CN115806503A - 一种选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用 - Google Patents
一种选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用 Download PDFInfo
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- CN115806503A CN115806503A CN202211544602.4A CN202211544602A CN115806503A CN 115806503 A CN115806503 A CN 115806503A CN 202211544602 A CN202211544602 A CN 202211544602A CN 115806503 A CN115806503 A CN 115806503A
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- benzyl
- carbonyl
- benzamide
- hydrazine
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Abstract
本发明公开了一种选择性组蛋白去乙酰化酶抑制剂及其制备方法和应用。所述的组蛋白去乙酰化酶抑制剂是以六元骈环为母核,以酰肼为锌离子螯合基团的化合物,其具有如通式(I)所示的结构,本发明还提供了该类化合物的制备方法。本发明的化合物对组蛋白去乙酰化酶11(HDAC11)具有明显抑制作用,能够用于制备治疗与组蛋白去乙酰化酶活性异常表达相关疾病的药物,如肿瘤、肝脏疾病、高脂血症、糖尿病、心血管疾病、肥胖和动脉粥样硬化等。
Description
技术领域
本发明涉及化学合成药物技术领域,具体涉及一种含有酰肼类组蛋白去乙酰化酶抑制剂及其制备方法和应用。
背景技术
组蛋白去乙酰化酶(HDAC)通过组蛋白去乙酰化和非组蛋白赖氨酸翻译后修饰参与多种生理反应。靶向HDAC已表现出明显的临床作用,尤其是用于癌症治疗,美国和中国食品药品管理局已批准五种HDAC抑制剂(HDACIs)用于治疗皮肤T细胞淋巴瘤、外周T细胞淋巴瘤及多发性骨髓瘤(Journal of Medicinal Chemistry,2020,63,12460-12484)。在所有锌离子依赖性的HDAC酶中,HDAC11是最晚被发现的。据报道,HDAC11参与免疫功能(NatureImmunology,2009,10,92-100)、成肌细胞分化(Molecules and Cells,2017,40,667-676)、代谢(EBioMedicine 2018,33,157-168)和癌症(International Journal of Cancer,2013,132,2200-2208;Blood,2020,135,191-207;American Journal of TranslationalResearch,2019,11,983-990)。近年来,研究表明HDAC11在肝细胞癌(HCC)中高度表达,HDAC11的缺失导致癌症干性和HCC进展的抑制,这是通过增加LKB1的转录、激活AMPK信号通路和抑制糖酵解途径介导的(Cancer Research,2021,81,2015-2028)。另一项研究还显示,敲除HDAC11可抑制HCC的增殖和索拉非尼耐药性(Frontiers in Cell and DevelopmentalBiology,2020,8,724)。此外,HDAC11还与糖脂代谢异常密切相关(EBioMedicine 2018,33,157-168;PNAS 2022,119,e2119678119);研究者还发现HDAC11的缺失能够增加骨骼肌中氧化肌纤维的数量(The FEBS Journal 2021,288,902–919);也有研究发现HDAC11通过激活NLRP3/caspase-1/GSDMD以及caspase-3/GSDME通路诱导血管内皮细胞焦亡,最终导致动脉粥样硬化的发生(Cell Death Discovery 2022,8,112)。因此,抑制HDAC11可能是克服肝癌治疗中激酶耐药性的潜在途径,也是治疗糖脂代谢相关疾病如肥胖、脂肪肝、糖尿病、动脉粥样硬化等疾病的潜在方式。由于抑制HDAC11可能有助于治疗多种人类疾病,因此开发HDAC11选择性抑制剂不仅对深入研究HDAC11的生物学功能,而且对治疗HDAC11相关适应症具有重要意义。
与其他HDAC亚型选择性抑制剂的蓬勃发展不同,HDAC11特异性抑制剂仍处于开发的初始阶段,仅有少数报道,如:FT895(Bioorganic&Medicinal Chemistry Letters,2018,28,2143-2147)、SIS17(ACS Chemical Biology,2019,14,1393-1397)和Garcinol(ACSChemical Biology,2020,15,2866-2871)。其中,FT895抑制HDAC11的IC50值为0.74μM,而它对HDAC4和HDAC8也具有微摩尔级抑制活性。Garcinol是一种天然产物,对HDAC11的IC50值约为10μM。SIS17是目前最具选择性的HDAC11抑制剂,它对HDAC11的IC50为0.83μM。现有HDAC11抑制剂并未表现出理想的活性,因此HDAC11抑制剂仍有巨大的开发空间。
发明内容
针对上述问题,本发明的第一目的在于提供一类具有良好的抗肿瘤、抗代谢性疾病的活性,并表现出优异的HDAC11抑制作用的组蛋白去乙酰化酶抑制剂。
本发明的第二目的在于提供一种组蛋白去乙酰化酶抑制剂化合物的制备方法,该方法以价格低廉、易得的原料、较高的产率合成所需化合物,并且所制备化合物的性质稳定。
本发明的第三目的在于提供上述化合物用于制备HDAC11抑制剂以及抗肿瘤、抗代谢性疾病如脂肪肝、糖尿病、肥胖、动脉粥样硬化等的药物中的用途。
本发明设计合成了一类以取代或无取代的芳香环等结构为母核,以不同长度碳链及含杂原子碳链的酰肼基团为锌离子螯合基团的化合物,并在体外实验中验证了其具有显著的治疗作用。
一方面,本发明提供了一种组蛋白去乙酰化酶抑制剂,其特征在于其为以取代或无取代的芳香环等结构为母核,以酰肼为锌离子螯合基团的酰肼类化合物。所述抑制剂为具有如通式(I)所示结构的化合物、其氘代物或药学上可接受的盐:
其中:
或R2取代基是一个或多个且在环上的位置不定,选自H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基任选的被1-2个C1-C2烷基、C2-C3炔基取代;所述的羟基任选的被C1-C2烷基、C2-C3炔基取代;X选自NH、O或S;Y选自CH或N;W选自CH2、O或NCH3;J1、J2、J3、J4分别独立地选自C、CH或N;
Z选自键或五元芳杂环;
R1选自H、C1-C20烷烃、C1-C20烷基取代的C3-C6环烷烃、C1-C20烷基取代的羟基、
B、D、E、F、G分别独立地选自C、CR4或N;其中R4选自一个或多个H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基无取代或任选的被1-2个C1-C2烷基、C1-C2烷氧基、C2-C3炔氧基取代;所述的羟基无取代或任选的被C1-C2烷基、C1-C2烷氧基或C2-C3炔氧基取代。
所述通式(I)化合物进一步具有如通式(Ⅱ)或通式(Ⅲ)所示结构:
所述通式(II)或(III)中,L连接于B或G;通式(II)中B为碳原子;通式(III)中G为碳原子。
另一方面,本发明还提供了如上所述的通式(I)的化合物、其氘代物或药学上可接受的盐的制备方法,包括以下步骤:
其中X为NH、O或S,n为1-18之间的整数,R5选自H、C1-C18烷基或含氧烷基。
首先以化合物2为原料,在氢氧化钾的作用下生成相应的钾盐,与相应化合物1反应得到中间体3,随后以二氯甲烷或四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1-羟基苯并三唑作用下与N,O-二甲羟胺盐酸盐反应得到相应的酰胺类中间体4,最后以四氢呋喃为溶剂经过氢化铝锂还原得到相应的醛类中间体5。以四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂,丙烯酸叔丁酯与相应中间体7发生Michael加成得到中间体8,以二氯甲烷或乙酸乙酯或四氢呋喃为溶剂,经过三氟乙酸或饱和氯化氢溶液脱除叔丁基后得到羧酸中间体9,随后以二氯甲烷或四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1-羟基苯并三唑作用下与N,O-二甲羟胺盐酸盐反应得到相应的酰胺类中间体10,最后以四氢呋喃为溶剂经过氢化铝锂还原得到相应的醛类中间体11。随后以中间体12为原料,以二氯甲烷或四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1-羟基苯并三唑作用下或三光气和三乙胺的作用下与取代或未取代的4-氨甲基苯甲酸甲酯盐酸盐、4-氨基苯甲酸甲酯或3-氨甲基苯甲酸甲酯盐酸盐反应得到中间体13;所述中间体2,以甲醇或乙醇为溶剂,再与水合肼反应得到中间体14;所述中间体14进一步与相应的醛反应得到最终的目标化合物。
此外,本发明还提供了一种药物组合物,其包含如上所述的通式(I)、(II)或(III)所示的化合物、其氘代物或药学上可接受的盐以及药学上可接受的稀释剂或载体;所述化合物、其氘代物或药学上可接受的盐的含量为0.1-99.9wt%。
最后,本发明提供了如上所述的通式(I)、(II)或(III)的化合物、其氘代物或药学上可接受的盐在制备HDAC11抑制剂中的用途。
另一方面,本发明还提供了如上所述的通式(I)、(II)或(III)的化合物、其氘代物或药学上可接受的盐在制备与HDAC11活性异常表达相关的疾病的药物中的用途,所述与HDAC11活性异常表达相关疾病包括肿瘤、神经退行性疾病、代谢性疾病、炎症反应等。
所述肿瘤包括肝癌、甲状腺癌、各类白血病、淋巴瘤、骨髓瘤、三阴性乳腺癌、肺癌、黑色素瘤、食道癌、肾癌、口腔癌、舌癌、前列腺癌、乳腺癌、宫颈癌、卵巢癌、胃癌、胰腺癌、膀胱癌、结肠直肠癌、鼻咽癌、脑肿瘤、胶质瘤、成人胶质母细胞红斑、骨癌或软组织肉瘤。
所述的代谢性疾病包括脂肪肝、肥胖、高脂血症、高血压、动脉粥样硬化、糖尿病。
特别的,本发明所述的通式(I)、(II)或(III)的化合物、其氘代物或药学上可接受的盐在制备治疗肝癌或代谢性疾病的药物中的用途。
本发明的优点:
1、本发明在现有技术的基础上,针对现有HDAC11抑制剂的不足,提供了一种以单环、并环和联环等结构为母核,以不同长度碳链及含杂原子碳链的酰肼基团为锌离子螯合基团的HDAC抑制剂,并在体外实验中验证了其具有显著的治疗作用,该类化合物具有高度的亚型选择性、HDAC靶向性及优良的药代动力学性质,是一类具有发展潜力的抑制剂。
2、本发明所提供的合成方法具有以下优点:以廉价易得的原料通过4-5步简单绿色的合成方法即可以高收率得到所描述的化合物,为该类化合物的合成提供了新的方法。
附图说明
图1是索拉非尼与不同浓度化合物I-18联用时对肝癌细胞HUH7生长抑制的IC50值。
图2是索拉非尼与不同浓度化合物I-18联用时对肝癌细胞MHCC97H生长抑制的IC50值。
图3是小鼠肥胖模型中阳性对照组、阴性对照度及化合物I-18分别以1mg/kg和2mg/kg给药组的体重变化。
图4是小鼠肥胖模型中阳性对照组、阴性对照度及化合物I-18分别以1mg/kg和2mg/kg给药组的血液中甘油三酯的含量。
图5是小鼠肥胖模型中阳性对照组及化合物I-18以1mg/kg给药组肝脏组织中的脂滴对比图。
其中,A为HFD组,B为HFD+I-18 1mg/kg组。
具体实施方式
下面通过具体实施例来进一步详细说明本发明,其目的在于帮助更好地理解本发明内容而非限制本发明的保护范围。
I.本发明化合物:
如通式(I)所示的化合物、其氘代物或其药学上可接受的盐:
B、D、E、F和G分别独立地选自C、CR4或N;其中R4选自一个或多个H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基或羟基无取代或任选的被1-2个C1-C2烷基、C1-C2烷氧基、C2-C3炔氧基取代。
在一些实施例中,B、D、E、F和G中的0-2个选自N。
R2取代基是一个或多个且在环上的位置不定,选自H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基或羟基任选得被1-2个C1-C2烷基、C2-C3炔基取代;X选自NH、O或S;Y选自CH或N;W选自CH2、O或NCH3;J1、J2、J3、J4分别独立地选自C、CH或N;
Z选自键或五元芳杂环;
R1选自H、C1-C20烷烃、C1-C20烷基取代的C3-C6环烷烃、C1-C20烷基取代的羟基、
B、D、E、F和G分别独立地选自C、CR4或N;其中R4选自一个或多个H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基或羟基无取代或任选的被1-2个C1-C2烷基、C1-C2烷氧基、C2-C3炔氧基取代。
