CN107827908B - 一种雷帕霉素三氮唑衍生物及其制备方法和用途 - Google Patents
一种雷帕霉素三氮唑衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明属于医药技术领域范畴,具体涉及一种雷帕霉素三氮唑衍生物及其制备方法和用途。所述衍生物为下式Ⅰ所示的化合物或其药学可接受的盐、异构体、酯类,其制备方法为:(1)从化合物A‑1制备得到式A‑2化合物;(2)使化合物A‑2与R1芳基取代的炔类化合物经碘化亚铜和N,N‑二异丙基乙胺反应得到式Ⅰ化合物。本发明还保护了所述衍生物在制备抗肿瘤药物中的用途。本发明的衍生物均具有较强的抗肿瘤活性,且制备方法简单,为临床提供一种更理想的选择。
Description
技术领域
本发明属于医药技术领域范畴,涉及新的雷帕霉素类衍生物,特别是涉及一类取代的雷帕霉素三氮唑衍生物。本发明还涉及它们的制备方法以及含有所述化合物的药物组合物。本发明还涉及该衍生物具有优良抗癌活性潜在化合物的研究。
背景技术
肿瘤的靶向治疗是继手术治疗、化学药物治疗、放射性治疗后又一重要的治疗方式,这种治疗方式能够根据肿瘤的遗传背景、有针对性地抑制肿瘤细胞的生长、增殖、促进肿瘤细胞凋亡以及程序性坏死等达到***的目的,因而与化学药物治疗和放射治疗相比选择性强、毒副作用低,治疗效果好;不仅能单独使用,还可与化学治疗药物和放射性治疗联合使用,提高肿瘤的治疗效果。因此开发新的高效低毒的靶向抗癌药物成为抗肿瘤药物研发的趋势。哺乳动物雷帕霉素靶位(mammaliantarget ofrapamycin,mTOR)是最新发现的癌症治疗靶位之一,雷帕霉素是最早发现的mTOR抑制剂,雷帕霉素***的临床试验正在进行中,雷帕霉素衍生物替西罗莫司和依维莫司已作为mTOR靶向抗癌药物应用于临床。目前针对雷帕霉素的结构修饰主要是在C43-OH进行结构修饰,新的衍生物可以明显的改善抗癌活性和水溶性。
雷帕霉素(Rapamycin,RPM),又被称为西罗莫司(Sirolimus),其化学结构式如下:
替西罗莫司(Temsirolimus)结构如下:
雷帕霉素CAS登记号53123-88-9,分子式C51H79NO13,分子量914.17,从***中得到的无色结晶性固体,mp:183-185℃,[α]D25-58.2℃(甲醇),溶于***、氯仿、丙酮、甲醇和DMF,微溶于己烷和石油醚,不溶于水。小鼠LD50(mg/Kg)>600(腹腔注射),>2,500(口服)(Vezina)。
Vezina等1975年报道从吸水链霉菌发酵液获得低毒性抗真菌含氮三烯大环内酯抗生素雷帕霉素,体内和体外均具有抗真菌活性,尤其是抗白色念珠菌[C.Vein等人;J.Antibiot.28,721(1975);S.N.Sega等人;J.Antibiot.28,727(1975);H.A.Baker等人;J.Antibiot.31,539(1978);美国专利3,929,992;和美国专利3,993,749]。另外,雷帕霉素单独(美国专利4,885,171)或与沙培林组合使用(美国专利4,401,653)已表明具有抗肿瘤活性。
已发现雷帕霉素具有免疫抑制作用,能用于防止移植排斥[R.Y.Calne等人,Lancet 1183(1978);和美国专利5,100,899]。R.Martel等人[Can,J.Physiol.Pharmacol.55,48(1977)]发现了雷帕霉素在实验性过敏性脑脊髓炎模型、多发性硬化模型、辅助关节炎模型、类风湿性关节炎模型中都有效;并且有效抑制类IgE抗体的形成。
雷帕霉素也可以用来预防或治疗全身性红斑狼疮[美国专利5,078,999]、肺炎[美国专利5,080,899]、胰岛素依赖性糖尿病[美国专利5,321,009]、皮肤病比如牛皮癣[美国专利5,286,730]、肠病[美国专利5,286,731]、平滑肌细胞增生和血管损伤后的内膜增厚[美国专利5,288,711和5,516,781]、成人T-细胞性白血病/淋巴瘤[欧洲专利申请525,960Al]、眼炎症[美国专利5,387,589]、恶性癌病[美国专利5,206,018]、心炎症性疾病[美国专利5,496,832]、和贫血[美国专利5,561,138]。
经20余年的努力,雷帕霉素已被成功地开发为预防和治疗器官移植排斥反应的药物。雷帕霉素的免疫抑制活性比环孢素强数十倍,毒副作用比环孢素和FK506小。它不仅用于器官移植的急性排斥反应,而且还能逆转正在进行的移植排斥反应;可以治疗各种自身免疫性疾病。
近年来,随着对雷帕霉素衍生物研究的不断深入,发现雷帕霉素及其衍生物具有抑制多种肿瘤生长的作用,对其作用机制研究表明,雷帕霉素及其衍生物为mTOR变构抑制剂,都是通过与FKBP12蛋白生成复合物,此复合物与mTORC1的FRB区域结合,抑制mTOR的功能,从而抑制下游相关因子的表达,抑制肿瘤细胞的增殖、促使细胞凋亡等发挥其独特的靶向抗肿瘤作用。
近年,仅有3个雷帕霉素的化学半合成衍生物由FDA批准应用于癌症的治疗或用于临床试验,惠氏制药(Wyeth)开发的替西罗莫司(CCI-779)和诺华公司(Novartis)研发的依维莫司分别于2007年和于2009年被FDA批准用于晚期肾癌治疗;Deferolimus为Ariad公司研发,现正处于***的临床试验中。
mTOR是细胞内复杂的信号传导途径的中心,在细胞生长、增殖、细胞代谢、吞噬及血管形成中起关键作用。雷帕霉素等mTOR变构抑制剂与FKBP12蛋白结合形成复合物抑制mTORC1的过度活化,遏制核糖体的生物发生和蛋白质翻译,从而抑制肿瘤的细胞周期于G1期、促进肿瘤细胞的凋亡和自吞噬等抑制肿瘤细胞的生长和增殖,达到***的目的。
尽管人们在雷帕霉素及其衍生物的研究和临床应用方面已取得很大成就,然而本领域技术人员仍然期待有更具临床应用价值的药物为临床提供一种更理想的选择。
发明内容
本发明的目的在于为临床提供一种更具应用价值的药物特别是雷帕霉素衍生物。本发明人发现一系列的雷帕霉素C-28位三氮唑衍生物,显示出对多种肿瘤细胞株具有很强的抗肿瘤活性。本发明还提供了上述衍生物的制备方法。
为此,本发明第一方面提供了以下式Ι化合物:
或其药学上可接受的盐、溶剂合物、异构体、酯、前药,其中,
n为1或者2;
W为
R为氢、甲基、或(C1-C4)烷基;
R1为羟基(C1-C4)烷基-、苯基、N,N-二乙基甲基-、或苯胺基甲基-,其中苯基-或者苯基胺基甲基-上的苯环任选被1-4个相同或不同的R2基团取代;
R2选自:氢、卤素、氨基、羧基、氰基、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C4)烷基羟基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、(C1-C4)烷基硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷氧基乙基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、(C1-C3)亚烷基二氧基。
根据本发明第一方面任一实施方案的化合物,其中n为1或者2。
根据本发明第一方面任一实施方案的化合物,其中R为氢、甲基、或(C1-C4)烷基。
根据本发明第一方面任一实施方案的化合物,其中R1为羟基(C1-C4)烷基-、苯基、N,N-二乙基甲基-、或苯胺基甲基-,其中苯基-或者苯基胺基甲基-上的苯环任选被1-4个相同或不同的R2基团取代;R2选自:氢、卤素、氨基、羧基、氰基、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C4)烷基羟基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、(C1-C4)烷基硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷氧基乙基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、(C1-C3)亚烷基二氧基。
根据本发明第一方面任一实施方案的化合物,其中n为1。
R为氢、甲基、或(C1-C4)烷基;
R1为羟基(C1-C4)烷基-、苯基、N,N-二乙基甲基-、或苯胺基甲基-,其中苯基-或者苯基胺基甲基-上的苯环任选被1-4个相同或不同的R2基团取代;
R2选自:氢、卤素、氨基、羧基、氰基、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C4)烷基羟基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、(C1-C4)烷基硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷氧基乙基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、(C1-C3)亚烷基二氧基。
根据本发明第一方面任一实施方案的化合物,其中n为2。
R为氢、甲基、或(C1-C4)烷基;
R1为羟基(C1-C4)烷基-、苯基、N,N-二乙基甲基-、或苯胺基甲基-,其中苯基-或者苯基胺基甲基-上的苯环任选被1-4个相同或不同的R2基团取代;
R2选自:氢、卤素、氨基、羧基、氰基、三氟甲基、三氟甲氧基、(C1-C6)烷基、(C1-C4)烷基羟基、(C1-C4)烷氧基、(C1-C4)烯基、(C1-C4)炔基、N-(C1-C4)烷基氨基、N,N-二(C1-C4)烷基氨基、(C1-C4)烷基硫基、(C1-C4)烷基亚磺酰基、(C1-C4)烷基磺酰基、(C1-C4)烷氧基甲基、(C1-C4)烷氧基乙基、(C1-C4)烷基酰基、氨基甲酰基、N-(C1-C4)烷基氨基甲酰基、N,N-二(C1-C4)烷基氨基甲酰基、(C1-C3)亚烷基二氧基。
根据本发明第一方面任一实施方案的化合物,其选自:
28-O-(2-(4-((2,4二氯苯基)氨基甲基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-121),其化学结构为
28-O-(2-(4-(3-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-123),其化学结构为
28-O-(2-(4-(2-氯苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-124),其化学结构为
28-O-(2-(4-(4-甲氧基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-125),其化学结构为
28-O-(2-(4-(4-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-126),其化学结构为
28-O-(2-(4-(4-氟苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-127),其化学结构为
28-O-(2-(4-(2-羟基异丙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-128),其化学结构为
28-O-(2-(4-(羟乙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(其在本发明中可缩写为X-129),其化学结构为
28-O-(2-(4-(亚甲基-(N,N-二乙基))-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(其在本发明中可缩写为X-150),其化学结构为
28-O-(2-(4-((2-氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(其在本发明中可缩写为X-151),其化学结构为
28-O-(2-(4-((2,6-二氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(其在本发明中可缩写为X-152),其化学结构为
28-O-(2-(4-(3-氨基苯基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(其在本发明中可缩写为X-153),其化学结构为
或上述化合物药学上可接受的盐、溶剂合物、异构体、酯、前药。
