CN116120254A - 13,14-双一氧化氮供体-β-榄香烯衍生物及其制备和应用 - Google Patents
13,14-双一氧化氮供体-β-榄香烯衍生物及其制备和应用 Download PDFInfo
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- CN116120254A CN116120254A CN202211412756.8A CN202211412756A CN116120254A CN 116120254 A CN116120254 A CN 116120254A CN 202211412756 A CN202211412756 A CN 202211412756A CN 116120254 A CN116120254 A CN 116120254A
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/02—Antineoplastic agents specific for leukemia
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
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- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了13,14‑双一氧化氮供体‑β‑榄香烯衍生物及其制备和应用。本发明提供一种结构如式(I)所示的13,14‑双一氧化氮供体‑β‑榄香烯衍生物,或其可药用盐,或溶剂化物,或其对映异构体、非对映异构体。本发明衍生物在设计策略上优于以往的β‑榄香烯一氧化氮供体型衍生物,引入了可提高体内抗肿瘤活性的酰胺结构作为连接臂,提高了体内稳定性,并且对临床上缺乏有效治疗药物的白血病具有很好的治疗活性。
Description
技术领域
本发明涉及药物化学和新药研发领域,具体涉及13,14-双一氧化氮供体-β-榄香烯衍生物及其制备和应用。
背景技术
天然产物是天然药物自然进化和长期更新所保留的优势结构,可参与多种靶蛋白的作用并发挥特定的活性,具有广泛的生物活性,如,抗炎症、抗肿瘤、抗抑郁等。在过去的几十年里,天然产物已经成为新药开发的重要来源。绝大多数抗癌和抗炎药物来自天然产品或其衍生物,如从莪术中提取的抗肿瘤药物榄香烯。
小分子化合物榄香烯是从莪术干燥块茎中提取分离的倍半萜类挥发油。截至目前,榄香烯已发现多种构型,其中β-榄香烯是发挥抗肿瘤活性的主要成分。在我国,榄香烯其口服乳和注射液已被国家食品药品监督局批准,具有广谱抗肿瘤活性,是临床上广泛应用的晚期肿瘤治疗药物。但因其水溶性差、生物利用度低而受到限制。因此,有必要对β-榄香烯进行结构修饰和改造,引入一氧化氮(NO)供体等其他抗肿瘤药效团,一方面改善其理化性质,另一方面提高其抗肿瘤活性。
NO作为气体信使分子,在体内产生广泛的生物活性作用。研究发现,在巨噬细胞内,由细胞毒素刺激下产生的NO,能够有效阻断肿瘤细胞DNA的生成,起到抗肿瘤作用。但是,NO作为水溶性自由基气体小分子,因其在体内扩散、转移迅速,半衰期较短,导致不能有效积累和转移。因此,在新药研发中一般使用NO供体与药物进行拼接,在要入进入体内后,可释放出NO,进而发挥抗肿瘤作用。但是,NO供体对NO的释放缺乏靶向性,不会仅仅在肿瘤部位释放NO。在药物分子进入血液循环后,就可能代谢分解,释放NO。这虽然是NO供体型药物的一个不足,但是这血液中释放的NO却可以杀灭血液中的肿瘤细胞,为白血病的治疗提供了机会。
发明内容
本发明的第一个目的是针对现有技术的不足,提供一种13,14-双一氧化氮供体-β-榄香烯衍生物,以13,14-双氯-β-榄香烯为原料,首先引入含氮结构作为连接臂,制备得到13,14-双胺-β-榄香烯中间体,再与呋咱NO供体连接,最终制备得到具有新型连接臂的13,14-双一氧化氮供体-β-榄香烯衍生物。
一种13,14-双一氧化氮供体-β-榄香烯衍生物,或其可药用盐,或溶剂化物,或其对映异构体、非对映异构体,所述13,14-双一氧化氮供体-β-榄香烯衍生物的结构如式(I)所示:
其中:
R1为含氮原子的直链或环状胺结构;
R2、R3分别独立选自C1-10链烷基、C3-12环烷基、C6-12芳基、5-10元环杂芳基、C2-10烯基、C2-10炔基或C2-10烷氧基。
作为优选,式(I)中:
R1为C2-5的含氮原子的直链胺结构或C3-10的环状胺结构;
R2、R3分别独立选自C2-6的链烷基、C2-6的烯基、C2-6的炔基。
在一优选例中,式(I)中:
R2、R3分别独立选自-CH2CH2-、-CH=CH-、--C≡C--、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH=CHCH2-、--CH2C≡CCH2-、--CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-、-CH2CH2CH=CHCH2CH2-、-CH2CH2C≡CCH2CH2-。
作为优选,式(I)中:
R2、R3分别独立选自-CH2CH2-、-CH=CH-、--C≡C-、-CH2CH2CH2-、-CH2CH2CH2CH2-、-CH2CH=CHCH2--、--CH2C≡CCH2-、-CH2CH2CH2CH2CH2-、-CH2CH2CH2CH2CH2CH2-、-CH2CH2CH=CHCH2CH2-、-CH2CH2C≡CCH2CH2-。
作为优选,所述13,14-双一氧化氮供体-β-榄香烯衍生物选自如下结构所示的化合物1~12:
本发明的第二个目的是提供上述13,14-双一氧化氮供体-β-榄香烯衍生物的制备方法,采用如下技术方案:
(1)β-榄香烯A-1进行13、14位烯丙位氯代反应得到中间体A-2;
(2)含有氮杂原子官能团的R1结构片段A-3通过选择性亲核取代到中间体A-2的13,14位上,得到中间体A-4;
(3)中间体A-4脱去保护得到中间体A-5;
(4)苯巯基乙酸A-6经过30%H2O2氧化处理,又经发烟硝酸处理闭环得到中间体A-7;
(5)含有羟基官能团的R3结构片段A-8通过选择性亲核取代至中间体A-7,得到中间体A-9;
(6)含有羰基官能团的R2结构片段A-10与中间体A-9酯化得到中间体A-11;
(7)中间体A-5和中间体A-11进行分子间酰胺缩合,得到通式(I)所示的衍生物;
本发明的第三个目的是提供所述的13,14-双一氧化氮供体-β-榄香烯衍生物,或其可药用盐,或溶剂化物,或其对映异构体、非对映异构体在制备抗肿瘤药物中的应用。