在一些实施例中,R4为H;在一些实施例中,R4为甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基或叔丁基。
在一些实施例中,R2或R3独立的选自一个或多个卤素、卤代烷基、(C1-C2)烷氧基、酚羟基、氰基。在一些实施例中,R2或R3选自一个或多个卤素、卤代烷基、(C1-C2)烷氧基、酚羟基。在一些实施例中,R2或R3选自一个或多个卤素、卤代烷基、(C1-C2)烷氧基。在一些实施例中,R2或R3选自一个或多个卤素、卤代烷基。在一些实施例中,R2或R3基选自一个或多个卤素。在一些实施例中,R2或R3选自F、Cl、Br或I中一个或多个。在一些实施例中,R2或R3选自卤代烷基。在一些实施例中,R2或R3为卤代烷基,其中卤原子选自F、Cl、Br或I。在一些实施例中,R2或R3为卤代烷基,其中卤原子为F。在一些实施例中,R2或R3为卤代烷基,其中卤原子为Cl。在一些实施例中,R2或R3为卤代烷基,其中卤原子为Br。在一些实施例中,R2或R3为卤代烷基,其中卤原子为I。在一些实施例中,R2或R3为-CH2Cl、CH2F、-CH2Br、CHF2、CF3、-CFClBr、CH2CH2F、-CH2CH2Cl、CH2CHF2、CH2CF3、-CH2CCl3、CH2CH2CH2F、CH2CH2CHF2或CH2CH2CF3等。
R2取代基是一个或多个且在环上的位置不定,选自H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基或羟基任选得被1-2个C1-C2烷基、C2-C3炔基取代;X选自NH、O或S;Y选自CH或N;W选自CH2、O或NCH3;J1、J2、J3、J4分别独立地选自C、CH或N;
本发明还提供了如上所述的通式(I)的化合物、其氘代物或其药学上可接受的盐,其用作药物。
II.制备方法:
通式(I)化合物的制备方法,包括以下步骤:
路线一:
在反应1中,起始原料2在KOH的作用下生成醇钾,然后与原料1反应得到中间体3,反应条件为:KOH,90℃,12h;在反应2中,中间体3在EDCI和HOBt的作用下与N,O-二甲羟胺盐酸盐缩合得到中间体4,反应条件为:EDCI,HOBt,DCM,r.t.,6h;TEA,DCM,r.t.,6h;在反应3中,中间体4经氢化铝锂还原得到醛类中间体5,反应条件为:LiAlH4,THF,-20℃,2h。
路线二:
在反应4中,中间体6和7发生Michael加成反应,得到中间体8,反应条件为:NaH,rt,24h;在反应5中,中间体8在碱性条件下水解得到羧酸化合物9,反应条件为:3N KOH,rt,2h;反应6和7与路线一一致。
路线三:
在反应8中,起始原料12在EDCI和HOBt或三光气和三乙胺的作用下与取代或未取代的4-氨甲基苯甲酸甲酯盐酸盐或4-氨基苯甲酸甲酯反应得到中间体13,反应条件为:EDCI,HOBt,DCM,r.t.,6h或TEA,DCM,r.t.,6h。
在反应9中,中间体13与水合肼反应得到酰肼关键中间体14,反应条件为:水合肼,MeOH,80℃,24h。
在反应10中,中间体14先与醛生成席夫碱,再经过NaBH3CN还原得到式(I)的化合物,反应条件为:醛,MeOH,NaBH3CN,r.t.,4h。
以上以氧原子为例,同样适用于相应的N和S原子。
III.定义
前缀“Cx-Cy”表示后续基团具有x(例如1)至y(例如12)个碳原子,在某些基团中,其中一个或多个可由一个或多个杂原子或杂原子基团置换。例如,“(C1-C12)烷基”表示所述烷基具有1至12个碳原子。类似地,术语“x-y元”环,其中x和y为数值范围,例如“5至6元杂环”,是指含有x-y个原子(例如5-6)的环,诸如N、O、S,且其余原子为碳。
“烷基”是指衍生自直链或支链饱和烃的任何基团。烷基包括但不限于甲基、乙基、丙基诸如丙-1-基、丙-2-基(异丙基)、丁基诸如丁-1-基(正丁基)、丁-2-基(仲丁基)、2-甲基-丙-1-基(异丁基)、2-甲基-丙-2-基(叔丁基)、戊基、己基、辛基、癸基等。除非另有说明,否则烷基具有1至12个碳原子,例如1至8个碳原子,例如1至6个碳原子,例如1至4个碳原子、例如1至2个碳原子。
“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述所定义的烷基,“C1-C12烯基”指含有1-12个碳的直链或支链烯基,包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-、2-或3-丁烯基等,除非另有说明,否则烯基具有1至12个碳原子,例如1至8个碳原子,例如1至6个碳原子,例如1至4个碳原子、例如1至2个碳原子。所述烯基可以是取代的或未取代的。
“卤代烷基”是指其中一个或多个氢原子各自被卤素取代的烷基。实例包括但不限于-CH2Cl、CH2F、-CH2Br、CHF2、CF3、-CFClBr、CH2CH2F、-CH2CH2Cl、CH2CHF2、CH2CF3、-CH2CCl3、CH2CH2CH2F、CH2CH2CHF2、CH2CH2CF3等,以及烷基诸如全氟烷基,其中所有氢原子都被氟原子取代。
“烷氧基”是指式-O-烷基的部分,其中烷基部分如上所定义。例如,C1-C2烷氧基是指具有与氧连接的1-2个碳原子的烷基部分。“卤代烷氧基”是指式-O-卤代烷基的部分,其中卤代烷基部分如上所定义。例如,(C1-C2)烷氧基是指具有与氧连接的1-2个碳卤代烷基的部分。
“多个”独立地指1、2、3、4、5、6、7、8、9或10个。
“任选”意味着随后所描述地事件或环境可以但不必发生,该说明包括该事件或环境发生或不发生地场合。例如,“任选的被一个或多个取代基取代”意味着取代基可以但不必须存在,该说明包括杂环基团被取代基取代的情形和杂环基团不被取代基取代的情形。
“取代的”指基团中的一个或多个氢原子、优选为最多5个、更优选为1~3个氢原子彼此独立地被相应数目的取代基取代。不言而喻、取代基仅处在它们的可能的化学位置、本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如:具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。
本领域技术人员应当理解,可以制备通式(I)(I)的化合物的盐,包括药学上可接受的盐。这些盐类可以在所述化合物最终分离和纯化过程中原位制备,或者通过独立地分别将以其游离酸或游离碱形式的纯化的化合物与适合的碱或酸反应制备。
可以与无机酸和有机酸形成药学上可接受的酸加成盐,例如,乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴酸盐、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/盐酸盐、柠檬酸盐、乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、马尿酸盐、氢碘化物/碘化物、羟乙基磺酸盐、乳酸盐、乳糖酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、甲磺酸盐、甲基硫酸盐、萘甲酸盐、萘磺酸盐、烟酸盐、硝酸盐、硬脂酸盐、油酸盐、草酸盐、软脂酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、聚半乳糖醛酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐或三氟乙酸盐。
可以生成盐的无机酸包括,例如,盐酸、氢溴酸、硫酸、硝酸、磷酸等。
可以生成盐的有机酸包括,例如,乙酸、丙酸、羟乙酸、草酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、扁桃酸、甲磺酸、乙磺酸、甲苯磺酸、磺基水杨酸等。药学上可接受的碱加成盐可以与无机或有机碱形成。
可以生成盐的无机碱包括,例如,铵盐和元素周期表的I至XII族的金属。在某些实施方案中,所述盐是衍生自钠、钾、铵、钙、镁、铁、银、锌或铜;特别适合的盐包括铵盐、钾盐、钠盐、钙盐或镁盐。
可以生成盐的有机碱包括,例如,伯胺、仲胺和叔胺,取代的胺包括天然产生的取代胺类,环胺、碱离子交换树脂等。某些有机胺类包括异丙胺、二乙醇胺、二乙胺、赖氨酸、葡甲胺、哌嗪及氨基丁三醇。
本发明的药学上可接受的盐能够通过常规的化学方法由碱性或酸性部分合成而来。通常,这些盐能够通过将这些化合物的游离酸形式与化学量的合适的碱(Na、Ca、Mg或K的氢氧化物、碳酸盐、碳酸氢盐等)反应、或者通过将这些化合物的游离碱形式与化学量的合适的酸反应而进行制备。这些反应通常在水中或在有机溶剂中、或在两者的混合物中进行。通常,在适宜时,需要使用非水介质,例如乙醚、乙酸乙酯、乙醇、异丙醇或乙腈。其它合适的盐的列表可在“Remington's Pharmaceutical Sciences”,第20版,Mack PublishingCompany,Easton,Pa.,(1985);以及Stahl和Wermuth的“Handbook of PharmaceuticalSalts:Properties,Selection,and Use”(Wiley-VCH,Weinheim,德国,2002)中找到。
还可以制备通式(I)(I)的化合物的溶剂化物,包括药学上可接受的溶剂化物。“溶剂化物”是指由溶质和溶剂形成的可变化学量的复合物。为了本发明目的的此类溶剂不影响所述溶质的生物活性。适合溶剂的实例包括但不限于水、MeOH、EtOH或AcOH。其中水是溶剂分子的溶剂化物通常是指水合物。水合物包括包含化学计量的量的水的组分,以及包含可变量的水的组分。
如本文所用,术语“药学上可接受的”的含义是适用于药物用途的化合物。适用于药物的本发明化合物的盐和溶剂化物(例如水合物和盐的水合物)是其中平衡离子或结合溶剂是药学上可接受的那些。但是,具有非药学上可接受的平衡离子或结合溶剂的盐和溶剂化物也包含在本发明范围内,例如,用作制备其它本发明化合物和其药学上可接受的盐和溶剂化物的中间体。
通式(I)的化合物(包括其盐和溶剂化物)可以以结晶形式、非结晶形式或其混合物存在。所述化合物、其氘代物或其盐或溶剂化物还可以表现出多晶现象,即以不同结晶形式出现的能力。这些不同的结晶形式通常已知为“多晶型”。多晶型具有相同的化学组成,但是结晶固体状态的堆积、几何排列和其它描述特性不同。因此,多晶型可以具有不同的物理性质,例如形状、密度、硬度、变形性、稳定性和溶解度性质。多晶型通常表现出不同的熔点、IR光谱和X-射线粉末衍射图谱,其全部都可以用于鉴别。本领域技术人员能够了解,例如,通过改变或调整在式(I)的化合物的结晶/重结晶中所使用的条件而可能产生不同的多晶型。
本发明还包含通式(I)的化合物的不同异构体。“异构体”是指具有相同构成和分子量,但是物理和/或化学性质不同的化合物。结构的区别可以是在结构中(几何异构体)或者在旋转平面偏振光的能力上(立体异构体)。关于立体异构体,式(I)的化合物可以具有一个或多个不对称碳原子,并可以以外消旋体、外消旋混合物以及以单个对映异构体或非对映异构体出现。全部此类异构体形式都包含在本发明范围内,包括其混合物。如果所述化合物含有双键,取代基可以是E或Z构型。如果所述化合物包含二取代的环烷基,该环烷基的取代基可以具有顺式-或反式-构型。也期望包含全部的互变异构体形式。
通式(I)的化合物的任意不对称原子(例如碳等)都能够以外消旋或对映异构体富集存在,例如(R)-、(S)-或(R,S)-构型。在某些实施方案中,每一个不对称原子在(R)-或(S)-构型中有至少50%对映异构体过量、至少60%对映异构体过量、至少70%对映异构体过量、至少80%对映异构体过量、至少90%对映异构体过量、至少95%对映异构体过量、或至少99%对映异构体过量。如有可能,在具有不饱和双键的原子上的取代基以顺式-(Z)-或反式-(E)-形式存在。
因此,如本文所用,通式(I)的化合物能够是可能的异构体、旋转异构体、阻转异构体、互变异构体或其混合物之一的形式,例如作为基本上纯的几何异构体(顺式或反式)、非对映异构体、旋光异构体(对映异构体)、外消旋体或其混合物。
任何所得的异构体的混合物都能够基于组分的物理化学差异被分离成纯的或基本上纯的几何或旋光异构体、非对映异构体、外消旋体,例如通过色谱法和/或分步结晶。
任何所得的终产物或中间体的外消旋体能够通过已知的方法(例如通过其非对映体盐的分离)被拆分成旋光对映异构体,其用有光学活性的酸或碱获得,并且释放出有光学活性的酸性或碱性化合物。特别地,碱性部分因此可以用于将本发明的化合物拆分成其旋光对映异构体,例如通过与有光学活性的酸(例如酒石酸、二苯甲酰酒石酸、二乙酰酒石酸、二-O,O'-对甲苯酰酒石酸、扁桃酸、苹果酸或樟脑-10-磺酸)形成的盐的分步结晶。外消旋产物也能够通过手性色谱法进行拆分,例如使用手性吸附剂的高效液相色谱法(HPLC)。