本发明化合物本质上是雷帕霉素的C-28位羟基取代的衍生物,因此其名称可以仍然以雷帕霉素母核为准,以C-28位羟基上的取代基表述,如上文所述的。
进一步地,本发明第二方面提供了一种药物组合物,其中包括本发明第一方面任一实施方案所述化合物,以及任选的药学可接受的载体或辅料。根据此方面,本发明还涉及所述药物组合物作为用于预防或***和/或癌症等疾病的药物中的应用。
进一步地,本发明第三方面提供了本发明第一方面任一实施方案所述化合物在制备用于预防或***和/或癌症的药物中的用途。根据本发明的用途,其中所述肿瘤和/或癌症选自:肺癌、食道癌、胃癌、***癌、乳腺癌、肾癌。
进一步地,本发明第四方面提供了预防和/或***和/或癌症的方法,该方法包括向有此需要的受试者给予预防和/或治疗有效量的本发明第一方面的式I化合物。
进一步地,本发明第五方面提供了制备本发明第一方面任一实施方案所述化合物的方法,其包括以下步骤:
从以下化合物A-1制备得到下式A-2化合物:
接着使A-2化合物与R1芳基取代的炔类化合物经碘化亚铜和N,N-二异丙基乙胺反应得到式Ⅰ化合物:
任选地使式I化合物形成其药学上可接受的盐、溶剂合物、异构体、酯、前药。其中各取代基如本发明第一方面任一实施方案所述。
根据本发明第五方面的方法,W为时,A-2化合物的制备方法为:
以A-1化合物为原料与三甲基氯硅烷反应得到B-1化合物然后与叔丁基二甲基氯硅烷反应,得到以下式B-2化合物:
接着使B-4化合物脱保护得到化合物B-5:
最后使B-5化合物与叠氮化钠反应得到A-2化合物。
本发明任一方面或该任一方面的任一项所具有的特征同样适用于其它任一方面或该其它任一方面的任一项,只要它们不会相互矛盾,当然在相互之间适用时,必要的话可对相应特征作适当修饰。在本发明中,例如,提及“本发明第一方面任一项”时,该“任一项”是指本发明第一方面的任一子方面;在其它方面以类似方式提及时,亦具有相同含义。
下面对本发明的各个方面和特点作进一步的描述。
本发明所引述的所有文献,它们的全部内容通过引用并入本文,并且如果这些文献所表达的含义与本发明不一致时,以本发明的表述为准。此外,本发明使用的各种术语和短语具有本领域技术人员公知的一般含义,即便如此,本发明仍然希望在此对这些术语和短语作更详尽的说明和解释,提及的术语和短语如有与公知含义不一致的,以本发明所表述的含义为准。
在本发明中,基团“C1-C4烷基”、“C1-4烷基”、“(C1-C4)烷基”
等,它们具有相同含义,均表示具有1-4个碳原子的直链或支链烷基。其它情况亦可作类似理解。
在本发明中,基团“C1-4烷基”,包括其单独表述的、以及与其它基团组合存在的,例如可以选自C1-3烷基、C1-2烷基。同样地,C1-4烷氧基例如可以选自C1-3烷氧基、C1-2烷氧基。
在本发明合成式I化合物的方法中,反应所用的各种原材料是本领域技术人员根据已有知识可以制备得到的,或者是可以通过文献公知的方法制得的,或者是可以通过商业购得的。以上反应方案中所用的中间体、原材料、试剂、反应条件等均可以根据本领域技术人员已有知识可以作适当改变的。或者,本领域技术人员也可以根据本发明第二方面方法合成本发明未具体列举的其它式I化合物。
下面示意性合成路线A描述了本发明的通式Ⅰ化合物的制备,所有的原料都是通过这些示意合成路线中描述的方法、通过有机化学领域普通技术人员熟知的方法制备的或者可商购。本发明的全部最终化合物都是通过这些示意中描述的方法或通过与其类似的方法制备的,这些方法是有机化学领域普通技术人员熟知的。这些示意中应用的全部可变因数如下文的定义或如权利要求中的定义。
按照本发明的通式Ⅰ衍生物,在路线A中,R、R1、R2、W和n如发明内容所定义。
路线A:通式Ⅰ化合物的合成路线
将化合物A-1经2-6步反应,生成叠氮化合物A-2。将化合物A-2与炔基醇类或苯基炔化合物经CuI和DIPEA反应得到通式为Ⅰ所示的衍生物。
具体的,A-2根据步骤1描述的方法制备:以A-1为原料,经硅醚保护、酯化、脱保护和叠氮化得到A-2。(TMSCl中文全称:三甲基氯硅烷,TBSCl中文全称:叔丁基二甲基氯硅烷)。
步骤1(路线B)
本发明的有益效果在于:本发明的衍生物均具有较强的抗肿瘤活性。且制备方法简单,为临床提供一种更理想的选择制备的化合物具有较好的抗肿瘤活性。
具体实施方式
下面的具体实施例旨在阐述而不是限制本发明的范围。
本发明中所制备化合物的核磁共振氢谱用BrukerARX-300测定,质谱用Agilent1100LC/MSD测定;所用试剂均为分析纯或化学纯。
在下文的一些实施例中制备了一些本发明的典型化合物,它们以如下通式I表示,各取代基以及这些化合物的示例性名称分别见表1。
表1:实施例1-9的结构式
实施例1:28-O-(2-(4-((2,4二氯苯基)氨基甲基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-121)的制备
步骤A:28-氧基三甲基硅烷基-氧雷帕霉素的制备
将10g(10.94mmol)雷帕霉素倒入250ml烧瓶中,加入EA 115ml,室温下搅拌10min,降温至0℃,加入9.34g(137.19mmol)咪唑,搅拌5min后,滴加9.3g(85.33mmol)三甲基氯硅烷,在滴加过程中有白色固体析出,38min后滴加完毕,滴加完7min后,TLC检测,显示雷帕霉素已反应完全。加入66ml(33.37mmol)0.5N H2SO4搅拌,反应3h,TLC检测反应完全,得到单保护产品。用EA萃取,依次用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗,最后无水Na2SO4脱水,抽滤,减压浓缩干燥,得到12.28g白色固体。MS(ESI)m/z:1008.6(M+Na)+。1HNMR(600MHz,DMSO)δ6.47(s,1H),6.41(dd,J=14.3,11.5Hz,1H),6.23(dd,J=24.6,13.7Hz,1H),6.15(dd,J=21.1,10.9Hz,1H),6.10(d,J=15.1Hz,1H),5.46(dd,J=14.8,9.6Hz,1H),5.11(d,J=10.2Hz,1H),5.01(d,J=3.6Hz,1H),4.95(d,J=4.8Hz,1H),4.68–4.62(m,1H),4.02(t,J=9.3Hz,2H),3.87(d,J=5.7Hz,1H),3.61(dd,J=33.1,18.7Hz,1H),3.45(d,J=12.6Hz,1H),3.33(s,3H),3.29(dd,J=19.4,8.7Hz,1H),3.17(s,3H),3.14(t,J=5.7Hz,2H),3.08(d,J=21.0Hz,3H),2.82(dd,J=15.5,8.0Hz,1H),2.72(dd,J=33.3,11.9Hz,1H),2.50(d,J=12.8Hz,1H),2.23(s,1H),2.13(d,J=9.6Hz,1H),2.05–2.01(m,1H),1.85(d,J=9.3Hz,1H),1.83(s,1H),1.77(s,3H),1.67(s,1H),1.64(s,3H),1.61(s,1H),1.38(d,J=12.7Hz,1H),1.30(s,1H),1.24(d,J=11.3Hz,1H),1.20(d,J=11.1Hz,1H),0.99(d,J=6.3Hz,3H),0.88(d,J=6.3Hz,3H),0.83(d,J=6.3Hz,3H),0.78(d,J=6.5Hz,3H),0.74(d,J=6.4Hz,3H),0.03–-0.05(m,9H)。13C NMR(151MHz,DMSO)δ209.74,207.76,199.26,169.67,167.43,139.57,138.33,136.86,132.82,130.92,127.54,125.72,99.47,85.45,84.32,82.63,77.98,74.17,73.69,71.82,66.65,57.47,57.31,56.29,55.95,51.46,45.47,44.09,40.68,40.41,40.27,40.13,39.99,39.85,39.71,39.58,38.57,35.54,35.24,34.07,33.39,33.03,31.89,30.05,28.67,26.85,24.93,22.20,21.47,20.94,19.74,16.08,15.95,15.51,14.07,13.67,11.04。
步骤B:43-氧基叔丁基二甲基硅烷基-氧雷帕霉素的制备
将12.28g(12.45mmol)28-氧基三甲基硅烷基-氧雷帕霉素倒入250ml烧瓶中,用110ml N,N-二甲基甲酰胺(DMF)溶解,加入24.54g(360.43mmol)咪唑,60℃下溶解,最后分次加入14.72g(138.26mmol)TBSCl,60℃下反应5h,TLC检测。反应完毕,用EA萃取,依次用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗涤,最后无水Na2SO4脱水,抽滤,减压浓缩至干,得到淡黄色固体。硅胶柱层析,PE:EA=6:1~4:1梯度洗脱,最后得到6g白色固体。收率:46.3%。MS(ESI)m/z:1050.6(M+Na)+。1H NMR(600MHz,DMSO)δ6.46(d,J=1.4Hz,1H),6.44–6.37(m,1H),6.23(dd,J=14.5,10.6Hz,1H),6.17–6.11(m,1H),6.11(d,J=4.5Hz,1H),5.47(dd,J=14.9,9.6Hz,1H),5.28(d,J=4.5Hz,1H),5.11(d,J=10.1Hz,1H),5.01–4.97(m,1H),4.95(d,J=6.0Hz,1H),4.05–3.99(m,2H),3.95(d,J=4.6Hz,1H),3.45(d,J=12.7Hz,1H),3.33(s,4H),3.20–3.17(m,1H),3.16(s,3H),3.13(s,1H),3.06(s,3H),2.76–2.71(m,1H),2.44–2.39(m,1H),2.24–2.18(m,1H),2.14–2.08(m,1H),2.04(dd,J=15.0,6.9Hz,1H),1.85–1.80(m,1H),1.74(s,4H),1.68(s,1H),1.68–1.66(m,1H),1.64(s,4H),1.60(d,J=4.8Hz,1H),1.59–1.56(m,2H),1.53(s,2H),1.38(d,J=10.5Hz,1H),1.29(d,J=11.8Hz,3H),1.25(d,J=11.1Hz,2H),0.98(d,J=6.5Hz,3H),0.88(d,J=6.5Hz,3H),0.86(s,9H),0.83(d,J=6.4Hz,4H),0.78(d,J=6.7Hz,3H),0.74(d,J=6.7Hz,3H),0.04(d,J=1.4Hz,6H)。13C NMR(151MHz,DMSO)δ210.93,207.98,199.35,169.68,167.48,139.83,138.36,137.66,132.82,130.87,127.49,125.44,99.51,85.96,84.08,82.76,76.24,75.75,74.13,66.67,57.58,57.39,55.94,51.25,45.71,44.00,40.53,40.41,40.27,40.13,39.99,39.86,39.72,39.58,38.78,35.89,35.74,35.29,33.95,32.79,31.52,30.14,26.94,26.72,26.23,24.96,22.15,20.89,18.32,16.04,15.24,13.92,13.88,10.96。
步骤C:28-O-(2-溴乙酰基)-43-氧基叔丁基二甲基硅烷基-氧雷帕霉素的制备
