CN116143661A - β-榄香烯不对称取代衍生物及其制备和用途 - Google Patents
β-榄香烯不对称取代衍生物及其制备和用途 Download PDFInfo
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- CN116143661A CN116143661A CN202310169630.0A CN202310169630A CN116143661A CN 116143661 A CN116143661 A CN 116143661A CN 202310169630 A CN202310169630 A CN 202310169630A CN 116143661 A CN116143661 A CN 116143661A
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- C07C271/62—Compounds containing any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylcarbamates
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Abstract
本发明公开β‑榄香烯不对称取代衍生物及其制备和用途。本发明β‑榄香烯不对称取代衍生物结构式如下式所示。这些不对称取代的衍生物包含了原有的β‑榄香烯的三个双键,同时拥有药物化学中常用的增大亲水性利用生物体吸收,增进与机体结合的策略。此类化合物既保留了β‑榄香烯的三个双键,又通过引入极性的氮原子与氧原子基团调节药物的物理化学性质,增加其水溶性,改善机体吸收的效果,另外带电离子基团更容易穿越多膜结构,使榄香烯更容易穿越血脑屏障,提高治疗脑胶质瘤的疗效。
Description
技术领域
本发明属于β-榄香烯衍生物的制备及应用领域,涉及β-榄香烯不对称取代衍生物及其制备和用途,具体涉及一种β-榄香烯不对称取代物的制备以及这些不对称衍生物在治疗各种疾病特别是治疗各种癌症上的应用。
背景技术
β-榄香稀是我国自主研发的从温郁金(Curcuma wenyujin Y.H.Chen&C.Ling),又称莪术油的挥发油中提取分离得到的广谱抗肿瘤药物榄香烯乳的有效成分。同紫杉醇、羟基喜树碱、长春碱等其它植物抗癌药相比,具有分子量最小、毒性最小、抗肿瘤作用广谱等优点,1994年国家药监局批准其为我国具有自主知识产权的抗肿瘤植物药。β-榄香稀的抗肿瘤机制不同于一般细胞毒性的抗肿瘤药物,其能够通过诱导癌细胞凋亡、抑制癌细胞增殖和生长、抑制肿瘤细胞的迁移和侵袭、抑制肿瘤血管生成、逆转耐药及增敏、诱导细胞保护性自噬等多种途径发挥抗肿瘤作用(朱琳芳,王秋岩,吴慧丽.榄香烯抗肿瘤活性机理及其衍生物活性研究进展[J].杭州师范大学学报:自然科学版,2018,17(2):170-176.)。以榄香烯为主要成分的乳剂已于2008年被卫生部批准为国家二类抗癌新药进入二期临床研究,这种新的抗肿瘤天然产物在各种肿瘤中逐步表现出很强的临床治疗作用。目前,其在临床上主要用于恶性浆膜腔积液、肺癌、消化道肿瘤、脑瘤以及其它浅表性肿瘤的化疗,对食管癌、胃癌、乳腺癌、肝癌、膀胱癌等亦有一定疗效。研究表明,榄香烯几乎不产生副作用,对肾、肝的功能都不产生药物诱导毒性,特别是对脊髓没有抑制作用(张殊佳,周鹏段,华鑫,袁韩,化学通报,2010,6:499)。同时,榄香烯由于其分子量较小的原因可以通过血脑屏障到达脑部,对普通药物难以治疗的脑肿瘤具有一定的疗效(Qian,J.,New anti-tumor drug,Elemene's pharmaco1ogyand Clinical results,Chineses Journal ofClinicalOncology,July:1-3,1999)。此外,榄香烯对和其它的靶向小分子药物联合用药,还表现出增敏增效的功效,同时还可以逆转或延缓小分子靶向药物的耐药性。近年来,科学家在榄香烯领域取得了丰硕成果,先后获得国家科技进步二等奖、何梁何利科学技术创新奖、教育部科技一等奖、吴阶平医药创新奖等多个奖项。在榄香烯的基础上开发出新一代的活性更好的抗癌新药,具有非常广阔的前景。
榄香烯中含有多种异构体,包括α-、β-、γ-、δ-等。研究表明β-榄香烯是其中的主要成分,也是抗肿瘤效果最好的异构体,β-榄香烯结构如下:
研究还表明,β-榄香烯上的三个独立的双键可能是抗肿瘤药效的主要贡献者(但没有具体的证据),但β-榄香烯的作用机制还不清楚。
发明人在对β-榄香烯的长期研究中,结合创新药研究开发的经验,提出了通过β-榄香烯的13-位,14-位二氯代物与不同的含氮含氧的化学试剂反应,形成一类新颖结构的β-榄香烯不对称取代物。此类化合物既保留了β-榄香烯的三个双键(可能是抗肿瘤药效的关键贡献者),又通过引入极性的氮原子与氧原子基团调节药物的物理化学性质,增加其水溶性,改善机体吸收的效果,另外带电离子基团更容易穿越多膜结构,使榄香烯更容易穿越血脑屏障,提高治疗脑胶质瘤的疗效。
发明内容
本发明的目的是针对现有技术的不足,提供一类结构新颖的β-榄香烯不对称取代物,并提供了这些化合物的通用合成方法,对一些具体的化合物提供了具体的合成方法。本发明还提供了这些大环化合物的生物活性测试,以及它们在治疗各种疾病中的应用。特别是,这些化合物具有抗肿瘤活性,可以单独用于治疗各种癌症,也可以和其它的化疗药物和靶向药物联合用药,达到更好的治疗癌症的作用。这些应用都在本发明的包含范围内。
本发明的第一方面,提供了一种如下式所示结构的化合物,或其光学异构体,包括消旋体、单一的对映异构体、可能的非对映异构体;或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂合物:
R1,R2,R3和R4各自独立选自以下基团:H、碳酸叔丁酯、C1-4烷基、C3-6烯基、C3-6炔基、C6-10芳基、5-至10-元杂芳基、5-至10-元杂环基、-C(O)-(C1-4烷基)。
n=0、1、2、3;
R7为C1-6的烷基、C2-6的烯基、C2-6的炔基、C3-6的环烷基、或C3-6的杂环基(含1-3个独立的选自N、O、S的杂原子)。
上述的烷基、芳基、杂芳基、环烷基、杂环基可以选择性地被0-3个如下基团取代:-OH、-SH、-CN、卤素、-CO2H、-CO2R5、-C(O)-NH2、-C(O)-NR6aR6b、-OR5、C1-8烷基、C1-8的烷氧基、C1-8卤代烷基、C1-8的卤代烷氧基、C2-8的烯基、C2-8的炔基、-NR6aR6b、-CH2OH、-CH2-NR6aR6b。
其中R6a、R6b各自独立为C1-6的烷基、C2-6的烯基、C2-6的炔基、C3-6的环烷基、或C3-6的杂环基(含1-3个独立的选自N、O、S的杂原子);R5为6-至10-元芳基或6-至10-元杂芳基。
作为优选,所述5-至-10元杂芳基中杂原子含有O、N、S中的1-3个。
作为优选,所述3-至9-元杂环基中杂原子含有O、N、S中的1-3个。
作为优选,式(I)和(II)结构式如下式之一:
本发明的第二方面,提供了一种如第一方面所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物的用途,包括:
(a)用于制备治疗榄香烯可预防、缓解或治愈的各种疾病的药物;或
(b)用于体外非治疗性地抑制各种肿瘤细胞株增殖。
作为优选,所述疾病包括肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌和实体瘤等等。
本发明的第三方面,提供了一种药物组合物,所述的药物组合物包括:(i)有效量的如本发明第一方面所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物;和(ii)药学上可接受的载体。
药物组合物包括但不限于:化合物和各种蛋白激酶抑制剂的组合;化合物和抗体如PD-1或PD-L1的组合。
本发明的第四方面,提供了一种β-榄香烯不对称取代物的制备方法,具体是通过二氯代β-榄香烯中间体I-a与化合物进行取代反应,在中间体I-a中榄香烯的13-位上装上取代基/>得到式(Ⅱ)化合物I-b;然后化合物I-b与化合物/>进行再次取代反应,在中间体I-b中榄香烯的14-位上再装上取代基/>得到最终式(I)产物。
二氯代β-榄香烯中间体I-a是实现上述合成和官能团转化的关键中间体,其化学结构式如下:
所述化合物的取代基中,R1,R2,R3和R4各自独立选自以下基团:H、碳酸叔丁酯、C1-4烷基、C3-6烯基、C3-6炔基、C6-10芳基、5-至10-元杂芳基、5-至10-元杂环基、-C(O)-(C1-4烷基)。