本发明包括通式(I)的化合物的未标记的形式以及同位素标记的形式。同位素标记的化合物具有由本文所给出的化学式描述的结构,除了一个或多个原子被具有所选择的原子量或质量数的原子替换。能够被掺入本发明化合物的同位素的实例包括氢、碳、氮、氧、磷、氟和氯的同位素,分别例如2H、3H、11C、13C、14C、15N、18F、31P、32P、35S、36Cl、125I。本发明包括如本文所定义的各种同位素标记的化合物,例如其中出现放射性同位素(例如3H和14C)的那些或其中出现非放射性同位素(例如2H和13C)的那些。这些同位素标记的化合物可用于代谢研究(例如使用14C)、反应动力学研究(例如用2H或3H)、检测或成像技术,例如正电子发射断层扫描术(PET)或单光子发射计算体层摄影术(SPECT),包括药物底物组织分布分析,或者用于患者的放射治疗。特别地,对于PET或SPECT研究可能特别需要18F或标记的化合物。同位素标记的式(I)的化合物通常能够通过本领域的技术人员已知的常规技术或者通过与所附实施例和制备例中所述方法类似的方法、使用合适的同位素标记的试剂代替以前所用的未标记的试剂进行制备。
此外,用较重的同位素、特别是氘(即2H或D))的取代可能带来由更强的代谢稳定性导致的某些治疗优势,例如增加的体内半衰期或减少的剂量需求或治疗指数的改善。可以理解,在本文中氘被视为式(I)的化合物的取代基。该较重同位素、特别是氘的浓度可能由同位素富集因子决定。如本文所用的术语“同位素富集因子”是指特定同位素的同位素丰度和天然丰度之间的比例。如果本发明化合物中的取代基被标为氘,那么对于每一个标出的氘原子,该化合物具有至少3500(在每一个标出的氘原子处52.5%氘掺入)-、至少4000(60%氘掺入)、至少4500(67.5%氘掺入)、至少5000(75%氘掺入)、至少5500(82.5%氘掺入)、至少6000(90%氘掺入)、至少6333.3(95%氘掺入)、至少6466.7(97%氘掺入)、至少6600(99%氘掺入)、或至少6633.3(99.5%氘掺入)的同位素富集因子。
本领域技术人员将能够识别在通式(I)的化合物中是否存在立体中心。因此,本发明包括可能的立体异构体,并且既包括外消旋化合物又包括单个对映异构体。当所需化合物是单个对映异构体时,其可以通过立体特异性合成或通过终产物或任何方便的中间体拆分获得。终产物、中间体或起始原料的拆分可以通过本领域已知的任何适合的方法实现。参见,例如E.L.Eliel,S.H.Wilen和L.N.Mander的“Stereochemistry of OrganicCompounds”(Wiley-interscience,1994)。
IV.药物组合物:
本发明提供了药物组合物,其包含如上所述的通式(I)的化合物、其氘代物或其药学上可接受的盐以及药学上可接受的稀释剂或载体。
药物组合物能够针对特定的给药途径进行配制,例如口服给药、肠胃外给药和直肠给药等。此外,本发明的药物组合物能够以固体形式(非限制性地包括胶囊、片剂、丸剂、颗粒剂、粉末剂或栓剂)或以液体形式(非限制性地包括溶液剂、混悬剂或乳剂)制成。药物组合物能够经历常规的制药操作(例如灭菌)和/或能够含有常规的惰性稀释剂、润滑剂或缓冲剂以及辅料,例如防腐剂、稳定剂、润湿剂、乳化剂和缓冲剂等。
通常,药物组合物是片剂或胶囊,其包含活性成分以及
a)稀释剂,例如乳糖、右旋糖、蔗糖、甘露醇、山梨醇、纤维素、甘氨酸等;
b)润滑剂,例如二氧化硅、滑石粉、硬脂酸、其镁或钙盐和/或聚乙二醇;对于片剂也包含
c)粘合剂,例如硅酸镁铝、淀粉糊、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮;如果需要,还有
d)崩解剂,例如淀粉、琼脂、海藻酸或其钠盐、或泡腾混合物;和/或
e)吸收剂、着色剂、调味剂和增甜剂。
根据本领域中已知的方法,片剂可以是薄膜包衣或肠溶包衣的。
用于口服给药的合适的组合物包括有效量的通式(I)的化合物、其氘代物或其药学上可接受的盐,其为片剂、锭剂、水或油混悬液、可分散的粉末或颗粒、乳剂、硬或软胶囊、或糖浆或酏剂的形式。根据本领域中已知的用于制备药物组合物的任意方法制备用于口服使用的组合物,并且为了提供精制和适口的制剂该组合物能够含有一种或多种选自增甜剂、调味剂、着色剂和防腐剂的试剂。片剂可以含有与适合于制备片剂的无毒的药学上可接受的赋形剂混合在一起的活性成分。这些赋形剂是例如惰性的稀释剂(例如碳酸钙、碳酸钠、乳糖、磷酸钙或磷酸钠);成粒剂和崩解剂(例如玉米淀粉、或海藻酸);粘合剂(例如淀粉、明胶或阿拉伯胶);和润滑剂(例如硬脂酸镁、硬脂酸或滑石粉)。片剂是未经包衣的或者通过已知的技术进行包衣从而延缓在胃肠道的崩解和吸收,从而在较长的时期内提供持久的作用。例如,能够使用延时材料,例如单硬脂酸甘油酯或二硬脂酸甘油酯。用于口服的制剂能够以硬明胶胶囊呈递,其中活性成分与惰性的固体稀释剂(例如碳酸钙、磷酸钙或高岭土)混合,或者以软明胶胶囊呈递,其中活性成分与水或油介质(例如花生油、液体石蜡或橄榄油)混合。
某些可注射的组合物是等渗水溶液或混悬液,栓剂有利地由脂肪乳或混悬液制得。所述的组合物可以进行灭菌和/或含有辅料,例如防腐、稳定、润湿或乳化剂、溶解促进剂、用于调节渗透压的盐和/或缓冲剂。此外,其也可以含有其他的治疗上有价值的物质。所述的组合物分别根据常规的混合、制粒或包衣法进行制备,并且含有大约0.1-75%或含有大约1-50%的活性成分。
由于水可能促进某些化合物的降解,本发明还提供无水的药物组合物和剂型,其包含作为活性成分的本发明化合物。
使用无水或低水含量的成分和低水含量或低湿度的条件能够制备本发明的无水的药物组合物和剂型。可以制备和贮存无水的药物组合物以便保持其无水的性质。因此,使用已知防止与水接触的材料包装无水的组合物以便其能够包含于合适的配方药盒中。合适的包装的实例非限制性地包括气密的箔、塑料、单位剂量容器(例如管形瓶)、泡罩包装和条带包装。
本发明进一步提供药物组合物和剂型,其包含1种或多种降低作为活性成分的本发明化合物的分解速率的试剂。该试剂(其在本文中称作“稳定剂”)非限制性地包括抗氧化剂(例如抗坏血酸)、pH缓冲剂或盐缓冲剂等。
对于大约50-70kg的个体,本发明的药物组合物或组合产品能够是大约1-1000mg活性成分的单位剂量,或者大约1-500mg或大约1-250mg或大约1-150mg或大约0.5-100mg、或大约1-50mg活性成分。化合物、药物组合物或其组合产品的治疗有效剂量取决于个体的物种、体重、年龄和个体情况、其正在接受治疗的病症或疾病或其严重程度。普通技术的内科医生、临床医师或兽医能够容易地确定为了预防、治疗或抑制病症或疾病的发展所需的每一种活性成分的有效量。
V.治疗用途
在一些实施例中,提供了如上所述的式(I)的化合物、其氘代物或其药学上可接受的盐在制备HDACs抑制剂中的用途。
在一些实施例中,提供了如上所述的式(I)的化合物、其氘代物或其药学上可接受的盐在制备治疗HDAC活性异常表达相关疾病的药物中的用途。
在一些实施例中,所述与HDAC活性异常表达相关疾病包括发育异常、肿瘤、神经退行性疾病、代谢性疾病、炎症反应或心脏病等,其中所述肿瘤包括肝癌、各类白血病、淋巴瘤、骨髓瘤、三阴性乳腺癌、肺癌、黑色素瘤、食道癌、前列腺癌、乳腺癌等。所述代谢性疾病包括脂肪肝、肥胖、高脂血症、高血压、动脉粥样硬化和糖尿病。
在一些实施例中,提供了一种治疗或预防与HDACs活性异常表达相关疾病的方法,其包括向有需要的受试者施用治疗有效量的通式(I)的化合物、其氘代物或其药学上可接受的盐。
在一些实施例中,所述方法包括与一种、两种、三种或四种其他治疗剂组合施用通式(I)的化合物、其氘代物或其药学上可接受的盐。
本文中,如果术语“组合”是用来描述组合施用,则应理解这可以表示同时施用、独立施用或序贯施用。在本发明的一个方面,“组合施用”是指同时施用。在本发明的另一方面,“组合施用”是指独立施用。在本发明的另一方面,“组合施用”是指序贯施用。当序贯施用或独立施用时,施用第二组分的延迟不应例如失去使用组合产生的效果的利益。
下面通过具体的制备实施例和应用实施例进一步说明本发明。
实施例中化合物的编号、名称与结构如下表所示。
路线一:
中间体5a:9-甲氧基壬醛(5a)
具体合成步骤如下:
a.化合物[9-甲氧基壬酸]的合成(3a)
将KOH(700mg,12.6mmol)置于100mL单口瓶中,加入30mL干燥的MeOH溶解,将溶液加热至90℃反应1小时。将9-溴壬酸(1g,4.2mmol)加入上述反应液,反应过夜。TLC检测原料反应完全,蒸干溶剂后用1M HCl调pH至4。用乙酸乙酯(20mL×3)萃取,合并有机相后用无水MgSO4干燥,过滤蒸干得到白色固体654mg,收率83%。ESI-MS m/z:187.92[M-H]-。
b.化合物[N,9-二甲氧基-N-甲基壬酰胺]的合成(4a)
将化合物3a(500mg,2.66mmol)置于50mL单口瓶中,加入15mL干燥二氯甲烷溶解,于冰浴下加入EDCI(612mg,3.2mmol)、HOBt(432mg,3.2mmol)和三乙胺(807mg,8mmol),反应30min。向反应液中加入N,O-二甲羟胺盐酸盐(312mg,3.2mmol)后室温反应过夜。TLC检测原料反应完全,反应液用1M HCl(20mL×3)洗涤,用无水MgSO4干燥有机相。经柱色谱分离,得无色油状物342mg,收率56%。1H NMR(400MHz,Chloroform-d)δ3.66(s,3H),3.34(t,J=6.6Hz,2H),3.31(s,3H),3.16(s,3H),2.39(t,J=7.6Hz,2H),1.66-1.49(m,6H),1.31-1.28(m,6H).
c.化合物[9-甲氧基壬醛]的合成(5a)
将化合物4a(231mg,1mmol)置于50mL双口瓶中,在N2保护下溶于干燥的四氢呋喃中,在-20℃下加入氢化铝锂(76mg,2mmol),反应2h。TLC检测原料反应完全,加入5mL 1MHCl淬灭反应,蒸除溶剂,用二氯甲烷萃取(20mL×3),合并有机相后用无水MgSO4干燥,蒸干溶剂得到123mg无色油状物,收率71%。ESI-MS m/z:172.92[M+H]+。
中间体5b:8-乙氧基辛醛(5b)
具体合成步骤如下:
将中间体5a中的甲醇替换为乙醇,9-溴壬酸替换为8-溴辛酸,其余均与5a中的制备方法相同,总收率35%。
中间体5c:7-丙氧基庚醛(5c)
将中间体5a中甲醇替换为正丙醇,9-溴壬酸替换为7-溴庚酸,其余均与5a中的制备方法相同。总收率32%。
中间体5d:6-丁氧基己醛(5d)
将中间体5a中甲醇替换为正丁醇,9-溴壬酸替换为6-溴己酸,其余均与5a中的制备方法相同。总收率32%。
中间体5e:5-(戊氧基)戊醛(5e)
将中间体5a中甲醇替换为正戊醇,9-溴壬酸替换为5-溴戊酸,其余均与5a中的制备方法相同。总收率37%。
中间体5f:12-甲氧基十二醛(5f)
将中间体5a中9-溴壬酸替换为12-溴十二烷酸,其余均与5a中的制备方法相同。总收率36%。
中间体5g:6-(2-甲氧基乙氧基)己醛(5f)
将中间体5a中甲醇替换为乙二醇单甲醚,9-溴壬酸替换为6-溴己酸,其余均与5a中的制备方法相同。总收率36%。
中间体5h:6-(2-甲氧基乙氧基)己醛(5f)
将中间体5a中甲醇替换为乙二醇单乙醚,9-溴壬酸替换为5-溴戊酸,其余均与5a中的制备方法相同。总收率39%。
中间体5i:6-(2-甲氧基乙氧基)己醛(5f)
将中间体5a中9-甲氧基壬酸替换为10-羟基癸酸,其余均与5a中的制备方法相同。总收率25%。
路线二:
中间体11:
a.化合物[2,5,8,11-四氧叔丁酯丙酸甲醚]的合成(8)
将丙烯酸叔丁酯(2g,15.6mmol)、三乙二醇单甲醚(2.6g,15.6mmol)和催化量NaH置于100mL双口瓶中,N2保护下加入干燥的四氢呋喃溶解,反应24h。TLC检测原料反应完全,柱色谱分离得无色油状物3.2g,收率70%。ESI-MS m/z:292.96[M+H]+。
b.化合物[2,5,8,11-四氧丙酸甲醚]的合成(9)
将化合物8(2.9g,10mmol)置于100mL单口瓶中,加入20mL甲醇和10mL 3N KOH,室温反应2h。TLC检测原料反应完全,蒸干溶剂后用1M HCl调pH至4。用乙酸乙酯(20mL×3)萃取,合并有机相后用无水MgSO4干燥,过滤蒸干得到无色油状物2.1g,收率89%。ESI-MS m/z:235.91[M-H]-。
c.化合物[N-甲氧基-N-甲基-2,5,8,11-四氧基丙酸-14-酰胺]的合成(10)
制备方法与化合物4a相同。
1H NMR(400MHz,Chloroform-d)δ3.76(t,J=6.7Hz,2H),3.67(s,3H),3.63-3.60(m,12H),3.35(d,J=13.4Hz,3H),3.15(s,3H),2.72(t,J=6.8Hz,2H).ESI-MS m/z:279.94[M+H]+
d.化合物[2,5,8,11-四氧基丙酸-14-醛]的合成(11)
制备方法与化合物5a相同。
中间体12:N-(4-(肼羰基)苄基)苯甲酰胺(12)
具体合成步骤如下:
a.化合物[4-(苯甲酰胺甲基)苯甲酸甲酯]的合成
