CN110467627B - L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 - Google Patents
L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 Download PDFInfo
- Publication number
- CN110467627B CN110467627B CN201910786502.4A CN201910786502A CN110467627B CN 110467627 B CN110467627 B CN 110467627B CN 201910786502 A CN201910786502 A CN 201910786502A CN 110467627 B CN110467627 B CN 110467627B
- Authority
- CN
- China
- Prior art keywords
- formula
- dihydroartemisinin
- fluoroquinolone
- serine
- conjugate
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
- A61P31/06—Antibacterial agents for tuberculosis
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/12—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains three hetero rings
- C07D493/20—Spiro-condensed systems
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Obesity (AREA)
- Engineering & Computer Science (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Pulmonology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了式I所示的L‑丝氨酸连接的双氢青蒿素‑氟喹诺酮偶联物,式II所示的中间体,式I和式II所示化合物的制备方法,以及式I所示化合物在制备抗结核分枝杆菌的药物或/和降血脂的药物中的用途,
Description
技术领域
本发明属于药物合成技术领域,涉及一类L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其合成中间体,以及它们的制备方法和制药用途。
背景技术
近年来结核病重新在全球肆虐,治疗难题之一在于结核分枝杆菌(MTB)的耐药性。氟喹诺酮药物(如环丙沙星、氧氟沙星、左氧氟沙星、莫西沙星和加替沙星)是目前治疗广泛耐多药结核病(MDR-TB)的首选药物,其对结核分枝杆菌有很好的抑制或杀灭作用,且与非喹诺酮类抗结核药物不产生明显的交叉耐药性,联合用药时对这些药物的活性无抑制作用,但氟喹诺酮药物长期使用会促使产生对上市喹诺酮药物耐药的结核分枝杆菌。
双氢青蒿素是青蒿素衍生物,具有高效、低毒的抗疟活性。近年来研究表明,双氢青蒿素及其衍生物还具有抗肿瘤、抗炎、抗组织纤维化等多种生物活性。
氨基酸是维持生命的基本物质,是蛋白质的基本组成单位,是合成人体激素、酶类的原料,参与人体新陈代谢和各种生理机能。除了制备复方氨基酸输液,氨基酸也用作治疗药物或用于合成一些重要医药中间体。
发明内容
本发明的目的在于以L-丝氨酸为linker,将双氢青蒿素结构单元与氟喹诺酮结构单元偶联,设计合成一类L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物,并对其生物活性进行测试,得到对结核分枝杆菌具有良好的选择性抑制活性或/和在其它方面具有良好活性且毒性小的新化合物,以用作抗结核药物或其它用途的药物。
经研究,本发明提供如下技术方案:
1.式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其消旋体、立体异构体、氮氧化物、药学上可接受的盐:
式I中,
X选自:C1-C6烷基;C3-C6环烷基;或者,取代或未取代的C6-C10芳基,所述芳基上的取代基为一个或多个,独立选自卤素、羟基、氨基、C1-C6烷基或C3-C6环烷基;
Z选自:N或C-R1;R1选自氢、卤素或C1-C6烷氧基;
进一步,式I中,
X选自:C1-C3烷基;环丙基;取代或未取代的苯基,所述苯基上的取代基为一个或多个,独立选自卤素、羟基、氨基或C1-C3烷基;
Z选自:N或C-R1;R1选自氢、卤素或C1-C3烷氧基;
进一步,式I中,
X选自:甲基、乙基、环丙基、苯基或卤素取代苯基;
Z选自:N或C-R1;R1选自氢、卤素、甲氧基或乙氧基;
进一步,式I中,
X选自:乙基、环丙基或4-卤素取代苯基;
Z选自:N或C-R1;R1选自氢、卤素或甲氧基;
R选自:苯甲氧基、叔丁氧基或甲基。
进一步,式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物为以下化合物中的任一种:
2.式II所示的中间体或其消旋体、立体异构体、药学上可接受的盐,用于制备前面任一项方案所述的式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其消旋体、立体异构体、氮氧化物、药学上可接受的盐:
式II中,R具有前面任一项方案所述式I中的定义。
3.式II所示的中间体或其消旋体、立体异构体、药学上可接受的盐的制备方法,包括以下步骤:由双氢青蒿素与式III所示的氨基修饰的L-丝氨酸经醚化连接制得式II所示的中间体;或者,由双氢青蒿素与式IV所示的氨基修饰并羧基酯化的L-丝氨酸经醚化连接、酯基水解制得式II所示的中间体;
式III和式IV中,R具有前面任一项方案所述式I中的定义;式IV中,R’选自C1-C3烷基。
进一步,所述醚化反应的溶剂为乙醚、温度为-5℃~-10℃。
4.式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其消旋体、立体异构体、氮氧化物、药学上可接受的盐的制备方法,包括以下步骤:由式II所示的中间体与式V所示的氟喹诺酮化合物经酰胺型偶联制得式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物;
式V中,X、Z和Y具有前面任一项方案所述式I中的定义。
5.式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其消旋体、立体异构体、氮氧化物、药学上可接受的盐在制备抗结核分枝杆菌的药物中的应用。
6.式I所示的L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其消旋体、立体异构体、氮氧化物、药学上可接受的盐在制备降血脂的药物中的应用。
除另有说明外,本发明中的术语“消旋体”是指由等量对映体构成的光学不活性的有机物。“立体异构体”是指原子组成及键接相同而原子在三维空间排列上不同的分子。“氮氧化物”是指三级氮连接氧原子形成+N-O-结构单元的有机物。“药学上可接受的盐”可以是酸性盐,也可以是碱性盐,例如无机酸盐、有机酸盐、无机碱盐或有机碱盐。
术语“C1-C6烷基”指具有1-6个碳原子的直链或支链饱和一价烃基,例如甲基、乙基、丙基、丁基、戊基、己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基或它们的异构体。
术语“C3-C6环烷基”指具有3-6个碳原子的饱和环烃基,例如环丙基、环戊基、环己基。
术语“C6-C10芳基”指具有6-10个碳原子的芳香性或部分芳香性的单环、双环或三环烃,特别是具有6个碳原子的环(“C6芳基”),例如苯基;或联苯基;或具有9个碳原子的环(“C9芳基”),例如茚满基或茚基;或具有10个碳原子的环(“C10芳基”),例如四氢化萘基、二氢萘基或萘基。
术语“卤素”指F、Cl、Br和I。
本发明的有益效果在于:本发明采用片段拼合法,以含有羟基的手性氨基酸——L-丝氨酸为Linker,选择含有NH或NH2的氟喹诺酮药物,将双氢青蒿素结构单元与氟喹诺酮结构单元偶联,设计合成了一类L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物,并对其进行了生物活性筛选,结果显示,本发明合成化合物对结核分枝杆菌均表现出一定的抑制活性,部分化合物的抑制活性超过80%,抑制率最高达到98.3%,而对铜绿假单胞杆菌、金黄色葡萄球菌及大肠杆菌均没有表现出较好的抗菌活性,说明本发明合成化合物对结核分枝杆菌具有良好的选择性抑制作用,可用于制备抗结核药物;此外,本发明合成化合物大多数对降血脂靶点——前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin 9,PCSK9)有一定的抑制作用,部分化合物对PCSK9表现出良好的抑制作用和较低的细胞毒性,说明本发明合成化合物可用于制备降血脂药物;而且,经美国Simulations Plus公司开发的ADMET-Predictor 7.0软件预测,本发明合成化合物的MlogP(脂水分配系数)、TOX hERG(心脏毒性)、TOX BRM Rat(大鼠肿瘤毒性)、TOX BRM Mouse(小鼠肿瘤毒性)、TOX MUT Risk(致突变性)和TOX Risk(毒性风险系数)均在安全范围内,说明本发明合成化合物毒性小。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚,下面将对本发明的优选实施例进行详细的描述。
