1H),8.28(d,J=8.4Hz,2H),8.21(d,J=8.0Hz,1H),8.12(d,J=8.2Hz,1H),8.04(t,J=10.0Hz,4H),7.93(t,J=7.7Hz,1H),7.87(s,2H),7.83(d,J=6.9Hz,1H),7.63(dq,J=13.3,7.2,6.6Hz,3H),7.51–7.45(m,1H)。
实施例5
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环己烷甲酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环己烷甲酰胺的结构式为:
(1)、4-(环己基甲酰胺)苯甲酸甲酯的合成,化学方程式为:
将环己甲酸(1.01g、7.88mmol)、4-氨基苯甲酸甲酯(1.81g、7.81mmol)和CMPI(2.39g、9.35mmol)加入到100mL的单颈圆底烧瓶中,再加入2-MeTHF(25mL)溶解;然后在室温下,滴加DIPEA(3.03g、23.44mmol),搅拌5min后,升温至70℃,搅拌过夜,期间TLC监测反应情况(PE/EA=2:1,Rf=0.73);然后旋蒸除去溶剂2-MeTHF,向残余物中加入1M的HCl(20mL)和EA(20mL),用125mL的分液漏斗萃取,收集有机相,再向水相中分别加入20mL EA萃取2次,收集有机相,然后将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(EA)后得到粗产物;粗产物经过柱层析纯化(PE:EA=20:1,PE:EA=10:1,PE:EA=4:1),得到1.14g的白色固体,即4-(环己基甲酰胺)苯甲酸甲酯(收率:55%);
(2)、4-(环己基甲酰胺)苯甲酸的合成,化学方程式为:
将4-(环己基甲酰胺)苯甲酸甲酯(1.14g、4.36mmol)加入到100mL的单颈圆底烧瓶中,再加入THF(15mL)搅拌2min,溶解;随后,在室温下滴加15mL的LiOH·H2O(920mg、21.92mmol)水溶液,滴毕,在室温下剧烈搅拌过夜;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得910mg的白色固体,即4-(环己基甲酰胺)苯甲酸粗产物(收率:84%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环己烷甲酰胺的合成,化学方程式为:
将4-(环己基甲酰胺)苯甲酸(199mg、0.80mmol),3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(131mg、0.81mmol)、EDCI(309mg、1.62mmol)和DMAP(200mg、1.64mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,再在冰浴条件下,加入无水DMF(4mL)搅拌1h,然后升温至室温,搅拌2h,期间TLC监测反应情况(DCM/MeOH=10:1,Rf=0.86);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,然后分别用EA(5mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得108mg的淡黄色固体,即N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环己烷甲酰胺(收率:35%);MS m/z(ESI):391.1973[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.27(s,1H),8.67(d,J=5.0Hz,1H),8.19(d,J=8.9Hz,2H),8.02(d,J=7.8Hz,1H),7.92(t,J=7.8Hz,1H),7.84–7.77(m,4H),7.50–7.45(m,1H),2.38(t,J=11.6Hz,1H),1.83(d,J=10.0Hz,2H),1.76(d,J=12.9Hz,2H),1.65(d,J=12.2Hz,1H),1.42(q,J=15.8,14.2Hz,2H),1.32–1.13(m,4H)。
实施例6
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环庚酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环庚酰胺的结构式为:
(1)、4-(环庚基甲酰胺)苯甲酸甲酯的合成,化学方程式为:
将环庚甲酸(1.00g、7.03mmol)、4-氨基苯甲酸甲酯(1.06g、7.01mmol)和CMPI(2.16g、8.45mmol)加入到100mL的单颈圆底烧瓶中,再加入2-MeTHF(20mL)溶解,然后在室温下,滴加DIPEA(2.73g、21.12mmol),搅拌5min后升温至70℃,搅拌过夜,期间TLC监测反应情况(PE:EA=4:1,Rf=0.51);然后旋蒸除去溶剂2-MeTHF,向残余物中加入1M的HCl(20mL)和EA(20mL),用125mL的分液漏斗萃取,收集有机相,再向水相中分别加入20mL的EA萃取2次,收集有机相,然后将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(EA)后,得到粗产物;粗产物经过柱层析纯化(PE:EA=20:1,PE:EA=10:1,PE:EA=4:1),得到990mg的白色固体,即4-(环庚基甲酰胺)苯甲酸甲酯(收率:35%);