室温条件下,将苯甲酸(244mg,2mmol)置于100mL茄型瓶中,加入30mL二氯甲烷溶解。冰浴下加入1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐(EDC·HCl)(460mg,2.4mmol),1-羟基苯并三唑(HOBt)(325mg,2.4mmol)和三乙胺(506mg,5mmol),反应0.5h。加入4-氨甲基苯甲酸甲酯盐酸盐(483mg,2.4mmol)后室温反应过夜。TLC检测原料反应完全,随后将反应物用水(20mL×3)洗涤,有机相用无水Na2SO4干燥。经柱色谱分离,得到化合物4-(苯甲酰胺甲基)苯甲酸甲酯(379mg,收率70%),为白色固体,直接用于下一步合成。ESI-MSm/z:269.92[M+H]+
b.中间体[N-(4-(肼羰基)苄基)苯甲酰胺]的合成
室温条件下,将4-(苯甲酰胺甲基)苯甲酸甲酯(269mg,1mmol)置于100mL茄型瓶中,加入30mL甲醇溶解。加入水合肼(840mg,15mmol)后回流24小时。TLC检测原料反应完全,蒸除甲醇后得到12(261mg,收率97%),直接用于下一步反应。ESI-MS m/z:269.94[M+H]+。
实施例1:N-(4-(2-十一烷基肼-1-羰基)苄基)苯甲酰胺(I-12)
具体合成步骤如下:
室温条件下,将中间体12(269mg,1mmol)置于100mL茄型瓶中,加入30mL甲醇溶解,然后加入十一醛(170mg,1mmol)。反应2h后,加入NaBH3CN(250mg,4mmol)并用HCl甲醇溶液调至酸性,反应6h。TLC检测原料反应完全,加入20mL饱和碳酸氢钠溶液,反应0.5h后蒸除甲醇,用二氯甲烷(20mL×3)萃取,合并有机相用无水Na2SO4干燥。经柱色谱分离,得到化合物I-12,(262mg,收率62%)。1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),9.08(t,J=6.0Hz,1H),7.91-7.86(m,2H),7.79-7.73(m,2H),7.57-7.50(m,1H),7.50-7.44(m,2H),7.37(d,J=8.3Hz,2H),5.08(s,1H),4.51(d,J=6.0Hz,2H),2.75(t,J=7.1Hz,2H),1.48-1.38(m,2H),1.34-1.15(m,16H),0.87-0.81(m,3H).13C NMR(126MHz,DMSO-d6)δ166.76,165.58,143.48,134.66,132.17,131.78,128.81,127.69,127.53,127.43,51.65,42.85,31.74,29.46,29.41,29.15,28.04,27.10,22.54,14.40.HRMS(ESI)for C26H36N3O2[M-H]-calcd422.28130,found 422.28137。
实施例2:N-(4-(2-(9-甲氧基壬基)肼-1-羰基)苄基)苯甲酰胺(I-13)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5a,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.07(t,J=6.0Hz,1H),7.88-7.82(m,2H),7.74(d,J=8.3Hz,2H),7.55-7.48(m,1H),7.44(dd,J=8.2,6.5Hz,2H),7.36-7.30(m,2H),5.04(s,1H),4.48(d,J=6.0Hz,2H),3.24(t,J=6.5Hz,2H),2.72(t,J=7.1Hz,2H),1.46-1.36(m,4H),1.28-1.18(m,10H).13C NMR(101MHz,DMSO-d6)δ166.79,165.65,143.57,134.72,132.26,131.87,128.90,127.79,127.62,127.50,72.42,58.31,51.72,42.90,29.56,29.53,29.47,29.37,28.14,27.18,26.20.HRMS(ESI)for C25H34N3O3[M-H]-calcd424.26057,found 424.26059。
实施例3:N-(4-(2-(8-乙氧基辛基)肼-1-羰基)苄基)苯甲酰胺(I-14)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5b,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.07(t,J=5.9Hz,1H),7.89-7.82(m,2H),7.77-7.69(m,2H),7.51(t,J=7.2Hz,1H),7.47-7.41(m,2H),7.34(d,J=8.1Hz,2H),5.03(s,1H),4.48(d,J=5.9Hz,2H),3.34(d,J=6.9Hz,2H),3.27(t,J=6.6Hz,2H),2.72(t,J=7.1Hz,2H),1.45-1.37(m,4H),1.26-1.19(m,8H),1.04(t,J=6.9Hz,3H).13C NMR(101MHz,DMSO-d6)δ166.79,165.66,143.57,134.72,132.25,131.87,128.90,127.78,127.62,127.50,70.26,65.70,51.73,42.90,29.81,29.50,29.41,28.13,27.16,26.25,15.69.HRMS(ESI)forC25H34N3O3[M-H]-calcd 424.26057,found424.26065。
实施例4:N-(4-(2-(7-丙氧基庚基)肼-1-羰基)苄基)苯甲酰胺(I-15)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5c,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(d,J=5.4Hz,1H),9.07(t,J=6.0Hz,1H),7.91-7.81(m,2H),7.74(d,J=8.3Hz,2H),7.56-7.48(m,1H),7.48-7.41(m,2H),7.34(d,J=8.2Hz,2H),5.01(d,J=6.5Hz,1H),4.48(d,J=6.0Hz,2H),3.28(t,J=6.5Hz,2H),3.24(t,J=6.6Hz,2H),2.76-2.68(m,2H),1.47-1.36(m,6H),1.30-1.21(m,6H),0.80(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ166.80,165.66,143.57,134.72,132.27,131.87,128.90,127.79,127.62,127.50,72.08,70.43,51.72,42.90,29.76,29.36,28.12,27.19,26.25,23.01,11.13.HRMS(ESI)for C25H34N3O3[M-H]-calcd 424.26057,found 424.26065。
实施例5:N-(4-(2-(6-丁氧基己基)肼-1-羰基)苄基)苯甲酰胺(I-16)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5d,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(d,J=5.8Hz,1H),9.07(t,J=6.0Hz,1H),7.89-7.83(m,2H),7.74(d,J=8.3Hz,2H),7.54-7.48(m,1H),7.48-7.41(m,2H),7.34(d,J=8.3Hz,2H),5.02(d,J=5.9Hz,1H),4.48(d,J=6.0Hz,2H),3.28(t,J=6.5Hz,4H),2.76-2.68(m,2H),1.48-1.35(m,6H),1.34-1.22(m,6H),0.82(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ166.80,165.66,143.57,134.73,132.27,131.87,128.90,127.79,127.62,127.51,70.44,70.14,51.70,42.91,31.88,29.76,28.15,27.05,26.22,19.44,14.32.HRMS(ESI)for C26H40N3O3[M-H]-calcd 466.30752,found 466.30746。
实施例6:N-(4-(2-(10-羟基癸基)肼-1-羰基)苄基)苯甲酰胺(I-17)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5i,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.09(t,J=6.0Hz,1H),7.86(d,J=7.2Hz,2H),7.74(d,J=8.0Hz,2H),7.51(t,J=7.2Hz,1H),7.44(t,J=7.4Hz,2H),7.34(d,J=8.0Hz,2H),5.06(s,1H),4.48(d,J=6.0Hz,2H),4.30(t,J=5.2Hz,1H),2.72(t,J=7.1Hz,2H),1.46-1.32(m,4H),1.30-1.19(m,12H).13C NMR(101MHz,DMSO-d6)δ166.80,165.66,143.58,134.71,132.24,131.88,128.91,127.79,127.62,127.51,61.24,51.73,42.90,33.08,29.62,29.54,29.51,28.15,27.21,26.04.HRMS(ESI)for C25H34N3O3[M-H]-calcd 424.26057,found 424.26059。
实施例7:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-18)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5e,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.07(t,J=6.0Hz,1H),7.91-7.82(m,2H),7.74(d,J=8.3Hz,2H),7.54-7.48(m,1H),7.47-7.41(m,2H),7.34(d,J=8.1Hz,2H),5.04(s,1H),4.48(d,J=6.0Hz,2H),3.31-3.22(m,4H),2.72(t,J=7.0Hz,2H),1.51-1.36(m,6H),1.36-1.27(m,2H),1.25-1.16(m,4H),0.85-0.76(m,3H).13C NMR(101MHz,DMSO-d6)δ166.83,165.69,143.57,134.73,132.26,131.86,129.95,128.89,127.79,127.63,127.51,70.48,70.42,51.71,42.92,29.69,29.45,28.46,27.97,23.94,22.49,14.47.HRMS(ESI)for C25H34N3O3[M-H]-calcd 424.26057,found 424.26047。
实施例8:4-氟-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-19)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-氟苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.09(t,J=6.0Hz,1H),7.96-7.89(m,2H),7.76-7.71(m,2H),7.34(d,J=8.3Hz,2H),7.30-7.25(m,2H),5.16-4.96(m,1H),4.47(d,J=6.0Hz,2H),4.29(t,J=5.2Hz,1H),3.34(t,J=5.6Hz,2H),3.28-3.26(m,2H),2.72(t,J=7.0Hz,2H),1.47-1.38(m,6H),1.34-1.27(m,2H),1.25-1.20(m,4H),0.81(t,J=6.9Hz,3H).(M+H+)/z=444.03。
实施例9:4-氯-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-20)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-氯苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率35%。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.22-9.18(m,1H),7.89(d,J=8.3Hz,2H),7.74(d,J=7.9Hz,2H),7.52(d,J=8.3Hz,2H),7.34(d,J=8.0Hz,2H),4.47(d,J=6.0Hz,2H),3.29-3.28(m,2H),3.27(s,2H),2.76-2.69(m,2H),1.44-1.20(m,12H),0.82-0.79(m,3H).13C NMR(101MHz,DMSO-d6)δ165.77,165.65,143.39,136.69,133.44,132.25,129.76,128.98,127.65,127.57,70.47,70.41,51.66,42.97,29.68,29.45,28.46,27.92,23.93,22.49,14.47.(M+H+)/z=459.98。