优选实施例中使用的主要试剂及规格:克林沙星、沙拉沙星(郑州克尔泰生化科技有限公司,>95%);诺氟沙星、环丙沙星、洛美沙星、加替沙星、莫西沙星(成都爱斯特贸易有限公司,AR);依诺沙星、巴洛沙星(上海达瑞精细化工有限公司,AR);双氢青蒿素(DHA)(重庆华立武陵山制药有限公司,AR);46.5%三氟化硼乙醚溶液(BF3·Et2O)(上海晶纯试剂有限公司,AR);氯甲酸苄酯(Cbz-Cl)(上海达瑞精细化学品有限公司,AR);L-丝氨酸(L-Ser)、N-苄氧羰氧基丁二酰亚胺(Z-OSu)、二碳酸二叔丁酯(Boc2O)(成都凯泰新技术有限责任公司,AR);其余试剂均为市售化学纯或分析纯产品,未经纯化直接使用。
优选实施例中使用的主要仪器及型号:磁力搅拌低温恒温水槽(PSL-1810,上海爱朗仪器有限公司);集热式恒温加热磁力搅拌器(DF-101S,郑州长城科工贸有限公司);旋转蒸发仪(R-1001N,长城科工贸有限公司);熔点测定仪(X-6,北京福凯仪器有限公司);自动旋光仪(WZZ-2S,上海精密科学仪器有限公司);紫外分析仪(ZF-1,上海顾村电光仪器厂);核磁共振仪(600MHz,Bruker,瑞士;DD2-400MR,Agilent,USA;TMS为内标);高分辨质谱仪(HR ESI MS)(Varian7.0T,Varian,USA)。
实施例1.目标化合物TM1系列及其中间体的合成
1.1中间体IM1-2的合成
IM1-1的多次制备实验结果见表1。以表1中Entry 1为例,制备方法如下:于100mL反应瓶中加入L-Ser(1mmol)、冷却的饱和Na2CO3溶液3mL,冰浴搅拌溶解;滴加Boc2O(1.5mmol)的丙酮溶液2mL;室温搅拌反应,TLC-茚三酮显色法监测反应进程。反应结束后,加水15mL,在pH>9时以乙醚(Et2O)(10mL×2)萃取,收集水相,1N HCl调节pH至3~4,乙酸乙酯(EtOAc)(10mL×3)萃取,合并有机相,无水Na2SO4干燥,TLC-茚三酮显色法检查纯度,减压蒸干,真空干燥,得无色油状液体IM1-1,低温保存。
表1 制备IM1-1的实验结果
IM1-2的多次制备实验结果见表2.1和表2.2。以表2.1中Entry 1为例,制备方法如下:于100mL反应瓶中依次加入DHA(1mmol)、IM1-1(1.2mmol)及溶剂3mL,室温搅拌溶解,控温加入BF3·Et2O 0.2mL,继续控温搅拌反应,TLC监测反应进程。反应结束后,加饱和NaHCO3溶液20mL终止反应,再加Et2O 15mL,静置分层,收集水相,用1N HCl调节pH至3~4,EtOAc(10mL×3)萃取,合并有机相,饱和NaCl溶液(10mL×3)洗涤,无水Na2SO4干燥,减压蒸干得到粗品;柱层析纯化(以石油醚(PE)-乙酸乙酯(EA)混合溶剂为洗脱剂),收集洗脱液,减压蒸干,TLC-紫外荧光和磷钼酸显色法检查纯度,真空干燥,得白色粉末状固体IM1-2,m.p.166-168℃,低温保存。
表2.1为溶剂探索实验结果。用CH2Cl2和CHCl3作溶剂,反应完后溶液呈棕红色,杂质较多,后处理困难;采用四氢呋喃(THF)作溶剂,没有目标产物生成;采用Et2O作溶剂,反应完后溶液澄清透明,杂质较少,后处理相对容易。所以优选Et2O作溶剂。
表2.1 制备IM1-2的实验结果
表2.2为温度探索实验结果。反应完后溶液的颜色:室温反应呈橙红色,冰水浴温度反应呈橙黄色,-10℃反应呈微黄色。TLC监测表明,在室温和冰水浴下反应,杂质明显较-10℃反应多,说明室温及冰水浴不利于该反应的进行,所以优选-10℃进行反应。
表2.2 制备IM1-2的实验结果
从表2.1和表2.2可以看出,溶剂和温度是影响DHA和醇成醚的关键因素。
1.2目标化合物TM1系列的合成
于100mL反应瓶中依次加入IM1-2(1mmol)、1-羟基苯并三唑(HOBT)(1.2mmol)及二氯甲烷(DCM)3mL,冰浴搅拌溶解,再加入N,N'-二异丙基乙胺(DIPEA)(1.2mmol)和二环己基碳二亚胺(DCC)(1.2mmol),冰浴搅拌;与此同时,将FQ(克林沙星、诺氟沙星、环丙沙星、沙拉沙星、莫西沙星、洛美沙星、加替沙星、依诺沙星或巴洛沙星)(1mmol)溶解于DCM3mL中(成盐的沙星需另加DIPEA 1.5mmol中和酸),冰浴搅拌10-30min;两液合并,室温搅拌反应,TLC监测反应进程。反应结束后,减压抽滤,滤饼用DCM(2mL×5)洗涤,合并洗液及滤液,依次用饱和NaHCO3溶液(15mL×2)、5%柠檬酸水溶液(10mL×2)、饱和NaCl溶液(10mL×2)洗涤,无水Na2SO4干燥,减压蒸干得到粗品;柱层析纯化(PE:EA=1:1(体积比)),收集洗脱液,减压蒸干,TLC-紫外荧光和磷钼酸显色法检查纯度,真空干燥,即得TM1。具体合成条件及结果见表3。
表3 制备TM1的实验结果
HY和X结构式中的虚线均表示连接键。
TM1系列化合物的表征数据如下:
TM1-1:淡黄色固体,m.p.:147-149℃.1H NMR(600MHz,DMSO-d6)δ:14.51(1H,s),8.85(1H,s),7.99-7.96(1H,t,J=6.6and 18Hz),7.22-7.20(1H,d,J=9Hz),5.45(1H,s),4.73-4.72(1H,d,J=9Hz),4.71-4.70(1H,d),4.42-4.40(1H,m),4.05-4.01(1H,m),3.92-3.70(4H,m),3.48-3.45(2H,m),2.40-2.38(1H,m),2.21-2.16(1H,td,J=3.6,13.8and27.6Hz),2.01-1.99(2H,m),1.82-1.80(1H,m),1.71-1.51(3H,m),1.40-1.33(13H,m),1.29(3H,s,H-15),1.20-1.11(4H,m),1.00(2H,s),0.90-0.88(3H,d,J=6.6Hz),0.85-0.84(3H,d,J=7.8Hz).13C NMR(151MHz,DMSO-d6)δ:176.74,169.16,165.62,157.04,155.64,153.40,146.98,143.95,138.52,123.69,120.42,111.294,108.30,101.99,87.62,81.03,78.96,68.62,60.30,52.56,51.17,50.63,46.40,44.33,42.87,42.11,37.10,36.57,34.82,31.03,28.67,26.19,24.91,24.42,24.26,23.47,20.61,14.64,13.23,11.46,11.30.HR MS:C40H52ClFN4O11[M+Na]+计算值841.3203,测定值841.3198.
TM1-2:淡黄色固体,m.p.:180-182℃.1H NMR(600MHz,DMSO-d6)δ:14.93(1H,s),8.70(1H,s),8.36(1H,s),7.91(1H,s),7.17-7.15(1H,d,J=8.4Hz),5.46(1H,s),4.74-4.71(2H,m),4.05-4.01(1H,q),3.91-3.70(5H,m),3.55-3.54(1H,m),3.50-3.47(1H,dd,J=7.8and 9.6Hz),3.15-3.02(4H,m),2.40-2.38(1H,m),2.21-2.15(1H,td,J=3.6,13.8and 27.6Hz),2.01-1.99(2H,m),1.82-1.80(1H,m),1.71-1.51(3H,m),1.40-1.30(13H,m),1.29(3H,s),1.20-1.11(4H,m),0.90-0.89(3H,d,J=6.6Hz),0.85-0.84(3H,d,J=7.2Hz).13C NMR(151MHz,DMSO-d6)δ:177.20,168.74,165.92,155.35,148.41,147.28,137.60,135.33,125.00,120.71,115.89,107.66,103.55,101.79,87.35,80.75,78.66,68.45,52.28,51.52,51.20,50.50,45.36,44.06,41.95,36.79,36.29,36.22,34.55,30.76,28.40,25.90,24.63,23.98,21.30,20.32,14.36,12.97,7.80.HR MS:C39H53FN4O11[M+H]+计算值773.3774,测定值773.3772.
TM1-3:淡黄色固体,m.p.:183-185℃.1H NMR(600MHz,DMSO-d6)δ:15.30(1H,s),8.96(1H,s),7.96-7.94(1H,d,J=13.2Hz),7.20-7.19(1H,d,J=7.2Hz),7.17-7.16(1H,d,J=9Hz),5.45(1H,s),4.78-4.70(2H,m),4.61-4.54(2H,m),4.05-3.72(4H,m),3.54-3.42(5H,m),2.41-2.36(1H,m),2.21-2.16(1H,td,J=3.6,14.4and 28.2Hz),2.01-1.99(1H,m),1.83-1.79(1H,m),1.69-1.49(5H,m),1.39-1.34(10H,m),1.29(3H,s),1.19-1.11(4H,m),0.89-0.88(3H,d,J=6Hz),0.84-0.83(3H,d,J=7.2Hz),0.78-0.75(2H,m).13C NMR(151MHz,DMSO-d6)δ:177.26,168.86,166.21,162.28,155.59,152.63,149.33,139.72,136.73,130.43,119.49,117.81,111.80,108.06,107.16,103.79,101.91,87.58,81.01,78.91,68.40,60.29,52.54,50.51,49.67,44.99,44.30,41.73,37.04,36.56,34.79,30.99,28.62,26.17,24.88,24.21,21.57,20.57,14.63,13.19.HR MS:C40H53FN4O11[M+K]+计算值823.3269,测定值823.3326.