上述的烷基、芳基、杂芳基、环烷基、杂环基可以选择性地被0-3个如下基团取代:-OH、-SH、-CN、卤素、-CO2H、-CO2R5、-C(O)-NH2、-C(O)-NR6aR6b、-OR5、C1-8烷基、C1-8的烷氧基、C1-8卤代烷基、C1-8的卤代烷氧基、C2-8的烯基、C2-8的炔基、-NR6aR6b、-CH2OH、-CH2-NR6aR6b。
其中R6a、R6b为C1-6的烷基、C2-6的烯基、C2-6的炔基、C3-6的环烷基、或C3-6的杂环基(含1-3个独立的选自N、O、S的杂原子);R5为6-至10-元芳基或6-至10-元杂芳基。
作为优选,所述5-10元杂芳基中杂原子含有O、N、S中的1-3个。
作为优选,所述3-至9-元杂环基中杂原子含有O、N、S中的1-3个。
其合成路线如下:
化合物中的氮原子可以作为亲核取代基,将榄香烯上的氯取代下来。由于13-位的氯位阻相对于14-位的氯的位阻来得小,所以通过条件的控制,可以选择性地在13-位上先进行取代反应,然后在更苛刻的条件(如相对于第一步更高的温度下)进行14-位的亲核取代反应。这样就跟可以得到13,14-位不对称的双取代的榄香烯衍生物。具体的如下:
①在0~55℃搅拌条件下,向二氯代β-榄香烯中间体I-a溶液中依次加入碱和化合物进行取代反应,经后处理得到的粗品再经过柱层析纯化(乙酸乙酯/石油醚体系洗脱),得到β-榄香烯13-位取代14-氯代的化合物II。式(II)本身就是本发明所要包含的化合物,同时它也是合成式(I)的中间体。
②向β-榄香烯13-位取代14-氯代的化合物I-b溶液中加入碱和化合物进行反应,在相对于第一步反应更苛刻的条件下(如较高的反应温度--100~120℃)进行亲核取代反应,经后处理得到的粗品再经过柱层析纯化(通常为乙酸乙酯/石油醚体系,也可以是甲醇/二氯甲烷体系,或其它体系洗脱)得到13-位与14-位连有不同取代基的β-榄香烯不对称取代衍生物,即式(I)。
所述碱采用有机碱或无机碱;
作为优选,所述有机碱采用N,N-二异丙基乙基胺、三乙胺等中的一种,所述无机碱采用K2CO3、Cs2CO3、NaH等中的一种。
作为优选,所述二氯代β-榄香烯中间体I-a溶液的摩尔浓度为0.1-0.5mol/L;
作为优选,二氯代β-榄香烯中间体I-a溶液和β-榄香烯13-位取代14-氯代的化合物II溶液的溶剂为二氯甲烷、四氢呋喃和N,N-二甲基甲酰胺中的一种,更为优选为N,N-二甲基甲酰胺。
作为优选,步骤①的反应时间为55℃;
作为优选,步骤②的反应温度为100℃,反应时间为8h。
本发明上述β-榄香烯不对称取代物的制备过程中所用溶剂为常用溶剂,如甲醇、石油醚、正己烷、N,N-二甲基甲酰胺、二氯甲烷、乙酸乙酯。
本发明的所合成的β-榄香烯不对称衍生物多是带有极性含氮或含氧原基团,更有利于改善β-榄香烯的水溶性并提高其抗癌活性。
与现有技术相比,本发明具有以下优点:
(1)本发明提供了一种如式(I)或(Ⅱ)所示的化合物及其组合物,这类化合物的显著特点是结构新颖,β-榄香烯的13-位的碳原子与14-位的碳原子各自连接一些不同的含氮含氧化合物基团。这些不对称取代的衍生物包含了原有的β-榄香烯的三个双键,同时拥有药物化学中常用的增大亲水性利用生物体吸收,增进与机体结合的策略。
(2)本发明还提供了式(I)或(Ⅱ)所示部分化合物的制备方法。这些不对称取代物并未被报道过,也没有它们的合成方法。
具体实施方式
发明人经长期的研究得出了本发明的成果,就是用特定的研究方法对β-榄香烯13-位与14-位分别进行含氮含氧取代基团的衍生化,从而得到多个β-榄香烯不对称取代产物。通过比较这些化合物在抑制肿瘤细胞株的增殖实验中显示出的抑制作用的差别,进而深入研究取代基团和药物活性之间的构效关系。毫无疑问,这些β-榄香烯化合物将有望在抗肿瘤的药物研发中得到应用。另一方面,这些化合物将作为有用的中间体,制备其它榄香烯衍生物。本发明对进一步β-榄香烯衍生化及抗肿瘤活性的研究,乃至研究β-榄香烯的作用机制和细胞通路,都具有非常重大的意义。
术语
除非特别说明,术语“药学上可接受的盐”指适合与对象(例如,人)的组织接触,而不会产生不适度的副作用的盐。在一些实施例中,本发明的某一化合物的药学上可接受的盐包括具有酸性基团的本发明的化合物的盐(例如,钾盐,钠盐,镁盐,钙盐)或具有碱性基团的本发明的化合物的盐(例如,硫酸盐,盐酸盐,磷酸盐,硝酸盐,碳酸盐)。
用途
本发明提供了一类式(I)化合物,或其氘代衍生物、它的盐、异构体(对映异构体或非对映异构体,如果存在的情况下)、水合物、可药用载体或赋形剂用于抑制体外肿瘤细胞株的增殖的用途。这类化合物属β-榄香烯的衍生物,在某种程度上,这类化合物在体外抑制各种肿瘤细胞株的增殖活性比榄香烯本身强。
由于本发明所述的这类化合物具有和榄香烯同等的、或更强的体外抑制各种肿瘤细胞株的活性,而榄香烯是已经获国家药品管理局批准的抗肿瘤药物,本发明所述的化合物,有望在各种癌症病人身上取得抗肿瘤的疗效,得到预防、缓解或治愈疾病。所指疾病包括肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌和实体瘤等等。
可将本发明化合物及其氘代衍生物,以及药学上可接受的盐或其异构体(如果存在的情况下)或其水合物和/或组合物与药学上可接受的赋形剂或载体配制在一起,得到的组合物可在体内给予哺乳动物,例如男人、妇女和动物,用于治疗病症、症状和疾病。组合物可以是:片剂、丸剂、混悬剂、溶液剂、乳剂、胶囊、气雾剂、无菌注射液、无菌粉末等。一些实施例中,药学上可接受的赋形剂包括微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙、甘露醇、羟丙基-β-环糊精、β-环糊精(增加)、甘氨酸、崩解剂(如淀粉、交联羧甲基纤维素钠、复合硅酸盐和高分子聚乙二醇)、造粒粘合剂(如聚乙烯吡咯烷酮、蔗糖、明胶和阿拉伯胶)和润滑剂(如硬脂酸镁、甘油和滑石粉)。在优选的实施方式中,所述药物组合物是适于口服的剂型,包括但不限于片剂、溶液剂、混悬液、胶囊剂、颗粒剂、粉剂。向患者施用本发明化合物或药物组合物的量不固定,通常按药用有效量给药。同时,实际给予的化合物的量可由医师根据实际情况决定,包括治疗的病症、选择的给药途径、给予的实际化合物、患者的个体情况等。本发明化合物的剂量取决于治疗的具体用途、给药方式、患者状态、医师判断。本发明化合物在药物组合物中的比例或浓度取决于多种因素,包括剂量、理化性质、给药途径等。
化合物的通用合成方法
本发明的式(I)或(Ⅱ)化合物可以通过以下方法制备得到:
具体的,β-榄香烯在特定的条件下进行烯丙位卤代反应(详细见CN 110683932),得到13,14-位双取代氯化榄香烯(I-a)。该中间体依次分别与等试剂进行反应(通常为亲核取代反应),得到式(I)化合物。这样的一步反应。
更具体地,本发明通式I所示化合物可通过如下的方法制得,然而该方法的条件,例如反应物、溶剂、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得,这样的组合可由本发明所属领域的技术人员容易地进行。
在本发明的制备方法中,各反应通常在惰性溶剂中,反应温度通常为-10~100℃(优选0~室温下进行,各步反应时间通常为0.5~48h,较佳地为2~12h。本发明所选用碱多为N,N-二异丙基乙基胺、碳酸铯、氢化钠等。通用步骤为:向β-榄香烯二氯代物溶液中依次加入N,N-二异丙基乙基胺和含氮或含氧取代基化合物进行反应,经后处理得到的粗品再经过柱层析纯化(乙酸乙酯/石油醚体系洗脱),优先得到β-榄香烯13-位取代化合物,在向此化合物溶液中加入N,N-二异丙基乙基胺和不同的含氮或含氧取代基化合物进行反应,经后处理得到的粗品再经过柱层析纯化(乙酸乙酯/石油醚体系洗脱)得到13-位与14-位连有不同取代基的β-榄香烯不对称取代衍生物。其中,β-榄香烯衍生物的溶液的摩尔浓度为0.1-0.5mol/L;所述中间体β-榄香烯衍生物和碱以及含氮化合物的摩尔比为1:(1.0-2.0):(1.1-4.0);优选为1:(1.0-1.5):(1.1-1.4)。进一步,β-榄香烯氯代物/DIPEA/的比例大约为1:1.2:1.1。进一步优选地,溶解β-榄香烯所用溶剂可以为二氯甲烷、四氢呋喃和N,N-二甲基甲酰胺中的一种,更进一步优选为N,N-二甲基甲酰胺。
药物组合物和施用方法
由于本发明化合物具有与榄香烯同等的或更强的抑制各种肿瘤细胞株的增殖活性,因此本发明化合物及其各种晶型,药学上可接受的无机或有机盐,水合物或溶剂合物,以及含有本发明化合物为主要活性成分的药物组合物可用于治疗、预防以及缓解各种榄香烯可以治疗的疾病,包括各种癌症。