(2)、4-(环庚基甲酰胺)苯甲酸的合成,化学方程式为:
将4-(环庚基甲酰胺)苯甲酸甲酯(690mg、2.56mmol)加入到100mL的单颈圆底烧瓶中,再加入THF(5mL)搅拌2min,溶解;随后,在室温下,滴加5mL的LiOH·H2O(561mg、13.37mmol)水溶液,滴毕,在室温下,剧烈搅拌过夜;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得540mg的白色固体,即4-(环庚基甲酰胺)苯甲酸粗产物(收率:81%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环庚酰胺的合成,化学方程式为:
将4-(环庚基甲酰胺)苯甲酸(200mg、0.77mmol)粗产物,3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(120mg、0.74mmol)、EDCI(290mg、1.52mmol)和DMAP(190mg、1.56mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,再在冰浴条件下加入无水DMF(3mL)搅拌1h,然后升温至室温,搅拌2h,期间TLC监测反应情况(DCM:MeOH=10:1,Rf=0.76);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,
再过滤,收集滤渣,用水洗涤,然后分别用EA(5mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得99mg的白色固体,即N-(4-(5-氨基-3-
(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)环庚酰胺(收率:32%);MS m/z(ESI):405.2028[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.25(s,1H),8.67(d,J=4.7Hz,1H),8.19(d,J=8.4Hz,2H),8.02(d,J=7.8Hz,1H),7.92(t,J=7.7Hz,1H),7.87–7.76(m,4H),7.47(s,1H),2.55(p,J=5.2Hz,1H),1.86(s,2H),1.72(s,2H),1.63(q,J=11.9,10.6Hz,2H),1.60–1.40(m,6H)。
实施例7
N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)-2-氟苯基)噻吩-2-甲酰胺的制备方法,具体包括有以下步骤:
其中,N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)-2-氟苯基)噻吩-2-甲酰胺的结构式为:
(1)、3-氟-4-(噻吩-2-甲酰胺)苯甲酸甲酯的合成,化学方程式为:
将噻吩-2-羧酸(460mg、3.59mmol)和4-氨基-3-氟苯甲酸甲酯(610mg、3.61mmol)加入到单颈圆底烧瓶中,在加入无水DCM(10mL)溶解,然后在冰浴条件下加入Py(1.71g、21.65mmol),搅拌5min后,缓慢滴加POCl3(830mg、5.42mmol),保持冰浴条件反应25min,期间TLC监测反应情况(PE:EA=4:1,Rf=0.69);反应完全后加入1M的HCl(10mL)进行淬灭反应;再将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相;然后,向水相中分别加入10mL的DCM萃取2次,收集有机相;再将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后得到粗产物;粗产物经过柱层析纯化(PE:EA=20:1,PE:EA=6:1),得到330mg的淡黄色固体,即3-氟-4-(噻吩-2-甲酰胺)苯甲酸甲酯(收率:33%);
(2)、3-氟-4-(噻吩-2-甲酰胺)苯甲酸的合成,化学方程式为:
将3-氟-4-(噻吩-2-甲酰胺)苯甲酸甲酯(330mg、1.18mmol)加入到100mL的单颈圆底烧瓶中,再加入THF(5mL)搅拌2min,溶解;随后,在室温下,滴加5mL的LiOH·H2O(250mg、5.96mmol)水溶液,滴毕,在室温下剧烈搅拌过夜;然后旋蒸除去反应液中的THF,室温下,向反应液中滴加1M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得260mg的白色固体,即3-氟-4-(噻吩-2-甲酰胺)苯甲酸粗产物(收率:98%),无需进一步纯化即可进行下一步反应;