TM1-4:淡黄色固体,m.p.:143-145℃;1H NMR(600MHz,DMSO-d6)δ:15.06(1H,s),8.64(1H,s),8.03-8.01(1H,d,J=13.2Hz),7.79-7.77(2H,dd,J=4.8and 8.4Hz),7.54-7.52(2H,t,J=8.4and16.2Hz),7.17-7.16(1H,d,J=9Hz),6.38-6.37(1H,d,J=7.2Hz),5.41(1H,s),4.69-4.68(1H,d,J=3Hz),4.64-4.61(1H,q),3.86-3.77(3H,m),3.62-3.59(1H,t,J=9and 19.2Hz),3.41-3.36(2H,m),3.31-2.92(4H,m),2.38-2.35(1H,m),2.20-2.15(1H,td,J=3.6,14.4and 28.2Hz),2.00-1.99(1H,m),1.81-1.79(1H,m),1.64-1.42(4H,m),1.35-1.29(12H,m),1.15-1.10(1H,m),0.87-0.86(1H,d,J=6.6Hz),0.80-0.79(1H,d,J=7.2Hz).13C NMR(151MHz,DMSO-d6)δ:176.10,171.85,168.36,165.95,155.01,153.52,151.87,148.48,144.99,137.08,131.08,129.28,119.46,111.30,111.15,107.10,105.97,103.19,101.41,86.97,80.38,78.30,67.96,51.90,50.09,48.97,44.53,43.68,41.18,36.44,35.93,34.18,30.38,28.03,25.53,24.26,23.59,20.94,19.94,14.25,12.59.HR MS:C43H52F2N4O11[M+Na]+计算值861.3499,测定值861.3506.
TM1-5:淡黄色固体,m.p.:177-179℃.1H NMR(600MHz,DMSO-d6)δ:14.86(1H,s),8.94(1H,s),7.90-7.88(1H,d,J=11.4Hz),5.49-5.34(1H,m),4.75-4.25(6H,m),3.92-3.89(1H,m),3.52-3.42(6H,m),3.13-3.00(1H,m,Ha-28),2.40-2.38(1H,m),2.21-2.16(1H,td,J=3.6,14.4and 28.2Hz),2.01-1.99(2H,m,),1.82-1.80(1H,s),1.73-1.50(5H,m),1.39-1.35(13H,m),1.29-1.24(6H,m),1.14-1.13(1H,m),0.89-0.88(1H,d,J=6Hz),0.85-0.82(1H,t,J=7.8Hz).13C NMR(151MHz,DMSO)δ:175.82,172.21,165.74,155.39,151.50,134.52,129.63,127.54,121.59,107.41,107.12,103.53,87.35,80.76,78.81,60.01,55.43,55.02,54.07,52.29,50.71,45.35,44.08,38.52,36.78,36.29,34.51,33.62,30.77,28.36,25.89,24.62,21.29,21.01,20.29,16.13,14.98,14.35,12.94.HRMS:C40H54F2N4O11[M+H]+计算值805.3836,测定值805.3834.
TM1-6:淡黄色固体,m.p.:170-172℃.1H NMR(600MHz,DMSO-d6)δ:15.10(1H,s),8.66(1H,s),7.68-7.65(1H,dd,J=3.6and 13.8Hz),7.23-7.11(1H,m)5.49-5.41(1H,m),4.82-4.66(2H,m),4.38-3.95(6H,m),3.61-3.60(3H,d,J=4.2Hz),3.45-3.38(2H,m),2.78-2.69(2H,m),2.39-2.30(1H,m),2.25-2.15(2H,m),1.99-1.97(1H,m),1.80-1.65(4H,m),1.60-1.46(3H,m),1.40(3H,s),1.35-1.10(16H,m),1.02-0.94(1H,m),0.88-0.87(3H,d,J=6.6Hz),0.83-0.82(3H,d,J=7.2Hz),0.78-0.76(1H,m).13C NMR(151MHz,DMSO)δ:176.57,172.49,169.85,166.33,155.50,150.83,141.39,137.38,135.03,118.04,106.98,103.78,101.88,87.62,81.03,78.93,68.65,61.92,60.29,54.07,52.61,50.71,44.38,41.11,38.80,37.14,36.58,36.10,35.60,34.83,31.03,28.44,26.13,25.41,24.86,24.20,21.57,21.29,20.58,14.63,13.21,10.45,8.56.HR MS:C44H59FN4O12[M+H]+计算值855.4193,测定值855.4195.
TM1-7:淡黄色固体,m.p.:159-161℃;1H NMR(600MHz,DMSO-d6)δ:14.90(1H,s),8.71(1H,s),7.79-7.77(1H,d,J=12Hz),7.37-7.08(1H,m),5.52-5.35(1H,m),4.77-4.61(3H,m),4.35-3.87(4H,m),3.73-3.71(3H,t,J=9Hz),3.51-3.42(4H,m),3.15-3.04(1H,m),2.40-2.38(1H,m),2.21-2.16(1H,td,J=3,13.8and 27Hz),2.02-1.99(2H,m),1.82-1.50(5H,m),1.40-1.36(12H,m),1.29-1.24(5H,m),1.14-1.03(5H,m),0.90-0.89(3H,d,J=5.4Hz),0.85-0.83(3H,t,J=7.8Hz).13C NMR(151MHz,DMSO-d6)δ:176.27,165.49,160.01,156.35,155.02,150.60,146.10,134.10,126.28,124.48,122.02,106.67,103.17,86.99,80.41,67.70,63.49,59.64,54.77,51.93,50.67,43.68,40.54,38.16,36.43,34.17,30.57,30.37,28.80,28.00,25.54,24.43,23.62,20.65,19.93,16.42,16.24,14.87,13.99,12.60,8.82,7.08.HR MS:C42H57FN4O12[M+H]+计算值829.4036,测定值829.4029.
TM1-8:淡黄色固体,m.p.:153-155℃;1H NMR(400MHz,CDCl3)δ:8.72(1H,s),8.18-8.14(1H,d,J=12.8Hz),5.57(1H,s),5.39-5.37(1H,d,J=9.2Hz),4.96-4.90(1H,dd,J=6.4and 14.8Hz),4.83-4.82(1H,d,J=3.2Hz),4.45-4.40(2H,q),4.07-3.92(5H,m),3.82-3.72(3H,m),3.64-3.44(2H,m),2.66-2.62(1H,m),2.41-2.34(1H,td,J=3.2,14and28Hz),2.09-2.02(2H,m),1.95-1.87(2H,m),1.70-1.56(5H,m),1.53-1.44(12H,m),1.36-1.20(4H),0.95-0.94(3H,d,J=6.4Hz),0.91-0.89(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:177.25,169.31,166.96,155.40,150.54,148.34,146.81,145.03,120.94,114.62,109.60,104.30,103.20,88.13,81.18,80.29,69.93,50.56,47.96,47.17,46.87,45.41,44.31,41.86,37.22,36.47,34.82,33.91,30.95,28.45,26.27,25.68,25.03,24.80,24.30,20.47,15.22,13.13.HR MS:C38H52FN5O11[M+Na]+计算值796.3545,测定值796.3547.
TM1-9:淡黄色固体,m.p.:135-137℃;1H NMR(400MHz,CDCl3)δ:8.82(1H,s),7.97-7.84(1H,m),5.79-5.61(1H,m),5.47-5.39(1H,m),5.13-5.05(2H,m),4.97-4.86(1H,m),4.81-4.62(2H,m),4.07-4.01(1H,m),3.86-3.83(3H,m),3.59-3.43(3H,m),3.10(3H,s),2.93-2.90(1H,m),2.63-2.62(1H,m),2.40-2.31(1H,m),1.90-1.40(20H,m),1.28-1.15(10H,m),0.94-0.86(6H,m).13C NMR(151MHz,CDCl3)δ:177.17,170.13,166.94,155.90,150.06,139.49,136.30,133.89,128.68,128.35,128.12,127.70,107.81,104.31,103.17,88.08,81.10,69.75,67.14,62.50,54.30,52.57,51.68,44.24,40.78,37.35,36.47,34.80,32.77,32.09,30.90,29.86,27.76,26.25,25.66,24.76,24.35,22.50,20.53,14.32,13.05,9.86,9.53.