本发明的药物组合物包含安全有效量范围内的本发明化合物或其药理上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全有效量”指的是:化合物的量足以明显改善病情,而不至于产生严重的副作用。通常,药物组合物含有1-2000mg本发明化合物/剂,更佳地,含有5-1000mg本发明化合物/剂。较佳地,所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是:一种或多种相容性固体或液体填料或凝胶物质,它们适合于人使用,而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的化合物以及它们之间相互掺和,而不明显降低化合物的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增溶剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明化合物可以单独给药,或者与其他药学上可接受的化合物联合给药。
使用药物组合物时,是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人),其中施用时剂量为药学上认为的有效给药剂量,对于60kg体重的人而言,日给药剂量通常为1~5000mg,优选5~2000mg。当然,具体剂量还应考虑给药途径、病人健康状况等因素,这些都是熟练医师技能范围之内的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
实施例1:化合物1的制备
将β-榄香烯1-a(3.8g,18.6mmoL)溶于二氯甲烷(25mL)与冰乙酸(22mL)的混合溶液中。加入催化量的TBAF,冰浴下缓慢滴入NaClO(M=3.0,28mL,84mmoL)水溶液,耗时5小时,滴完继续保持0℃搅拌1小时。加入10%亚硫酸钠水溶液(30mL)及饱和碳酸氢钠水溶液(20mL)淬灭反应。上述的反应液用乙酸乙酯萃取(3x50 mL)。合并的有机相用饱和食盐水洗(30mL),并用无水硫酸钠干燥。过滤除去干燥剂,滤液在减压条件下浓缩,所得粗品经硅胶柱层析(100%石油醚)得到无色液体化合物1-b(1.84g,收率37%)。1H NMR(400MHz,CDCl3)δ5.80(dd,J=17.1,11.1Hz,1H),5.29(d,J=1.0Hz,1H),5.18(d,J=1.0Hz,1H),5.05(s,1H),4.98–4.90(m,3H),4.14–4.08(dd,J=11.6,0.8Hz,1H),4.11(s,2H),3.98(dd,J=11.6,0.8Hz,1H),2.37–2.22(m,2H),1.79–1.63(m,2H),1.59–1.43(m,4H),0.99(s,3H)。
将化合物1-b(237mg,0.87mmoL)溶于干燥DMF(5mL)。于室温下加入真空干燥的碳酸铯(255mg,0.79mmoL)和双(叔丁氧羰基)胺1-c(265mg,1.22mmoL),55℃搅拌8小时。加入饱和碳酸氢钠水溶液(1mL)淬灭反应。减压除去DMF,剩余物用乙酸乙酯稀释(20mL),并用水洗(10mL),水相用乙酸乙酯反萃(10mL)。合并的有机相用饱和食盐水洗(10mL),并用无水硫酸钠干燥。过滤除去干燥剂,滤液在减压条件下浓缩后所得粗品经硅胶柱层析(石油醚:乙酸乙酯=8:1)得到无色液体化合物1(290mg,收率74%)。1H NMR(400MHz,CDCl3)δ5.71(dd,J=17.1,11.2Hz,1H),5.20(s,1H),4.92–4.78(m,4H),4.70(s,1H),4.13(s,2H),4.07–3.85(m,2H),2.21(dd,J=11.8,4.2Hz,1H),1.93(dd,J=11.0,4.1Hz,1H),1.60-1.55(m,4H),1.46-1.35(m,2H),1.41(s,18H),0.91(s,3H)。
实施例2:化合物2的制备
将化合物1(66mg,0.15mmoL)溶于干燥DMF(2mL)。于室温下加入无水的DIPEA(69mg,0.61mmoL)和叔丁氧羰基哌嗪2-a(105mg,0.56mmoL),55℃搅拌18小时。加入饱和碳酸氢钠水溶液(0.5mL)淬灭反应。减压除去N,N-二甲基甲酰胺,剩余物用乙酸乙酯稀释(20mL),并用水洗(10mL),水相用乙酸乙酯反萃(10mL)。合并的有机相用饱和食盐水洗(10mL),并用无水硫酸钠干燥。过滤除去干燥剂,滤液在减压条件下浓缩后所得粗品经硅胶柱层析(石油醚:乙酸乙酯=5:1)得到无色液体化合物2(50mg,收率57%)。1HNMR(400MHz,CDCl3)δ5.94–5.68(m,1H),4.98–4.80(m,4H),4.76–4.68(m,1H),4.65–4.55(m,1H),4.16–3.95(m,2H),3.79(dd,J=82.9,11.2Hz,1H),3.55–3.45(m,1H),,2.46–2.19(m,2H),2.18–1.83(m,6H),1.83–1.60(m,27H),1.68-1.44(m,6H),1.43–1.30(m,2H),1.00(s,3H)。
实施例3:化合物3的制备
将化合物2(50mg,0.08mmoL)溶于干燥二氯甲烷(2mL)。于0℃下加入三氟乙酸(0.5mL,6.7mmoL),逐渐升至室温搅拌3小时。减压除去三氟乙酸和溶剂,剩余物用乙酸乙酯稀释(20mL),用饱和碳酸钾溶液(3mL)洗涤,水层反萃一次(10mL),合并的有机相用饱和食盐水洗(3mL),并用无水硫酸钠干燥。过滤除去干燥剂,滤液在减压条件下浓缩后抽干后得黄色液体化合物3(24mg,收率96%)。1H NMR(400MHz,CD3OD)δ5.85(dd,J=17.5,10.8Hz,1H),5.11–4.96(m,3H),4.91(m,3H),3.11(d,J=13.5Hz,1H),2.85(td,J=6.3,3.8Hz,2H),2.65(d,J=13.4Hz,1H),2.50–2.13(m,6H),2.03(d,J=11.5Hz,2H),1.73–1.32(m,8H),1.03(s,3H)。
实施例4:化合物4的制备
化合物4是化合物1和化合物4-a反应得到的。详细的反应步骤参照化合物2的合成。化合物4为黄色油状液体。1HNMR(400MHz,CDCl3)δ5.72(dd,J=17.4,10.8Hz,1H),4.99(s,1H),4.86–4.76(m,3H),4.67(d,J=1.8Hz,2H),4.12(s,2H),3.47(s,2H),3.14(s,2H),3.09(d,J=13.9Hz,1H),2.68(d,J=7.3Hz,2H),2.60(d,J=13.9Hz,1H),2.51(dd,J=19.7,12.7Hz,2H),2.17(ddd,J=65.6,10.9,3.2Hz,2H),1.88(d,J=11.0Hz,1H),1.79(s,2H),1.63–1.46(m,2H),1.41(s,18H),1.39(s,9H),1.27–1.14(m,1H),0.92(s,3H)。
实施例5:化合物5的制备
化合物5是化合物1和化合物5-a反应得到的。详细的反应步骤参照化合物2的合成。化合物5为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.50(d,J=1.8Hz,1H),7.32(d,J=2.3Hz,1H),6.26(t,J=2.1Hz,1H),5.84(dd,J=17.4,10.8Hz,1H),5.05–4.96(m,2H),4.86(d,J=14.9Hz,2H),4.78(s,1H),4.76–4.70(m,2H),4.65(d,J=15.6Hz,1H),4.14(s,2H),1.94–1.81(m,2H),1.66–1.63(m,2H),1.61–1.49(m,4H),1.47(s,18H),1.03(s,3H)。
实施例6:化合物6的制备
化合物6是化合物5和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物6为黄色油状液体。1H NMR(400MHz,CD3OD)δ7.54(d,J=2.4Hz,1H),7.48(d,J=1.9Hz,1H),6.31(t,J=2.1Hz,1H),5.89(dd,J=17.4,10.9Hz,1H),5.13(s,1H),5.09–4.99(m,3H),4.92(s,1H),4.78(s,1H),4.72(s,2H),3.47(s,2H),2.02–1.91(m,2H),1.67–1.50(m,2H),1.57–1.46(m,4H),1.07(s,3H)。