实施例10:4-溴-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-21)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-溴苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率31%。1H NMR(400MHz,DMSO-d6)δ10.02(s,1H),9.28-9.20(m,1H),7.82(d,J=8.7Hz,2H),7.74(d,J=8.2Hz,2H),7.66(d,J=8.4Hz,2H),7.34(d,J=8.1Hz,2H),4.50-4.43(m,2H),3.31-3.26(m,4H),2.79-2.66(m,2H),1.45-1.21(m,12H),0.84-0.77(m,3H).(M+H+)/z=503.94。
实施例11:4-碘-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-22)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-碘苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率33%。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.13(t,J=5.9Hz,1H),7.83(d,J=8.4Hz,2H),7.73(d,J=8.1Hz,2H),7.64(d,J=8.4Hz,2H),7.33(d,J=8.1Hz,2H),4.46(d,J=5.8Hz,2H),3.28(d,J=4.1Hz,4H),2.72(d,J=6.9Hz,2H),1.43-1.20(m,12H),0.80(d,J=7.0Hz,3H).13C NMR(101MHz,DMSO-d6)δ166.17,165.66,143.37,137.79,134.12,132.27,129.78,127.64,127.55,99.56,70.47,70.41,51.67,42.95,29.68,29.45,28.46,27.93,23.93,22.49,14.49.(M+H+)/z=551.96。
实施例12:4-甲氧基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-23)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-甲氧基苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率36%。1H NMR(400MHz,DMSO-d6)δ9.84(d,J=15.0Hz,2H),8.76(t,J=6.0Hz,1H),7.53(d,J=8.5Hz,4H),7.24(d,J=8.1Hz,2H),6.81-6.72(m,2H),4.44(d,J=6.0Hz,2H),3.81(s,1H),3.33-3.23(m,4H),2.72(t,J=7.0Hz,2H),1.52-1.34(m,7H),1.38-1.25(m,3H),1.27-1.16(m,6H),0.86-0.75(m,4H).(M+H+)/z=456.05。
实施例13:4-羟基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-24)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-羟基苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率39%。1H NMR(400MHz,DMSO-d6)δ9.94(d,J=15.0Hz,2H),8.80(t,J=6.0Hz,1H),7.73(d,J=8.5Hz,4H),7.32(d,J=8.1Hz,2H),6.81-6.72(m,2H),4.44(d,J=6.0Hz,2H),3.33-3.23(m,4H),2.72(t,J=7.0Hz,2H),1.52-1.34(m,7H),1.38-1.25(m,3H),1.27-1.16(m,6H),0.86-0.75(m,4H).(M+H+)/z=441.95。
实施例14:4-硝基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-25)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为4-硝基苯甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率29%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.47-9.34(m,1H),8.36-8.25(m,2H),8.14-8.05(m,2H),7.80-7.71(m,2H),7.42-7.28(m,2H),5.02(s,1H),4.59-4.44(m,2H),3.28(t,J=3.3Hz,2H),2.73(s,2H),1.58-1.37(m,6H),1.37-1.28(m,2H),1.26-1.17(m,4H),0.81(t,J=3.9Hz,3H).(M+H+)/z=470.96。
实施例15:4-氨基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-26)
具体合成步骤如下:
将I-25(100mg,0.21mmol)置于25mL单口瓶中,加入50mL甲醇溶解后,加入10%Pd/C,在氢气环境下反应2h。TLC检测原料反应完全,滤除钯碳后,柱色谱分离得到白色固体83mg,收率89%。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.58(t,J=6.0Hz,1H),7.87-7.68(m,2H),7.63-7.53(m,2H),7.37-7.26(m,2H),6.53-6.48(m,2H),5.60(s,2H),4.51-4.37(m,2H),3.28(t,J=3.3Hz,2H),2.72(t,J=7.0Hz,1H),1.52-1.36(m,6H),1.36-1.27(m,2H),1.26-1.19(m,4H),0.85-0.78(m,3H).(M+H+)/z=441.02。
实施例16:N-(4-(2-(6-(2-甲氧基乙氧基)己基)肼-1-羰基)苄基)苯甲酰胺(I-27)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5g,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.09(t,J=6.0Hz,1H),7.90-7.84(m,2H),7.75(d,J=8.3Hz,2H),7.54-7.47(m,1H),7.47-7.41(m,2H),7.35(d,J=8.1Hz,2H),5.04(s,1H),4.49(d,J=6.0Hz,2H),3.46-3.36(m,5H),3.31(t,J=6.6Hz,2H),3.19(s,3H),2.73(t,J=7.1Hz,2H),1.49-1.35(m,4H),1.34-1.21(m,4H).13C NMR(101MHz,DMSO-d6)δ166.83,165.69,143.58,134.73,132.27,131.86,128.89,127.79,127.63,127.53,71.83,70.82,69.81,58.59,51.72,42.93,29.72,28.14,27.05,26.14.HRMS(ESI)for C24H32N3O4[M-H]-calcd 426.23963,found 426.23962。
实施例17:N-(4-(2-(5-(2-乙氧基乙氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-28)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5h,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ10.00(d,J=7.5Hz,1H),9.20-9.07(m,1H),7.90(d,J=7.7Hz,2H),7.78(d,J=8.0Hz,2H),7.59-7.44(m,3H),7.38(d,J=8.0Hz,2H),4.52(d,J=6.2Hz,2H),3.48-3.37(m,8H),2.84-2.69(m,2H),1.58-1.40(m,4H),1.39-1.25(m,2H),1.08(t,J=7.2Hz,3H).13C NMR(101MHz,DMSO-d6)δ166.82,165.68,143.58,134.72,132.26,131.87,128.91,127.80,127.64,127.52,70.81,70.06,69.76,66.08,51.69,42.92,29.65,27.98,23.88,15.66.HRMS(ESI)for C24H32N3O4[M-H]-calcd 426.23963,found 426.24023。
实施例18:N-(4-(2-十二烷基肼-1-羰基)苄基)苯甲酰胺(I-29)
具体合成步骤如下:
将实施例1中十一醛替换为十二醛,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.06(t,J=6.0Hz,1H),7.89-7.82(m,2H),7.74(d,J=8.3Hz,2H),7.55-7.48(m,1H),7.46–7.40(m,2H),7.34(d,J=8.1Hz,2H),4.48(d,J=6.0Hz,2H),2.72(t,J=7.1Hz,2H),1.47-1.35(m,2H),1.20(s,18H),0.83-0.78(m,3H).13CNMR(101MHz,DMSO-d6)δ166.80,165.65,143.56,134.74,132.27,131.86,128.89,127.78,127.61,127.50,51.74,42.92,31.83,29.60,29.55,29.52,29.25,28.15,27.20,22.63,14.49.HRMS(ESI)for C27H38N3O2[M-H]-calcd436.29695,found 436.29691。
实施例19:N-(4-(2-十三烷基肼-1-羰基)苄基)苯甲酰胺(I-30)
具体合成步骤如下:
将实施例1中十一醛替换为十三醛,其余与实施例1相同。总收率34%。1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),9.08(t,J=6.0Hz,1H),7.92-7.86(m,2H),7.76(d,J=8.2Hz,2H),7.57-7.50(m,1H),7.50-7.44(m,2H),7.37(d,J=8.3Hz,2H),5.10(s,1H),4.51(d,J=5.9Hz,2H),2.75(t,J=7.1Hz,2H),1.51-1.38(m,2H),1.35-1.19(m,20H),0.84(t,J=6.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ166.75,165.58,143.49,134.66,132.17,131.78,128.81,127.69,127.53,127.43,51.65,42.85,31.74,29.49,29.45,29.41,29.14,28.04,27.10,22.54,14.40.HRMS(ESI)for C28H40N3O2[M-H]-calcd 450.31260,found 450.31253。
实施例20:N-(4-(2-十四烷基肼-1-羰基)苄基)苯甲酰胺(I-31)
具体合成步骤如下:
将实施例1中十一醛替换为十四醛,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.06(t,J=6.0Hz,1H),7.89-7.84(m,2H),7.74(d,J=8.2Hz,2H),7.53-7.48(m,1H),7.47-7.41(m,2H),7.34(d,J=8.1Hz,2H),4.48(d,J=6.0Hz,2H),2.72(t,J=7.1Hz,2H),1.46-1.32(m,2H),1.19(s,22H),0.86-0.75(m,3H).13CNMR(101MHz,DMSO-d6)δ166.80,165.65,143.56,134.74,132.27,131.84,128.88,127.78,127.61,127.50,51.76,42.92,31.84,29.60,29.56,29.53,29.26,28.17,27.21,22.64,14.48.HRMS(ESI)for C29H42N3O2[M-H]-calcd464.32825,found 464.32819。