实施例2.目标化合物TM2系列及其中间体的合成
2.1中间体IM2-2的合成
IM2-1的多次制备实验结果见表4。以表4中Entry 1为例,制备方法如下:于100mL反应瓶中加入L-Ser(1mmol)、冷却的饱和Na2CO3溶液3mL,冰浴搅拌;溶解后,滴加Z-OSu(1.5mmol)的丙酮溶液2mL;室温搅拌反应,TLC-茚三酮显色法监测反应进程。反应结束后,加水15mL,在pH>9时以EtOAc(10mL×2)萃取,收集水相,用1.5N HCl调节pH至3~4,EtOAc(10mL×3)萃取,合并有机相,饱和NaCl溶液(10mL×2)洗涤,无水Na2SO4干燥,TLC-茚三酮显色法检查纯度,减压蒸干,真空干燥,得白色粉末状固体IM2-1,m.p.118-120℃,低温保存。
表4 制备IM2-1的实验结果
IM2-2的多次制备实验结果见表5。以表5中Entry 1为例,制备方法如下:于100mL反应瓶中依次加入DHA(1mmol)、IM2-1(1.2mmol)及Et2O 5mL,室温搅拌溶解,-10℃加入BF3·Et2O 0.2mL,继续-10℃搅拌反应,TLC-紫外荧光和磷钼酸显色法监测反应进程。反应结束后,加饱和NaHCO3溶液15mL终止反应,加Et2O 10mL,收集水相,用一水合柠檬酸固体调节pH至4~5,析出白色固体,减压抽滤,滤饼用H2O(2mL×3)洗涤,TLC-紫外荧光和磷钼酸显色法检查纯度,室温敞放一天,真空干燥,得白色粉末状固体IM2-2,m.p.193-195℃,低温保存。
表5 制备IM2-2的实验结果
由表5可以看出,Entry 4的收率明显提高,原因在于,其在-5℃反应,反应时间从12h延长到24h,并且采用了氮气保护隔绝空气的条件,既有利于该反应的完全进行,又防止了DHA的半缩醛结构长时间处于酸性条件下被氧化。
2.2目标化合物TM2系列的合成
方法一:EDCI/HOBt/DIPEA法
于100mL反应瓶中依次加入IM2-2(0.5mmol)、HOBt(0.6mmol)及DCM 2mL,冰浴搅拌溶解,再加入DIPEA(1.5mmol)和1-(3-二甲胺基丙基)-3-乙基碳二亚胺(EDCI)(0.6mmol),继续冰浴搅拌;与此同时,将FQ(克林沙星、诺氟沙星、环丙沙星、沙拉沙星、莫西沙星、洛美沙星或加替沙星)(0.5mmol)溶解在DCM 2mL中(成盐的沙星需另加DIPEA0.7mmol中和酸),冰浴搅拌10-30min;两液合并,室温搅拌反应,TLC监测反应进程。反应结束后,减压抽滤,滤饼用DCM(2mL×5)洗涤,合并洗液及滤液,依次用饱和NaHCO3溶液(10mL×2)、5%柠檬酸水溶液(10mL×2)、饱和NaCl溶液(10mL×2)洗涤,无水Na2SO4干燥,减压蒸干得到粗品;柱层析纯化(PE:EA=1:1(体积比)),收集洗脱液,减压蒸干,TLC-紫外荧光和磷钼酸显色法检查纯度,真空干燥,即得TM2。具体合成条件及结果见表6。
表6 EDCI/HOBt/DIPEA法制备TM2的实验结果
HY和X结构式中的虚线均表示连接键。
方法二:DCC/HOBt/DIPEA法
于100mL反应瓶中依次加入IM2-2(1mmol)、HOBt(1.2mmol)及DCM 3mL,冰浴搅拌溶解,再加入DIPEA(1.5mmol)和DCC(1.5mmol),继续冰浴搅拌约0.5h,加入FQ(1mmol)(成盐的沙星需另加DIPEA1.5mmol中和酸),室温搅拌反应,TLC监测反应进程。反应结束后,减压抽滤,滤饼用DCM(2mL×5)洗涤,合并洗液及滤液,依次用饱和NaHCO3溶液、5%柠檬酸水溶液、饱和NaCl溶液(均为10mL×2)洗涤,无水Na2SO4干燥,减压蒸干得到粗品;柱层析纯化(PE:EA=1:1(体积比)),收集洗脱液,减压蒸干,TLC-紫外荧光和磷钼酸显色法检查纯度,真空干燥,即得TM2。具体合成条件及结果见表7。
表7 DCC/HOBt/DIPEA法制备TM2的实验结果
HY和X结构式中的虚线均表示连接键。
方法三:特戊酰氯法
于100mL反应瓶中加入IM2-2(1.2mmol)和DCM 3mL,室温搅拌,部分溶解,在-3℃的条件下顺次加入DIPEA(1.5mmol)和特戊酰氯(1.5mmol),继续-3℃搅拌约0.5h,加入FQ(1mmol)(成盐的沙星需另加DIPEA 1.5mmol中和酸),-3℃搅拌反应,TLC监测反应进程。反应结束后,减压抽滤,滤饼用DCM(2mL×3)洗涤,收集洗液及滤液,加DCM 10mL,依次用饱和NaHCO3溶液、5%柠檬酸水溶液、饱和NaCl溶液(均为10mL×2)洗涤,无水Na2SO4干燥,减压蒸干得到粗品;柱层析纯化(PE:EA=1:1(体积比)),收集洗脱液,减压蒸干,乙醚重结晶,TLC-紫外荧光和磷钼酸显色法检查纯度,真空干燥,即得TM2。具体合成条件及结果见表8。
表8 特戊酰氯法制备TM2的实验结果
HY和X结构式中的虚线均表示连接键。
TM2系列化合物的表征数据如下:
TM2-1:淡黄色固体,m.p.:146-148℃.1H NMR(600MHz,CDCl3)δ:8.93(1H,s),8.08-8.07(1H,d,J=10.8Hz),7.36-7.31(5H,m),5.79-5.77(1H,d,J=8.4Hz),5.50(1H,s),5.14-5.09(2H,dd,J=12and 19.2Hz),5.00-4.95(1H,d,J=7.2Hz),4.81-4.79(1H,t,J=3and 12.6Hz),4.36(1H,m),4.04-4.01(1H,dd,J=5.4and 9.6Hz),3.97-3.90(1H,m),3.75-3.74(1H,dd,J=5.4and 9.6Hz),3.65-3.62(1H,dd,J=6.6and 9.6Hz),3.38-3.33(3H,m),2.65-2.62(1h,m),2.39-2.33(1H,td,J=4.2,14.4and 28.2Hz),2.04-2.01(2H,m),1.89-1.85(1H,m),1.71-1.59(3H,m),1.53-1.41(5H,m,H-15),1.33-1.32(2H,d,J=5.4Hz),1.27-1.20(4H,m),0.98-0.97(2H,d,J=10.8Hz),0.95-0.94(3H,d,J=6.6Hz),0.90-0.88(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:175.81,167.78,164.90,156.25,154.93,154.574,151.27,142.71,136.87,135.28,135.10,127.54,126.95,123.52,119.51,111.16,107.87,103.14,101.97,95.43,90.22,87.02,79.99,68.54,66.31,59.38,51.54,49.94,43.25,41.91,40.32,36.18,35.40,33.71,29.84,28.68,25.09,23.65,23.27,19.37,13.19,11.92,10.53.HR MS:C43H50ClFN4O11[M+Na]+计算值875.3047,测定值875.3040.
TM2-2:淡黄色固体,m.p.:157-159℃.1H NMR(400MHz,CDCl3)δ8.68(1H,s),8.09-8.06(1H,d,J=12.8Hz),7.34-1.732(5H,m),6.85-6.83(1H,d,J=6Hz),5.75-5.73(1H,d,J=8.8Hz),5.50(1H,s),5.14-5.10(2H,dd,J=12and 17.2Hz),5.07-5.00(1H,d,J=6.8Hz),4.98-4.80(2H,d,J=6.8Hz),4.34-3.58(6H,m),3.4-3.25(4H,m),2.64-2.62(1H,m),2.40-2.32(1H,td,J=2.8,14and 27.6Hz),2.08-2.01(1H,m),1.89-1.86(1H,m),1.72-1.58(6H,m),1.46-1.37(5H,m),1.26-1.19(3H,m),0.95-0.93(3H,d,J=5.6Hz),0.89-0.87(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:178.15,176.29,172.13,166.61,156.02,154.57,150.39,145.81,136.33,134.25,128.63,127.15,122.39,108.30,104.23,91.25,88.16,81.16,68.48,67.13,61.79,55.57,54.71,52.61,51.66,51.26,44.33,41.54,38.89,37.20,36.47,34.73,30.89,29.80,29.35,26.21,24.93,20.50,16.50,15.17,14.26,13.04.HR MS:C42H51FN4O11[M+Na]+计算值829.3436,测定值829.3437.
TM2-3:淡黄色固体,m.p.:150-152℃.1H NMR(400MHz,CDCl3)δ:8.70(1H,s),8.16-8.15(1H,d,J=4Hz),8.13-8.12(1H,d,J=3.6Hz),7.37-7.28(5H,m),5.72-5.70(1H,d,J=8.8Hz),5.49(1H,s),5.15-5.09(2H,m),5.00-4.95(1H,dd,J=6.4and 14.8Hz),4.80-4.79(1H,d,J=3.6Hz),4.44-4.39(2H,q),4.06-3.95(4H,m),3.80-3.73(3H,m),3.65-3.54(2H,m),2.64-2.60(1H,m),2.40-2.32(1H,td,J=3.6,13.6and 28Hz),2.05-2.01(2H,m),1.90-1.84(1H,m),1.68-1.57(3H,m),1.54-1.49(4H,m),1.41(3H,s),1.38-1.18(4H,m),0.94-0.92(3H,d,J=6Hz),0.87-0.85(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:177.74,168.79,166.71,156.04,147.89,147.48,137.49,136.47,135.82,135.66,128.65,127.36,125.63,119.71,117.13,108.86,104.41,104.24,103.03,101.81,88.13,81.14,69.59,68.30,67.16,52.69,46.00,44.40,42.39,38.73,37.65,36.54,35.52,34.85,30.97,27.42,26.22,25.06,24.77,24.37,20.49,13.06,8.38.HR MS:C43H51FN4O11[M+K]+计算值857.3175,测定值857.3000.