(3)、N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)-2-氟苯基)噻吩-2-甲酰胺的合成,化学方程式为:
将3-氟-4-(噻吩-2-甲酰胺)苯甲酸(200mg、0.75mmol)粗产物、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(120mg、0.74mmol)、EDCI(290mg、1.52mmol)和DMAP(180mg、1.47mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,再在冰浴条件下加入无水DMF(3mL)搅拌1h,然后升温至室温搅拌2h,期间TLC监测反应情况(DCM:MeOH=10:1,Rf=0.71);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤;然后,分别用EA(5mL)和MeOH(5mL)打浆过夜,过滤后收集滤渣,干燥,得110mg的淡黄色固体,即N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)-2-氟苯基)噻吩-2-甲酰胺(收率:36%);MS m/z(ESI):409.4185[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.44(s,1H),8.69(d,J=7.0Hz,1H),8.16(d,J=9.5Hz,1H),8.09(d,J=2.6Hz,1H),8.07–8.01(m,2H),7.95–7.87(m,5H),7.52–7.46(m,1H),7.29–7.24(m,1H)。
实施例8
(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3-环己基-2-(环己基氨基)丙酰胺的制备方法,具体包括有以下步骤:
其中,(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3-环己基-2-(环己基氨基)丙酰胺的结构式为:
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(1)、(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸甲酯的合成,化学方程式为:
将(R)-3-环己基-2-(环己基氨基)丙酸(710mg、2.80mmol)和4-氨基苯甲酸甲酯(420mg、2.78mmol)加入到单颈圆底烧瓶中,再加入无水DCM(10mL),溶解,然后在冰浴条件下加入Py(1.33g、16.84mmol),搅拌5min后,缓慢滴加POCl3(640mg、4.18mmol),保持冰浴条件反应25min,期间TLC监测反应情况(PE:EA:Et3N=6:1:0.4,Rf=0.79);反应完全后加入1M的HCl(10mL)进行淬灭反应;然后将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相;然后,向水相中分别加入10mL的DCM萃取2次,收集有机相,再将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后得到粗产物;粗产物经过柱层析纯化(PE:Et3N=40:1,PE:EA:Et3N=40:2:1),得到260mg的白色固体,即(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸甲酯(收率:24%);
(2)、(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸的合成,化学方程式为:
将(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸甲酯(260mg、0.67mmol)加入到100mL的单颈圆底烧瓶中,再加入THF(5mL)搅拌2min,溶解;随后,在室温下,滴加5mL的LiOH·H2O(140mg、3.34mmol)的水溶液,滴毕,在50℃下,剧烈搅拌过夜;然后旋蒸除去反应液中的THF后,在室温下,向反应液中滴加2M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得210mg的白色固体,即(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸粗产物(收率:84%),无需进一步纯化即可进行下一步反应;
(3)、(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3-环己基-2-(环己基氨基)丙酰胺的合成,化学方程式为:
将(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸(200mg、0.54mmol)粗产物、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(87mg、0.54mmol)、EDCI(210mg、1.10mmol)和DMAP(130mg、1.06mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,再在冰浴条件下加入无水DMF(3mL)搅拌1h,然后升温至室温搅拌2h,期间TLC监测反应情况(DCM:MeOH=20:1,Rf=0.66);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,
再过滤,收集滤渣,用水洗涤;然后,分别用EA(5mL)和甲醇(5mL)打浆,过滤后收集滤渣,干燥,得125mg的白色固体,即(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-3-环己基-2-(环己基氨基)丙酰胺(收率:45%);MS m/z(ESI):516.3076[M+H]+;1H NMR(600MHz,DMSO-d6)δ(ppm):10.28(s,1H),8.67(d,J=4.4Hz,1H),8.18(d,J=8.4Hz,2H),8.02(d,J=7.9Hz,1H),7.92(t,J=7.7Hz,1H),7.87–7.77(m,3H),7.50–7.44(m,1H),3.40(s,1H),2.32(s,1H),2.02–1.83(m,2H),1.66(td,J=39.9,36.7,11.8Hz,7H),1.55–1.34(m,4H),1.26–0.98(m,8H),0.89(t,J=12.7Hz,2H)。
实施例9
(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-2-(环己基氨基)-3-苯基丙酰胺的制备方法,具体包括有以下步骤:
其中,(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-2-(环己基氨基)-3-苯基丙酰胺的结构式为:
(1)、(R)-4-(2-(环己基氨基)-3-苯基丙酰胺基)苯甲酸甲酯的合成,化学方程式为:
将环己基-D-苯丙氨酸(1.00g、4.04mmol)和4-氨基苯甲酸甲酯(610mg、4.04mmol)加入到单颈圆底烧瓶中,再加入无水DCM(12mL)溶解,然后在冰浴条件下加入Py(1.92g、24.30mmol),搅拌5min后,缓慢滴加POCl3(930mg、6.08mmol),保持冰浴条件反应25min,期间TLC监测反应情况(PE:EA:Et3N=6:1:0.4,Rf=0.71);反应完全后,加入1M的HCl(10mL)进行淬灭反应;再将混合后的溶液加入到125mL的分液漏斗中萃取,收集有机相,然后,向水相中分别加入10mL的DCM萃取2次,收集有机相;再将有机相合并,随后加入无水Na2SO4干燥,过滤后收集滤液,再旋蒸除去溶剂(DCM)后,得到粗产物;粗产物经过柱层析纯化(PE:Et3N=40:1,PE:EA:Et3N=40:2:1),得到590mg的白色固体,即(R)-4-(3-环己基-2-(环己基氨基)丙酰胺基)苯甲酸甲酯(收率:38%);
(2)、(R)-4-(2-(环己基氨基)-3-苯基丙酰胺基)苯甲酸的合成,化学方程式为:
将(R)-4-(2-(环己基氨基)-3-苯基丙酰胺基)苯甲酸甲酯(590mg、1.55mmol)加入到100mL的单颈圆底烧瓶中,再加入THF(5mL)搅拌2min,溶解;随后,在室温下,滴加5mL的LiOH·H2O(330mg、7.86mmol)的水溶液,滴毕,在50℃下剧烈搅拌过夜;然后旋蒸除去反应液中的THF后,在室温下,向反应液中滴加2M的HCl(反应液酸碱性接近中性时有固体析出),至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤,干燥,得430mg的白色固体,即(R)-4-(2-(环己基氨基)-3-苯基丙酰胺基)苯甲酸粗产物(收率:76%),无需进一步纯化即可进行下一步反应;
(3)、(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-2-(环己基氨基)-3-苯基丙酰胺的合成,化学方程式为:
将(R)-4-(2-(环己基氨基)-3-苯基丙酰胺基)苯甲酸(200mg、0.55mmol)粗产物、3-(吡啶-2-基)-1H-1,2,4-三唑-5-胺(88mg、0.55mmol)、EDCI(210mg、1.10mmol)和DMAP(130mg、1.06mmol)加入到带三通节门的25mL反应管中,采用N2抽换气3次,再在冰浴条件下加入无水DMF(3mL)搅拌1h,然后升温至室温搅拌2h,期间TLC监测反应情况(DCM:MeOH=20:1,Rf=0.60);反应完全后,滴加水稀释反应液,有固体析出,至再无固体析出时停止滴加,再过滤,收集滤渣,用水洗涤;然后,分别用EA(5mL)和甲醇(5mL)打浆,过滤后收集滤渣,干燥,得140mg的白色固体,即(R)-N-(4-(5-氨基-3-(吡啶-2-基)-1H-1,2,4-三唑-1-羰基)苯基)-2-(环己基氨基)-3-苯基丙酰胺(收率:50%);MS m/z(ESI):510.2611[M+H]+;1H NMR(600MHz,Chloroform-d)δ(ppm):9.97(s,1H),8.74(d,J=4.8Hz,1H),8.38(s,2H),8.12(d,J=7.9Hz,1H),7.83–7.76(m,3H),7.34(dd,J=13.7,8.5Hz,3H),7.28(d,J=7.3Hz,1H),7.24(d,J=7.4Hz,2H),6.95(s,2H),3.53(d,J=6.0Hz,1H),3.32(d,J=10.0Hz,1H),2.75(d,J=12.1Hz,1H),2.25(s,1H),1.78(d,J=12.5Hz,1H),1.58(d,J=54.5Hz,3H),1.40–0.99(m,6H),0.75(d,J=11.8Hz,1H)。