作为优选,所述肿瘤包括白血病、黑色素瘤等。
本发明的第四个目的是提供一种抗肿瘤药物,含有安全有效量的所述的13-杂环-β-榄香烯一氧化氮供体型衍生物,或其可药用盐,或溶剂化物,或其对映异构体、非对映异构体。
作为优选,所述抗肿瘤药物还可以包括药理上可接受的盐及药理上可以接受的赋形剂或载体。
本发明与现有技术相比,主要优点包括:
本发明引入了可提高体内抗肿瘤活性的酰胺结构作为连接臂,提高了体内稳定性,并且对临床上缺乏有效治疗药物的白血病具有很好的治疗活性。在13,14-双氯-β-榄香烯的13、14位同时引入含氮基团,不仅可以大大地提高榄香烯的水溶性,而且增强榄香烯的抗增殖活性。进一步在含氮基团中引入呋咱NO供体,可使衍生物在进入血液循环后,首先释放大量NO,以杀灭血液肿瘤细胞;再者,释放NO后生成的β-榄香烯含氮衍生物可进一步发挥强效的抗肿瘤作用。因此,在β-榄香烯的13、14位同时引入含有含氮连接臂的NO供体,可以提高单个NO供体的释放量,并发挥协同抗血液癌症的作用,并可改善β-榄香烯的理化性质,有希望获得疗效更好的抗白血病药物。
具体实施方式
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的操作方法,通常按照常规条件,或按照制造厂商所建议的条件。
(一)中间体2的制备
如反应式1所示,在0℃条件下,向含β-榄香烯(29.4mmol)的二氯甲烷(40mL)和乙酸(35mL)混合溶液中,加入TBAF(1.0mol/L in THF,0.5mL),使用微量注射泵加入NaClO(50mL),在0℃下反应5h。反应结束时,用饱和NaHCO3淬灭,用乙酸乙酯萃取,合并有机相,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,残留物经硅胶柱层析分离(纯石油醚),得到无色液体化合物,即中间体2,产率为25%。
反应式1:β-榄香烯的合成路线。反应条件和试剂:NaClO,TBAF,DCM,HOAc,0℃。
1H NMR(500MHz,CDCl3)δ5.79(dd,J=17.2,11.0Hz,1H),5.28(s,1H),5.18(s,1H),5.04(s,1H),4.97–4.89(m,3H),4.11(s,3H),3.97(d,J=11.7Hz,1H),2.35–2.22(m,2H),1.77–1.42(m,9H),0.99(s,3H).13C NMR(125MHz,CDCl3)δ149.51,148.95,147.44,116.29,113.33,111.42,50.88,47.63,47.56,41.01,39.72,39.61,33.76,26.97,15.73.
(二)中间体3-4的制备
如反应式2所示,向含有中间体2(1.0mmol)的DMF(6mL)中,依次加入反应物哌嗪Boc(3.0mmol)和Cs2CO3(3.0mmol),60℃搅拌12h。反应结束时,向混合溶液加水稀释,用乙酸乙酯萃取,合并有机液,依次用水和饱和食盐水洗涤,无水硫酸钠干燥后,残留物经硅胶柱层析分离(二氯甲烷:甲醇体积比100:1),得到淡黄色液体,即中间体5(58%)。
1H NMR(500MHz,CDCl3)δ5.8(dd,J=10.8,17.5Hz,1H),5.0(s,1H),4.9–4.8(m,4H),4.8(s,1H),3.4(s,8H),3.1–2.6(m,4H),2.4–2.2(m,9H),2.1(t,J=11.5Hz,1H),1.4(s,24H),1.0(s,3H).13C NMR(126MHz,CDCl3)δ154.9,154.9,150.6,150.6,150.1,113.8,111.3,110.3,79.6,66.4,63.6,53.1,53.0,48.2,42.4,40.1,40.0,34.0,28.5,28.5,27.2,16.0.MS(ESI)m/z:573.4[M+H]+.
反应式2:中间体3、4和5、6的合成路线。试剂和条件:(a)Cs2CO3,DMF,60℃,12h;(b)HCl-dioxane,MeOH,0℃,12h。
按上述相同的方法,更换反应物,制得中间体4。
5,5'-二叔丁基双((1R,3R,4S)-4-甲基-4-乙烯基环己烷-1,3-二基)双(丙-2-烯-2,1-二基)双(六氢吡咯并[3,4-c]吡咯-2(1H)-羧酸酯)(4)
棕色液体,产率68%,1H NMR(500MHz,CDCl3)δ5.8(dd,J=10.8,17.5Hz,1H),5.1(s,1H),5.0–4.8(m,4H),4.7(s,1H),3.6–3.5(m,4H),3.2(s,5H),3.1–2.9(m,2H),2.8–2.7(m,5H),2.6–2.5(m,3H),2.4–2.3(m,4H),2.2(d,J=11.6Hz,1H),2.0(d,J=19.2Hz,2H),1.4(s,25H),1.0(s,3H).13C NMR(125MHz,CDCl3)δ154.4,151.8,150.1,149.4,112.8,110.2,109.9,79.1,63.0,60.3,60.2,60.0,51.6,48.5,42.7,42.1,41.3,40.0,39.9,34.1,28.6,27.2,16.0.MS(ESI)m/z:625.4[M+H]+.
(三)中间体5-6的制备
在0℃条件下,向含有5(1.0mmol)的甲醇溶液中缓慢滴加氯化氢-二氧六环溶液(4mol/L),室温反应12h。减压蒸馏除去溶剂,在0℃条件下,用饱和NaHCO3溶液将pH调至中性,用用二氯甲烷萃取,合并有机相,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,得到淡黄色液体,即中间体5(97%)(反应式2)。
1H NMR(500MHz,DMSO-d6)δ5.8(dd,J=10.7,17.5Hz,1H),5.0(s,1H),5.0–4.8(m,4H),4.8(s,1H),3.0(d,J=13.6Hz,1H),2.8(d,J=44.3Hz,10H),2.6(d,J=13.6Hz,1H),2.4–2.1(m,9H),2.1–2.0(m,1H),1.6(dt,J=11.8,27.2Hz,2H),1.5–1.3(m,4H),1.0(s,3H).13C NMR(125MHz,CDCl3)δ150.6,150.1,148.1,114.0,111.1,110.2,67.0,64.2,53.9,53.8,48.1,45.6,42.1,39.9,34.1,27.2,16.0.MS(ESI)m/z:373.2[M+H]+.