将6g(5.8mmol)43-氧基叔丁基二甲基硅烷基-氧雷帕霉素倒入250ml烧瓶中,加入100mL二氯甲烷(DCM)溶解,降温至-2℃,加入18ml吡啶,5min后滴加9ml(104.2mmol)溴乙酰溴,40min滴加完毕,TLC检测。反应完毕,用DCM萃取,依次用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥,得到红黑色固体。硅胶柱层析纯化,PE:EA=10:1~4:1梯度洗脱,共得到4.77g样品,收率70.8%。MS(ESI)m/z:1170.5(M+Na)+。1H NMR(600MHz,DMSO)δ6.42(d,J=3.8Hz,1H),6.41–6.37(m,1H),6.23(dd,J=10.3,4.8Hz,1H),6.15(dd,J=12.9,7.1Hz,1H),6.12(d,J=7.0Hz,1H),5.51–5.47(m,1H),5.05(d,J=11.3Hz,1H),5.02–4.96(m,2H),4.94(d,J=5.4Hz,5H),4.57(s,1H),4.08–3.98(m,3H),3.91(d,J=2.8Hz,1H),3.63(dd,J=20.6,9.3Hz,1H),3.45(d,J=12.6Hz,1H),3.33(dd,J=2.6,1.5Hz,3H),3.32–3.27(m,1H),3.22–3.19(m,3H),3.17(d,J=2.2Hz,3H),3.15–3.13(m,2H),3.05(d,J=2.8Hz,3H),2.88–2.80(m,1H),2.67(dd,J=9.2,6.2Hz,1H),2.39(dd,J=16.1,9.2Hz,1H),2.12(d,J=13.1Hz,1H),2.04–1.99(m,1H),1.90(d,J=13.1Hz,1H),1.86–1.80(m,1H),1.78–1.73(m,1H),1.67(s,1H),1.63–1.59(m,1H),1.55(d,J=12.8Hz,1H),1.53(s,1H),1.27(s,1H),1.26–1.22(m,1H),1.21–1.16(m,1H),0.98(d,J=2.1Hz,3H),0.87(d,J=1.9Hz,3H),0.85–0.83(m,12H),0.83–0.82(m,3H),0.78(d,J=7.8Hz,3H),0.74(dd,J=6.5,2.4Hz,3H),0.59(dd,J=23.8,11.9Hz,1H),-0.03–-0.06(m,6H)。13C NMR(151MHz,DMSO)δ212.26,204.25,198.86,169.73,167.47,138.66,138.47,132.85,129.92,127.49,126.40,123.31,99.33,84.28,83.07,82.15,76.84,74.21,73.58,66.94,59.76,57.23,55.85,51.21,49.03,45.52,40.40,40.26,40.12,39.98,39.84,39.70,39.56,39.49,35.66,35.19,33.42,32.77,31.57,31.49,26.67,26.27,24.95,21.76,20.86,18.25,16.06,15.40,13.84,10.68。
步骤D:28-O-(2-溴乙酰基)-氧雷帕霉素的制备
将4.77g(4.15mmol)28-O-(2-溴乙酰基)-43-氧基叔丁基二甲基硅烷基-氧雷帕霉素倒入250ml烧瓶中,用70ml丙酮(AC)溶解,降温至0℃,然后加入18ml(0.018mmol)2NH2SO4溶液,18h后TLC检测。反应完毕,用EA萃取,依次用水、饱和NaHCO3溶液和饱和NaCl溶液洗涤,最后无水Na2SO4脱水,减压浓缩,得到淡黄色固体。硅胶柱层析纯化,PE:EA=6:1~1:1梯度洗脱,最后得到3.6g样品,收率:79.5%。MS(ESI)m/z:1056.5(M+Na)+。1HNMR(600MHz,DMSO)δ6.42(d,J=4.5Hz,1H),6.40(d,J=3.6Hz,1H),6.23(d,J=4.0Hz,1H),6.19–6.15(m,1H),6.12(s,1H),5.47(d,J=5.3Hz,1H),5.09(s,1H),4.98(d,J=3.8Hz,1H),4.94(s,1H),4.65(s,1H),4.02–4.00(m,2H),3.91(d,J=2.7Hz,1H),3.62(d,J=6.2Hz,1H),3.44(d,J=2.1Hz,1H),3.33(s,3H),3.26(s,1H),3.22(s,3H),3.19(d,J=2.1Hz,1H),3.05(s,3H),2.84–2.82(m,1H),2.73(dd,J=8.8,5.2Hz,1H),2.51(dt,J=3.6,1.8Hz,2H),2.46–2.42(m,1H),2.10(d,J=11.8Hz,2H),1.82(s,3H),1.66–1.65(m,1H),1.61(s,3H),1.58(s,1H),1.41(s,1H),1.30(s,1H),0.99(d,J=6.6Hz,3H),0.88–0.86(m,3H),0.84(dd,J=4.8,3.8Hz,3H),0.77(d,J=6.8Hz,3H),0.74(d,J=6.6Hz,3H)。13C NMR(151MHz,DMSO)δ209.33,207.25,199.30,169.64,167.41,166.24,139.64,138.42,132.92,132.61,131.04,127.48,99.44,84.32,82.63,78.27,74.25,73.70,66.65,60.21,57.67,57.24,55.94,51.45,51.44,45.55,44.09,40.40,40.26,40.12,39.98,39.84,39.70,39.57,35.69,33.40,33.03,31.84,26.99,26.27,22.04,20.95,16.09,15.76,15.51,14.67,14.55,13.79,10.93。
步骤E:28-O-(2-叠氮乙酰基)-氧雷帕霉素的制备
将3.6g(3.48mmol)28-O-(2-溴乙酰基)-氧雷帕霉素倒入250ml烧瓶中,然后加入50mLN,N-二甲基甲酰胺(DMF)和催化量的KI,放置于50℃的油浴中5min后加入0.9g(13.8mmol)NaN3,TLC检测。反应完全后。用EA萃取,依次采用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗涤,最后无水Na2SO4脱水,抽滤,减压浓缩干燥得到白色固体。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1梯度洗脱,最后得到1.4g样品,收率:40.3%。MS(ESI)m/z:1011.9(M+Na)+。1HNMR(600MHz,DMSO)δ6.47(s,1H),6.40(dd,J=14.6,11.3Hz,1H),6.24(dd,J=14.5,10.7Hz,1H),6.15(dd,J=15.7,5.3Hz,1H),6.12(d,J=4.6Hz,1H),5.47(dd,J=15.0,9.7Hz,1H),5.34(t,J=5.9Hz,1H),5.05(d,J=10.1Hz,1H),4.98–4.93(m,2H),4.61(s,1H),4.36(d,J=3.8Hz,1H),4.09–3.97(m,2H),3.95(d,J=9.8Hz,1H),3.63(dd,J=17.2,5.6Hz,1H),3.46(d,J=13.9Hz,1H),3.33(s,3H),3.30–3.27(m,1H),3.27–3.24(m,1H),3.22(s,3H),3.13–3.08(m,1H),3.05(s,3H),2.86–2.82(m,1H),2.67(dd,J=17.5,2.7Hz,1H),2.52–2.49(m,1H),2.44–2.36(m,2H),2.24(s,2H),2.13(d,J=12.5Hz,1H),1.85(s,1H),1.82(s,3H),1.62(s,3H),1.59–1.55(m,4H),1.28(s,1H),1.00(d,J=6.5Hz,6H),0.89–0.86(m,6H),0.84–0.82(m,1H),0.77(d,J=6.7Hz,3H),0.74(d,J=6.6Hz,3H)。13C NMR(151MHz,DMSO)δ209.42,207.45,199.27,169.67,167.83,167.43,139.61,138.41,132.92,132.58,131.04,127.49,99.45,84.33,82.64,82.41,78.01,74.33,73.70,66.65,57.64,57.22,55.93,51.42,49.87,45.62,44.12,41.28,40.97,40.74,40.39,40.25,40.11,39.97,39.83,39.70,39.56,38.52,35.66,35.59,35.20,34.13,33.40,33.06,31.86,26.82,24.95,22.02,20.95,16.08,15.78,15.42,14.65,13.71,10.91.
步骤F:28-O-(2-(4-((2,4二氯苯基)氨基甲基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-121)的制备
将0.3g(0.3mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入N,N-二异丙基乙胺(DIPEA),最后加入0.15g(0.81mmol)2,4-二氯苯基丙炔胺,在室温下反应30min,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,最后无水Na2SO4干燥,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,最后得到0.15g样品。收率:42.9%。MS(ESI)m/z:1204.5(M+Na)+。1H NMR(600MHz,DMSO)δ7.91–7.87(m,1H),7.36(t,J=6.7Hz,1H),7.14(dt,J=7.0,3.5Hz,1H),6.81(d,J=8.9Hz,1H),6.47(s,1H),6.39(dd,J=14.3,11.5Hz,1H),6.20(dd,J=23.1,8.5Hz,1H),6.16–6.08(m,2H),6.06(d,J=5.9Hz,1H),5.49(dd,J=21.0,10.7Hz,1H),5.36–5.25(m,2H),5.08(d,J=7.4Hz,1H),5.00(d,J=9.9Hz,1H),4.96(d,J=4.1Hz,1H),4.61(d,J=4.0Hz,1H),4.44(d,J=5.9Hz,2H),4.29(d,J=3.5Hz,1H),4.05–3.94(m,2H),3.93(d,J=7.1Hz,1H),3.63(d,J=12.0Hz,1H),3.46(d,J=12.8Hz,1H),3.34(s,3H),3.29–3.20(m,2H),3.19(d,J=5.5Hz,3H),3.04(d,J=18.5Hz,3H),2.85–2.79(m,1H),2.72–2.60(m,1H),2.44–2.31(m,2H),2.24(d,J=28.6Hz,1H),2.17–2.11(m,1H),2.05–1.97(m,1H),1.89(dt,J=25.7,14.6Hz,3H),1.68(s,3H),1.59–1.47(m,5H),1.45–1.35(m,2H),1.27(dd,J=25.5,13.6Hz,2H),1.22–1.13(m,3H),1.08–1.03(m,2H),0.98(d,J=6.3Hz,3H),0.94(d,J=7.0Hz,1H),0.86(d,J=6.4Hz,3H),0.85–0.82(m,1H),0.80(d,J=6.3Hz,3H),0.74(t,J=6.4Hz,6H),0.57(dd,J=23.7,11.9Hz,1H)。13C NMR(151MHz,DMSO)δ209.37,207.29,199.29,169.72,167.42,166.19,145.47,143.24,139.51,138.40,132.94,132.23,130.97,128.65,128.17,127.46,126.50,124.70,119.75,118.87,112.92,107.45,99.45,84.29,82.63,82.29,78.15,74.29,73.71,71.83,66.64,57.67,57.23,55.94,51.42,50.60,45.66,44.14,41.00,40.41,40.27,40.13,39.99,39.85,39.71,39.57,38.71,35.66,35.20,34.17,33.39,33.01,31.85,30.07,26.52,25.11,22.04,20.99,19.59,16.08,15.77,15.44,14.45,13.78,10.94.