实施例7:化合物7的制备
化合物7是化合物1-b和化合物5-a反应得到的。详细的反应步骤参照化合物1的合成。化合物7为黄色油状液体。
实施例8:化合物8的制备
化合物8是化合物7和化合物2-a反应得到的。详细的反应步骤参照化合物2的合成。化合物8为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.51(d,J=1.8Hz,1H),7.38(d,J=2.3Hz,1H),6.27(t,J=2.1Hz,1H),5.76(dd,J=17.5,10.7Hz,1H),5.02(d,J=8.0Hz,2H),4.90–4.82(m,2H),4.77(s,1H),4.76(s,3H),3.39(s,4H),3.02(d,J=13.8Hz,1H),2.60(d,J=13.7Hz,1H),2.39–2.27(m,2H),2.21–2.14(m,2H),1.88(d,J=11.1Hz,1H),1.76(s,1H),1.64–1.57(m,1H),1.56–1.46(m,2H),1.45(s,9H),1.44–1.38(m,3H),0.96(s,3H)。
实施例9:化合物9的制备
化合物9是化合物8和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物9为黄色油状液体。1H NMR(400MHz,CD3OD)δ7.62(d,J=2.3Hz,1H),7.50(d,J=1.9Hz,1H),6.33(t,J=2.2Hz,1H),5.81(dd,J=17.6,10.8Hz,1H),5.05(d,J=15.7Hz,2H),4.88(s,1H),4.88–4.83(m,2H),4.81(d,J=2.1Hz,2H),4.77(s,1H),3.13(d,J=13.4Hz,1H),3.07–2.94(m,4H),2.66(d,J=13.4Hz,1H),2.44(d,J=49.7Hz,4H),2.23(dd,J=12.9,3.3Hz,1H),1.95–1.86(m,1H),1.66–1.52(m,3H),1.52–1.38(m,3H),1.00(s,3H)
实施例10:化合物10的制备
化合物10是化合物7和化合物4-a反应得到的。详细的反应步骤参照化合物2的合成。化合物10为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.51(d,J=1.8Hz,1H),7.42(d,J=2.2Hz,1H),6.27(t,J=2.1Hz,1H),5.77(dd,J=17.4,10.9Hz,1H),5.17(s,1H),5.00(s,1H),4.95–4.83(m,3H),4.75(d,J=14.2Hz,3H),3.48(s,3H),3.30(s,2H),2.93(s,3H),2.41(s,2H),2.21(q,J=7.9Hz,1H),2.02–1.89(m,2H),1.62(s,1H),1.59(d,J=8.1Hz,1H),1.55–1.52(m,1H),1.48(d,J=3.9Hz,1H),1.46(s,9H),1.45–1.38(m,3H),0.94(s,3H)。
实施例11:化合物11的制备
化合物11是化合物10和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物11为黄色油状液体。1H NMR(400MHz,CD3OD)δ7.63(d,J=2.3Hz,1H),7.50(d,J=1.9Hz,1H),6.33(t,J=2.2Hz,1H),5.80(dd,J=17.5,10.8Hz,1H),5.09(s,1H),5.03(s,1H),4.88(d,J=1.3Hz,1H),4.86(q,J=1.4Hz,1H),4.81(s,3H),4.76(s,1H),3.43(s,2H),3.24(d,J=13.6Hz,1H),3.02(d,J=11.0Hz,1H),2.91(s,3H),2.72–2.58(m,3H),2.37(s,1H),2.26–2.15(m,2H),1.95–1.85(m,1H),1.67–1.52(m,3H),1.52–1.37(m,3H),0.99(s,3H)。
实施例12:化合物12的制备
化合物12是化合物7和化合物1-c反应得到的。详细的反应步骤参照化合物2的合成。化合物12为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.51(d,J=1.8Hz,1H),7.39(d,J=2.2Hz,1H),6.27(t,J=2.1Hz,1H),5.80(dd,J=17.9,10.5Hz,1H),5.01(s,1H),4.94(q,J=1.3Hz,1H),4.92–4.89(m,1H),4.86(d,J=1.8Hz,1H),4.75(s,3H),4.74(s,1H),4.22(dt,J=17.0,2.0Hz,1H),3.89(d,J=17.0Hz,1H),1.96–1.82(m,2H),1.66–1.54(m,3H),1.47(s,18H),1.46–1.41(m,3H),0.99(s,3H)。
实施例13:化合物13的制备
化合物13是化合物12和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物13为黄色油状液体。1H NMR(400MHz,CD3OD)δ7.48(d,J=2.3Hz,1H),7.42(d,J=1.8Hz,1H),6.25(t,J=2.2Hz,1H),5.82(dd,J=17.4,10.9Hz,1H),5.06(s,1H),5.00–4.92(m,3H),4.88(s,1H),4.71(s,1H),4.65(s,2H),3.39(s,2H),1.99–1.84(m,2H),1.60(q,J=12.7Hz,2H),1.52–1.31(m,4H),1.00(s,3H)。
实施例14:化合物14的制备
化合物14-a是化合物1-b和化合物2-a反应得到的。详细的反应步骤参照化合物1的合成。化合物14是化合物14-b和化合物5-a反应得到的。详细的反应步骤参照化合物2的合成。化合物14为黄色油状液体。1HNMR(500MHz,CDCl3)δ7.50(d,J=1.9Hz,1H),7.33(d,J=2.3Hz,1H),6.25(t,J=2.1Hz,1H),5.83(dd,J=17.4,10.8Hz,1H),5.03–4.96(m,2H),4.92(s,1H),4.89(s,1H),4.87(s,1H),4.77(s,1H),4.71(d,J=1.3Hz,1H),4.65(d,J=15.6Hz,1H),3.39(s,5H),2.88(d,J=8.6Hz,2H),2.36–2.24(m,4H),2.01(d,J=13.5Hz,1H),1.96–1.89(m,1H),1.59(d,J=12.7Hz,1H),1.50(s,1H),1.47(d,J=3.7Hz,1H),1.46(s,10H),1.41(s,1H),1.03(s,3H)。
实施例15:化合物15的制备
化合物15是化合物14和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物15为黄色油状液体。1H NMR(400MHz,CD3OD)δ7.55(d,J=2.0Hz,1H),7.49(d,J=2.0Hz,1H),6.32(q,J=2.0Hz,1H),5.89(dd,J=17.5,10.9Hz,1H),5.07–4.99(m,2H),4.97(s,2H),4.80(s,2H),4.71(d,J=3.9Hz,2H),3.13(t,J=5.2Hz,4H),2.98(s,2H),2.56(s,4H),2.06–1.89(m,2H),1.70–1.57(m,2H),1.54–1.42(m,4H),1.06(s,3H)。
实施例16:化合物16的制备
化合物16是化合物14-a和化合物4-a反应得到的。详细的反应步骤参照化合物2的合成。化合物16为黄色油状液体。1HNMR(400MHz,CDCl3)δ5.81(dd,J=17.5,10.7Hz,1H),5.07(s,1H),4.95(d,J=5.6Hz,2H),4.91(dd,J=9.5,1.3Hz,1H),4.89–4.82(m,3H),4.75(s,1H),3.55(s,2H),3.43(t,J=5.0Hz,4H),3.20(d,J=13.7Hz,3H),2.97(d,J=13.3Hz,1H),2.90(d,J=13.4Hz,1H),2.78(s,2H),2.71–2.54(m,3H),2.34(s,4H),2.19(m,1H),2.08(m,1H),1.62(m,3H),1.56–1.49(m,3H),1.47(s,18H),1.01(s,3H)。