实施例21:N-(4-(2-(12-甲氧基十二烷基)肼-1-羰基)苄基)苯甲酰胺(I-32)
具体合成步骤如下:
将实施例1中十一醛替换为中间体5f,其余与实施例1相同。总收率34%。1H NMR(500MHz,DMSO-d6)δ9.95(s,1H),9.08(t,J=6.0Hz,1H),7.92-7.86(m,2H),7.77(d,J=8.4Hz,2H),7.57-7.50(m,1H),7.51-7.44(m,2H),7.37(d,J=8.2Hz,2H),5.03(s,1H),4.51(d,J=6.0Hz,2H),3.27(t,J=6.6Hz,2H),3.19(s,3H),2.75(t,J=7.1Hz,2H),1.50-1.37(m,4H),1.27-1.20(m,16H).13C NMR(126MHz,DMSO-d6)δ166.72,165.57,143.47,134.68,132.21,131.76,128.80,127.70,127.53,127.43,72.35,58.22,51.67,42.85,29.47,29.44,29.42,29.31,28.08,27.12,26.11.HRMS(ESI)for C28H40N3O3[M-H]-calcd466.30752,found 466.30746。
实施例22:N-(4-(7,10,13,16-四氧代-2,3-重氮十七烷基)苄基)苯甲酰胺(I-33)
具体合成步骤如下:
将实施例1中十一醛替换为中间体11,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ10.09(s,1H),9.09(t,J=6.0Hz,1H),7.87(d,J=6.8Hz,2H),7.75(d,J=7.9Hz,2H),7.51(t,J=7.2Hz,1H),7.44(t,J=7.5Hz,2H),7.35(d,J=7.9Hz,2H),4.48(d,J=5.9Hz,2H),3.50-3.38(m,14H),3.18(s,3H),2.83(t,J=7.0Hz,2H),1.66(p,J=6.6Hz,2H).13C NMR(101MHz,DMSO-d6)δ166.83,165.74,143.77,134.72,132.00,131.87,128.90,127.79,127.70,127.55,71.79,70.34,70.30,70.10,70.07,68.97,58.56,48.91,42.92,28.17.HRMS(ESI)for C25H34N3O6[M-H]-calcd 472.24531,found 472.24521。
实施例23:N-(4-(2-十四烷基肼-1-羰基)苄基)苯并呋喃-2-甲酰胺(I-34)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为苯并呋喃-2-甲酸,将实施例1中的十一醛替换为十四醛,其余与实施例1相同。总收率34%。1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),9.33(t,J=6.2Hz,1H),7.77(dd,J=8.4,2.3Hz,3H),7.65(d,J=8.3Hz,1H),7.57(s,1H),7.46(t,J=7.7Hz,1H),7.39(d,J=8.0Hz,2H),7.33(t,J=7.5Hz,1H),4.51(d,J=6.2Hz,2H),2.75(t,J=7.1Hz,2H),1.49-1.37(m,2H),1.31-1.11(m,24H),0.83(t,J=6.7Hz,3H).13C NMR(126MHz,DMSO-d6)δ165.54,158.68,154.72,149.44,142.97,132.31,129.88,127.76,127.60,127.56,127.33,124.17,123.24,112.24,110.10,51.66,42.39,31.74,29.49,29.46,29.42,29.15,28.06,27.11,22.54,14.39.HRMS(ESI)for C31H42N3O3[M-H]-calcd 504.32317,found 504.32324。
实施例24:N-(4-(2-十四烷基肼-1-羰基)苄基)苯并[b]噻吩-2-甲酰胺(I-35)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为苯并噻吩-2-甲酸,将实施例1中的十一醛替换为十四醛,其余与实施例1相同。总收率34%。1H NMR(500MHz,DMSO-d6)δ9.97(s,1H),9.36(t,J=6.1Hz,1H),8.13(s,1H),8.01(d,J=7.4Hz,1H),7.96-7.89(m,1H),7.81-7.76(m,2H),7.49-7.41(m,3H),7.40(d,J=8.2Hz,3H),4.52(d,J=6.0Hz,2H),2.75(t,J=7.1Hz,2H),1.48-1.36(m,2H),1.30-1.19(m,24H),0.83(t,J=6.9Hz,3H).13C NMR(126MHz,DMSO-d6)δ165.55,162.09,143.00,140.69,140.09,139.60,132.33,129.92,127.76,127.59,127.57,126.71,125.66,125.42,125.39,123.25,51.66,42.92,31.73,29.48,29.45,29.41,29.14,28.05,27.10,22.53,14.38.HRMS(ESI)for C31H42N3O2S[M-H]-calcd520.30032,found 520.30054。
实施例25:2-(吡啶-3-基)-N'-十四烷基噻唑-4-碳酰肼(I-36)
具体合成步骤如下:
将实施例1中的中间体12替换为2-(吡啶-3-基)噻唑-4-碳酰肼,将十一醛替换为十四醛,其余与实施例1相同。总收率34%。(M+H+)/z=416.93。
实施例26:N-(4-(2-十五烷基肼-1-羰基)苄基)苯甲酰胺(I-37)
具体合成步骤如下:
将实施例1中十一醛替换为十五醛,其余与实施例1相同。总收率34%。1H NMR(500MHz,DMSO-d6)δ10.00(s,1H),9.08(t,J=6.1Hz,1H),7.91-7.86(m,2H),7.77(d,J=8.0Hz,2H),7.53(t,J=7.3Hz,1H),7.47(t,J=7.5Hz,2H),7.37(d,J=8.0Hz,2H),4.51(d,J=6.0Hz,2H),2.76(t,J=7.1Hz,2H),1.48-1.37(m,2H),1.25-1.17(m,24H),0.84(t,J=6.8Hz,3H).13CNMR(126MHz,DMSO-d6)δ166.74,165.58,143.54,134.66,131.76,129.85,128.80,127.69,127.55,127.44,51.63,42.85,31.74,29.49,29.45,29.15,27.95,27.09,22.54,14.40.HRMS(ESI)for C30H44N3O2[M-H]-calcd 478.34390,found 478.34372。
实施例27:N-(4-(2-十六烷基肼-1-羰基)苄基)苯甲酰胺(I-38)
具体合成步骤如下:
将实施例1中十一醛替换为十六醛,其余与实施例1相同。总收率34%。1H NMR(500MHz,DMSO-d6)δ9.96(s,1H),9.08(t,J=6.0Hz,1H),7.92-7.86(m,2H),7.76(d,J=8.3Hz,2H),7.57-7.50(m,1H),7.50-7.44(m,2H),7.37(d,J=8.3Hz,2H),5.08(s,1H),4.51(d,J=6.0Hz,2H),2.75(t,J=7.1Hz,2H),1.47-1.37(m,2H),1.33-1.19(m,26H),0.88–0.80(m,3H).13C NMR(126MHz,DMSO-d6)δ166.76,165.58,143.48,134.65,132.17,131.78,128.81,127.69,127.53,127.44,51.65,42.85,31.73,29.47,29.44,29.41,29.14,28.03,27.10,22.54,14.40.HRMS(ESI)for C31H46N3O2[M-H]-calcd 492.35955,found 492.35962。
实施例28:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)烟酰胺(I-39)
具体合成步骤如下:
将中间体12的合成方法中的苯甲酸替换为烟酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率31%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.26(t,J=6.0Hz,1H),9.02(dd,J=2.4,0.9Hz,1H),8.68(dd,J=4.8,1.7Hz,1H),8.23-8.16(m,1H),7.78-7.69(m,2H),7.52-7.44(m,1H),7.39-7.32(m,2H),5.02(s,1H),4.50(d,J=5.9Hz,2H),3.30-3.25(m,4H),2.72(t,J=7.1Hz,2H),1.47-1.21(m,12H),0.86-0.76(m,3H).HRMS(ESI)for C25H35N4O3[M-H]-calcd 425.21586,found 425.21372。
实施例29:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)吡嗪-2-甲酰胺(I-40)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为2-甲酸吡嗪,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率30%。1H NMR(400MHz,Chloroform-d)δ9.96(s,1H),9.08(s,1H),8.87(s,1H),8.28-7.71(m,1H),7.70-7.48(m,2H),7.41-7.04(m,3H),4.51-4.20(m,2H),3.43-3.31(m,4H),2.92-2.84(m,2H),1.67-1.17(m,14H),0.92-0.80(m,3H).HRMS(ESI)for C23H32N5O3[M-H]-calcd 426.13646,found 426.13578。
实施例30:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)环己烷甲酰胺(I-41)
具体合成步骤如下:
将中间体12的合成方法中的苯甲酸替换为环己甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率31%。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.24(t,J=6.0Hz,1H),7.75-7.68(m,2H),7.28-7.20(m,2H),4.24(d,J=6.0Hz,2H),3.30-3.22(m,4H),2.72(t,J=7.0Hz,2H),2.20-2.06(m,1H),1.74-1.64(m,4H),1.62-1.52(m,1H),1.51-1.18(m,16H),0.88-0.75(m,3H).HRMS(ESI)for C25H42N3O3[M+H]+calcd 432.08534,found 432.07957。
实施例31:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)噻吩-2-甲酰胺N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)噻吩-2-甲酰胺(I-42)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为噻吩2-甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率38%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.07(t,J=6.0Hz,1H),7.80-7.70(m,4H),7.36-7.30(m,2H),7.12(dd,J=5.0,3.7Hz,1H),4.45(d,J=6.0Hz,2H),3.30-3.24(m,4H),2.72(t,J=7.0Hz,2H),1.52-1.19(m,12H),0.85-0.77(m,3H).HRMS(ESI)for C23H34N3O3S[M+H]+calcd 432.18247,found 432.18153。