实施例2:28-O-(2-(4-(苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-122)的制备
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-122)的制备
将0.12g(0.12mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.06g(0.60mmol)的苯乙炔在室温下反应90min,TLC检测。反应完毕后,用EA萃取,然后依次用水、1NHCl洗、饱和NaHCO3和饱和NaCl洗涤,最后无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.09g样品。收率:69.2%。MS(ESI)m/z:1107.6(M+Na)+。1H NMR(500MHz,DMSO)δ8.43(s,1H),7.86(d,J=1.0Hz,1H),7.84(s,1H),7.46(d,J=7.4Hz,1H),7.43(s,1H),7.33(dd,J=13.3,5.9Hz,1H),6.44(d,J=1.1Hz,1H),6.37(dd,J=14.3,11.4Hz,1H),6.22(dd,J=17.0,6.4Hz,1H),6.19–6.11(m,1H),6.10(d,J=4.1Hz,1H),5.63–5.48(m,1H),5.37(dd,J=23.2,10.0Hz,2H),5.09(d,J=7.3Hz,1H),5.03–4.94(m,2H),4.57–4.52(m,1H),4.35(d,J=3.6Hz,1H),4.31–4.10(m,1H),4.06–3.96(m,1H),3.65(dd,J=33.1,11.7Hz,1H),3.46(d,J=13.5Hz,1H),3.29(d,J=6.6Hz,3H),3.27–3.22(m,1H),3.21(s,3H),3.19–3.07(m,2H),3.03(d,J=16.7Hz,3H),2.85–2.75(m,1H),2.72–2.60(m,1H),2.40(dd,J=17.5,8.2Hz,1H),2.35–2.27(m,1H),2.16(dd,J=27.4,14.1Hz,1H),2.02(dd,J=15.4,7.9Hz,1H),1.90(d,J=12.0Hz,1H),1.83(d,J=13.9Hz,1H),1.74–1.64(m,3H),1.62–1.49(m,6H),1.41(dd,J=27.3,13.6Hz,2H),1.24(dd,J=13.6,7.8Hz,2H),1.20–1.10(m,3H),1.10–1.00(m,2H),0.98(t,J=6.4Hz,3H),0.91–0.79(m,6H),0.79–0.69(m,6H),0.56(dd,J=23.7,11.9Hz,1H)。13C NMR(126MHz,DMSO)δ208.76,206.89,198.66,169.24,166.89,165.58,146.35,139.05,137.91,132.36,131.75,130.51,128.79,127.85,126.99,125.66,125.16,122.65,98.95,83.77,82.11,81.75,77.81,73.95,73.15,66.14,57.10,56.65,55.42,50.93,50.34,45.22,43.64,40.85,40.64,40.01,39.84,39.67,39.51,39.34,39.17,39.01,37.93,35.12,35.01,34.68,33.76,32.85,32.51,31.35,29.73,28.64,26.18,24.45,22.47,21.48,20.46,19.45,18.99,15.55,15.24,14.93,14.11,13.01,11.10,10.42。
实施例3:28-O-(2-(4-(3-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-123)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(3-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-123)的制备
将0.12g(0.12mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.07g(0.60mmol)的3-甲基苯乙炔,室温下反应11个小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1NHCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.05g样品。收率:38.2%。MS(ESI)m/z:1198.6(M+Na)+。1H NMR(500MHz,DMSO)δ8.40(d,J=6.2Hz,1H),7.67(s,1H),7.63(d,J=7.6Hz,1H),7.33(dd,J=14.0,6.5Hz,1H),7.15(d,J=7.2Hz,1H),5.45(dd,J=22.4,12.7Hz,1H),5.38–5.31(m,2H),5.15–5.05(m,1H),5.03–4.93(m,2H),4.55(t,J=6.2Hz,1H),4.35(d,J=3.5Hz,1H),4.27(d,J=3.9Hz,1H),4.06–3.95(m,1H),3.65(dd,J=32.2,11.9Hz,1H),3.46(d,J=13.5Hz,1H),3.29(d,J=7.7Hz,3H),3.27–3.23(m,1H),3.19(d,J=13.9Hz,3H),3.12(dd,J=15.7,10.7Hz,2H),3.03(d,J=16.4Hz,3H),2.84–2.76(m,1H),2.66(d,J=15.3Hz,1H),2.43–2.37(m,1H),2.36(s,3H),2.33–2.29(m,1H),2.19–2.11(m,1H),2.02(dd,J=15.0,7.6Hz,1H),1.86(dd,J=30.5,14.0Hz,3H),1.74–1.66(m,3H),1.54(d,J=14.8Hz,5H),1.45–1.36(m,2H),1.34–1.27(m,2H),1.22(d,J=13.9Hz,2H),1.20–1.12(m,3H),1.04(dd,J=18.7,6.3Hz,3H),0.97(d,J=6.3Hz,3H),0.87(t,J=9.6Hz,4H),0.77–0.70(m,8H),0.55(dd,J=23.8,11.9Hz,1H)。13C NMR(126MHz,DMSO)δ208.72,206.88,198.71,169.24,166.89,165.64,146.45,139.07,137.89,132.38,131.85,130.42,128.69,128.51,126.99,125.72,122.54,122.35,110.00,98.95,83.77,82.10,81.70,77.83,73.97,73.15,66.15,57.11,56.64,55.42,50.93,50.31,45.27,43.66,40.91,40.62,40.01,39.84,39.68,39.51,39.34,39.18,39.01,37.89,35.15,34.96,34.68,33.80,32.85,32.50,31.36,29.74,26.19,24.46,21.48,20.98,20.47,15.55,15.20,14.93,14.16,13.02,10.41.
实施例4:28-O-(2-(4-(2-氯苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-124)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(2-氯苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-124)的制备
将0.1g(0.1mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.068g(0.50mmol)的2-氯苯乙炔,室温下反应40min,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.04g样品。收率:36.4%。MS(ESI)m/z:1141.5(M+Na)+。1HNMR(600MHz,DMSO)δ8.63(d,J=13.4Hz,1H),8.12(t,J=8.6Hz,1H),7.60(dd,J=31.5,7.7Hz,1H),7.55–7.44(m,1H),7.40(t,J=7.1Hz,1H),6.47(s,1H),6.39(dd,J=26.1,14.6Hz,1H),6.28(dd,J=36.5,27.6Hz,1H),6.18(dd,J=21.6,10.2Hz,1H),6.11(d,J=10.9Hz,1H),5.47–5.40(m,1H),5.37(d,J=14.6Hz,1H),5.03(d,J=9.9Hz,1H),4.96(d,J=18.6Hz,1H),4.58(dd,J=15.6,11.9Hz,1H),4.30(dd,J=30.2,11.6Hz,1H),4.23–4.10(m,1H),4.00(t,J=19.6Hz,1H),3.65(dd,J=37.1,12.7Hz,1H),3.46(d,J=11.3Hz,2H),3.29(s,3H),3.25(dd,J=12.4,4.7Hz,1H),3.20(s,1H),3.13(dd,J=27.6,13.4Hz,3H),3.05(s,3H),2.81(dd,J=15.3,8.2Hz,1H),2.68(t,J=16.1Hz,1H),2.40(dd,J=17.3,8.1Hz,1H),2.19(s,1H),2.12(t,J=14.2Hz,1H),2.02(d,J=7.2Hz,1H),1.89–1.81(m,3H),1.75–1.65(m,3H),1.59–1.50(m,5H),1.45–1.33(m,2H),1.25(dd,J=40.0,14.1Hz,2H),1.16(dd,J=21.8,7.9Hz,2H),1.04(dd,J=18.6,6.3Hz,2H),1.00–0.95(m,3H),0.94(s,3H),0.88–0.81(m,6H),0.76–0.70(m,3H),0.56(dd,J=23.9,12.0Hz,1H)。13C NMR(151MHz,DMSO)δ208.82,207.15,199.14,185.06,182.33,169.64,167.40,142.99,139.62,139.23,138.35,138.17,132.89,132.27,130.77,130.71,129.85,129.44,127.94,127.46,126.13,99.45,84.29,82.53,78.22,74.38,73.65,71.83,66.54,57.57,57.15,55.93,51.40,50.69,45.59,44.05,40.41,40.27,40.13,39.99,39.85,39.71,39.57,38.45,35.64,33.37,33.03,31.86,30.06,28.67,26.84,24.97,22.02,21.47,19.74,16.07,15.78,15.41,14.46,13.67,10.94,9.99.