实施例10-实施例12制得化合物的质谱和核磁氢谱参数见下表1。
表1
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按照以下方法测试本发明实施例制得化合物对于凝血因子XIIa的抑制活性。
首先,将购自Enzyme Research Laboratories的凝血因子XIIa(HFXIIa1212a)加入纯化水稀释至2.5μM,然后再将其用缓冲液(50mM Tris/HCl,pH:7.4,100mM NaCl,0.1%BSA)稀释至10nM;然后,将购自的显色底物H-D-CHA-Gly-Arg-pNA·2AcOH加入纯化水,稀释至2.5mM,然后再将其用缓冲液稀释至500μM;制得的化合物溶于DMSO中,用DMSO稀释后浓度为76μM,随后,在96孔板透明底板中,向每个孔加入75μL的凝血因子XIIa酶溶液(10nM)和2μL含有化合物的DMSO溶液(76μM)后,置于37℃的烘箱中孵育15min,再加入75μL的显色底物溶液(500μM),此时,化合物终浓度为1μM,然后,将96孔板放于酶标仪中、于27℃下读数(λ=405nm),每分钟读数1次,共读数60min。将酶活性定量为吸光度的变化率,其对应于底物裂解的速率。
表2为实施例1-5、实施例20和实施例21制得化合物其分子量和对于凝血因子XIIa抑制率的测试结果。
表2
表2中,“A”表示抑制率为80%-90%;“B”表示抑制率为70%-80%。
从表2化合物对于凝血因子XIIa抑制率的测试结果可知,其抑制率均高于70%,可良好地抑制凝血因子XIIa的活性。
尽管已经示出和描述了本发明的实施例,对于本领域的普通技术人员而言,可以理解在不脱离本发明的原理和精神的情况下可以对这些实施例进行多种变化、修改、替换和变型,本发明的范围由所附权利要求及其等同物限定。
Claims (5)
1.一种化合物及其立体异构体、或其药学上可接受盐,其特征在于:所述的化合物的结构式如下通式(Ⅰ)所示:
式(1)中,R1选自氢、氘、卤素、Cl-3烷基、Cl-3卤代烷基和Cl-3烷氧基;R2选自未取代的单环烷基、环上有取代基的单环烷基、未取代的苯基、苯环上有取代基的苯基、杂芳基、双环系统和烷胺基叉链系统;
其中,所述的未取代的单环烷基选自环丙烷、环丁烷、环戊烷、环己烷、环庚烷和环辛烷;
所述的环上有取代基的单环烷基选自环上有取代基的环丙烷、环上有取代基的环丁烷、环上有取代基的环戊烷、环上有取代基的环己烷、环上有取代基的环庚烷和环上有取代基的环辛烷;其中,环上的取代基选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基和氰基;当环上的取代基为一个时,单取代基取代于环烷基的任意亚甲基上;当环上的取代基为多个时,多个取代基分别取代于环烷基不同位置的亚甲基上;
所述的杂芳基选自咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、三唑基、四唑基、吡啶基、嘧啶基、噻二唑、哒嗪基和吡嗪基;
所述的双环系统选自萘基、1,2,3,4-四氢萘基、2,3-二氢苯并[b][1,4]二噁烷基、吲哚基、异吲哚基、羟吲哚基、四氢吲哚基、二氢吲哚基、异二氢吲哚基、四氢喹啉基、四氢异喹啉基、3,4-二氢-1H-异色烯基、3,4-二氢-2H-色烯基、苯并呋喃基、二氢苯并呋喃基、四氢苯并呋喃基、苯并噻吩基、四氢苯并噻吩基、吲唑基、四氢吲唑基、2,3-二氢-1H-茚基、萘基和异色满基;
所述的烷胺基叉链系统选自下式(Ⅱ-1)-(Ⅱ-9):
(Ⅱ-1)-(Ⅱ-9)中,表示此处手性C原子上的C-N键内翻。
2.根据权利要求1所述的一种化合物及其立体异构体、或其药学上可接受盐,其特征在于:所述的苯环上有取代基的苯基其结构式为下式(Ⅲ):
式(Ⅲ)中,取代基R3-R7均选自氢、氘、卤素、C1-4烷基、C1-4氘代烷基、二氟甲基、三氟甲基、C1-3烷氧基、二氟甲氧基、三氟甲氧基、C1-3烷硫基、羟基、氨基、氰基和硝基;为取代基的连接点位。
3.一种药物组合物,其特征在于:包括权利要求1所述的一种化合物及其立体异构体、或其药学上可接受盐。
4.根据权利要求1或2所述的化合物及其立体异构体、或其药学上可接受盐或权利要求3所述的药物组合物在制备一种用于抑制凝血因子XIIa的药物的用途。
5.根据权利要求4所述的用途,其特征在于:所述的抑制凝血因子XIIa的药物是通过抑制凝血因子XIIa,用于预防和治疗与血液增稠、凝血或血凝块形成有关的疾病。
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