实施例32:N-(3-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺(I-43)
具体合成步骤如下:
将中间体12合成方法中的4-氨甲基苯甲酸盐酸盐替换为3-氨甲基苯甲酸盐酸盐,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.05(t,J=6.0Hz,1H),7.90-7.83(m,2H),7.75(d,J=1.8Hz,1H),7.67-7.62(m,1H),7.55-7.48(m,1H),7.46-7.42(m,2H),7.36(t,J=7.6Hz,1H),4.48(d,J=6.0Hz,2H),3.30-3.25(m,4H),2.72(t,J=7.0Hz,2H),1.46-1.20(m,12H),0.87-0.76(m,3H).HRMS(ESI)for C25H34N3O3[M-H]-calcd 424.26057,found 424.26047。
实施例33:5-氯-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)烟酰胺(I-44)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为3-氯烟酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率37%。1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),9.35(t,J=5.9Hz,1H),8.96(d,J=1.8Hz,1H),8.77(d,J=2.4Hz,1H),8.31(t,J=2.1Hz,1H),7.78-7.71(m,2H),7.41-7.33(m,2H),5.05(s,1H),4.50(d,J=5.9Hz,2H),3.30-3.26(m,4H),2.73(t,J=7.0Hz,2H),1.45-1.21(m,12H),0.85-0.80(m,3H).HRMS(ESI)forC24H32N4O3Cl[M-H]-calcd459.34196,found 459.35047。
实施例34:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)恶唑-4-甲酰胺(I-45)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为恶唑-4-羧酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率28%。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.91(t,J=6.3Hz,1H),8.62(d,J=1.0Hz,1H),8.50(d,J=1.0Hz,1H),7.75-7.69(m,2H),7.35-7.27(m,2H),4.42(d,J=6.3Hz,2H),3.30-3.26(m,4H),2.72(t,J=7.0Hz,2H),1.46-1.21(m,12H),0.84-0.79(m,3H).HRMS(ESI)for C22H31N4O4[M-H]-calcd 415.18244,found415.18368。
实施例35:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)嘧啶-5-甲酰胺(I-46)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为嘧啶-5-羧酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率24%。1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),8.63(t,J=6.1Hz,1H),8.10(s,2H),7.74(d,J=8.1Hz,2H),7.32(d,J=8.0Hz,2H),4.42(d,J=6.0Hz,2H),3.28-3.24(m,4H),2.77(t,J=7.1Hz,2H),1.44-1.19(m,12H),0.81(t,J=6.8Hz,3H).HRMS(ESI)for C23H32N5O3[M-H]-calcd 426.27851,found 426.27936。
实施例36:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)异恶唑-3-甲酰胺(I-47)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为3-异恶唑甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率27%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.38(t,J=6.2Hz,1H),9.06(d,J=1.7Hz,1H),7.76-7.71(m,2H),7.36-7.30(m,2H),6.88(d,J=1.7Hz,1H),4.45(d,J=6.2Hz,3H),3.30-3.26(m,4H),2.72(t,J=7.0Hz,2H),1.45-1.21(m,12H),0.83 -0.79(m,3H).HRMS(ESI)for C22H31N4O4[M-H]-calcd 415.18354,found415.18378。
实施例37:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)呋喃-3-甲酰胺(I-48)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为3-呋喃甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率34%。1H NMR(400MHz,DMSO-d6)δ9.94(s,1H),8.75(t,J=6.1Hz,1H),8.18(dd,J=1.6,0.8Hz,1H),7.80-7.72(m,2H),7.70(t,J=1.7Hz,1H),7.35-7.28(m,2H),6.84(dd,J=1.9,0.8Hz,1H),4.42(d,J=6.0Hz,2H),3.30-3.25(m,4H),2.72(t,J=7.0Hz,2H),1.45-1.22(m,12H),0.84-0.79(m,3H).HRMS(ESI)for C23H32N3O4[M-H]-calcd414.19624,found 414.19732。
实施例38:N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)四氢-2H-吡喃-4-甲酰胺(I-49)
具体合成步骤如下:
将中间体12中的苯甲酸替换为4-吡喃甲酸,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率29%。1H NMR(400MHz,Chloroform-d)δ9.94(s,1H),9.38(t,J=6.2Hz,1H),7.76-7.71(m,2H),7.36-7.30(m,2H),4.49-4.32(m,2H),4.09-3.90(m,2H),3.40-3.34(m,4H),3.04-2.78(m,2H),2.54-2.33(m,2H),1.90-1.69(m,4H),1.66-1.51(m,6H),1.28(m,6H),0.90-0.83(m,3H).HRMS(ESI)for C24H38N3O4[M-H]-calcd 432.34871,found 432.34914。
实施例39:1-(2,6-二甲基苯基)-3-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)脲(I-50)
具体合成步骤如下:
将中间体12合成方法中的苯甲酸替换为2,6-二甲基苯基异氰酸酯,将实施例1中的十一醛替换为中间体5e,其余与实施例1相同。总收率45%。1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),7.78-7.71(m,2H),7.57(s,1H),7.31(d,J=8.2Hz,2H),7.04-6.95(m,3H),6.57(s,1H),5.04(s,1H),4.27(d,J=6.1Hz,2H),3.30-3.23(m,4H),2.73(t,J=7.0Hz,2H),2.13(s,6H),1.46-1.21(m,12H),0.85-0.77(m,3H).HRMS(ESI)for C27H39N4O3[M-H]-calcd 467.53571,found467.53764。
实施例12:体内外活性测试
一、HDAC1,4,6,11体外抑制活性测试
1.实验方法:
将50μL含有药物的HDAC buffer与10μL酶液混合预先孵育5min,加入40μL底物后,在37℃下反应30min,然后加入100μL胰蛋白酶终止液终止上述反应,并在37℃下反应20min,于390nm/460nm测定荧光强度。
最后将化合物的抑制率(%)和其相应浓度进行S曲线拟合,计算出IC50值。
2.细胞增殖抑制活性测定方法:
目标化合物体外与索拉菲尼协同的细胞增殖抑制活性试验采用刃天青显色检测法。实验采用人肝癌细胞HUH7和MHCC97H细胞系,均在含百分之十胎牛血清的DMEM培养基中培养。实验使用处于对数生长期细胞,经0.5%的胰酶消化,1000r/min离心5min后弃上清,将细胞沉淀用培养基吹打混匀制成细胞悬液。取上述细胞的细胞悬液于倒置显微镜下计数,并加入培养基将细胞浓度调整至5×104/mL。取96孔细胞培养板,设立空白对照组、索拉菲尼组、化合物组和索拉菲尼与化合物联用组,每组设置两个平行复孔,每孔加入100μL细胞混悬液,周边孔填充无菌PBS。待6小时细胞贴壁后加药,其中空白对照组每孔加100μL细胞培养液,索拉菲尼组每孔加入含梯度稀释的不同浓度索拉菲尼的细胞培养液100μL,化合物组每孔加入含梯度稀释的不同浓度化合物的细胞培养液100μL,索拉菲尼与化合物联用组每孔加入含固定浓度的化合物和梯度稀释的不同浓度索拉菲尼的细胞培养液100μL。药物加入完毕后,将96孔细胞培养板于37℃、5%CO2的培养箱中培养72h。72h后,每孔加入15μL刃天青(1mg/mL),继续孵育2h后,随后用酶标仪以Ex/Em=560nm/590nm测定荧光强度值,用Graphpad prism 8.0软件进行数据分析,绘制抗增殖曲线并计算IC50。
3.实验结果:
抑制活性结果见下面表1,实验结果表明所述化合物对HDAC11均具有低纳摩尔级的抑制活性,多数化合物活性明显高于阳性对照SIS17并且对于其他HDAC亚型不具有明显的抑制活性,说明本发明所涉及的化合物具有较强的亚型选择性。其中<100nM=A,100~500nM=B,500~1000nM=C,>1000nM=D。
表1化合物对HDAC1、4、6和11的IC50值
在索拉非尼耐药的肝癌细胞HUH7和MHCC97H中,化合物I-18与索拉非尼表现出显著的协同作用,并表现出剂量依赖性,其IC50在3-10μM之间(如图1和2所示),但化合物I-18不具有抗肝癌活性。因此,本发明所涉及的化合物具有明显的逆转肝癌耐药的作用,同时不具有明显细胞毒性。
二、体内活性测试
1.实验方法:
将8周的雄性C57/BL6随机分为四组(n=10),其中阴性对照组喂食10%脂肪饲料,阳性对照和给药组喂食高脂饲料,并每周记录体重。喂食12周后处死小鼠,每组取3只测定血脂含量(图3)。另取阳性对照组和给药组的3只小鼠,进行肝脏切片,用甲醛溶液固定后用油红染色,使用荧光显微镜成像。
2.实验结果
在高脂饮食诱导的小鼠肥胖模型中,1mg/kg和2mg/kg的给药剂量下,实施例I-18在能够显著降低小鼠体重和血脂含量(如图3和图4所示),并且明显减少了组织中的脂滴的数量和大小(如图5所示)。因此,本发明所涉及的化合物具有显著的减肥和调节脂代谢的功能。
需要说明的是,以上所述的仅是本发明的优选实施方式,应当指出,对于本领域的普通技术人员来说,在不脱离发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也不应排除在本发明的保护范围之外。
Claims (10)
1.一种如通式(I)所示的化合物、其氘代物或药学上可接受的盐:
其中:
R2取代基是一个或多个且在环上的位置不定,选自H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基选的被1-2个C1-C2烷基、C2-C3炔基取代;所述的羟基任选的被C1-C2烷基、C2-C3炔基取代;X选自NH、O或S;Y选自CH或N;W选自CH2、O或NCH3;J1、J2、J3、J4分别独立地选自C、CH或N;
Z选自键或五元芳杂环;
R1选自H、C1-C20烷烃、C1-C20烷基取代的C3-C6环烷烃、C1-C20烷基取代的羟基、