按上述相同的方法,更换反应物,制得中间体6。
2,2'-双(1R,3R,4S)-4-甲基-4-乙烯基环己烷-1,3-二基)双(丙-2-烯-2,1-二基)双(六氢吡咯[3,4-c]吡咯)(6)
棕色液体,产率95%,1H NMR(500MHz,CDCl3)δ5.8(dd,J=10.8,17.5Hz,1H),5.0(s,1H),4.9–4.8(m,4H),4.7(s,1H),3.5–3.3(m,4H),3.1(d,J=12.2Hz,1H),3.0–2.8(m,8H),2.8–2.6(m,6H),2.5–2.4(m,2H),2.3(dd,J=5.8,9.2Hz,1H),2.2–2.1(m,3H),2.0(dd,J=5.4,9.3Hz,1H),1.7–1.4(m,6H),1.0(s,3H).13C NMR(125MHz,CDCl3)δ152.0,150.1,149.8,113.6,110.4,110.3,76.9,63.3,60.2,59.4,59.3,58.7,53.5,53.3,52.9,52.3,47.2,42.0,41.8,41.6,40.8,40.0,39.9,34.1,27.6,15.7.MS(ESI)m/z:425.4[M+H]+.
(四)中间体9-11的制备
反应式3:中间体9-11和9-11a-b的合成路线。试剂和条件:(a)15%NaOH,THF,0℃→r.t.,2h;(b)DMAP,DCM,r.t.,12h。
在0℃条件下,向含有3,4-双(苯磺酰基)-1,2,5-噁二唑2-氧化物(2.0mmol)的四氢呋喃溶液中,缓慢滴加15%NaOH水溶液(0.4mmol),滴加完毕后,继续搅拌10min,加入反应物乙二醇(20.0mmol),室温条件下反应4h。减压蒸馏除去溶剂,加入水稀释,用二氯甲烷萃取,合并有机相,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,残留物经硅胶层析(二氯甲烷:甲醇体积比100:1)得到白色固体9(77%)(反应式3)。
m.p.128-130℃.1H NMR(400MHz,CDCl3)δ8.07(d,J=8.2Hz,2H),7.77(t,J=
7.5Hz,1H),7.63(t,J=7.8Hz,2H),4.59–4.49(m,2H),4.08–4.02(m,2H).13C NMR(100MHz,CDCl3)δ159.1,137.8,135.9,129.9,128.7,110.7,73.0,60.5.HRMS(ESI)calcdfor C10H10N2NaO6S 309.0152[M+Na]+,found 309.0142.
按照反应式3和上述相同的方法,更换反应物,制得中间体10、11。
4-(3-羟基丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(10)
白色固体,产率73%,m.p.109-110℃.1HNMR(500MHz,CDCl3)δ8.05(dd,J=8.5,1.1Hz,2H),7.78–7.73(m,1H),7.64–7.60(m,2H),4.59(t,J=6.0Hz,2H),3.87(t,J=5.8Hz,2H),2.13(p,J=5.9Hz,2H).13CNMR(125MHz,CDCl3)δ159.0,135.8,129.8,110.6,69.4,59.4,31.4.MS(ESI)m/z:323.0[M+Na]+.
4-((4-羟基丁基2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(11)
白色固体,产率59%,m.p.116-118℃.1HNMR(400MHz,CDCl3)δ8.07(d,J=7.7Hz,2H),7.76(t,J=7.4Hz,1H),7.63(t,J=7.7Hz,2H),5.10(s,2H),4.34(s,2H).13CNMR(100MHz,CDCl3)δ158.2,138.0,135.9,129.8,128.8,110.8,88.3,77.7,59.0,51.1.HRMS(ESI)calcdforC12H10N2NaO6S333.0512[M+Na]+,found333.0512.
(五)中间体9a、9b、10a、10b、11a、11b的制备
如反应式3所示,向含有中间体9(2.0mmol)的二氯甲烷(10mL)溶液中,依次加入丁二酸酐(2.2mmol)和DMAP(1.0mmol),在30℃条件下搅拌3h,采用薄层色谱法检测反应。用二氯甲烷稀释反应混合物。有机相依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,残留物经硅胶柱层析分离(二氯甲烷:甲醇体积比100:1)得到白色固体,即中间体9a(58%)。
m.p.118-120℃.1HNMR(400MHz,CDCl3)δ8.13–8.06(m,2H),7.82–7.76(m,1H),7.65(t,J=7.9Hz,2H),4.65(dd,J=5.4,3.4Hz,2H),4.56(dd,J=5.4,3.4Hz,2H),2.73(t,J=2.7Hz,4H).13CNMR(100MHz,CDCl3)δ176.9,171.9,158.8,138.2,135.8,129.8,128.8,110.6,69.0,61.6,29.0,28.9.HRMS(ESI)calcdforC14H14N2NaO9S409.0312[M+Na]+,found409.0295.
按上述相同的方法,更换反应物,制得中间体9b、10a、10b、11a、11b。
中间体9b、10a、10b、11a、11b的1HNMR
4-(2-((4-羧基丁酰基)氧基)乙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(9b)
白色固体,产率63%,m.p.91-93℃.1HNMR(500MHz,CDCl3)δ8.06(dd,J=8.5,1.2Hz,2H),7.78–7.73(m,1H),7.62(td,J=7.6,1.7Hz,2H),4.65–4.61(m,2H),4.51(dd,J=5.4,3.7Hz,2H),2.47(dt,J=8.3,7.3Hz,4H),1.99(p,J=7.2Hz,2H).13CNMR(100MHz,CDCl3)δ178.6,172.7,158.8,138.0,135.8,129.8,128.8,110.6,69.0,61.3,33.0,32.9,19.7.HRMS(ESI)calcdforC15H16N2NaO9S423.0469[M+Na]+,found423.0465.
4-(3-((3-羧基丙酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(10a)
白色固体,产率77%,m.p.104-105℃,1HNMR(500MHz,CDCl3)δ8.05(dd,J=8.5,1.2Hz,2H),7.78–7.73(m,1H),7.65–7.59(m,2H),4.50(t,J=6.1Hz,2H),4.31(t,J=6.1Hz,2H),2.70–2.60(m,4H),2.22(p,J=6.1Hz,2H).13CNMR(125MHz,CDCl3)δ178.0,172.2,159.0,138.1,135.8,129.8,128.6,110.6,67.9,60.7,28.9,28.0.MS(ESI)m/z:423.0[M+Na]+.
4-(3-((4-羧基丁酰基)氧基)丙氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(10b)
白色固体,产率77%,m.p.96-98℃,1HNMR(500MHz,CDCl3)δ8.06(dd,J=8.4,1.1Hz,2H),7.79–7.74(m,1H),7.63(t,J=7.9Hz,2H),4.51(t,J=6.1Hz,2H),4.28(t,J=6.1Hz,2H),2.43(td,J=7.3,1.4Hz,4H),2.22(p,J=6.1Hz,2H),1.96(p,J=7.3Hz,2H).13CNMR(125MHz,CDCl3)δ178.6,172.9,159.0,138.1,135.8,129.8,128.7,110.6,68.1,60.5,33.1,33.0,28.0,19.9.MS(ESI)m/z:437.0[M+Na]+.