实施例5:28-O-(2-(4-(4-甲氧基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-125)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(4-甲氧基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-125)的制备
将0.12g(0.12mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.08g(0.60mmol)的4-甲氧基苯乙炔,室温下反应50min,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.02g样品。收率:15.4%。MS(ESI)m/z:1137.6(M+Na)+。1H NMR(600MHz,DMSO)δ8.32(d,J=5.5Hz,1H),7.85–7.74(m,2H),7.12–6.99(m,2H),6.47(d,J=8.0Hz,1H),6.38(dd,J=14.5,11.4Hz,1H),6.21(dd,J=14.4,10.9Hz,1H),6.11(dd,J=18.5,10.6Hz,2H),5.43(dd,J=15.0,9.8Hz,1H),5.39–5.32(m,2H),5.13–5.05(m,1H),5.02–4.92(m,2H),4.59(d,J=4.0Hz,1H),4.37(d,J=3.2Hz,1H),4.31–4.11(m,1H),4.03(d,J=10.9Hz,1H),3.79(s,3H),3.63(dd,J=32.8,21.3Hz,1H),3.47(d,J=12.9Hz,1H),3.29(s,3H),3.21(s,3H),3.17–3.13(m,2H),3.05(s,3H),2.80(dd,J=15.6,8.3Hz,1H),2.66(dd,J=31.8,16.8Hz,1H),2.40(dd,J=17.3,8.2Hz,2H),2.24–2.13(m,1H),2.10(d,J=23.6Hz,1H),2.05–1.97(m,1H),1.87(dd,J=38.0,13.4Hz,3H),1.75–1.65(m,3H),1.55–1.40(m,5H),1.33(d,J=34.9Hz,2H),1.25(d,J=14.3Hz,2H),1.20–1.12(m,3H),1.06(ddd,J=22.1,14.7,6.2Hz,3H),0.98(d,J=6.3Hz,3H),0.90–0.80(m,6H),0.76–0.70(m,6H),0.58–0.52(m,1H)。13C NMR(151MHz,DMSO)δ207.86,200.43,198.44,185.33,181.76,180.75,174.12,169.71,166.39,159.59,152.81,147.97,135.87,126.83,114.82,99.67,84.02,73.58,64.57,56.85,55.61,46.19,40.41,40.27,40.13,39.99,39.85,39.71,39.58,33.11,21.76,16.05,15.55,15.42,14.07,11.26,10.50。
实施例6:28-O-(2-(4-(4-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-126)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(4-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-126)的制备
将0.15g(0.15mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.087g(0.75mmol)的4-甲基苯乙炔在室温下反应7个小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1NHCl、饱和NaHCO3和饱和NaCl洗涤,最后无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.1g样品。收率:62.5%。MS(ESI)m/z:1121.6(M+Na)+。1H NMR(500MHz,DMSO)δ8.36(s,1H),7.73(d,J=7.0Hz,2H),7.27(t,J=17.0Hz,2H),6.43(s,1H),6.41–6.30(m,1H),6.30–6.15(m,1H),6.15–6.03(m,2H),5.54–5.41(m,1H),5.36(d,J=23.1Hz,2H),5.05(d,J=39.3Hz,1H),4.97(d,J=11.1Hz,2H),4.30(d,J=41.9Hz,2H),4.01(s,1H),3.62(d,J=11.0Hz,1H),3.46(d,J=11.5Hz,1H),3.28(s,3H),3.20(s,3H),3.18–3.10(m,2H),3.04(s,3H),2.79(s,1H),2.66(d,J=16.8Hz,1H),2.44–2.38(m,1H),2.33(s,3H),2.15(d,J=13.3Hz,1H),2.01(d,J=6.6Hz,1H),1.86(dd,J=33.4,12.8Hz,3H),1.78(s,1H),1.67(d,J=8.8Hz,3H),1.50(d,J=27.5Hz,5H),1.46–1.35(m,2H),1.23(s,2H),1.20–1.10(m,3H),1.05(d,J=7.4Hz,3H),0.97(d,J=5.4Hz,3H),0.83(dd,J=17.8,5.8Hz,6H),0.74(s,6H),0.60–0.53(m,1H)。13C NMR(126MHz,DMSO)δ208.34,206.68,198.66,169.25,166.89,165.61,146.42,139.06,137.91,137.14,132.37,131.77,130.48,129.34,127.75,126.92,125.66,125.10,122.22,108.22,98.95,83.76,82.11,81.77,77.81,73.95,73.15,66.15,57.12,56.65,55.42,50.94,50.31,45.22,40.85,40.64,40.01,39.84,39.67,39.51,39.34,39.17,39.01,37.93,35.12,35.01,34.69,33.76,32.86,32.51,31.35,29.74,26.18,24.45,21.49,20.78,20.47,15.55,15.25,14.93,14.12,13.04,10.42。
实施例7:28-O-(2-(4-(4-氟苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-127)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(4-氟苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-127)的制备
将0.15g(0.15mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.09g(0.75mmol)的4-氟苯乙炔,室温下反应24小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.05g样品。收率:30.3%。MS(ESI)m/z:1125.6(M+Na)+。1H NMR(500MHz,DMSO)δ8.42(d,J=4.9Hz,1H),7.88(dd,J=8.5,5.5Hz,2H),7.29(t,J=8.8Hz,2H),6.44(s,1H),6.37(dd,J=14.4,11.3Hz,1H),6.24–6.16(m,1H),6.12(t,J=12.6Hz,1H),6.08(d,J=10.7Hz,1H),5.46–5.41(m,1H),5.33(s,2H),5.07(d,J=22.9Hz,1H),4.98(d,J=10.9Hz,2H),4.59–4.52(m,1H),4.35(d,J=3.3Hz,1H),4.28(s,1H),4.05–3.97(m,1H),3.62(d,J=12.3Hz,1H),3.46(d,J=13.5Hz,1H),3.28(s,3H),3.26–3.22(m,1H),3.20(s,3H),3.17(d,J=6.3Hz,2H),3.04(s,3H),2.80(dd,J=15.6,8.3Hz,1H),2.66(d,J=14.9Hz,1H),2.39(dd,J=17.4,8.2Hz,1H),2.15(d,J=13.5Hz,1H),2.03–1.98(m,1H),1.86(dd,J=31.1,14.9Hz,3H),1.74–1.65(m,3H),1.54(d,J=15.5Hz,5H),1.43(dd,J=24.6,12.6Hz,2H),1.22(d,J=15.2Hz,2H),1.19–1.13(m,3H),1.04(dd,J=14.9,9.0Hz,3H),0.97(d,J=6.4Hz,3H),0.85(d,J=6.4Hz,6H),0.75–0.70(m,6H),0.55(d,J=11.7Hz,1H)。13C NMR(126MHz,DMSO)δ208.74,206.58,198.79,169.29,166.90,165.55,160.77,145.49,139.04,137.92,132.36,131.75,130.49,127.22,127.16,122.58,115.82,115.65,98.95,83.76,82.10,81.70,77.81,73.96,73.14,66.14,57.08,56.65,55.43,50.97,50.36,45.21,43.64,40.89,40.59,40.01,39.85,39.68,39.51,39.35,39.18,39.01,37.94,35.11,35.01,34.68,33.75,32.85,32.51,31.34,26.28,24.46,21.47,20.47,15.55,15.24,14.91,14.14,12.92,10.42。
实施例8:28-O-(2-(4-(2-羟基异丙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-128)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(2-羟基异丙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素的制备
将0.1g(0.1mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.042g(0.5mmol)的2-乙炔基异丙醇,室温下反应1小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.04g样品。收率:37.7%。MS(ESI)m/z:1089.6(M+Na)+。1H NMR(600MHz,DMSO)δ7.81(s,1H),6.47(d,J=1.1Hz,1H),6.40(dd,J=14.5,11.3Hz,1H),6.22(dd,J=14.7,10.7Hz,1H),6.14(dd,J=26.7,12.2Hz,2H),5.42(dd,J=17.3,7.7Hz,1H),5.34(d,J=3.0Hz,1H),5.12(d,J=6.4Hz,1H),5.07(d,J=3.3Hz,1H),4.99–4.93(m,2H),4.61(d,J=4.3Hz,1H),4.31(d,J=3.9Hz,1H),4.30–4.24(m,1H),4.04–3.97(m,1H),3.63(d,J=13.3Hz,1H),3.46(d,J=12.5Hz,1H),3.31(s,3H),3.28(d,J=4.4Hz,1H),3.20(s,3H),3.15(d,J=4.5Hz,2H),3.05(s,3H),2.84–2.80(m,1H),2.67(dd,J=17.7,2.8Hz,1H),2.43(dd,J=17.7,8.3Hz,2H),2.21(d,J=8.6Hz,1H),2.12(s,1H),2.04–2.01(m,1H),1.88–1.81(m,3H),1.77(s,3H),1.69–1.65(m,3H),1.62(s,3H),1.60–1.50(m,5H),1.47(s,6H),1.44–1.35(m,2H),1.22–1.14(m,3H),1.10–1.01(m,3H),0.99(d,J=6.5Hz,3H),0.88(d,J=6.5Hz,3H),0.84(d,J=6.5Hz,3H),0.74(t,J=6.0Hz,6H),0.58(d,J=11.9Hz,1H)。13C NMR(151MHz,DMSO)δ209.52,207.48,199.15,169.35,167.31,166.20,156.21,138.28,132.17,127.51,122.30,99.30,84.25,73.61,67.43,57.78,57.24,55.99,51.17,50.57,45.50,40.41,40.27,40.13,40.00,39.86,39.72,39.58,35.63,32.81,31.07,29.97,26.53,22.09,20.99,16.07,15.88,13.98,10.82。
实施例9:28-O-(2-(4-(羟乙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素(X-129)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(羟乙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素的制备