B、D、E、F、G分别独立地选自C、CR4或N;其中R4选自一个或多个H、卤素、C1-C2烷烃、C1-C2卤代烷、氨基、硝基、羟基或氰基;所述的氨基无取代或任选的被1-2个C1-C2烷基、C1-C2烷氧基、C2-C3炔氧基取代;所述的羟基无取代或任选的被C1-C2烷基、C1-C2烷氧基或C2-C3炔氧基取代。
3.如权利要求1所述的化合物、其氘代物或药学上可接受的盐,其特征在于,所述通式(I)化合物是下列之一:
N-(4-(肼羰基)苄基)苯甲酰胺;
N-(4-(2-甲基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-乙基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-丙基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-丁基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-戊酰肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-戊酰肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-戊酰肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-己基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-庚酰肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-辛基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-壬基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-癸基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-十一烷基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(9-甲氧基壬基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(8-乙氧基辛基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(7-丙氧基庚基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(6-丁氧基己基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(10-羟基癸基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
4-氟-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
4-氯-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
4-溴-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
4-碘-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
4-甲氧基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;4-羟基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;4-硝基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;4-氨基-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(6-(2-甲氧基乙氧基)己基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(5-(2-乙氧基乙氧基)戊基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-十二烷基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-十三烷基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-十四烷基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(12-甲氧基十二烷基)肼-1-羰基)苄基)苯甲酰胺;
N-(4-(7,10,13,16-四氧代-2,3-重氮十七烷基)苄基)苯甲酰胺;
N-(4-(2-十四烷基肼-1-羰基)苄基)苯并呋喃-2-甲酰胺;
N-(4-(2-十四烷基肼-1-羰基)苄基)苯并[b]噻吩-2-甲酰胺;
2-(吡啶-3-基)-N'-十四烷基噻唑-4-碳酰肼;
N-(4-(2-十五烷基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-十六烷基肼-1-羰基)苄基)苯甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)烟酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)吡嗪-2-甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)环己烷甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)噻吩-2-甲酰胺;
5-氯-N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)烟酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)恶唑-4-甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)嘧啶-5-甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)异恶唑-3-甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)呋喃-3-甲酰胺;
N-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)四氢-2H-吡喃-4-甲酰胺;
1-(2,6-二甲基苯基)-3-(4-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)脲。
5.如权利要求4所述的化合物、其氘代物或药学上可接受的盐,其特征在于,所述通式(Ⅲ)化合物为N-(3-(2-(5-(戊氧基)戊基)肼-1-羰基)苄基)苯甲酰胺。
6.如权利要求1-5中任一项所述的化合物、其氘代物或药学上可接受的盐的制备方法,其特征在于,包括以下步骤:
其中X为NH、O或S,n为1-18之间的整数,R5选自H、C1-C18烷基或含氧烷基;
首先以化合物2为原料,在氢氧化钾的作用下生成相应的钾盐,与相应化合物1反应得到中间体3,随后以二氯甲烷或四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1-羟基苯并三唑作用下与N,O-二甲羟胺盐酸盐反应得到相应的酰胺类中间体4,最后以四氢呋喃为溶剂经过氢化铝锂还原得到相应的醛类中间体5;以四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂,丙烯酸叔丁酯与相应中间体7发生Michael加成得到中间体8,以二氯甲烷或乙酸乙酯或四氢呋喃为溶剂,经过三氟乙酸或饱和氯化氢溶液脱除叔丁基后得到羧酸中间体9,随后以二氯甲烷或四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1-羟基苯并三唑作用下与N,O-二甲羟胺盐酸盐反应得到相应的酰胺类中间体10,最后以四氢呋喃为溶剂经过氢化铝锂还原得到相应的醛类中间体11;随后以中间体12为原料,以二氯甲烷或四氢呋喃或N,N-二甲基甲酰胺或N,N-二甲基乙酰胺或二甲亚砜为溶剂在1-乙基-(3-二甲基氨基丙基)碳酰二亚胺和1-羟基苯并三唑作用下或三光气和三乙胺的作用下与取代或未取代的4-氨甲基苯甲酸甲酯盐酸盐、4-氨基苯甲酸甲酯或3-氨甲基苯甲酸甲酯盐酸盐反应得到中间体13;所述中间体2,以甲醇或乙醇为溶剂,再与水合肼反应得到中间体14;所述中间体14进一步与相应的醛反应得到最终的目标化合物。
7.一种药物组合物,其特征在于包含如权利要求1-5中任一项所述的化合物、其氘代物或药学上可接受的盐作为主要活性成分以及药学上可接受的稀释剂或载体,所述的化合物、其氘代物或药学上可接受的盐的含量为0.1-99.9wt%。
8.如权利要求1-5中任一项所述的化合物、其氘代物或药学上可接受的盐在制备组蛋白去乙酰化酶11抑制剂中的用途。
9.如权利要求1-5中任一项所述的化合物、其氘代物或药学上可接受的盐在制备治疗与组蛋白去乙酰化酶活性异常表达相关疾病的药物中的用途,所述与组蛋白去乙酰化酶活性异常表达相关疾病包括肿瘤、代谢性疾病、神经退行性疾病或炎症。
10.如权利要求9所述的用途,其特征在于所述与组蛋白去乙酰化酶活性异常表达相关疾病包括肝癌、脂肪肝、肥胖、高脂血症、高血压、动脉粥样硬化、糖尿病、甲状腺癌、各类白血病、淋巴瘤、骨髓瘤、三阴性乳腺癌、肺癌、黑色素瘤、食道癌、肾癌、口腔癌、舌癌、前列腺癌、乳腺癌、宫颈癌、卵巢癌、胃癌、胰腺癌、膀胱癌、结肠直肠癌、鼻咽癌、脑肿瘤、胶质瘤、成人胶质母细胞红斑、骨癌或软组织肉瘤。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109641889A (zh) * | 2016-06-23 | 2019-04-16 | 百欧伊米克思有限公司 | 抗感染杂环化合物及其用途 |
US20190308932A1 (en) * | 2016-10-13 | 2019-10-10 | Musc Foundation For Research Development | Histone deacetylase inhibitors and uses thereof |
CN113164775A (zh) * | 2018-09-07 | 2021-07-23 | 阿尔维纳斯运营股份有限公司 | 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法 |
WO2021222404A1 (en) * | 2020-04-30 | 2021-11-04 | Janssen Biotech, Inc. | Imidazopyridazines as modulators of il-17 |
CN113831338A (zh) * | 2021-09-20 | 2021-12-24 | 中国海洋大学 | 一种组蛋白去乙酰化酶抑制剂及其制备方法和应用 |
-
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- 2022-12-02 CN CN202211544602.4A patent/CN115806503A/zh active Pending
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109641889A (zh) * | 2016-06-23 | 2019-04-16 | 百欧伊米克思有限公司 | 抗感染杂环化合物及其用途 |
US20190308932A1 (en) * | 2016-10-13 | 2019-10-10 | Musc Foundation For Research Development | Histone deacetylase inhibitors and uses thereof |
CN113164775A (zh) * | 2018-09-07 | 2021-07-23 | 阿尔维纳斯运营股份有限公司 | 用于迅速加速性纤维肉瘤多肽的靶向降解的多环化合物和方法 |
WO2021222404A1 (en) * | 2020-04-30 | 2021-11-04 | Janssen Biotech, Inc. | Imidazopyridazines as modulators of il-17 |
CN113831338A (zh) * | 2021-09-20 | 2021-12-24 | 中国海洋大学 | 一种组蛋白去乙酰化酶抑制剂及其制备方法和应用 |
Non-Patent Citations (1)
Title |
---|
CHEMICAL ABSTRACT RN: "RN:2837127-72-5等", STN ON THE WEB REGISTRY数据库 * |
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