实施例17:化合物17的制备
化合物17是化合物16和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物17为黄色油状液体。1H NMR(400MHz,CD3OD)δ5.84(dd,J=17.5,10.9Hz,1H),5.12(s,1H),4.99(m,3H),4.92(s,2H),4.87(d,J=2.5Hz,1H),4.84(s,1H),3.25(d,J=14.3Hz,1H),2.98(t,J=5.4Hz,6H),2.87(s,2H),2.73(d,J=13.6Hz,1H),2.61(s,2H),2.49(s,4H),2.44(m,1H),2.34–2.16(m,3H),2.14(m,1H),2.07–2.01(m,1H),1.77–1.42(m,6H),1.02(s,3H)。
实施例18:化合物18的制备
化合物18是化合物14-a和化合物1-c反应得到的。详细的反应步骤参照化合物2的合成。化合物18为黄色油状液体。1HNMR(400MHz,CDCl3)δ6.76(s,2H),5.83(dd,J=17.7,10.6Hz,1H),4.97–4.92(m,2H),4.91(s,2H),4.85(s,1H),4.74(s,1H),4.28–4.21(m,1H),3.90(d,J=17.1Hz,1H),3.40(t,J=5.1Hz,4H),2.90(d,J=7.3Hz,2H),2.36–2.25(m,4H),2.10–2.00(m,1H),1.96(dd,J=11.3,4.6Hz,1H),1.64–1.55(m,4H),1.54–1.50(m,2H),1.47(s,27H),1.01(s,3H)。
实施例19:化合物19的制备
化合物19是化合物18和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物19为黄色油状液体。1H NMR(400MHz,CD3OD)δ5.82(dd,J=17.8,10.5Hz,1H),5.13(d,J=1.7Hz,1H),5.00(s,1H),4.99–4.95(m,4H),4.83(d,J=18.8Hz,1H),3.41(d,J=15.4Hz,1H),2.98(s,2H),2.94(t,J=5.0Hz,4H),2.46(s,4H),2.22–2.12(m,1H),2.12–2.01(m,1H),1.78–1.42(m,6H),1.04(s,3H)。
实施例20:化合物20的制备
化合物20-a是化合物1-b和化合物4-a反应得到的。详细的反应步骤参照化合物1的合成。化合物20是化合物20-a和化合物2-a反应得到的。详细的反应步骤参照化合物2的合成。化合物20为黄色油状液体。1H NMR(400MHz,CDCl3)δ5.80(dd,J=17.6,10.8Hz,1H),5.05(s,1H),4.94(s,1H),4.89(dd,J=10.8,1.4Hz,1H),4.86(q,J=1.5Hz,2H),4.80(d,J=1.6Hz,1H),3.55(s,2H),3.38–3.34(m,4H),3.21(s,2H),3.08–2.92(m,3H),2.77(s,2H),2.62(dd,J=19.2,11.0Hz,3H),2.35(s,4H),2.22(dd,J=12.4,4.3Hz,2H),2.18(d,J=3.4Hz,1H),2.11–2.02(m,1H),1.62–1.48(m,4H),1.46(d,J=1.1Hz,18H),1.44–1.39(m,2H),0.99(s,3H)。
实施例21:化合物21的制备
化合物21是化合物20和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物21为黄色油状液体。1H NMR(400MHz,CD3OD)δ5.85(dd,J=17.5,10.8Hz,1H),5.08(s,1H),4.99(s,1H),4.94(d,J=3.9Hz,2H),4.92(s,1H),4.89(d,J=1.5Hz,1H),4.87(d,J=2.6Hz,2H),3.22(s,2H),3.13(d,J=13.2Hz,1H),3.06(s,2H),3.01–2.88(m,5H),2.85(s,2H),2.68(d,J=13.5Hz,1H),2.50(s,2H),2.44–2.27(m,5H),2.21–2.01(m,2H),1.72–1.60(m,2H),1.58–1.37(m,4H),1.02(s,3H)。
实施例22:化合物22的制备
化合物22是化合物20-b和化合物5-b反应得到的。详细的反应步骤参照化合物2的合成。化合物22为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.50(d,J=1.9Hz,1H),7.33(d,J=2.2Hz,1H),6.25(t,J=2.1Hz,1H),5.83(dd,J=17.5,10.8Hz,1H),5.05–4.95(m,2H),4.91(d,J=1.6Hz,1H),4.84(d,J=16.5Hz,2H),4.77–4.63(m,3H),3.56(s,2H),3.16(s,2H),2.96(q,J=13.4Hz,2H),2.75(s,2H),2.58–2.46(m,2H),2.35(d,J=9.1Hz,2H),2.04–1.87(m,2H),1.64–1.46(m,5H),1.45(s,9H),1.44–1.41(m,1H),1.02(s,3H)。
实施例23:化合物23的制备
化合物23是化合物22和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物23为黄色油状液体。1H NMR(400MHz,CD3OD)δ7.55(d,J=2.2Hz,1H),7.50(d,J=1.9Hz,1H),6.32(t,J=2.2Hz,1H),5.89(dd,J=17.5,10.9Hz,1H),5.06–4.93(m,5H),4.77(s,1H),4.72(s,2H),3.21(d,J=5.1Hz,2H),3.01(s,2H),2.82(d,J=7.8Hz,4H),2.55(s,2H),2.38(dd,J=9.6,5.1Hz,2H),2.07–1.92(m,2H),1.69–1.59(m,2H),1.55–1.44(m,4H),1.06(s,3H)。
实施例24:化合物24的制备
化合物24是化合物20-a和化合物24-a反应得到的。详细的反应步骤参照化合物2的合成。化合物24为黄色油状液体。1HNMR(400MHz,CDCl3)δ5.74(dd,J=17.1,11.0Hz,1H),5.35(t,J=4.7Hz,1H),5.15(s,1H),5.03–4.81(m,5H),4.43(s,1H),3.86(s,2H),3.53(s,2H),3.39–2.97(m,5H),2.85(s,2H),2.45(d,J=9.7Hz,2H),2.33–1.93(m,2H),1.69–1.59(m,2H),1.57–1.49(m,3H),1.47(s,9H),1.43(s,9H),1.37–1.24(m,3H),0.97(s,3H)。
实施例25:化合物25的制备
将3-氨基吡唑25-a(25.92mg,0.312mmol)溶于干燥DMF(3mL)中冷却至0℃,加入氢化钠(60%)(12.5mg,0.312mmol),搅拌0.5h,然后加入化合物14-a(100mg,0.24mmol),逐渐升至室温搅拌8h。向反应液加入冰水(5mL)淬灭反应,再用乙酸乙酯萃取(3×5mL)。合并的有机相用饱和食盐水(5mL)洗两次,并用无水硫酸钠干燥。过滤除去干燥剂,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析(甲醇:二氯甲烷=1:100)纯化,回收未反应原料33.4mg,得黄色油状液体化合物25(16mg,收率21.62%)。1HNMR(400MHz,CD3OD)δ7.22(d,J=2.4Hz,1H),5.88(dd,J=17.4,10.9Hz,1H),5.62(d,J=2.3Hz,1H),5.04–4.98(m,2H),4.96(d,J=4.0Hz,2H),4.91(d,J=2.5Hz,1H),4.88–4.83(m,2H),4.46(s,1H),3.40(s,4H),2.93(d,J=12.3Hz,2H),2.33(t,J=5.2Hz,4H),2.10–2.02(m,1H),1.98(s,1H),1.68–1.58(m,3H),1.55–1.47(m,3H),1.46(s,9H),1.05(s,3H)。