将0.12g(0.12mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入到50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.042g(0.6mmol)的2-乙炔基乙醇,室温下反应1小时,TLC检测。反应完毕后,用EA萃取,然后依次用水洗,1N HCl洗,饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.05g样品。收率:39.7%。MS(ESI)m/z:1057.6(M+Na)+。1H NMR(600MHz,DMSO)δ7.77(s,1H),6.47(d,J=1.4Hz,1H),6.39(dd,J=14.7,11.3Hz,1H),6.25–6.19(m,1H),6.15–6.12(m,1H),6.11(d,J=10.5Hz,1H),5.50–5.43(m,1H),5.31(t,J=4.7Hz,2H),5.27(s,1H),5.11–5.06(m,1H),5.00–4.93(m,2H),4.71–4.67(m,2H),4.62–4.57(m,1H),4.34(d,J=3.7Hz,1H),4.26(dd,J=18.8,3.8Hz,1H),4.01(t,J=9.9Hz,1H),3.66–3.60(m,1H),3.49–3.43(m,1H),3.32–3.29(m,3H),3.29(d,J=4.4Hz,1H),3.20(s,3H),3.16(dd,J=6.6,3.9Hz,2H),3.06(d,J=4.7Hz,3H),2.84–2.80(m,1H),2.77(dd,J=12.7,5.6Hz,2H),2.66(dd,J=17.6,2.6Hz,1H),2.40(dd,J=17.6,8.4Hz,1H),2.21(d,J=8.8Hz,1H),2.17–2.12(m,2H),2.02(dd,J=15.4,7.4Hz,1H),1.85(t,J=12.3Hz,3H),1.79(s,3H),1.71–1.65(m,3H),1.62(s,3H),1.60–1.50(m,5H),1.42(dd,J=26.9,14.2Hz,2H),1.29–1.23(m,2H),1.22–1.13(m,3H),1.10–1.01(m,3H),0.99(d,J=6.5Hz,3H),0.86(d,J=6.5Hz,3H),0.81(d,J=6.5Hz,3H),0.74(d,J=6.6Hz,6H),0.57(dd,J=23.8,12.0Hz,1H)。13C NMR(151MHz,DMSO)δ207.48,199.15,191.74,169.65,167.00,166.02,144.91,138.18,132.20,127.51,123.81,99.46,84.29,82.27,77.95,74.24,73.27,66.56,60.83,57.22,55.96,51.41,50.29,45.67,40.41,40.27,40.13,39.99,39.85,39.71,39.57,35.42,32.90,31.79,29.84,29.58,22.04,16.09,15.77,15.45,14.36,13.43,10.87。
实施例10:28-O-(2-(4-(亚甲基-(N,N-二乙基))-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(X-150)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(亚甲基-(N,N-二乙基))-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素的制备
将0.2g(0.2mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入到50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.1g(1mmol)的N,N-二乙基丙炔在室温下反应1.5小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,最后无水Na2SO4脱水,抽滤减压浓缩干燥得粗品。硅胶柱层析纯化,PE:AC=2:1,1:1,1:2梯度洗脱,得到0.15g样品。收率:67.6%。MS(ESI)m/z:1108.6(M+H)+。1H NMR(600MHz,DMSO)δ7.91(s,1H),6.45(d,J=22.6Hz,1H),6.39(dd,J=14.3,11.5Hz,1H),6.21(dd,J=24.1,9.5Hz,1H),6.16–6.12(m,1H),6.11(d,J=9.9Hz,1H),5.47–5.41(m,1H),5.32(s,2H),5.00(d,J=9.9Hz,1H),4.95(d,J=3.7Hz,2H),4.59(d,J=27.7Hz,1H),4.34(d,J=3.4Hz,1H),4.27(d,J=18.1Hz,1H),4.00(dd,J=12.6,9.0Hz,1H),3.77(s,2H),3.63(d,J=11.6Hz,1H),3.46(d,J=12.8Hz,1H),3.30(d,J=7.7Hz,3H),3.28(d,J=8.1Hz,1H),3.20(s,3H),3.16(d,J=12.6Hz,2H),3.05(s,3H),2.84–2.78(m,1H),2.65(d,J=15.7Hz,1H),2.53–2.46(m,4H),2.39(dd,J=17.5,8.3Hz,1H),2.23(s,1H),2.14(d,J=18.0Hz,1H),2.04–1.99(m,1H),1.85(t,J=11.8Hz,3H),1.79(s,3H),1.68(dd,J=18.4,9.8Hz,3H),1.62(s,3H),1.56(dd,J=18.9,12.3Hz,5H),1.41(dd,J=21.6,12.6Hz,2H),1.31–1.24(m,2H),1.17(dd,J=18.5,11.2Hz,3H),1.04(t,J=6.9Hz,9H),0.99(d,J=6.4Hz,3H),0.87(d,J=6.3Hz,3H),0.82(d,J=6.4Hz,3H),0.74(dd,J=5.9,3.5Hz,6H),0.56(d,J=11.8Hz,1H)。13C NMR(151MHz,DMSO)δ209.12,207.15,199.14,169.64,167.42,166.27,138.55,132.33,127.48,99.45,84.29,82.56,78.22,74.31,73.68,68.91,66.64,57.64,57.23,55.94,51.36,50.49,46.54,45.72,44.08,41.24,40.40,40.26,40.13,39.99,39.85,39.71,39.57,38.44,35.65,34.21,33.39,33.01,31.88,30.06,26.65,24.82,22.01,20.90,16.08,15.74,15.42,14.60,13.69,12.07,10.93。
实施例11:28-O-(2-(4-((2-氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(X-151)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-((2-氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素的制备
将0.25g(0.25mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.58g(3.9mmol)的3-(2-氟苯基)亚胺丙炔,室温下反应4小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1NHCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析,PE:EA=6:1~2:1梯度洗脱,得到0.2g样品。收率:69.7%。MS(ESI)m/z:1168.6(M+Na)+。1H NMR(600MHz,DMSO)δ7.89(s,1H),7.20–7.12(m,1H),7.02–6.98(m,1H),6.93(d,J=8.0Hz,1H),6.82–6.77(m,1H),6.57–6.52(m,1H),6.47(s,1H),6.39(dd,J=14.7,11.3Hz,1H),6.25–6.19(m,1H),6.17–6.12(m,1H),6.12–6.09(m,1H),5.43(dd,J=14.8,9.8Hz,1H),5.31(d,J=5.4Hz,2H),5.09(d,J=4.1Hz,1H),5.00(d,J=10.0Hz,1H),4.96(d,J=5.0Hz,1H),4.61(dd,J=6.4,4.4Hz,1H),4.39(d,J=5.8Hz,2H),4.01(dd,J=19.4,9.2Hz,1H),3.95(dd,J=6.3,1.1Hz,1H),3.63(d,J=12.8Hz,1H),3.45(t,J=14.0Hz,1H),3.31(s,3H),3.29(d,J=3.9Hz,1H),3.19(t,J=5.6Hz,3H),3.05(s,3H),2.85–2.80(m,1H),2.66(d,J=15.6Hz,1H),2.43–2.37(m,2H),2.24–2.20(m,1H),2.16–2.12(m,1H),2.02(dd,J=14.6,7.1Hz,1H),1.85(t,J=13.1Hz,3H),1.70–1.64(m,3H),1.59–1.50(m,5H),1.40(dd,J=27.2,13.9Hz,2H),1.27(dd,J=14.2,9.2Hz,2H),1.22–1.16(m,3H),1.05(ddd,J=16.3,10.9,9.1Hz,3H),0.99(d,J=6.4Hz,3H),0.87(d,J=6.4Hz,3H),0.82(d,J=6.5Hz,3H),0.74(dd,J=6.4,3.1Hz,6H),0.58(d,J=11.8Hz,1H)。13C NMR(151MHz,DMSO)δ209.12,207.46,199.28,169.63,167.42,166.23,152.24,150.27,146.02,143.67,139.60,138.44,136.66,132.91,132.24,130.98,127.48,125.10,121.80,118.51,116.28,114.77,112.69,99.45,84.29,82.62,79.59,78.22,76.31,74.31,74.03,73.70,71.83,66.64,57.65,57.23,55.94,51.43,50.47,45.60,44.13,40.41,40.27,40.13,39.99,39.85,39.71,39.57,38.59,35.66,35.20,33.39,33.00,31.86,30.06,28.67,26.65,22.04,21.48,20.99,19.75,16.09,15.75,15.43,14.48,13.75,10.94,10.00。
实施例12:28-O-(2-(4-((2,6-二氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(X-152)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-((2,6-氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素的制备
将0.25g(0.25mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.28g(1.68mmol)的3-(2,6-二氟苯基)亚胺丙炔,室温下反应5小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=6:1~2:1梯度洗脱,得到0.18g样品。收率:61.9%。MS(ESI)m/z:1186.6(M+Na)+.1H NMR(600MHz,DMSO)δ7.84(s,1H),7.07–6.94(m,2H),6.91(d,J=7.7Hz,1H),6.66(s,1H),6.47(s,1H),6.43–6.35(m,1H),6.24–6.17(m,1H),6.12(d,J=8.1Hz,2H),5.47–5.38(m,1H),5.28(d,J=24.9Hz,2H),5.12(d,J=31.5Hz,1H),5.03–4.92(m,2H),4.59(t,J=16.4Hz,1H),4.48(d,J=6.0Hz,2H),4.42–4.25(m,1H),3.96(dd,J=30.0,24.2Hz,1H),3.65(t,J=20.7Hz,1H),3.46(d,J=11.9Hz,1H),3.31(s,3H),3.29(s,1H),3.19(s,3H),3.15–3.09(m,2H),3.05(s,3H),2.82(s,1H),2.65(d,J=16.2Hz,1H),2.39(dd,J=17.5,8.8Hz,1H),2.22(s,1H),2.13(s,1H),2.04–1.97(m,1H),1.85(s,3H),1.77(s,3H),1.68(s,3H),1.62(s,3H),1.59–1.50(m,5H),1.42(d,J=10.4Hz,2H),1.27(s,2H),1.17(dd,J=22.2,8.5Hz,3H),1.05(d,J=12.6Hz,3H),0.99(d,J=5.1Hz,3H),0.89–0.84(m,3H),0.82(s,3H),0.74(d,J=5.2Hz,6H),0.57(d,J=11.3Hz,1H)。13C NMR(151MHz,DMSO)δ209.14,207.47,199.45,169.34,166.25,153.62,152.26,146.57,139.63,138.41,132.84,132.14,130.93,127.48,125.60,124.39,117.53,112.80,112.20,102.10,99.47,84.30,82.64,82.25,78.02,74.29,73.71,71.85,66.61,57.68,57.22,55.95,51.37,50.46,45.63,41.00,40.41,40.27,40.14,40.00,39.86,39.72,39.58,35.54,35.14,33.01,31.84,30.31,28.68,26.67,24.96,22.04,19.63,16.09,15.76,15.42,14.45,13.80,10.94,10.00。