4-((4-((3-羧基丙酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(11a)
白色固体,产率60%,m.p.106-108℃.1HNMR(400MHz,CDCl3)δ8.11–8.04(m,2H),7.77(t,J=7.5Hz,1H),7.63(t,J=7.9Hz,2H),5.10(t,J=1.6Hz,2H),4.81–4.73(m,2H),2.74–2.65(m,4H).13CNMR(100MHz,CDCl3)δ177.2,171.4,158.1,138.1,135.9,129.9,128.8,110.8,83.9,78.8,58.8,52.3,28.8,28.8.HRMS(ESI)calcdforC16H14N2NaO9S433.0312[M+Na]+,found433.0317.
4-(4-((4-羧基丁酰)氧基)丁-2-炔-1-基氧基)-3-(苯磺酰基)-1,2,5-噁二唑2-氧化物(11b)
白色固体,产率76%,m.p.94-96℃.1HNMR(400MHz,CDCl3)δ8.07(d,J=7.6Hz,2H),7.77(t,J=7.5Hz,1H),7.63(t,J=7.8Hz,2H),5.10(s,2H),4.74(s,2H),2.46(td,J=7.3,4.9Hz,4H),1.97(p,J=7.3Hz,2H).13CNMR(100MHz,CDCl3)δ179.0,172.1,158.0,137.7,135.8,129.8,128.7,110.6,83.9,78.6,58.6,52.0,32.8,19.6.HRMS(ESI)calcdforC16H14N2NaO9S,447.0469[M+Na]+,found447.0486.
(六)13,14-双一氧化氮供体-β-榄香烯衍生物终产物12a-f、13a-f的制备
反应式4:13,14-双一氧化氮供体-β-榄香烯衍生物终产物12a-f、13a-f的合成路线。试剂和条件:试剂和条件:HOBt,EDCI,DIPEA,DCM,r.t.。
如反应式4所示,将中间体5、6(0.1mmol)、NO供体中间体9a、9b、10a、10b、11a和11b(0.2mmol)、DIPEA(0.8mmol)、HOBt(0.2mmol)和EDCI(0.4mmol)在无水二氯甲烷(3mL)中在室温下搅拌12h。采用薄层色谱法检测反应。用二氯甲烷稀释反应混合物。有机层依次用水和盐水洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,残留物通过柱色层析(二氯甲烷:甲醇体积比60:1)纯化,使产物为无色透明液体。
所采用的各中间体均可按上述(一)~(五)进行制备,在此不再赘述。
实施例1:制备化合物1(12a)
4-(2-((4-(4-(2-((1R,3R,4S)-4-甲基-3-(3-(4-(4-(2-((2-氧化-3-(苯基磺酰基)-)-1,2,5-噁二唑-4-基)氧基)乙氧基)4-氧代丁酰基)哌嗪-1-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)哌嗪-1-基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备。
向含有中间体5(0.1mmol)的二氯甲烷(3mL)溶液中,依次加入中间体9a(0.2mmol)、DIPEA(0.8mmol)、HOBt(0.2mmol)和EDCI(0.4mmol),室温搅拌12h。加二氯甲烷稀释,依次用水和饱和食盐水洗涤,无水硫酸钠干燥,减压蒸馏除去溶剂,残留物经硅胶柱层析分离(二氯甲烷:甲醇体积比60:1),无色透明液体,产率54%。
1H NMR(500MHz,CDCl3)δ8.04(d,J=7.7Hz,4H),7.76(t,J=7.5Hz,2H),7.62(t,J=7.8Hz,4H),5.77(dd,J=10.8,17.5Hz,1H),5.03(s,1H),4.93–4.83(m,4H),4.78(s,1H),4.65–4.59(m,4H),4.53–4.46(m,4H),3.57(s,4H),3.44(s,4H),3.02(d,J=13.8Hz,1H),2.90(q,J=13.4Hz,2H),2.63(d,J=13.9Hz,1H),2.48(t,J=7.0Hz,4H),2.40(s,4H),2.34(s,4H),2.25(s,2H),2.01–1.95(m,4H),1.60(d,J=12.4Hz,2H),1.46(dd,J=13.5,26.4Hz,4H),0.98(s,3H).13C NMR(125MHz,CDCl3)δ173.0,169.5,169.5,158.8,150.4,150.1,148.1,138.1,135.8,129.8,128.7,114.0,111.4,110.5,110.4,69.0,66.1,63.4,61.3,53.3,53.2,52.9,52.9,48.2,45.4,42.4,42.0,40.1,40.0,34.0,29.3,28.0,27.2,26.5,16.0.HRMS(ESI)m/z:calcd for C51H64N8O16S2[M+H]+,1109.3954;found,1109.3953.
实施例2:制备化合物2(12b)
4-(3-((4-(4-(2-((1R,3R,4S)-4-甲基-3-(3-(4-(4-(3-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丙氧基)-4-氧代丁酰基)哌嗪-1-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)哌嗪-1-基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例1,区别在于,将(四)中的乙二醇替换为丙二醇。
本实施例制得无色透明液体,产率49%。
1HNMR(500MHz,CDCl3)δ8.10–8.02(m,4H),7.75(t,J=7.5Hz,2H),7.63(t,J=7.9Hz,4H),5.79(dd,J=10.9,17.2Hz,1H),5.06(s,1H),4.97–4.85(m,4H),4.81(s,1H),4.52(t,J=6.1Hz,4H),4.29(t,J=6.0Hz,4H),3.50(d,J=47.0Hz,8H),3.04(d,J=13.0Hz,1H),2.92(q,J=13.0,13.6Hz,2H),2.64(s,9H),2.36(d,J=17.6Hz,6H),2.26–2.18(m,6H),2.04(d,J=34.2Hz,2H),1.63(s,2H),1.53–1.40(m,4H),0.99(s,3H).13C NMR(125MHz,CDCl3)δ173.2,173.2,169.6,169.5,159.0,150.3,150.0,148.0,138.1,135.7,129.8,128.7,114.0,111.5,110.6,110.4,68.2,66.1,63.4,60.4,53.3,53.2,52.9,52.8,48.2,45.4,42.4,41.9,40.1,40.0,34.0,29.3,28.1,28.0,27.2,16.0.HRMS(ESI)m/z:calcd for C53H68N8O16S2[M+H]+,1137.4267;found,1137.4261.