实施例26:化合物26的制备
化合物26是化合物7和化合物25-a反应得到的。详细的反应步骤参照化合物25的合成。化合物26为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.50(d,J=1.9Hz,1H),7.36(d,J=2.3Hz,1H),7.05(d,J=2.2Hz,1H),6.26(t,J=2.1Hz,1H),5.77(dd,J=17.5,10.8Hz,1H),5.59(d,J=2.2Hz,1H),5.01–4.96(m,2H),4.85(d,J=8.7Hz,2H),4.75(s,1H),4.73(s,2H),4.43(s,1H),3.64(s,2H),2.05–1.97(m,1H),1.88–1.82(dd,J=9.3,6.7Hz,1H),1.80–1.40(m,6H),0.99(s,3H)。
实施例27:化合物27的制备
冰浴下,向化合物6(30mg,0.105mmol)的干燥DMF(3mL)溶液里,加入DIPEA(41mg,0.315mmol),搅拌5分钟后加入化合物27-a(41.7mg,0.137mmol)、HOBt(19mg,0.137mmol)和EDCI(53mg,0.274mmol)。保持冰浴搅拌10分钟,逐渐升至室温反应8小时。薄板层析检测原料基本完全反应,减压蒸去DMF,剩余物用乙酸乙酯(3x 5mL)萃取。合并的有机相依次用水(2x 5mL)和饱和食盐水(2x 5mL)洗涤,并用无水硫酸钠干燥。过滤除去干燥剂,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析(二氯甲烷/甲醇=10/1)纯化,得到化合物27(55mg,收率83%)。LCMS[M+H]+:572.7
实施例28:化合物28的制备
化合物28是化合物27和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物28为黄色油状液体。1H NMR(400MHz,CDCl3)δ8.65(s,1H),7.67(d,J=7.9Hz,1H),7.55–7.49(m,1H),7.42–7.30(m,3H),7.24–7.03(m,3H),6.27(s,1H),5.80(dd,J=17.4,10.8Hz,1H),5.05–4.95(m,2H),4.88(s,1H),4.86–4.78(m,3H),4.77–4.62(m,2H),3.83(qd,J=15.5,5.8Hz,3H),3.35(dd,J=14.5,4.5Hz,1H),3.05(dd,J=14.5,8.0Hz,1H),1.92(d,J=3.8Hz,1H),1.89(d,J=3.7Hz,1H),1.77(s,2H),1.60(s,1H),1.55–1.35(m,5H),1.01(s,3H)。LCMS[M+H]+:472.7
实施例29:化合物29的制备
化合物29是化合物6和化合物29-a反应得到的。详细的反应步骤参照化合物27的合成。化合物29为黄色油状液体。LCMS[M+H]+:483.7
实施例30:化合物30的制备
化合物30是化合物29和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物30为黄色油状液体。LCMS[M+H]+:383.7
实施例31:化合物31的制备
化合物31是化合物6和化合物31-a反应得到的。详细的反应步骤参照化合物27的合成。化合物31为黄色油状液体。LCMS[M+H]+:457.6
实施例32:化合物32的制备
化合物32是化合物31和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物32为黄色油状液体。LCMS[M+H]+:357.6
实施例33:化合物33的制备
化合物33是化合物6和化合物33-a反应得到的。详细的反应步骤参照化合物27的合成。化合物33为黄色油状液体。LCMS[M+H]+:485.5
实施例34:化合物34的制备
化合物34是化合物33和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物34为黄色油状液体。LCMS[M+H]+:385.5
实施例35:化合物35的制备
化合物35是化合物6和化合物35-a反应得到的。详细的反应步骤参照化合物27的合成。化合物35为黄色油状液体。1H NMR(400MHz,CDCl3)δ7.58–7.47(m,2H),7.38(d,J=2.3Hz,1H),6.83(s,1H),6.62(s,1H),6.30(t,J=2.1Hz,1H),5.70(dd,J=17.7,10.5Hz,1H),5.01–4.65(m,8H),4.47(s,1H),3.96(dd,J=15.1,7.1Hz,1H),3.71(s,1H),3.58(d,J=15.5Hz,1H),3.49(s,1H),3.25(d,J=14.7Hz,1H),3.10(d,J=5.1Hz,1H),2.93(dd,J=14.8,6.1Hz,1H),1.90(d,J=3.3Hz,1H),1.87(d,J=3.2Hz,1H),1.60(dd,J=69.5,13.0Hz,3H),1.46(s,9H),1.43(m,J=5.6Hz,2H),0.99(s,3H)。LCMS[M+H]+:523.8
实施例36:化合物36的制备
化合物36是化合物35和三氟乙酸反应得到的。详细的反应步骤参照化合物3的合成。化合物36为黄色油状液体。LCMS[M+H]+:423.8
实施例37:化合物37的制备
在室温条件下,向化合物1(355mg,1.22mmol)的无水DMF(5mL)溶液中,依次加入化合物37a(459mg,1.0mmol),碳酸铯(652mg,2.0mmol),逐渐升温至90℃搅拌约7h。在减压条件下将DMF蒸除,加入饱和碳酸氢钠水溶液(8mL),并用乙酸乙酯(5mLx 3)萃取。合并的有机相依次用饱和碳酸氢钠水溶液(6mLx 2)、水(6mL x 2)和饱和食盐水(6mL x 2)洗涤,然后用无水硫酸钠干燥。干燥剂经过滤除去,滤液在减压条件下浓缩,所得的粗品经硅胶柱层析(乙酸乙酯/石油醚/三乙胺(0.1%)体系洗脱)纯化,得到黄色油状化合物37(337mg,收率50%)。1H NMR(500MHz,CDCl3)δ6.04(s,1H),5.80(dd,J=17.5,10.8Hz,1H),5.02(s,1H),4.91–4.82(m,3H),4.74(d,J=9.5Hz,2H),4.18(s,2H),3.70(s,3H),3.51(q,J=6.1Hz,2H),2.96(d,J=13.9Hz,1H),2.76(d,J=9.7Hz,2H),2.60(d,J=13.9Hz,1H),2.57–2.48(m,2H),2.18(dd,J=12.9,3.1Hz,1H),2.13(t,J=7.6Hz,2H),1.99–1.83(m,2H),1.69–1.55(m,8H),1.54–1.49(m,2H),1.47(s,19H),1.45–1.40(m,2H),1.23–1.19(m,3H),0.98(s,3H)。
实施例38:化合物38的制备
参照实施例37的合成方法,得到化合物38(252mg,收率46%)。1H NMR(500MHz,CDCl3)δ6.13(t,J=4.9Hz,1H),5.79(dd,J=17.5,10.8Hz,1H),5.00(s,1H),4.95–4.81(m,4H),4.74(s,1H),3.68(s,3H),3.50(q,J=6.1Hz,2H),3.39(s,4H),2.97(d,J=13.9Hz,1H),2.90(q,J=13.3Hz,2H),2.81–2.71(m,2H),2.59(d,J=13.9Hz,1H),2.53(t,J=6.0Hz,2H),2.31(s,4H),2.20(dd,J=12.7,3.1Hz,1H),2.14–2.09(m,2H),2.07(d,J=12.1Hz,1H),1.89(t,J=11.3Hz,1H),1.56(dq,J=42.1,13.9,13.0Hz,9H),1.44(s,9H),1.40(d,J=12.7Hz,1H),1.30–1.05(m,6H),0.98(s,3H).LCMS m/z 643.0[M+H]+。
实施例39:化合物39的制备