实施例13:28-O-(2-(4-(3-氨基苯基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素(X-153)
步骤A-E同X-121中A-E的合成步骤。
步骤F:28-O-(2-(4-(3-氨基苯基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素的制备
将0.25g(0.25mmol)28-O-(2-叠氮乙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.293g(2.5mmol)的3-氨基苯乙炔,室温下反应4小时,TLC检测。反应完毕后,用EA萃取,然后依次用水洗,1NHCl洗,饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=6:1~3:1梯度洗脱,得到0.22g样品。收率:79.1%。MS(ESI)m/z:1136.6(M+Na)+。1HNMR(600MHz,DMSO)δ8.27(s,1H),7.12(s,1H),7.09–7.04(m,1H),6.95(t,J=7.2Hz,1H),6.54(dd,J=7.9,1.5Hz,1H),6.47(s,1H),6.39(dd,J=14.6,11.4Hz,1H),6.21(dd,J=14.5,10.8Hz,1H),6.11(dd,J=14.5,11.0Hz,2H),5.43(dd,J=14.9,9.7Hz,1H),5.35(dd,J=10.3,7.4Hz,2H),5.16(s,2H),5.10(d,J=9.1Hz,1H),5.01–4.95(m,2H),4.61–4.57(m,1H),4.34(d,J=3.7Hz,1H),4.31–4.25(m,1H),4.02(t,J=8.1Hz,1H),3.63(d,J=12.9Hz,1H),3.47(d,J=12.8Hz,1H),3.30(s,3H),3.27(s,1H),3.21(s,3H),3.05(d,J=3.9Hz,3H),2.84–2.79(m,1H),2.70–2.65(m,1H),2.42(dd,J=17.5,8.2Hz,1H),2.20(s,1H),2.16(d,J=13.0Hz,1H),2.02(dd,J=14.7,7.2Hz,1H),1.88–1.81(m,3H),1.79(s,3H),1.68(d,J=11.2Hz,3H),1.61(d,J=6.4Hz,3H),1.60–1.50(m,5H),1.46–1.36(m,2H),1.31–1.23(m,2H),1.22–1.13(m,3H),1.10–1.01(m,3H),0.98(d,J=6.5Hz,3H),0.86(t,J=5.7Hz,3H),0.77(d,J=6.5Hz,3H),0.74(t,J=6.9Hz,6H),0.57(d,J=11.8Hz,1H)。13C NMR(151MHz,DMSO)δ209.32,207.41,199.30,169.74,167.40,166.16,149.44,147.53,139.52,138.41,132.88,132.24,131.46,130.99,129.72,127.50,122.71,114.08,113.55,110.99,99.47,84.28,82.62,78.27,74.43,73.67,66.65,57.64,57.18,55.94,55.37,51.41,50.74,45.71,44.10,41.16,40.70,40.40,40.26,40.12,39.98,39.85,39.71,39.57,38.45,35.67,35.53,35.21,34.25,33.37,33.01,31.88,30.23,30.14,26.80,24.97,22.03,20.99,16.08,15.81,15.46,14.56,13.67,10.95。
实施例14:28-O-(2-(4-苯基-1H-1,2,3-三氮唑-1-基)丙酰基)氧雷帕霉素(X-154)
步骤A:28-氧基三甲基硅烷基-氧雷帕霉素的制备
将10g(10.94mmol)雷帕霉素倒入250ml烧瓶中,加入EA 115ml,室温下搅拌10min,降温至0℃,加入9.34g(137.19mmol)咪唑,搅拌5min后,滴加9.3g(85.33mmol)三甲基氯硅烷,在滴加过程中有白色固体析出,38min后滴加完毕,7min后,TLC检测,显示雷帕霉素已反应完全。加入66ml(33.37mmol)0.5NH2SO4,搅拌,反应3h,TLC检测,反应完全得到单保护产品。用EA萃取,依次用水、1N盐酸、饱和NaHCO3溶液、饱和NaCl溶液洗涤,无水Na2SO4脱水,抽滤,减压浓缩至干,得到12.28g白色固体。MS(ESI)m/z:1008.6(M+Na)+。1H NMR(600MHz,DMSO)δ6.47(s,1H),6.41(dd,J=14.3,11.5Hz,1H),6.23(dd,J=24.6,13.7Hz,1H),6.15(dd,J=21.1,10.9Hz,1H),6.10(d,J=15.1Hz,1H),5.46(dd,J=14.8,9.6Hz,1H),5.11(d,J=10.2Hz,1H),5.01(d,J=3.6Hz,1H),4.95(d,J=4.8Hz,1H),4.68–4.62(m,1H),4.02(t,J=9.3Hz,2H),3.87(d,J=5.7Hz,1H),3.61(dd,J=33.1,18.7Hz,1H),3.45(d,J=12.6Hz,1H),3.33(s,3H),3.29(dd,J=19.4,8.7Hz,1H),3.17(s,3H),3.14(t,J=5.7Hz,2H),3.08(d,J=21.0Hz,3H),2.82(dd,J=15.5,8.0Hz,1H),2.72(dd,J=33.3,11.9Hz,1H),2.50(d,J=12.8Hz,1H),2.23(s,1H),2.13(d,J=9.6Hz,1H),2.05–2.01(m,1H),1.85(d,J=9.3Hz,1H),1.83(s,1H),1.77(s,3H),1.67(s,1H),1.64(s,3H),1.61(s,1H),1.38(d,J=12.7Hz,1H),1.30(s,1H),1.24(d,J=11.3Hz,1H),1.20(d,J=11.1Hz,1H),0.99(d,J=6.3Hz,3H),0.88(d,J=6.3Hz,3H),0.83(d,J=6.3Hz,3H),0.78(d,J=6.5Hz,3H),0.74(d,J=6.4Hz,3H),0.03–-0.05(m,9H)。13C NMR(151MHz,DMSO)δ209.74,207.76,199.26,169.67,167.43,139.57,138.33,136.86,132.82,130.92,127.54,125.72,99.47,85.45,84.32,82.63,77.98,74.17,73.69,71.82,66.65,57.47,57.31,56.29,55.95,51.46,45.47,44.09,40.68,40.41,40.27,40.13,39.99,39.85,39.71,39.58,38.57,35.54,35.24,34.07,33.39,33.03,31.89,30.05,28.67,26.85,24.93,22.20,21.47,20.94,19.74,16.08,15.95,15.51,14.07,13.67,11.04。
步骤B:43-氧基叔丁基二甲基硅烷基-氧雷帕霉素的制备
将12.28g(12.45mmol)28-氧基三甲基硅烷基-氧雷帕霉素倒入250ml烧瓶中,用110ml N,N-二甲基甲酰胺(DMF)溶解,加入24.54g(360.43mmol)咪唑,6℃条件下溶解,分次加入14.72g(138.26mmol)TBSCl,反应5h,TLC检测。反应完毕,用EA萃取,依次用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗涤,无水Na2SO4脱水,抽滤,减压浓缩至干,得到淡黄色固体。硅胶柱层析纯化,PE:EA=6:1~4:1梯度洗脱,最后得到6g白色固体,收率:46.3%。MS(ESI)m/z:1050.6(M+Na)+。1H NMR(600MHz,DMSO)δ6.46(d,J=1.4Hz,1H),6.44–6.37(m,1H),6.23(dd,J=14.5,10.6Hz,1H),6.17–6.11(m,1H),6.11(d,J=4.5Hz,1H),5.47(dd,J=14.9,9.6Hz,1H),5.28(d,J=4.5Hz,1H),5.11(d,J=10.1Hz,1H),5.01–4.97(m,1H),4.95(d,J=6.0Hz,1H),4.05–3.99(m,2H),3.95(d,J=4.6Hz,1H),3.45(d,J=12.7Hz,1H),3.33(s,4H),3.20–3.17(m,1H),3.16(s,3H),3.13(s,1H),3.06(s,3H),2.76–2.71(m,1H),2.44–2.39(m,1H),2.24–2.18(m,1H),2.14–2.08(m,1H),2.04(dd,J=15.0,6.9Hz,1H),1.85–1.80(m,1H),1.74(s,4H),1.68(s,1H),1.68–1.66(m,1H),1.64(s,4H),1.60(d,J=4.8Hz,1H),1.59–1.56(m,2H),1.53(s,2H),1.38(d,J=10.5Hz,1H),1.29(d,J=11.8Hz,3H),1.25(d,J=11.1Hz,2H),0.98(d,J=6.5Hz,3H),0.88(d,J=6.5Hz,3H),0.86(s,9H),0.83(d,J=6.4Hz,4H),0.78(d,J=6.7Hz,3H),0.74(d,J=6.7Hz,3H),0.04(d,J=1.4Hz,6H)。13C NMR(151MHz,DMSO)δ210.93,207.98,199.35,169.68,167.48,139.83,138.36,137.66,132.82,130.87,127.49,125.44,99.51,85.96,84.08,82.76,76.24,75.75,74.13,66.67,57.58,57.39,55.94,51.25,45.71,44.00,40.53,40.41,40.27,40.13,39.99,39.86,39.72,39.58,38.78,35.89,35.74,35.29,33.95,32.79,31.52,30.14,26.94,26.72,26.23,24.96,22.15,20.89,18.32,16.04,15.24,13.92,13.88,10.96.
步骤C:28-O-(3-溴丙酰基)-43-氧基叔丁基二甲基硅烷基-氧雷帕霉素的制备
将6g(5.8mmol)43-氧基叔丁基二甲基硅烷基-氧雷帕霉素倒入250ml烧瓶中,加入100mL DCM溶解,降温至-2℃,加入18ml吡啶,5min后滴加9ml(104.2mmol)3-溴丙酰溴,40min滴加完毕后,TLC检测。反应完毕,用DCM萃取,依次用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗涤,无水Na2SO4脱水,抽滤,减压浓缩至干,得到红黑色固体。硅胶柱层析纯化,PE:EA=10:1~4:1梯度洗脱,得到4.5g样品,收率60%。MS(ESI)m/z:1184.5(M+Na)+。1H NMR(600MHz,DMSO)δ6.45(d,J=3.8Hz,1H),6.41–6.35(m,1H),6.22(dd,J=10.3,4.8Hz,1H),6.14(dd,J=12.9,7.1Hz,1H),6.12(d,J=7.0Hz,1H),5.51–5.47(m,1H),5.05(d,J=11.3Hz,1H),5.02–4.96(m,2H),4.94(d,J=5.4Hz,5H),4.57(s,1H),4.08–3.98(m,3H),3.91(d,J=2.8Hz,1H),3.63(dd,J=20.6,9.3Hz,1H),3.45(d,J=12.6Hz,1H),3.33(dd,J=2.6,1.5Hz,3H),3.32–3.27(m,1H),3.22–3.19(m,3H),3.17(d,J=2.2Hz,3H),3.15–3.13(m,2H),3.05(d,J=2.8Hz,3H),2.88–2.80(m,1H),2.67(dd,J=9.2,6.2Hz,1H),2.39(dd,J=16.1,9.2Hz,1H),2.12(d,J=13.1Hz,1H),2.04–1.99(m,1H),1.90(d,J=13.1Hz,1H),1.86–1.80(m,1H),1.78–1.73(m,1H),1.67(s,1H),1.63–1.59(m,1H),1.55(d,J=12.8Hz,1H),1.53(s,1H),1.27(s,1H),1.26–1.22(m,1H),1.21–1.16(m,1H),0.98(d,J=2.1Hz,3H),0.87(d,J=1.9Hz,3H),0.85–0.83(m,12H),0.83–0.82(m,3H),0.78(d,J=7.8Hz,3H),0.74(dd,J=6.5,2.4Hz,3H),0.59(dd,J=23.8,11.9Hz,1H),-0.03–-0.06(m,6H)。13C NMR(151MHz,DMSO)δ211.25,204.25,198.86,168.73,167.47,138.66,138.47,132.85,129.92,127.49,126.40,123.31,99.33,84.28,83.07,82.15,76.84,74.21,73.58,66.94,59.76,57.23,55.85,51.21,49.03,45.52,40.40,40.26,40.12,39.98,39.84,39.70,39.56,39.49,35.66,35.19,33.42,32.77,31.57,31.49,26.67,26.27,24.95,21.76,20.86,18.25,16.06,15.40,13.84,10.68。
步骤D:28-O-(3-溴丙酰基)-氧雷帕霉素的制备