实施例3:制备化合物3(12c)
4-(2-((5-(4-(2-((1R,3R,4S)-4-甲基-3-(3-(4-(5-(2-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)乙氧基)-5-氧代戊酰基)哌嗪-1-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)哌嗪-1-基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例1,区别在于,将(五)中的丁二酸酐替换为戊二酸酐。
本实施例制得无色透明液体,产率30%。
1HNMR(500MHz,CDCl3)δ8.07–8.00(m,4H),7.76(t,J=7.5Hz,2H),7.63(t,J=7.9Hz,4H),5.78(dd,J=10.8,17.3Hz,1H),5.04(s,1H),4.95–4.84(m,4H),4.79(s,1H),4.65–4.59(m,4H),4.52–4.47(m,4H),3.58(s,4H),3.44(s,4H),3.07–2.99(m,1H),2.90(q,J=12.2,13.1Hz,2H),2.64(d,J=13.8Hz,1H),2.48(t,J=6.9Hz,4H),2.40(td,J=2.7,7.4Hz,5H),2.34(s,5H),2.22(dd,J=10.1,17.7Hz,4H),2.00–1.96(m,4H),1.64–1.58(m,2H),1.52–1.40(m,4H),0.98(s,3H).13C NMR(125MHz,CDCl3)δ173.2,170.6,170.6,158.8,150.4,150.1,148.1,138.1,135.8,129.8,128.7,114.0,111.4,110.5,110.4,69.1,66.2,63.4,61.1,53.4,53.4,53.0,53.0,48.3,45.6,42.4,41.8,40.1,40.0,34.0,33.3,32.2,27.3,20.3,16.0.HRMS(ESI)m/z:calcd for C53H68N8O16S2[M+H]+,1137.4267;found,1137.4262.
实施例4:制备化合物4(12d)
4-(3-((5-(4-(2-((1R,3R,4S)-4-甲基-3-(3-(4-(5-(3-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丙氧基)-5-氧代戊酰基)哌嗪-1-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)哌嗪-1-基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例2,区别在于,将(五)中的丁二酸酐换成戊二酸酐。
本实施例制得无色透明液体,产率49%。
1HNMR(500MHz,CDCl3)δ8.10–8.01(m,4H),7.76(t,J=7.5Hz,2H),7.63(t,J=7.9Hz,4H),5.79(dd,J=10.9,16.9Hz,1H),5.05(s,1H),4.97–4.77(m,5H),4.50(t,J=6.1Hz,4H),4.26(t,J=6.1Hz,4H),3.64–3.38(m,8H),3.08–3.01(m,1H),2.92(q,J=13.1Hz,2H),2.69–2.62(m,1H),2.45–2.32(m,14H),2.26(d,J=8.7Hz,2H),2.23–2.19(m,4H),1.98–1.92(m,6H),1.66–1.59(m,2H),1.45(dd,J=11.9,22.8Hz,4H),0.99(s,3H).13CNMR(125MHz,CDCl3)δ173.3,170.6,159.0,150.4,150.1,148.1,138.1,135.8,129.8,128.7,114.0,111.4,110.6,110.4,68.1,66.2,63.4,60.3,53.4,53.4,53.0,52.9,48.3,45.7,42.4,41.8,40.1,40.0,34.0,33.4,32.3,28.1,27.3,20.5,16.0.HRMS(ESI)m/z:calcd for C55H72N8O16S2[M+H]+,1165.458;found,1165.4582.
实施例5:制备化合物5(12e)
4-((4-((4-(4-(2-((1R,3R,4S)-4-甲基-3-(3-(4-(4-((4-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丁-2-炔-1-基)氧基)-4-氧代丁酰基)哌嗪-1-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)哌嗪-1-基)-4-氧代丁酰基)氧基)丁-2-炔-1-基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例1,区别在于,将(四)中的乙二醇换成1,4-丁炔二醇。
本实施例中制得无色透明液体,产率32%。
1H NMR(500MHz,CDCl3)δ8.11–8.05(m,4H),7.78–7.74(m,2H),7.67–7.61(m,4H),5.79(dd,J=10.8,17.4Hz,1H),5.09(t,J=1.6Hz,4H),5.06–4.79(m,6H),4.74(d,J=8.7Hz,4H),3.71–3.40(m,8H),3.13–2.87(m,3H),2.72–2.61(m,9H),2.47–2.25(m,8H),2.23–2.16(m,1H),2.13–2.03(m,1H),1.61(d,J=11.9Hz,2H),1.55–1.39(m,4H),0.99(s,3H).13C NMR(125MHz,CDCl3)δ172.5,169.4,158.0,150.0,150.0,148.0,138.0,135.9,129.8,128.8,111.6,111.5,110.7,110.5,84.2,78.6,66.1,66.1,63.4,63.4,61.0,61.0,58.8,53.6,53.2,53.2,52.9,52.8,52.1,48.3,45.4,42.4,42.0,40.1,40.0,34.0,29.2,27.9,27.2,16.0.HRMS(ESI)m/z:calcd for C55H64N8O16S2[M+H]+,1157.3954;found,1157.3954.
实施例6:制备化合物6(12f)
4-((4-((5-(4-(2-((1R,3R,4S)-4-甲基-3-(3-(4-(5-((4-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丁-2-炔-1-基)氧基)-5-氧代戊酰基)哌嗪-1-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)哌嗪-1-基)-5-氧代戊酰基)氧基)丁-2-炔-1-基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例3,区别在于,将(四)中的乙二醇换成1,4-丁炔二醇。
本实施例中制得无色透明液体,产率26%。
1HNMR(500MHz,CDCl3)δ8.12–8.04(m,4H),7.77(t,J=7.5Hz,2H),7.64(t,J=7.9Hz,4H),5.80(dd,J=11.3,16.4Hz,1H),5.10(s,5H),5.00–4.77(m,5H),4.74(s,4H),3.70–3.34(m,8H),3.05(dd,J=2.8,13.5Hz,1H),2.99–2.86(m,2H),2.66(dd,J=5.3,12.4Hz,1H),2.46(t,J=6.9Hz,4H),2.39(dd,J=4.6,9.8Hz,7H),2.31–2.14(m,4H),2.11–2.05(m,1H),1.97(ddt,J=3.7,7.2,14.3Hz,6H),1.66–1.59(m,2H),1.53–1.39(m,4H),0.99(s,3H).13C NMR(125MHz,CDCl3)δ172.6,170.5,158.0,150.3,150.0,148.0,137.9,135.9,129.8,129.1,128.7,114.0,111.5,110.7,110.4,84.1,78.6,66.1,63.4,61.0,58.7,53.6,53.4,53.4,53.0,52.9,51.9,48.2,45.6,42.4,41.8,40.1,40.0,34.0,33.2,32.1,27.2,20.3,16.0.HRMS(ESI)m/z:calcd for C57H68N8O16S2[M+H]+,1185.4267;found,1185.4271.