参照实施例37的合成方法,得到化合物39(142mg,收率66%)。1H NMR(500MHz,CDCl3)δ5.80(dd,J=17.5,10.8Hz,1H),5.58(t,J=5.1Hz,1H),5.01(s,1H),4.92(d,J=7.3Hz,2H),4.90–4.81(m,2H),4.75(s,1H),3.65(s,3H),3.40(t,J=5.1Hz,4H),3.24(q,J=6.7Hz,2H),3.02(d,J=13.8Hz,1H),2.96–2.87(m,2H),2.87–2.78(m,2H),2.61(d,J=13.9Hz,1H),2.38–2.25(m,6H),2.21(dd,J=12.9,3.2Hz,1H),2.11–1.92(m,5H),1.81–1.57(m,9H),1.49(td,J=13.3,12.2,8.9Hz,5H),1.44(s,9H),1.41(t,J=2.6Hz,1H),1.40–1.29(m,3H).LCMS m/z 643.4[M+H]+。
实施例40:化合物40的制备
参照实施例37的合成方法,得到化合物40(170mg,收率50%)。1H NMR(500MHz,CDCl3)δ5.79(dd,J=17.5,10.8Hz,1H),5.62(t,J=5.8Hz,1H),5.00(s,1H),4.89–4.81(m,3H),4.76–4.69(m,2H),4.17(dt,J=3.7,1.8Hz,2H),3.64(s,3H),3.23(q,J=6.7Hz,2H),3.00(d,J=13.8Hz,1H),2.87–2.77(m,2H),2.59(d,J=13.8Hz,1H),2.29(t,J=7.4Hz,2H),2.21(dd,J=12.7,3.3Hz,1H),2.06–1.98(m,1H),1.98–1.88(m,3H),1.82–1.57(m,10H),1.49(t,J=7.5Hz,4H),1.46(s,18H),1.43–1.38(m,2H),0.97(s,3H).LCMS m/z674.4[M+H]+。
实施例41:化合物41的制备
参照实施例37的合成方法,得到化合物41(256mg,收率66.8%)。1H NMR(400MHz,CDCl3)δ5.81(dd,J=17.5,10.8Hz,1H),5.03(s,1H),4.93(s,1H),4.91–4.81(m,3H),4.77(s,1H),3.67(s,3H),3.57(s,2H),3.31–3.12(m,4H),3.10–2.90(m,3H),2.90–2.81(m,2H),2.77(s,2H),2.60(d,J=13.8Hz,1H),2.41(d,J=8.6Hz,3H),2.32(t,J=7.4Hz,2H),2.24(d,J=7.6Hz,1H),1.95(s,2H),1.84–1.75(m,3H),1.73–1.67(m,2H),1.63(dd,J=15.0,7.4Hz,4H),1.59–1.48(m,5H),1.46(s,10H),1.43(s,1H),1.41–1.27(m,4H),0.98(s,3H).LCMS m/z 669.4[M+H]+。
实施例42:化合物42的制备
参照实施例37的合成方法,得到化合物42(321mg,收率45%)。1H NMR(500MHz,CDCl3)δ6.24(t,J=5.5Hz,1H),5.83–5.67(m,1H),4.98(s,1H),4.90(s,1H),4.88–4.83(m,2H),4.74(d,J=4.1Hz,2H),4.19–4.15(m,2H),3.65(s,3H),3.38(t,J=7.4Hz,1H),3.31(t,J=7.4Hz,1H),3.26(q,J=6.8Hz,2H),3.21(t,J=6.6Hz,2H),3.05–2.98(m,2H),2.88(d,J=14.1Hz,1H),2.31(t,J=7.4Hz,2H),1.99(dd,J=12.5,3.3Hz,1H),1.94(d,J=8.0Hz,1H),1.67–1.62(m,3H),1.61–1.57(m,1H),1.53(dt,J=15.1,7.3Hz,4H),1.47(s,19H),1.41–1.30(m,3H),0.98(s,3H).LCMS m/z 646.4[M+H]+。
实施例43:化合物43的制备
参照实施例37的合成方法,得到化合物43(333mg,收率40%)。1H NMR(500MHz,CDCl3)δ5.79(dd,J=17.5,10.8Hz,1H),5.71(s,1H),5.01(s,1H),4.90–4.81(m,3H),4.73(d,J=8.4Hz,2H),4.17(s,2H),3.67(s,3H),3.28(q,J=6.5Hz,2H),2.96(d,J=14.0Hz,1H),2.75(d,J=9.7Hz,2H),2.60(d,J=14.0Hz,1H),2.36(t,J=7.1Hz,2H),2.17(dd,J=12.6,2.8Hz,1H),2.12(t,J=7.6Hz,2H),1.94(t,J=10.9Hz,1H),1.91–1.85(m,1H),1.85–1.80(m,2H),1.61(q,J=12.5,9.9Hz,8H),1.52(s,2H),1.47(s,20H),1.44–1.38(m,2H),1.13(dd,J=20.8,8.9Hz,2H),0.98(s,3H)。
实施例44:化合物对Hep3B肿瘤细胞增殖抑制试验
用DMEM培养基将Hep3B细胞悬液调整到3x 104/mL。每孔加100μL细胞悬液于96-孔细胞培养板,最终细胞浓度为3000细胞/孔。第二天,以DMSO溶解待测试化合物为50mM储存液。用储存液和DMSO制备5X系列梯度稀释液,然后用培养基各稀释1000倍。最后吸去每孔培养基,分别加入100μL相应的溶液,每个药物浓度各5个复孔。最终各化合物处理浓度分别为50μM,10μM,2μM,0.4μM,每孔DMSO终浓度为0.1%。置于37℃,5%CO2孵箱中培养24小时。药物处理24小时后,每孔加入10μL CCK-8增强型溶液,培养箱内继续培养2小时后用THERMOFISHER Multiskan FC酶标仪测定450nm吸光度。用以下公式计算存活率和抑制率
细胞存活率=[(As-Ab)/(Ac-Ab)]×100%
抑制率=[(Ac-As)/(Ac-Ab)]×100%
As:实验孔(含有细胞的培养基、CCK-8、待测药物)的吸光度
Ac:对照孔(含有细胞的培养基、CCK-8、没有待测药物)的吸光度Ab:空白孔(不含细胞和待测药物的培养基、CCK-8)的吸光度
应用GraphPad Prism 5.0软件,使用非线性回归模型绘制S型剂量-存活率曲线并计算IC50值。
实施例45:化合物对A549肿瘤细胞增殖抑制试验
细胞铺板:1)配制完全培养基,充分混匀。2)复苏细胞,传两代左右选择生长状态良好的细胞株。3)将细胞培养瓶从培养箱中取出,核对培养瓶上标记的细胞名称和培养基类型。4)贴壁细胞:吸掉培养基,用胰酶洗一遍,弃掉废液,加3mL新鲜胰酶于培养瓶消化。待细胞松动要脱离瓶壁时,加8mL完全培养基中止胰酶消化,并轻轻混匀。用移液管将细胞悬液移入离心管中,800-1000rpm的转速离心3-5分钟。悬浮细胞:吸取细胞悬液并移入离心管中,800-1000rpm的转速离心3-5分钟。5)
弃上清。6)向离心管中加适当体积的培养基,轻柔吹打使细胞重悬均匀。7)使用Vi-Cell XR细胞计数仪计数。8)将细胞悬液调至合适浓度。9)将细胞悬液加入384孔板中,40μL/孔。标记细胞名称,种板密度,日期等详细信息,将培养板放置于CO2培养箱中过夜。
化合物板的配制及添加:1)待测化合物:化合物在DMSO中配制成10mM溶液,将化合物在DMSO中稀释成2mM溶液加到化合物板中,并用液体处理工作站以DMSO进行3倍梯度稀释9个点。2)Staurosporine化合物配制,在DMSO中配制0.4mM的溶液,加到化合物板中。3)化合物添加:吸取4.1μL的待测化合物板及Staurosporine化合物板中的化合物,加入含有36μL无血清培养基的中间板中混匀。从中间板中吸取2μL已混匀的培养基,根据以下化合物的布局加入相应细胞孔中。Blk对照:没有细胞,含0.5%DMSO;DMSO对照:有细胞,含0.5%DMSO;4)在二氧化碳培养箱中孵育72小时。
试剂准备及检测:1)室温融化CellTiter-Glo Buffer。将冻干CellTiter Glo底物平衡至室温。2)将CellTiter-Glo Buffer加入CellTiter Glo底物中并充分混匀。3)将细胞板取出平衡至室温。4)每孔中加入混匀后的CellTiter Glo试剂25微升,避光振荡10min,孵育10min。5)将培养板放入EnSpire读板,记录luminescence读值结果;按下列公式计算抑制率:抑制率(%)=(1-(RLU compound-RLU blank)/(RLU DMSO–RLU blank))×100%。6)利用XLFit绘制药效抑制率曲线并计算IC50值。利用4参数模型[fit=(A+((B-A)/(1+((C/x)^D))]进行。