TM2-4:淡黄色固体,m.p.:155-157℃.1H NMR(600MHz,CDCl3)δ:14.75(1H,s),8.64(1H,s),8.08-8.06(1H,d,J=12.6Hz),7.46(2H,s),7.39-7.30(7H,m),6.33-6.32(2H,d,J=6,6Hz),5.71-5.70(1H,d,J=9Hz),5.46(1H,s),5.11-5.05(2H,q),4.93-4.90(1H,dd,J=6and H-13.2Hz),4.76-4.75(1H,d,J=1.8Hz)4.03-3.89(3H,m),3.66-3.44(3H,m),3.21-2.97(4H,m),2.62-2.60(1H,m),2.38-2.33(1H,td,J=3.6,14.4and 28.2Hz),2.04-1.96(2H,m),1.87-1.85(1H,m),1.68-1.35(9H,m),1.24-1.19(1H,m),0.94-0.92(1H,d,J=6Hz),0.85-0.84(1H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:177.39,168.70,166.68,164.35,162.67,156.06,154.51,152.84,148.07,145.47,139.26,136.34,136.11,129.18,128.69,128.09,120.42,118.10,112.85,108.87,106.15,104.30,103.12,102.00,88.13,81.08,69.57,68.38,67.22,60.52,52.65,50.97,49.39,45.56,44.35,41.92,37.32,36.52,34.84,30.94,26.22,24.78,21.16,20.49,14.34,13.04.HR MS:C46H50F2N4O11[M+Na]+计算值895.3342,测定值895.3310.
TM2-5:淡黄色固体,m.p.:142-144℃.1H NMR(400MHz,CDCl3)δ:8.64(1H,s),8.01-7.98(1H,d,J=11.4Hz),7.36-7.32(5H,m),5.91-5.74(1H,m),5.57-5.51(1H,m),5.12(2H,s),4.95-4.90(1H,m),4.80-4.77(1H,d,J=5.2Hz),4.50-4.48(2H,m),4.13-3.23(9H,m),2.65-2.62(1H,m),2.53-2.44(1H,m),2.41-2.32(2H,m),2.27-2.19(1H,m),2.07-1.98(1H,m),1.89-1.85(1H,m),1.71-1.67(2H,m,),1.59-1.52(4H,m),1.41-1.36(6H,m),1.26-1.21(2H,m),0.95-0.93(1H,d,J=6.4Hz),0.89-0.88(1H,d,J=5.2Hz).13C NMR(101MHz,CDCl3)δ:177.05,168.72,167.20,156.41,156.08,154.82,152.32,147.49,145.55,137.17,136.31,128.69,121.28,113.25,108.60,104.31,103.13,102.04,96.53,88.16,81.12,69.63,68.43,67.22,64.19,52.61,51.00,49.94,45.69,44.32,42.06,37.32,36.50,34.83,30.95,29.85,26.24,24.78,24.35,20.52,14.68,13.09.HR MS:C43H52F2N4O11[M+H]+计算值839.3680,测定值839.3683.
TM2-6:淡黄色固体,m.p.:151-153℃.1H NMR(600MHz,CDCl3)δ:8.78(1H,s),7.82-7.80(1H,d,J=13.8Hz),7.37-7.28(5H,m),5.90-5.81(1H,m),5.28(1H,s),5.14-4.93(3H,m),4.81-4.50(2H,m),4.08-3.73(6H,m),3.59(3H,s),3.51-3.23(3H,m),2.64-2.62(1H,m),2.41-2.30(2H,m),2.07-2.03(1H,m),1.90-1.85(3H,m),1.73-1.56(6H,m),1.42(3H,s),1.31-1.22(5H,m),1.14-1.08(2H,m),0.96-0.95(3H,d,J=5.4Hz),0.91-0.90(3H,t,J=7.8Hz),0.82-0.81(1H,m).13C NMR(151MHz,CDCl3)δ:176.97,175.08,171.32,170.04,167.18,156.08,149.98,136.41,134.56,128.72,128.40,128.19,107.97,104.32,103.26,101.83,88.18,81.08,68.57,67.24,61.32,60.56,52.69,51.63,44.32,41.73,40.58,38.81,36.56,35.70,34.83,31.01,29.85,26.28,24.79,24.66,24.31,21.18,20.49,14.36,13.05,10.68,8.69.HR MS:C47H57FN4O12[M+H]+计算值889.4036,测定值889.4034.
TM2-7:淡黄色固体,m.p.:149-151℃.1H NMR(600MHz,CDCl3)δ:14.67(1H,s),8.83(1H,s),7.92-7.90(1H,d,J=12Hz),7.40-7.31(5H,m),5.93-5.75(1H,m),5.60-5.21(2H,m),5.12(2H,s),4.97-4.74(2H,m),4.62-3.86(4H,m),3.77-3.18(8H,m),2.63-2.62(1H,m),2.38-2.34(1H,td,J=3.2,14and 28Hz),2.06-1.98(2H,m),1.87-1.85(1H,m),1.73-1.58(3H,m),1.44-1.35(7H,m),1.30-1.23(7H,m,),0.95-0.94(3H,d,J=6Hz),0.91-0.87(3H,m).13C NMR(151MHz,CDCl3)δ:177.20,166.75,156.11,150.34,145.85,139.72,136.44,134.18,129.58,128.72,128.36,108.68,108.29,104.30,103.27,100.17,88.19,81.21,81.07,67.23,63.58,60.56,52.72,44.44,40.54,37.28,36.57,34.84,32.09,30.98,29.86,29.52,26.27,26.24,25.01,24.83,22.85,20.54,14.36,13.09,9.83.HR MS:C45H55FN4O12[M+H]+计算值863.3880,测定值863.3882.
TM2-8:淡黄色固体,m.p.:152-154℃.1H NMR(400MHz,CDCl3)δ:8.82(1H,s),8.15(1H,s),8.01(1H,s),7.36-7.30(4H,m),5.76-5.74(1H,d,J=8.8Hz),5.51(1H,s),5.11(2H,s),5.01-4.96(1H,dd,J=6and H-14.4Hz),4.81-4.80(1H,d,J=3.2Hz),4.15(8H,m),3.56-3.06(4H,m),2.67-2.59(1H,m),2.40-2.32(1H,td,J=3.2,14and 28Hz),2.06-2.01(2H,),1.89-1.84(1H,m),1.72-1.58(4H,m),1.45-1.42(6H,m),1.24-1.19(3H,m),0.95-0.93(3H,d,J=6.4Hz),0.89-0.88(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:177.74,168.67,166.83,155.98,147.91,147.44,137.46,136.46,128.69,128.19,125.58,119.72,117.11,108.79,104.28,103.03,88.10,81.16,69.62,67.20,64.83,52.61,51.76,51.26,50.92,45.98,44.32,42.32,37.28,36.48,35.55,34.80,30.95,26.28,24.75,24.37,20.56,13.13,8.4.HR MS:C41H50FN5O11[M+H]+计算值808.3570,测定值808.3566.
TM2-9:淡黄色固体,m.p.:130-132℃.1H NMR(400MHz,CDCl3)δ:8.82(1H,s),7.97-7.86(1H,m),7.35-7.30(5H,m),5.80-5.60(1H,m),5.47-5.39(1H,m),5.13-5.03(2H,m),4.97-4.90(1H,m),4.80-4.75(1H,m),4.67-4.57(1H,m),4.05-3.97(2H,m),3.85-3.83(3H,m),3.66-3.18(4H,m),3.10(3H,s,H-27),2.96-2.90(1H,m),2.65-2.59(1H,m),2.41-2.29(1H,m),1.90-1.84(4H,m),1.78-1.55(5H,m),1.46-1.39(5H,m),1.35-1.17(7H,m),0.94-0.86(6H,m).13C NMR(151MHz,CDCl3)δ:177.18,170.22,167.01,166.96,157.44,155.92,150.07,139.49,136.30,133.89,128.68,127.69,108.43,107.81,104.32,103.16,102.55,88.08,81.10,69.72,69.32,67.14,66.88,64.84,62.55,62.50,60.60,54.32,52.57,51.67,44.29,40.78,37.35,36.47,34.81,30.93,29.86,27.77,27.34,26.27,26.24,25.67,24.76,20.53,13.05,9.53.HR MS:C46H57FN4O12[M+H]+计算值877.4036,测定值877.4037.
实施例3.目标化合物TM5系列及其中间体的合成
3.1中间体IM5-4的合成
IM5-1的多次制备实验结果见表9。以表9中Entry 1为例,制备方法如下:于100mL反应瓶中加入CH3OH 20mL,冰浴条件下搅拌滴加SOCl2(1mL,13.8mmol),继续冰浴搅拌0.5h,加入L-Ser(1.056g,10mmol),冰浴搅拌10min,转入70℃水浴回流反应,TLC-茚三酮显色法监测反应进程。反应结束后,减压旋蒸,加CH3OH 5mL搅拌,减压蒸干,加EtOAc 10mL搅拌,减压抽滤,滤饼用EtOAc(2mL×3)洗涤,TLC-茚三酮显色法检查纯度,真空干燥,得白色粉末状固体IM5-1,低温保存。
表9 制备IM5-1的实验结果
IM5-2的多次制备实验结果见表10。以表10中Entry 1为例,制备方法如下:于100mL反应瓶中依次加入IM5-1(1.388g,8.92mmol)、DCM 25mL及三乙胺(Et3N)(2.5mL,18mmol),搅拌溶解,冰浴冷却,滴加CH3COCl(0.7mL,9mmol),冰浴继续反应,TLC-茚三酮显色法监测反应进程。反应结束后,减压旋蒸(除去未反应完的CH3COCl和DCM),加DCM 5mL搅拌,减压蒸干,加EtOAc 15mL搅拌,减压抽滤,滤饼用EtOAc(2mL×3)洗涤,收集滤液和洗液,减压蒸干得到粗品;柱层析纯化(以CH3OH-DCM混合溶剂为洗脱剂),收集洗脱液,减压蒸干,TLC-茚三酮显色法检查纯度,真空干燥,得黄色油状液体IM5-2,低温保存。
表10 制备IM5-2的实验结果
*原料未完全反应,柱层析回收IM5-1 0.764g.