实施例7:制备化合物7(13a)
4-(2-((4-(5-(2-((1R,3R,4S)-4-甲基-3-(3-(5-(4-(2-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)乙氧基)-4-氧代丁酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-4-氧代丁酰基)氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例1,区别在于,将(三)中的哌嗪换成3,7-二氮杂双环[3.3.0]辛烷。
本实施例中制得无色透明液体,产率50%。
1HNMR(500MHz,CDCl3)δ8.10–8.03(m,4H),7.76(t,J=7.5Hz,2H),7.63(t,J=7.9Hz,4H),5.77(dd,J=11.0,16.8Hz,1H),5.06(s,1H),4.97–4.83(m,4H),4.74(s,1H),4.65–4.60(m,4H),4.51(dt,J=3.6,6.9Hz,4H),3.76–3.64(m,4H),3.43–3.25(m,4H),3.16(s,1H),3.00(s,2H),2.88(s,2H),2.79–2.68(m,5H),2.63–2.54(m,5H),2.50–2.33(m,7H),2.18–1.96(m,4H),1.64–1.56(m,2H),1.54–1.40(m,4H),0.96(s,3H).13C NMR(125MHz,CDCl3)δ173.0,169.2,158.8,151.6,150.1,150.0,138.2,135.8,129.8,128.7,113.0,110.5,110.4,110.1,109.9,69.1,62.9,62.8,61.4,61.3,60.3,60.2,60.2,60.0,53.6,52.4,51.5,48.8,48.6,42.5,42.5,42.4,40.6,40.6,40.0,39.9,34.0,29.4,29.1,27.4,16.1.HRMS(ESI)m/z:calcd for C55H68N8O16S2[M+H]+,1161.4267;found,1161.4258.
实施例8:制备化合物8(13b)
4-(3-((4-(5-(2-1R,3R,4S)-4-甲基-3-(3-(5-(4-(3-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丙氧基)-4-氧代丁酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-4-氧代丁酰基)氧基)丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例7,区别在于,将(四)中的乙二醇换成丙二醇。
本实施例中制得无色透明液体,产率59%。
1H NMR(500MHz,CDCl3)δ8.05(d,J=7.5Hz,4H),7.75(t,J=7.5Hz,2H),7.62(t,J=7.9Hz,4H),5.77(ddd,J=2.7,10.8,17.2Hz,1H),5.06(s,1H),4.94(s,1H),4.89–4.83(m,3H),4.74(s,1H),4.51(t,J=6.1Hz,4H),4.28(q,J=5.6Hz,4H),3.67(q,J=7.1,8.2Hz,4H),3.37–3.25(m,4H),3.21–3.11(m,1H),3.00(s,2H),2.88(s,2H),2.80–2.74(m,2H),2.71–2.53(m,12H),2.48–2.36(m,5H),2.21(p,J=6.1Hz,4H),2.16–2.09(m,1H),2.07–2.00(m,1H),1.64–1.56(m,2H),1.52–1.38(m,4H),0.96(s,3H).13C NMR(125MHz,CDCl3)δ173.2,169.3,159.0,150.1,150.0,149.9,138.1,135.7,129.8,128.7,110.7,110.6,110.5,110.4,110.4,68.2,62.9,62.8,62.8,60.4,60.1,60.1,59.9,52.2,52.2,51.4,51.3,48.5,42.4,42.4,42.3,40.5,40.5,40.5,39.9,34.0,29.4,29.1,28.1,27.3,15.9.HRMS(ESI)m/z:calcd for C57H72N8O16S2[M+H]+,1189.458;found,1189.4585.
实施例9:制备化合物9(13c)
4-(2-((5-(5-(2-((1R,3R,4S)-4-甲基-3-(3-(5-(5-(2-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)乙氧基)-5-氧代戊酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-5-氧代戊酰基)氧基)乙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例7,区别在于,将(五)中的丁二酸酐换成戊二酸酐。
本实施例中制得无色透明液体,产率71%。
1H NMR(500MHz,CDCl3)δ8.05(d,J=7.6Hz,4H),7.76(t,J=7.5Hz,2H),7.63(t,J=7.9Hz,4H),5.76(ddd,J=2.9,10.8,17.1Hz,1H),5.05(s,1H),4.95–4.82(m,4H),4.73(s,1H),4.62(t,J=4.5Hz,4H),4.50(q,J=4.0Hz,4H),3.73–3.59(m,4H),3.44–3.24(m,4H),3.21–3.11(m,1H),3.00(s,2H),2.92–2.83(m,2H),2.77(s,2H),2.68(d,J=14.3Hz,1H),2.63–2.53(m,3H),2.48(t,J=7.1Hz,4H),2.42(s,2H),2.37–2.30(m,7H),2.16–2.09(m,1H),1.99(dt,J=4.7,9.2Hz,5H),1.63–1.38(m,6H),0.96(s,3H).13C NMR(125MHz,CDCl3)δ173.2,170.4,158.8,150.9,150.0,149.9,138.1,135.8,129.9,128.7,110.8,110.5,110.5,110.5,110.0,69.1,62.9,62.8,61.2,61.1,60.1,60.0,60.0,59.9,53.6,52.2,52.2,51.2,48.5,42.5,42.4,42.3,42.3,40.5,40.5,39.9,33.9,33.6,33.3,27.3,20.0,16.0.HRMS(ESI)m/z:calcd for C57H72N8O16S2[M+H]+,1189.458;found,1189.4583.