将4.77g(4.15mmol)28-O-(3-溴丙酰基)-43-氧基叔丁基二甲基硅烷基-氧雷帕霉素倒入到250ml烧瓶中,用70ml丙酮(AC)溶解,降温至0℃,然后加入18ml(0.018mmol)2NH2SO4溶液,18h后TLC检测。反应完毕,用EA萃取,依次用水、饱和NaHCO3溶液和饱和NaCl溶液洗涤,无水Na2SO4脱水,抽滤,减压浓缩至干,得到淡黄色固体。硅胶柱层析纯化,PE:EA=6:1~1:1洗脱,得到3.8g样品,收率:80.2%。MS(ESI)m/z:1170.4(M+Na)+。1HNMR(600MHz,DMSO)δ6.43(d,J=4.5Hz,1H),6.40(d,J=3.6Hz,1H),6.22(d,J=4.0Hz,1H),6.18–6.15(m,1H),6.12(s,1H),5.47(d,J=5.3Hz,1H),5.08(s,1H),4.98(d,J=3.8Hz,1H),4.94(s,1H),4.65(s,1H),4.02–4.00(m,2H),3.91(d,J=2.7Hz,1H),3.62(d,J=6.2Hz,1H),3.44(d,J=2.1Hz,1H),3.33(s,3H),3.26(s,1H),3.22(s,3H),3.19(d,J=2.1Hz,1H),3.05(s,3H),2.84–2.82(m,1H),2.73(dd,J=8.8,5.2Hz,1H),2.51(dt,J=3.6,1.8Hz,2H),2.46–2.42(m,1H),2.10(d,J=11.8Hz,2H),1.82(s,3H),1.66–1.65(m,1H),1.61(s,3H),1.58(s,1H),1.41(s,1H),1.30(s,1H),0.99(d,J=6.6Hz,3H),0.88–0.86(m,3H),0.84(dd,J=4.8,3.8Hz,3H),0.77(d,J=6.8Hz,3H),0.74(d,J=6.6Hz,3H)。13C NMR(151MHz,DMSO)δ208.33,207.25,199.30,168.64,167.41,166.24,139.64,138.42,132.92,132.61,131.04,127.48,99.44,84.32,82.63,78.27,74.25,73.70,66.65,60.21,57.67,57.24,55.94,51.45,51.44,45.55,44.09,40.40,40.26,40.12,39.98,39.84,39.70,39.57,35.69,33.40,33.03,31.84,26.99,26.27,22.04,20.95,16.09,15.76,15.51,14.67,14.65,13.79,10.83。
步骤E:28-O-(3-叠氮丙酰基)-氧雷帕霉素的制备
将3.6g(3.48mmol)28-O-(3-溴丙酰基)-氧雷帕霉素倒入250ml烧瓶中,然后加入50mLDMF和催化量的KI,置50℃的油浴中加热5min后加入0.9g(13.8mmol)NaN3,反应1小时,TLC检测。反应完全后,用EA萃取,依次采用水、1N盐酸、饱和NaHCO3溶液和饱和NaCl溶液洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得到白色固体。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1梯度洗脱,得到1.6g样品,收率:44.5%。MS(ESI)m/z:1033.5(M+Na)+。1HNMR(600MHz,DMSO)δ6.45(s,1H),6.38(dd,J=14.6,11.3Hz,1H),6.24(dd,J=14.5,10.7Hz,1H),6.14(dd,J=15.7,5.3Hz,1H),6.11(d,J=4.6Hz,1H),5.47(dd,J=15.0,9.7Hz,1H),5.34(t,J=5.9Hz,1H),5.05(d,J=10.1Hz,1H),4.98–4.93(m,2H),4.61(s,1H),4.36(d,J=3.8Hz,1H),4.09–3.97(m,2H),3.95(d,J=9.8Hz,1H),3.63(dd,J=17.2,5.6Hz,1H),3.46(d,J=13.9Hz,1H),3.33(s,3H),3.30–3.27(m,1H),3.27–3.24(m,1H),3.22(s,3H),3.13–3.08(m,1H),3.05(s,3H),2.86–2.82(m,1H),2.67(dd,J=17.5,2.7Hz,1H),2.52–2.49(m,1H),2.44–2.36(m,2H),2.24(s,2H),2.13(d,J=12.5Hz,1H),1.85(s,1H),1.82(s,3H),1.62(s,3H),1.59–1.55(m,4H),1.28(s,1H),1.00(d,J=6.5Hz,6H),0.89–0.86(m,6H),0.84–0.82(m,1H),0.77(d,J=6.7Hz,3H),0.74(d,J=6.6Hz,3H)。13C NMR(151MHz,DMSO)δ210.42,207.45,199.27,168.67,167.83,167.43,139.61,138.41,132.92,132.58,131.04,127.49,99.45,84.33,82.64,82.41,78.01,74.33,73.70,66.65,57.64,57.22,55.93,51.42,49.87,45.62,44.12,41.28,40.97,40.74,40.39,40.25,40.11,39.97,38.83,39.70,39.56,38.52,35.66,35.59,35.20,34.13,33.40,33.06,31.86,26.82,24.95,22.02,20.95,16.08,15.78,15.42,14.65,13.71,10.81。
步骤F:28-O-(2-(4-苯基-1H-1,2,3-三氮唑-1-基)丙酰基)氧雷帕霉素的制备
将0.12g(0.12mmol)28-O-(3-叠氮丙酰基)-氧雷帕霉素倒入50ml烧瓶中,加入10ml乙腈溶解,再加入催化量的的CuI,然后加入DIPEA,最后加入0.042g(0.6mmol)的苯乙炔,室温下反应1小时,TLC检测。反应完毕后,用EA萃取,然后依次用水、1N HCl、饱和NaHCO3和饱和NaCl洗涤,无水Na2SO4脱水,抽滤,减压浓缩干燥得粗品。硅胶柱层析纯化,PE:EA=3:1,2:1,1:1,1:2梯度洗脱,得到0.05g样品。收率:39.7%。MS(ESI)m/z:1120.6(M+Na)+。1HNMR(500MHz,DMSO)δ8.33(s,1H),7.76(d,J=1.0Hz,1H),7.84(s,1H),7.45(d,J=7.4Hz,1H),7.42(s,1H),7.35(dd,J=13.3,5.9Hz,1H),6.44(d,J=1.1Hz,1H),6.36(dd,J=14.3,11.4Hz,1H),6.22(dd,J=17.0,6.4Hz,1H),6.19–6.11(m,1H),6.10(d,J=4.1Hz,1H),5.63–5.48(m,1H),5.37(dd,J=23.2,10.0Hz,2H),5.09(d,J=7.3Hz,1H),5.03–4.94(m,2H),4.57–4.52(m,1H),4.35(d,J=3.6Hz,1H),4.31–4.10(m,1H),4.06–3.96(m,1H),3.65(dd,J=33.1,11.7Hz,1H),3.46(d,J=13.5Hz,1H),3.29(d,J=6.6Hz,3H),3.27–3.22(m,1H),3.21(s,3H),3.19–3.07(m,2H),3.03(d,J=16.7Hz,3H),2.85–2.75(m,1H),2.72–2.60(m,1H),2.40(dd,J=17.5,8.2Hz,1H),2.35–2.27(m,1H),2.16(dd,J=27.4,14.1Hz,1H),2.02(dd,J=15.4,7.9Hz,1H),1.90(d,J=12.0Hz,1H),1.83(d,J=13.9Hz,1H),1.74–1.64(m,3H),1.62–1.49(m,6H),1.41(dd,J=27.3,13.6Hz,2H),1.24(dd,J=13.6,7.8Hz,2H),1.20–1.10(m,3H),1.10–1.00(m,2H),0.98(t,J=6.4Hz,3H),0.91–0.79(m,6H),0.79–0.69(m,6H),0.56(dd,J=23.7,11.9Hz,1H)。13C NMR(126MHz,DMSO)δ207.76,208.89,199.66,168.24,167.89,164.58,146.35,139.05,137.91,132.36,131.75,130.51,128.79,127.85,126.99,125.66,125.16,122.65,98.95,83.77,82.11,81.75,77.81,73.95,73.15,66.14,57.10,56.65,55.42,50.93,50.34,45.22,43.64,40.85,40.64,40.01,39.84,39.67,39.51,39.34,39.17,39.01,37.93,35.12,35.01,34.68,33.76,32.85,32.51,31.35,29.73,28.64,26.18,24.45,22.47,21.48,20.46,19.45,18.99,15.55,15.24,14.93,14.11,13.01,11.10,10.42。
试验例1:抗肿瘤活性测试
步骤1样品的制备
准确称取10.0mg各种化合物样品,用1ml二甲亚砜溶解,存-20℃备用。
步骤2肿瘤细胞的培养
人非小细胞肺癌细胞株A549、人***癌细胞株PC-3、人胃癌细胞株AGS培养在含10%胎牛血清、80000U·L-1庆大霉素的F12培养基中,人乳腺癌细胞株T47D培养在含10%胎牛血清、80000U·L-1庆大霉素的DEME培养基中,人食管癌细胞株ECA109和人肾癌细胞株769-P培养在含10%胎牛血清、80000U·L-1庆大霉素的RPMI培养基中,于37℃、含5%CO2的饱和湿度条件下培养。
步骤3磺酰罗丹明B(sulforhodamine B,SRB)蛋白染色法检测化合物的抗癌作用
将对数生长期的各种癌细胞以10000个/孔分别接种于96孔培养板,于37℃、含5%CO2的饱和湿度条件下在各自相应的培养基中培养24h,分别加入用相应培养基稀释至所需不同浓度梯度的各种化合物,以相同浓度梯度的雷帕霉素作为阳性对照,不加药培养基作空白对照。每个化合物的每个浓度设3个重复孔。在相同条件下继续培养48h,用预冷体积分数10%的三氯乙酸固定细胞,4℃放置1h后蒸馏水洗涤5次,室温自然干燥。加入由1%冰醋酸配制的0.4%SRB溶液,室温染色15min,去上清液,以1%醋酸洗涤5次,室温自然干燥。最后加入10mmol·L-1Tris溶液(pH 10.5),540nm波长下测定OD值。细胞增殖抑制率(%)=(1-实验组/空白对照组)×100%,计算各种化合物对癌细胞的IC50。
步骤4统计学分析
实验均重复3遍,数据以±S表示,采用SPSS20软件分析数据,多组间比较采用单因素方差检验,两组间比较采用成组t检验,P<0.05表示差异具有统计学意义。结果见表1。
表1本发明实施例各化合物的IC50值
表1表明,本发明实例所列的化合物对受试的6株肿瘤细胞株均具有抑制活性(除X125不抑制人乳腺癌株T47D以及X129不抑制人乳腺癌株T47D和人食管癌株ECA-109外)。大多数化合物对人非小细胞肺癌株A549、人胃癌株AGS和人乳腺癌株T47D的抑制活性均强于雷帕霉素,对人***癌株PC-3的活性相对弱。
虽然以上描述了本发明的具体实施方式,但是熟悉本技术领域的技术人员应当理解,我们所描述的具体的实施例只是说明性的,而不是用于对本发明的范围的限定,熟悉本领域的技术人员在依照本发明的精神所作的等效的修饰以及变化,都应当涵盖在本发明的权利要求所保护的范围内。
Claims (9)
2.根据权利要求1所述的雷帕霉素三氮唑衍生物,其特征在于:所述(C1-C4)烷基选自甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基。
3.根据权利要求1所述的雷帕霉素三氮唑衍生物,其特征在于:所述卤素选自氟、氯、溴、碘。
4.根据权利要求1所述的雷帕霉素三氮唑衍生物,其特征在于:其为选自下列的化合物或其药学可接受的盐;
28-O-(2-(4-((2,4二氯苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-苯基-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(3-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(2-氯苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(4-甲氧基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(4-甲基苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(4-氟苯基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(2-羟基异丙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-(羟乙基)-1H-1,2,3-三氮唑-1-基)乙酰基)氧雷帕霉素
28-O-(2-(4-((2-氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素
28-O-(2-(4-((2,6-二氟苯基)氨基亚甲基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素
28-O-(2-(4-(3-氨基苯基)-1H-1,2,3-三氮唑-1-基)-乙酰基)氧雷帕霉素
28-O-(2-(4-苯基-1H-1,2,3-三氮唑-1-基)丙酰基)氧雷帕霉素。
5.一种药物组合物,其中包括权利要求1-4任一项所述的雷帕霉素三氮唑衍生物,以及任选的药学可接受的载体或辅料。
6.如权利要求1-4中任一项所述的雷帕霉素三氮唑衍生物在制备抗肿瘤药物中的用途。
7.根据权利要求6所述的用途,其特征在于:所述肿瘤选自:肺癌、食道癌、胃癌、***癌、白血病、肾癌。
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