实施例46:化合物对U87-MG肿瘤细胞增殖抑制试验
测试的方法和实施例45相同。
实验结果
在上述实施例44-46中描述的细胞增殖方案中测试所选化合物的结果列于表1中。
表1目标化合物对Hep3B、A549和U87-MG细胞增殖的测试结果
注:其中“A”表示IC50小于或等于50μΜ,“B”表示IC50在50μΜ-150μΜ之间,“C”表示IC50在150μΜ以上。
上述测试结果表明3,7,8,11,12,21,28,39化合物Hep3B、A549和U87-MG细胞的增殖的抑制活性均优于β–elemene。
此外应理解,在阅读了本发明的上述描述内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
上述实施例并非是对于本发明的限制,本发明并非仅限于上述实施例,只要符合本发明要求,均属于本发明的保护范围。
Claims (9)
1.一种化合物,或其光学异构体,包括消旋体、单一的对映异构体、可能的非对映异构体;或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂合物,其特征在于其化学结构式如下:
R1,R2,R3和R4各自独立选自以下基团:H、碳酸叔丁酯、C1-4烷基、C3-6烯基、C3-6炔基、C6-10芳基、5-至10-元杂芳基、5-至10-元杂环基、-C(O)-(C1-4烷基);
n=0、1、2、3;
R7为C1-6的烷基、C2-6的烯基、C2-6的炔基、C3-6的环烷基、或C3-6的杂环基;所述C3-6的杂环基中含1-3个独立的选自N、O或S的杂原子。
2.如权利要求1所述的一种化合物,或其光学异构体,包括消旋体、单一的对映异构体、可能的非对映异构体;或其药学上可接受的盐、前药、氘代衍生物、水合物、溶剂合物,其特征在于所述烷基、芳基、杂芳基、环烷基、杂环基被0-3个如下基团取代:-OH、-SH、-CN、卤素、-CO2H、-CO2R5、-C(O)-NH2、-C(O)-NR6aR6b、-OR5、C1-8烷基、C1-8的烷氧基、C1-8卤代烷基、C1-8的卤代烷氧基、C2-8的烯基、C2-8的炔基、-NR6aR6b、-CH2OH、-CH2-NR6aR6b;
其中R6a、R6b各自独立为C1-6的烷基、C2-6的烯基、C2-6的炔基、C3-6的环烷基、或C3-6的杂环基;R5为6-至10-元芳基或6-至10-元杂芳基。
5.如权利要求1-4任一项所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物的用途,其特征在于,包括:
(a)用于制备治疗榄香烯可预防、缓解或治愈的各种疾病的药物;或
(b)用于体外非治疗性地抑制各种肿瘤细胞株增殖。
6.如权利要求5所述用途,其特征在于所述疾病包括肝癌、直肠癌、膀胱癌、咽喉癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、前列腺癌、神经胶质细胞瘤、卵巢癌、头颈部鳞癌、宫颈癌、食管癌、肾癌、胰腺癌、结肠癌、皮肤癌、淋巴瘤、胃癌、多发性骨髓癌或实体瘤。
7.一种药物组合物,其特征在于包括:(i)有效量的如权利要求1-4任一项所述的化合物,或其光学异构体,药学上可接受的盐,前药,氘代衍生物,水合物,溶剂合物;和(ii)药学上可接受的载体。
9.一种β-榄香烯不对称取代衍生物的制备方法,其特征在于该方法具体是:
通过二氯代β-榄香烯中间体I-a与化合物进行取代反应,在中间体I-a中榄香烯的13-位上装上取代基/>得到式(Ⅱ)化合物I-b;然后化合物I-b与化合物/>进行再次取代反应,在中间体I-b中榄香烯的14-位上再装上取代基/>得到最终式(I)产物;其合成路线如下:/>
R1,R2,R3和R4各自独立选自以下基团:H、碳酸叔丁酯、C1-4烷基、C3-6烯基、C3-6炔基、C6-10芳基、5-至10-元杂芳基、5-至10-元杂环基、-C(O)-(C1-4烷基);
C1-6的烷基、C2-6的烯基、C2-6的炔基、C3-6的环烷基、或C3-6的杂环基;所述C3-6的杂环基中含1-3个独立的选自N、O或S的杂原子。
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Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1153168A (zh) * | 1995-12-26 | 1997-07-02 | 中国科学院大连化学物理研究所 | 榄香烯羟基类衍生物及其作为抗癌药物 |
CN1153167A (zh) * | 1995-12-26 | 1997-07-02 | 中国科学院大连化学物理研究所 | 榄香烯含氮衍生物及其用作抗癌药物 |
CN1844105A (zh) * | 2006-05-07 | 2006-10-11 | 沈阳药科大学 | 一种β-榄香烯含氮衍生物及制备方法和用途 |
CN1850779A (zh) * | 2006-05-10 | 2006-10-25 | 沈阳药科大学 | β-榄香烯含氮衍生物及其制备方法和用途 |
CN101239918A (zh) * | 2007-02-06 | 2008-08-13 | 中国科学院上海应用物理研究所 | β-榄香烯二胺类衍生物及其合成方法和应用 |
CN101239915A (zh) * | 2007-02-06 | 2008-08-13 | 中国科学院上海应用物理研究所 | β-榄香烯单取代胺衍生物及其合成方法和应用 |
CN112707833A (zh) * | 2019-10-24 | 2021-04-27 | 沈阳药科大学 | 组蛋白去乙酰酶抑制剂及其制备和应用 |
CN113698401A (zh) * | 2021-09-14 | 2021-11-26 | 杭州师范大学 | β-榄香烯大环衍生物及其制备方法和应用 |
CN113801073A (zh) * | 2021-10-11 | 2021-12-17 | 杭州师范大学 | 14-氯-β-榄香烯一氧化氮供体型衍生物及其制备和应用 |
-
2023
- 2023-02-27 CN CN202310169630.0A patent/CN116143661A/zh active Pending
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1153168A (zh) * | 1995-12-26 | 1997-07-02 | 中国科学院大连化学物理研究所 | 榄香烯羟基类衍生物及其作为抗癌药物 |
CN1153167A (zh) * | 1995-12-26 | 1997-07-02 | 中国科学院大连化学物理研究所 | 榄香烯含氮衍生物及其用作抗癌药物 |
CN1844105A (zh) * | 2006-05-07 | 2006-10-11 | 沈阳药科大学 | 一种β-榄香烯含氮衍生物及制备方法和用途 |
CN1850779A (zh) * | 2006-05-10 | 2006-10-25 | 沈阳药科大学 | β-榄香烯含氮衍生物及其制备方法和用途 |
CN101239918A (zh) * | 2007-02-06 | 2008-08-13 | 中国科学院上海应用物理研究所 | β-榄香烯二胺类衍生物及其合成方法和应用 |
CN101239915A (zh) * | 2007-02-06 | 2008-08-13 | 中国科学院上海应用物理研究所 | β-榄香烯单取代胺衍生物及其合成方法和应用 |
CN112707833A (zh) * | 2019-10-24 | 2021-04-27 | 沈阳药科大学 | 组蛋白去乙酰酶抑制剂及其制备和应用 |
CN113698401A (zh) * | 2021-09-14 | 2021-11-26 | 杭州师范大学 | β-榄香烯大环衍生物及其制备方法和应用 |
CN113801073A (zh) * | 2021-10-11 | 2021-12-17 | 杭州师范大学 | 14-氯-β-榄香烯一氧化氮供体型衍生物及其制备和应用 |
Non-Patent Citations (1)
Title |
---|
徐莉英: ""β-榄香烯衍生物的合成及抗癌活性研究"", 中国博士学位论文全文数据库 医药卫生科技辑, no. 04, 15 April 2012 (2012-04-15), pages 20 - 21 * |
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