实施例10:制备化合物10(13d)
4-(3-((5-(5-(2-((1R,3R,4S)-4-甲基-3-(3-(5-(5-(3-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丙氧基)-5-氧代戊酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-5-氧代戊酰基)氧基)丙氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实施例8,区别在于,将(五)中的丁二酸酐换成戊二酸酐。
本实施例中制得无色透明液体,产率63%。
1HNMR(500MHz,CDCl3)δ8.08–8.00(m,4H),7.75(t,J=7.5Hz,2H),7.61(t,J=7.9Hz,4H),5.80–5.70(m,1H),5.05(s,1H),4.93(s,1H),4.89–4.81(m,3H),4.73(s,1H),4.49(t,J=6.1Hz,4H),4.25(t,J=6.1Hz,4H),3.66(dt,J=9.9,29.9Hz,4H),3.41–3.25(m,4H),3.08–2.50(m,16H),2.41(t,J=7.2Hz,6H),2.30(t,J=7.3Hz,4H),2.22–2.17(m,4H),1.97–1.91(m,4H),1.57(s,2H),1.49–1.38(m,4H),0.95(s,3H).13C NMR(125MHz,CDCl3)δ173.3,170.4,158.9,150.1,150.0,149.9,138.1,135.8,129.8,128.6,110.6,110.5,110.5,110.4,110.4,68.1,62.9,62.8,60.2,60.1,60.0,60.0,59.9,52.4,51.3,51.3,48.8,48.5,42.8,42.5,42.4,42.4,40.5,40.5,39.9,33.7,33.6,33.5,28.0,27.2,20.1,16.0.HRMS(ESI)m/z:calcd for C59H76N8O16S2[M+H]+,1217.4893;found,1217.4898.
实施例11:制备化合物11(13e)
4-((4-((4-(5-(2-((1R,3R,4S)-4-甲基-3-(3-(5-(4-((4-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丁-2炔-1-基)氧基)-4-氧代丁酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-4-氧代丁酰基)氧基)丁-2-炔1-基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实例7,区别在于,将(四)中的乙二醇换成1,4-丁炔二醇。
本实施例中制得无色透明液体,产率46%。
1H NMR(500MHz,CDCl3)δ8.09(dd,J=8.1,16.0Hz,4H),7.79–7.74(m,2H),7.64(t,J=7.0Hz,4H),5.83–5.73(m,1H),5.12–5.07(m,4H),5.05–4.82(m,6H),4.75(d,J=8.3Hz,4H),3.74–3.64(m,4H),3.44–3.31(m,4H),3.05(d,J=9.6Hz,2H),2.92(d,J=16.1Hz,2H),2.82(d,J=11.3Hz,2H),2.75–2.67(m,6H),2.59(s,6H),2.53–2.42(m,4H),2.33–1.99(m,4H),1.62–1.41(m,6H),0.97(s,3H).13C NMR(125MHz,CDCl3)δ172.5,169.1,158.0,150.1,150.0,149.1,138.0,135.9,129.8,128.8,110.9,110.7,110.4,110.3,110.1,84.2,78.6,62.8,60.2,58.8,53.6,52.4,52.1,51.5,48.8,48.5,42.8,42.5,42.4,41.6,40.6,40.0,39.9,34.0,29.3,29.0,27.4,16.0.HRMS(ESI)m/z:calcd for C59H68N8O16S2[M+H]+,1209.4267;found,1209.4269.
实施例12:制备化合物12(13f)
4-((4-((5-(5-(2-((1R,3R,4S)-4-甲基-3-(3-(5-(5-((4-((2-氧化-3-(苯基磺酰基)-1,2,5-噁二唑-4-基)氧基)丁-2炔-1-基)氧基)-5-氧代戊酰基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)丙-1-烯-2-基)-4-乙烯基环己基)烯丙基)六氢吡咯并[3,4-c]吡咯-2(1H)-基)-5-氧代戊酰基)氧基)丁-2-炔1-基)氧基)-3-(苯基磺酰基)-1,2,5-噁二唑2-氧化物的制备方法基本同实例9,区别在于,将(四)中的乙二醇换成1,4-丁炔二醇。
本实施例中制得无色透明液体,产率49%。
1H NMR(500MHz,CDCl3)δ8.07(t,J=7.9Hz,4H),7.77(t,J=7.5Hz,2H),7.63(t,J=7.8Hz,4H),5.77(dd,J=10.8,17.5Hz,1H),5.09(s,4H),5.04–4.82(m,5H),4.73(s,5H),3.73–3.61(m,4H),3.34(dd,J=12.0,30.2Hz,4H),3.22–3.11(m,1H),3.08–2.95(m,2H),2.92–2.75(m,4H),2.72–2.66(m,1H),2.63–2.52(m,3H),2.46(t,J=7.1Hz,8H),2.32(t,J=7.2Hz,5H),1.99(dp,J=6.3,7.5,22.2Hz,6H),1.59(dd,J=9.0,21.0Hz,2H),1.52–1.38(m,4H),0.96(s,3H).13C NMR(125MHz,CDCl3)δ172.6,170.3,158.1,150.0,150.0,149.4,138.0,135.9,129.9,128.8,110.8,110.7,110.6,110.5,110.4,110.2,84.2,78.6,61.0,60.2,58.8,53.6,52.5,51.9,51.8,51.3,48.9,48.5,42.5,42.5,42.4,41.2,40.6,40.0,39.9,33.6,33.3,29.8,27.4,20.1,16.1.HRMS(ESI)m/z:calcd for C61H72N8O16S2[M+H]+,1237.458;found,1237.4587.