IM5-3的多次制备实验结果见表11。以表11中Entry 1为例,制备方法如下:于100mL反应瓶中依次加入DHA(1mmol)、IM5-2(1.2mmol)及Et2O 5mL,室温搅拌部分溶解,控温加入BF3·Et2O 0.2mL,控温继续搅拌反应,TLC-磷钼酸显色法监测反应进程。反应结束后,加饱和NaHCO3溶液15mL,Et2O 20mL,静置分层,收集有机相,依次用5%柠檬酸水溶液、饱和NaCl溶液(10mL×2)洗涤,无水Na2SO4干燥,减压蒸干得到粗品;柱层析纯化(CH3OH:DCM=1:9(体积比)),收集洗脱液,减压蒸干,TLC-磷钼酸显色法检查纯度,真空干燥,得微黄色油状液体IM5-3,低温保存。
表11 制备IM5-3的实验结果
IM5-4的多次制备实验结果见表12。以表12中Entry 1为例,制备方法如下:于100mL反应瓶中加入IM5-3(7mmol)、MeOH-H2O(体积比3:1)(40mL),冰浴搅拌溶解,分批加入LiOH·H2O(35mmol),继续冰浴搅拌10min,撤去冰浴,23~27℃搅拌反应,TLC-磷钼酸显色法监测反应进程。反应结束后,减压旋蒸(除去CH3OH),Et2O(20mL×2)萃取,收集水相;有机相用H2O(15mL×2)洗涤,收集水相;合并水相,2N HCl调节pH至3~4,析出大量白色固体,减压抽滤,滤饼用H2O(5mL×3)洗涤,TLC-磷钼酸显色法检查纯度,室温敞放一天,真空干燥,得白色晶状固体IM5-4,m.p.165-167℃,低温保存。
表12 制备IM5-4的实验结果
3.2目标化合物TM5系列的合成
于100mL反应瓶中加入IM5-4(1.2mmol)和DCM 3mL,-3℃搅拌,部分溶解,顺次加入DIPEA(1.5mmol)和特戊酰氯(1.5mmol),-3℃搅拌;与此同时,将FQ(1mmol)溶解在DCM 3mL中(成盐的沙星需另加DIPEA 1.5mmol中和酸),冰浴搅拌10-30min;两液合并,-3℃搅拌反应,TLC监测反应进程。反应结束后,减压抽滤,滤饼用DCM(2mL×3)洗涤,收集洗液及滤液,加DCM 10mL,依次以饱和NaHCO3溶液、5%柠檬酸水溶液、饱和NaCl溶液(10mL×2)洗涤,无水Na2SO4干燥,减压蒸干得粗品;柱层析纯化(PE:EA=1:1(体积比)),收集洗脱液,减压蒸干,乙醚重结晶,TLC-紫外荧光和磷钼酸显色法检查纯度,真空干燥,即得TM5。具体合成条件及结果见表13。
表13 制备TM5的实验结果
HY和X结构式中的虚线均表示连接键。
*Entry 1克林沙星回收0.238g;Entry 7加替沙星回收0.178g;Entry 8依诺沙星回收0.064g;Entry 9巴洛沙星回收0.187g;收率是扣除回收原料之后计算的实际收率。
TM5系列化合物的表征数据如下:
TM5-1:淡黄色固体,m.p.:164-166℃.1H NMR(400MHz,CDCl3)δ:8.93(1H,s),8.08-8.05(1H,d,J=11.2Hz),6.68-6.63(1H,t,J=7.6Hz),5.50(1H,s),5.27-5.19(1H,m),4.80-4.78(1H,d,J=3.6Hz),4.38-4.35(1H,m),4.03-4.00(1H,dd,J=5.6and 10Hz)3.76-3.73(1H,dd,J=4.8and 10Hz),3.70-3.66(1H,dd,J=9and 10.4Hz),3.40(4H,m),2.67-2.63(1H,m),2.41-2.33(1H,td,J=3.6,14and 28Hz),2.10-1.98(5H,m),1.91-1.86(1H,m),1.75-20(13H,m),1.39-1.22(4H,m),0.99-0.85(9H,m).13C NMR(151MHz,CDCl3)δ:176.75,169.75,168.76,165.93,157.12,155.44,152.19,143.64,137.80,124.30,112.03,108.69,104.18,102.86,101.92,87.93,80.94,69.40,68.29,52.41,48.71,46.53,44.11,42.83,41.30,37.52,37.22,36.29,34.63,30.76,26.08,24.60,24.21,23.21,20.43,13.00,11.48.HR MS:C37H46ClFN4O10[M+Na]+计算值783.2784,测定值783.2795.
TM5-2:淡黄色固体,m.p.:170-172℃.1H NMR(400MHz,CDCl3)δ:8.68(1H,s),8.05-8.01(1H,dd,J=2.8and 12.8Hz),7.29,6.86-6.85(1H,d,J=6..8Hz),6.76-6.71(1H,t,J=8.4Hz),5.50(1H,s),5.31,-5.22(2H,m),4.80-4.78(1H,t,J=4Hz),4.38-4.33(2H,q),4.20-3.98(3H,m),3.82-3.62(2H,m),3.55-3.18(4H,m),2.68-2.61(1H,m),2.40-2.32(1H,td,J=7.6,14.4and 32Hz),2.14-1.98(5H,m),1.91-1.87(1H,m),1.75-1.22(13H,m),0.97-0.96(3H,d,J=6Hz),0.91-0.89(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:176.95,169.88,168.73,167.01,154.27,152.60,147.33,145.44,137.02,121.21,112.95,108.51,104.19,102.96,102.08,88.01,80.93,69.39,68.39,52.45,49.77,48.73,45.61,44.15,41.97,37.25,36.34,34.70,30.78,26.09,24.64,24.17,23.16,20.41,14.53,13.00,10.57.HR MS:C36H47FN4O10[M+H]+计算值715.3355,测定值715.3350.
TM5-3:淡黄色固体,m.p.:167-169℃.1H NMR(400MHz,CDCl3)δ:8.73(1H,s),8.08(1H,s),7.96-7.94(1H,d,J=10.8Hz),6.64-6.61(1H,t,J=7.2and 15.2Hz),5.43(1H,s),5.25-5.13(1H,m),4.72-4.70(1H,d,J=3.2Hz),4.07-3.66(5H,m),3.63-3.52(2H,m),3.17-3.04(4H,m),2.58-2.54(1H,m),2.33-2.25(1H,td,J=3.6,14.4and 28Hz),2.13-1.78(7H,m),1.68-1.64(1H,m),1.59-1.55(1H,m),1.50-1.26(8H,m),1.21-1.15(3H,m),0.90-0.88(3H,d,J=6.4Hz),0.84-0.82(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:177.60,169.68,168.72,166.59,147.77,147.30,137.35,136.32,125.50,119.54,117.04,108.75,104.15,102.90,87.98,80.97,69.46,52.51,51.69,51.10,48.81,45.89,44.20,42.24,37.24,36.37,35.37,34.70,30.81,26.10,24.64,24.23,23.19,20.42,13.02,8.29.HR MS:C37H47FN4O10[M+K]+计算值765.2913,测定值765.3000.
TM5-4:淡黄色固体,m.p.:191-193℃.1H NMR(400MHz,CDCl3)δ:8.64(1H,s),8.08-8.05(1H,d,J=18.6Hz),7.46-7.36(4H,m),6.62-6.61(1H,d,J=7.2Hz),6.33-6.31(1H,d,J=6Hz),5.46(1H,s),5.25-5.16(1H,m),4.75(1H,d,J=2.8Hz),4.09-2.97(10H,m),2.63-2.61(1H,m,H-11),2.40-2.32(1H,td,J=3.2,14and 27.6Hz),2.13-2.01(4H,m),1.90-1.86(1H,m),1.69-1.56(3H,m),1.45-1.23(8H,m,),0.96-0.94(3H,d,J=6Hz),0.87-0.85(3H,d,J=7.2Hz).13C NMR(151MHz,CDCl3)δ:177.29,166.74,164.19,162.51,154.38,152.71,148.02,145.29,139.10,135.88,129.13,120.31,118.07,112.74,108.66,106.09,104.25,102.97,102.03,87.99,80.94,69.36,56.27,52.43,48.68,45.53,44.11,41.87,39.32,37.26,36.33,34.67,30.76,29.50,26.12,24.63,23.19,20.46,13.04,11.05.HRMS:C40H46F2N4O10[M+H]+计算值781.3261,测定值781.3250.