药效学实验
1.一氧化氮体外释放试验
1.1实验设备与试剂
仪器
多功能酶标仪(美国MD Spectramac M3)
超净工作台(中国苏州净化SW-CJ-1FD)
试剂
一氧化碳(NO)测定试剂盒(中国南京建成生物工程研究所A013-2-1)
1.2实验方法
样本前处理:将样品稀释至100μM,充分混匀,取160μL操作。
2具体操作:取160μL双蒸水加入80μL显色剂,记作空白组;取160μL亚硝酸钠标准液(20μmmol/L)加入80μL显色剂,记作标准组;取160μL样品溶液加入80μL显色剂,记作测定组。混匀,用酶标仪记录波长550nm每孔吸光度OD值。
计算方法:
组织样本中NO含量计算公式:
1.3试验结果
表1.实施例1-12化合物的NO体外释放结果
由表1中数据可以看出,所有实施例化合物均能有效释放一氧化氮,且绝大多数实施例,随着时间的增加,一氧化氮的释放水平增加。
2.体外抗肿瘤活性评价试验
2.1实验设备
超净工作台(苏州净化设备有限公司)
CO2培养箱(日本SANYO)
倒置生物显微镜(日本OLYMPUS)
酶标仪(美国BioTek)
2.2实验方法
(1)将细胞消化、计数,配制细胞悬液(K562,CCRF-CEM 5×105个/mL,其余3.5×104个/mL),96孔细胞培养板中每孔加入100μL细胞悬液;
(2)96孔细胞培养板置于37℃,5%CO2培养箱中培养24h;
(3)用培养基稀释药物至所需工作液浓度,每孔加入100μL相应的含药培养基,同时设立阴性对照组;
(4)96孔细胞培养板置于37℃,5%CO2培养箱中培养72h;
(5)将96孔板进行CCK-8染色,λ=450nm,测定OD值;
(1)每孔加入10μL CCK-8,在培养箱继续培养1-2h;
(2)摇床10分钟轻轻地混匀,去除96孔板中气泡;
(3)λ=450nm,酶标仪读出每孔的OD值,计算抑制率。
(6)计算各组别抑制率。
2.3实验结果
表2.实施例1-12化合物对4种人类癌细胞株抗增殖活性的抑制率(1和10μM)
由表2可知,在1和10μM浓度下,12个化合物对四种人源肿瘤细胞K562、CCRF-CEM、A375和SK-MEL-2,均表现出不同程度的抑制作用,且抗增殖活性均显著强于β-榄香烯和阳性对照药,表明含氮基团和NO供体的引入,成功提高β-榄香烯的抗肿瘤作用。
表3.实施例1-5、7-12化合物对K562和CCRF-CEM细胞系的抗增殖活性的IC50(μM)
如表3所示,绝大部分化合物的抗增殖活性均显著强于β-榄香烯。对于K562细胞系,实施例13的活性强于β-榄香烯200倍以上,实施例1、4、7、8、11和12抗增殖活性强于β-榄香烯100倍以上;对于CCRF-CEM细胞系,实施例4、7、8和11的抗增殖活性强于β-榄香烯100倍以上。
3.人白血病细胞K562裸鼠移植瘤的体内抗肿瘤活性
3.1受试动物
来源、种系、品系:balb/c裸鼠,上海灵畅生物科技有限公司提供。
实验动物生产许可证:SCXK(沪)2018-0003
合格证编号:20180003025341
伦理批准文号:IACUC-20220804
实验动物使用许可证:SYXK(苏)2022-0038
日龄:6-8周
性别:雌性。
动物数:每组6只,共3组,共18只
3.2模型的制备
收集培养的人白血病细胞K562细胞悬液,浓度为5×107个/mL,以每只0.1mL接种于小鼠右侧腋窝皮下。
3.3分组与给药
小鼠移植瘤用游标卡尺测量移植瘤直径,肿瘤生长至50-100mm3时将动物随机分组。同时,各组小鼠开始给药,给药方案见组别与给药方案。实验结束后,随即处死小鼠,手术剥取瘤块称重。
3.4观测指标
3.4.1体重
每两天记录一次动物体重;
3.4.2肿瘤体积
每两天记录一次肿瘤体积大小;
肿瘤体积(tumorvolume,TV)的计算公式为:
TV=1/2×a×b2其中a、b分别表示长宽。
根据测量的结果计算出相对肿瘤体积(relative tumor volume,RTV),计算公式为:
RTV=Vt/V0其中V0为分笼给药时即(d0)测量所得肿瘤体积;Vt为每一次测量时的肿瘤体积。
抗肿瘤活性的评价指标:相对肿瘤增殖率T/C(%),计算公式如下:
TRTV:治疗组RTV;CRTV:模型组RTV。
抗肿瘤活性的评价指标:肿瘤生长抑制率(%),计算公式如下:
3.5实验结果
在给药4周内,模型组、β-榄香烯组和实施例10(13d)组的小鼠体重逐渐增加,表明在治疗期间,β-榄香烯组和实施例10(13d)组对小鼠无明显的毒性。随着治疗时间的增加而逐渐增加,模型组的肿瘤体积也在逐渐变大。相反,β-榄香烯组和实施例10(13d)组的肿瘤体积变大不明显,说明β-榄香烯组和实施例10(13d)组的肿瘤生长受到明显的抑制。在实验结束后,杀死老鼠取出肿瘤并称重,发现β-榄香烯组和实施例10(13d)组的肿瘤重量小于模型组,证明两者都能有效的抑制了肿瘤的生长。在肿瘤生长抑制率方面,两者均能抑制肿瘤生长。实施例10(13d)组抑制作用较β-榄香烯组强11%。总之,实施例10(13d)相比于β-榄香烯对K562细胞表现更强的抑制作用。
以上结果表明含氮基团和双NO供体的引入有效增强了β-榄香烯在体内的抗肿瘤作用,特别是对白血病K562细胞系的抑制活性,是基于β-榄香烯抗肿瘤药物研发的可行策略。
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发明所附权利要求书所限定的范围。
Claims (10)
2.根据权利要求1所述的一种13,14-双一氧化氮供体-β-榄香烯衍生物,其特征在于,式(I)中:
R1为C2-5的含氮原子的直链胺结构或C3-10的环状胺结构;
R2、R3分别独立选自C2-6的链烷基、C2-6的烯基、C2-6的炔基。
6.一种制备如权利要求1-5任一项所述的13,14-双一氧化氮供体-β-榄香烯衍生物的方法,其特征在于,包括以下步骤:
(1)β-榄香烯A-1进行13、14位烯丙位氯代反应得到中间体A-2;
(2)含有氮杂原子官能团的R1结构片段A-3通过选择性亲核取代到中间体A-2的13,14位上,得到中间体A-4;
(3)中间体A-4脱去保护得到中间体A-5;
(4)苯巯基乙酸A-6经过30%H2O2氧化处理,又经发烟硝酸处理闭环得到中间体A-7;
(5)含有羟基官能团的R3结构片段A-8通过选择性亲核取代至中间体A-7,得到中间体A-9;
(6)含有羰基官能团的R2结构片段A-10与中间体A-9酯化得到中间体A-11;
(7)中间体A-5和中间体A-11进行分子间酰胺缩合,得到通式(I)所示的衍生物;
7.权利要求1-6任一项所述的13,14-双一氧化氮供体-β-榄香烯衍生物,或其可药用盐,或溶剂化物,或其对映异构体、非对映异构体在制备抗肿瘤药物中的应用。
8.根据权利要求7所述的应用,其特征在于,所述肿瘤包括白血病和黑色素瘤。
9.一种抗肿瘤药物,含有安全有效量的所述的13,14-双一氧化氮供体-β-榄香烯衍生物,或其可药用盐,或溶剂化物,或其对映异构体、非对映异构体。
10.根据权利要求9所述的抗肿瘤药物,其特征在于,还包括药理上可接受的盐及药理上可以接受的赋形剂或载体。
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CN106866572A (zh) * | 2017-02-07 | 2017-06-20 | 石药集团远大(大连)制药有限公司 | 一氧化氮供体型β‑榄香烯衍生物及其制备方法和用途 |
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 |
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