TM5-5:淡黄色固体,m.p.:154-156℃.1H NMR(600MHz,CDCl3)δ:14.57(1H,s),8.64(1H,s),7.97-7.96(1H,d,J=3.6Hz),6.82-6.75(1H,m),5.56-5.50(1H,m),5.28-5.14(1H,m),4.82-4.78(1H,d,J=17.4Hz),4.52-4.50(2H,m),4.14-3.78(3H,m),3.69-3.16(6H,m),2.65-2.64(1H,m),2.39-2.34(1H,m),2.08-2.05(4H,m),1.90-1.88(1H,m),1.79-1.20(17H,m),0.96-0.90(6H,m).13C NMR(151MHz,CDCl3)δ:176.26,169.73,168.51,166.53,154.58,150.35,145.80,128.37,127.16,108.29,104.25,103.38,102.42,87.97,81.10,77.41,77.20,76.99,69.58,68.49,54.70,52.55,49.77,45.63,44.30,41.60,37.67,37.29,36.44,34.72,30.87,26.18,24.74,24.36,20.48,16.48,15.35,13.09.HR MS:C37H48F2N4O10[M+H]+计算值747.3418,测定值747.3420.
TM5-6:淡黄色固体,m.p.:161-163℃.1H NMR(400MHz,CDCl3)δ:8.78(1H,s),7.82-7.78(1H,d,J=13.6Hz),6.78-6.76(1H,d,J=8Hz),5.31-5.18(2H,m),5.10-5.04(1H,dd,J=8.4and 15.6Hz),4.79-4.78(1H,d,J=2.8Hz),4.30-3.92(4H,m),3.86-3.81(1H,t,J=10Hz),3.75-3.72(1H,dd,J=3.2and 9.6Hz),3.60(3H,s),3.51-3.46(1H,t,J=9.2Hz),3.42-3.35(1H,t),3.29-3.23(1H,t,J=12Hz),2.66-2.63(1H,m),2.43-2.33(2H,m),2.05(3H,s),1.93-1.91(3H,m),1.78-1.56(4H,m),1.51-1.39(5H,m),1.33-1.23(6H,m),1.16,-1.09(2H,m),0.99-0.84(7H,m).13C NMR(151MHz,CDCl3)δ:182.06,176.77,169.69,166.98,154.48,152.82,149.81,141.13,136.99,134.37,119.01,107.75,104.17,101.68,87.87,80.98,68.35,61.13,56.30,52.42,51.42,49.70,48.25,41.60,40.31,37.79,36.34,35.56,34.64,30.78,27.11,26.12,25.40,25.02,24.15,23.27,20.34,12.86,10.63,8.54.HR MS:C41H53FN4O11[M+H]+计算值797.3774,测定值797.3772.
TM5-7:淡黄色固体,m.p.:134-136℃.1H NMR(400MHz,CDCl3)δ:8.83(1H,s),7.91-7.89(1H,d,J=12Hz),7.00-6.98(1H,d,J=8.4Hz),5.57-5.49(1H,m),5.36-5.18(1H,m),4.79-4.78(1H,d,J=3.2Hz),4.70-4.53(1H,m),4.44-4.23(1H,m),4.02-3.97(2H,m),3.78-3.64(4H,m),3.58-3.12(5H,m),2.67-2.62(1H,m),2.41-2.33(1H,td,J=3.2,14and27.6Hz),2.09-2.02(4H,m),1.91-1.87(1H,m),1.80-1.57(4H,m),1.49-1.34(8H,m),1.27-1.26(3H,d,J=4.4Hz),1.24(3H,s),0.98-0.96(3H,d,J=5.6Hz),0.91-0.90(3H,d,J=5.6Hz).13C NMR(151MHz,CDCl3)δ:183.20,177.00,169.83,166.60,150.20,139.60,134.03,108.06,104.15,103.40,88.03,81.00,69.61,63.55,55.03,52.47,51.05,49.28,45.73,44.19,41.60,40.38,38.46,37.15,36.36,34.63,30.85,29.70,27.07,26.09,24.64,23.13,20.45,16.92,15.49,14.12,12.99,9.53.HR MS:C39H51FN4O11[M+H]+计算值771.3617,测定值771.3619.
TM5-8:淡黄色固体,m.p.:173-175℃.1H NMR(400MHz,CDCl3)δ:8.73(1H,s),8.18-8.15(1H,d,J=13.2Hz),6.80-6.78(1H,d,J=13.2Hz),5.49,(1H,s),5.31-5.23(1H,m),4.80-4.79(1H,d,J=3.6Hz),4.46-4.40(2H,q),4.15-3.97(5H,m),3.81-3.66(4H,m),3.60-3.49(1H,m),2.66-2.62(1H,m),2.41-2.33(1H,td,J=3.2,14and 28Hz),2.07-2.02(7H,m),1.98-1.87(1H,m),1.73-1.65(2H,m),1.53-1.50(3H,t,J=7.2Hz),1.43(3H,s),1.37-1.33(2H,m),1.27-1.24(1H,m),0.97-0.95(3H,d,J=6.4Hz),0.89-0.88(3H,d,J=7.2Hz).13C NMR(101MHz,CDCl3)δ:177.26,170.27,169.30,167.02,150.62,148.78,146.90,145.04,120.80,109.61,104.38,103.05,88.14,81.07,69.35,52.57,48.87,48.01,46.86,45.58,44.24,42.03,37.40,36.46,34.83,30.89,26.25,24.78,24.31,23.27,21.24,20.60,15.23,13.17.HR MS:C35H46FN5O10[M+H]+计算值716.3311,测定值716.3308.
TM5-9:淡黄色固体,m.p.:164-166℃.1H NMR(600MHz,CDCl3)δ:14.75-14.68(1H,m),8.81(1H,s),7.90-7.86(1H,t,J=12Hz),6.61-6.36(1H,m),5.48-5.44(1H,m),5.32-5.14(1H,m),4.78-4.75(1H,m),4.66-4.61(1H,m),4.29-4.01(2H,m),4.00-3.81(3H,m),3.68-3.10(7H,m),2.96-2.91(1H,m),2.64-2.62(1H,m),2.39-2.31(1H,m),2.07-1.57(13H,m),1.50-1.31(5H,m),1.25-1.16(4H,m),1.05-1.03(1H,m),0.99-0.85(6H,m),0.77-0.71(1H,m).13C NMR(151MHz,CDCl3)δ:177.20,170.43,169.73,166.90,150.07,139.50,133.92,108.44,107.94,104.35,103.28,102.15,88.08,81.08,70.09,69.80,68.37,66.02,62.56,54.41,52.62,52.05,51.44,49.63,44.33,44.27,40.76,37.40,36.51,34.90,30.94,28.63,27.85,27.39,26.24,24.81,24.39,23.41,20.55,15.45,13.12,9.85.HR MS:C40H53FN4O11[M+Na]+计算值807.3587,测定值807.3575.
实施例4.目标化合物TM1、TM2、TM5系列及其中间体的生物活性测试
4.1抗结核活性测试
目标化合物TM1、TM2、TM5系列及其中间体的抗结核活性由美国礼来公司OpenInnovation Drug Discovery(OIDD)program按照如下流程进行测试:首先测试单浓度样品对结核分枝杆菌(H37Rv)的百分抑制率(Primary SP),对初步筛选出的潜力分子进行多浓度测试(Primary CRC),然后进行复筛(Secondary),采用CellTiter-Glo试剂测试化合物对宫颈癌细胞HELA活力的影响(细胞毒性)。结果见表14。
表14 目标化合物及其中间体的抗结核活性测试结果
从表14可以看出,在20μM样品测试浓度下,TM1、TM2、TM5系列目标化合物对结核分枝杆菌均表现出一定的抑制活性(25.3%~98.3%),其中有8个化合物(TM1-1、TM1-6、TM2-9、TM5-1、TM5-2、TM5-4、TM5-6和TM5-7)的抑制活性超过80%,活性排名前三的化合物依次为TM5-1(98.3%)、TM1-1(97.9%)、TM5-6(91.3%);除TM5-5外所有目标化合物的抑制活性都强于DHA。构效关系初步分析如下:
1)不同氟喹诺酮药物母体对目标化合物抗结核活性的影响:TM1、TM2、TM5三个系列中编号1-9的化合物对应的氟喹诺酮药物母体分别为克林沙星(CF)、诺氟沙星(NFLX)、环丙沙星(CPFX)、沙拉沙星(SFLX)、洛美沙星(LFLX)、莫西沙星(MXFX)、加替沙星(GTFX)、依诺沙星(ENX)、巴洛沙星(BLFX)。当Linker相同时,TM1和TM5系列目标化合物中抗结核活性较强的是编号为1、6和7的化合物,即DHA与CF、MXFX或GTFX的偶联物;TM2系列目标化合物中抗结核活性较强的是编号为9、1和7的化合物,即DHA与BLFX、CF或GTFX的偶联物。
2)不同Linker修饰对目标化合物抗结核活性的影响:TM1、TM2、TM5三个系列对应的Linker分别为氨基被叔丁氧羰基(Boc)、苄氧羰基(Cbz)、乙酰基(Ac)保护的L-丝氨酸。当氟喹诺酮药物母体相同时,L-丝氨酸上氨基保护基的抗结核活性大约为Ac>Boc>Cbz(当沙星母体为洛美沙星或巴洛沙星时例外,Cbz修饰的抗结核活性最强),抗结核活性较强的目标化合物主要是以Ac保护的L-丝氨酸为Linker的TM5系列,说明以空间位阻较小的Ac保护氨基酸作Linker更有利于提高偶联物的抗结核活性。另外,当氟喹诺酮药物母体为莫西沙星时,Cbz修饰(TM2-6的活性仅为36.9%)相比Boc、Ac修饰(TM1-6、TM5-6的活性分别为87.4%、91.3%)使目标化合物的抗结核活性大大降低。
4.2对部分革兰阳性菌和革兰阴性菌的抑菌活性测试
长期使用氟喹诺酮药物易造成菌群失调和细菌耐药,理想的抗结核喹诺酮药物的抗菌谱应窄,最好仅对结核分枝杆菌起作用。
本试验以铜绿假单胞菌(P.aeruginosa)PS1.0050、金黄色葡萄球菌(S.aureus)ATCC29213和大肠杆菌(E.coli)临床分离株作为指示菌,采用琼脂扩散法中的打孔法对目标化合物及其中间体进行了抑菌活性检测,同时设置双氢青蒿素和对应的氟喹诺酮药物为对照,三种菌株接种量均为106CFU/mL,测试化合物浓度均为0.1μg/μL,37℃培养18小时后测量抑菌圈的直径。结果见表15。
表15 目标化合物及其中间体对部分革兰阳性菌和革兰阴性菌的抑菌圈直径(mm)
“--”表示抑菌圈小于3mm。
从表15可以看出,除诺氟沙星和环丙沙星外的7个氟喹诺酮药物对3种测试菌株均表现出良好的抗菌活性,而双氢青蒿素及目标化合物TM1、TM2、TM5系列对3种测试菌株均没有表现出较好的抗菌活性,说明双氢青蒿素-氟喹诺酮偶联物的抗菌活性低于氟喹诺酮药物本身,也说明了目标化合物TM1、TM2、TM5系列对结核分枝杆菌具有良好的选择性抑制作用。
4.3降血脂靶点PCSK9抑制活性研究
PCSK9是由肝脏合成的蛋白酶,该酶经分子内自身催化切开后分泌入血,与肝细胞表面低密度脂蛋白受体(LDL-R)结合,促进LDL-R降解,致使低密度脂蛋白胆固醇(LDL-C)水平升高。PCSK9抑制剂被认为是继他汀类药物后的新一代降脂药物,其中获益最大的是在强化降脂治疗后LDL-C仍无法达标的高风险冠心病患者和无法耐受大剂量他汀类药物治疗的高胆固醇血症患者。
目标化合物TM1、TM2、TM5系列及其中间体的PCSK9抑制活性由美国礼来公司OpenInnovation Drug Discovery(OIDD)program按照如下流程进行测试:首先进行单浓度初筛(Primary SP),采用AlphaLisa方法测试化合物对肝癌细胞HuH7分泌PCSK9的百分抑制率,并采用CellTiter-Glo试剂测试化合物对肝癌细胞Huh7活力的影响(细胞毒性);对初步筛选出的潜力分子进行多浓度测试(Primary CRC);然后进行复筛(Secondary),采用ELISA法检测24小时处理后Huh7细胞ApoA-I蛋白表达抑制。结果见表16。
表16 目标化合物及其中间体的PCSK9抑制活性测定结果
从表16可以看出,TM1、TM2、TM5系列中大多数化合物对PCSK9均有一定的抑制作用,其中有5个化合物(TM1-4、TM1-5、TM2-4、TM2-5、TM2-9)在10μM测试浓度下的PCSK9AlphaLisa Huh7抑制活性超过80%,对PCSK9表现出良好的抑制作用;部分化合物(TM1-7,TM2-3,TM2-5)不仅对PCSK9的抑制作用较强,而且在5μM测试浓度下的PCSK9Huh7Viability CellTiter-Glo抑制活性低于30%,显示较低的细胞毒性。此外,高活性、低毒性的分子,其相对IC50(Rel IC50)值很低,具有潜在的成药性。本发明是首次发现L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物具有PCSK9抑制活性。
实施例5.目标化合物TM1、TM2、TM5系列的毒性预测
采用美国Simulations Plus公司开发的ADMET-Predictor 6.0软件预测目标化合物TM1、TM2、TM5系列的毒性,结果见表17。各项参数的安全范围如下:-2.5≤MlogP≤4.15;TOX hERG≤6.0;TOX BRM Rat≥4;TOX BRM Mouse≥25;TOX MUT Risk≤2;TOX Risk≤3.0。
表17 目标化合物的毒性预测
从表17可以看出,TM1、TM2和TM5系列目标化合物的脂水分配系数、心脏毒性、大鼠肿瘤毒性、小鼠肿瘤毒性、致突变性均处于安全范围内,毒性风险系数小。
最后说明的是,以上优选实施例仅用以说明本发明的技术方案而非限制,尽管通过上述优选实施例已经对本发明进行了详细的描述,但本领域技术人员应当理解,可以在形式上和细节上对其作出各种各样的改变,而不偏离本发明权利要求书所限定的范围。
Claims (9)
8.权利要求1至5任一项所述L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其药学上可接受的盐在制备抗结核分枝杆菌的药物中的应用。
9.权利要求1至5任一项所述L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物或其药学上可接受的盐在制备降血脂的药物中的应用。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910786502.4A CN110467627B (zh) | 2019-08-23 | 2019-08-23 | L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201910786502.4A CN110467627B (zh) | 2019-08-23 | 2019-08-23 | L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN110467627A CN110467627A (zh) | 2019-11-19 |
CN110467627B true CN110467627B (zh) | 2023-02-28 |
Family
ID=68512168
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201910786502.4A Active CN110467627B (zh) | 2019-08-23 | 2019-08-23 | L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN110467627B (zh) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN112094279B (zh) * | 2020-09-25 | 2022-11-18 | 西南大学 | 对氨基水杨酸双氢青蒿素类衍生物及其制备方法和应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104418864A (zh) * | 2013-08-30 | 2015-03-18 | 西南大学 | 双氢青蒿素与喹诺酮类化合物的偶联物及其制备方法和应用 |
CN109096278A (zh) * | 2018-09-26 | 2018-12-28 | 西南大学 | 氟喹诺酮-氮唑杂合衍生物、制备方法及其用途 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11365202B2 (en) * | 2018-04-16 | 2022-06-21 | Council Of Scientific And Industrial Research | Antimalarial compounds, process for preparation and their use for drug resistant malaria |
-
2019
- 2019-08-23 CN CN201910786502.4A patent/CN110467627B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN104418864A (zh) * | 2013-08-30 | 2015-03-18 | 西南大学 | 双氢青蒿素与喹诺酮类化合物的偶联物及其制备方法和应用 |
CN109096278A (zh) * | 2018-09-26 | 2018-12-28 | 西南大学 | 氟喹诺酮-氮唑杂合衍生物、制备方法及其用途 |
Non-Patent Citations (2)
Title |
---|
Design, synthesis, and biological evaluation of dihydroartemisinin-fluoroquinolone conjugates as a novel type of potential antitubercular agents;Fu-Wei Zhou,等;《Bioorganic & Medicinal Chemistry Letters》;20141231;第24卷(第8期);1912-1917 * |
Quinoline Derivatives with Potential Activity Against Multidrug‐resistant Tuberculosis;Bi Liu,等;《Journal of Heterocyclic chemistry》;20181231;第55卷(第8期);1863-1873 * |
Also Published As
Publication number | Publication date |
---|---|
CN110467627A (zh) | 2019-11-19 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2796750C (en) | Novel hydroxamic acid derivative | |
US8765965B2 (en) | 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylic acid of the formula P-6 and/or methyl 1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate of the formula P-7 | |
CN103764637A (zh) | 卡巴他赛的固态形式及其制备方法 | |
EP3356361B1 (en) | Hydroxyalkyl thiadiazole derivatives | |
CN110467627B (zh) | L-丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 | |
Augustin et al. | C-Glycoside analogues of β-galactosylceramide with a simple ceramide substitute: Synthesis and binding to HIV-1 gp120 | |
CN112125914B (zh) | 5-取代的小檗胺衍生物,其制备方法和应用 | |
CN109942665B (zh) | 雷公藤内酯醇衍生物及其制备方法和应用 | |
CN110498806B (zh) | L-苏氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 | |
CN110407851B (zh) | L-高丝氨酸连接的双氢青蒿素-氟喹诺酮偶联物及其中间体、制备方法与用途 | |
WO2003068736A2 (en) | Mixed steroidal 1,2,4,5-tetraoxane compounds and methods of making and using thereof | |
EP4194454A1 (en) | Heterocyclic compound as bcl-2 inhibitor | |
CN106349180B (zh) | 4,5-二苯基异噁唑衍生物及其制备方法和应用 | |
CN114805454B (zh) | α-半乳糖神经酰胺类化合物及其制备方法和用途 | |
CN110496126B (zh) | 双氢青蒿素与喹诺酮偶联物在制备降血脂药物中的应用 | |
WO2017100153A1 (en) | Therapeutic compounds | |
CN110437264B (zh) | 高喜树碱5,6-二溴去甲斑蝥素酸酯衍生物及其区域选择性合成方法 | |
CA3056571C (en) | N-phosphonoxymethyl prodrugs of hydroxyalkyl thiadiazole derivatives | |
NO178729B (no) | Terapeutisk aktive sukkerderivater | |
CN116217582A (zh) | 一种鹤氏唐松草碱衍生物及应用 | |
IT201900012888A1 (it) | Inibitori della antibiotico-resistenza mediata da ArnT |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |