CN108129364B - 一种双苯环类化合物、其制备方法和医药用途 - Google Patents
一种双苯环类化合物、其制备方法和医药用途 Download PDFInfo
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- CN108129364B CN108129364B CN201711097889.XA CN201711097889A CN108129364B CN 108129364 B CN108129364 B CN 108129364B CN 201711097889 A CN201711097889 A CN 201711097889A CN 108129364 B CN108129364 B CN 108129364B
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- C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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- C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
- C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
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Abstract
本发明涉及一种双苯环类化合物、其制备方法和医药用途，属于药物化学领域。本发明还涉及该类化合物的制备方法以及含有它们的药物组合和用途。该类化合物具有抗纤维化的作用，可应用于制备与抗纤维化有关疾病的药物方面。
Description
技术领域
本发明涉及药物化学和药物治疗学领域，具体涉及一类双苯环类化合物。该类化合物具有抗纤维化的作用。本发明还涉及该类化合物的制备方法以及含有它们的药物组合。
背景技术
目前人们在研究治疗纤维化疾病的策略时，星状细胞(stellate cell)得到了广泛的关注。星状细胞是一种特殊的间质细胞，在组织产生炎症或损伤时，星状细胞被激活，表达纤维化相关基因，导致细胞外基质(extracellular matrix,ECM)大量沉积。研究表明，星状细胞的过度激活是肝纤维化、胰腺纤维化等纤维化疾病的重要原因。
Ronald M.Evans于2013年首次提出维生素D受体(vitamin D receptor，VDR)激动剂可逆转星状细胞的激活状态，抑制肝纤维化及胰腺纤维化的进程。VDR是一种核转录因子，属于核受体超家族的一员，广泛存在于人体各组织细胞中，其主要存在于骨骼、肾脏、结肠、前列腺、乳腺、免疫系统、皮肤等组织器官。VDR的天然内源性配体，1,25(OH)2D3，可通过与VDR结合，进而激活VDR发挥多种生物学效应。
1,25(OH)2D3具有甾体结构，具有很强的活性和广泛的生理功能。但是由于其能够与血液中的维生素D结合蛋白(vitamin D binding protein,DBP)相结合，使化合物半衰期得到延长，长期给药会造成血钙升高，对神经肌肉系统、心血管系统、胃肠系统、泌尿系统和骨骼系统造成损害，被称为高钙血症(hypercalcemia)。此副作用也成为限制1,25(OH)2D3在临床上广泛应用的关键问题。
为了降低此类药物的副作用，许多非甾体类的VDR激动剂被研发出来，并发现其能够在保持VDR激动活性的同时，不具备明显的升血钙作用。鉴于纤维化疾病的复杂性，本领域仍需研发高效的VDR激动剂。
发明内容
本发明的目的是在现有技术的基础上，提供一系列双苯环类化合物。药效学实验表明，本发明的化合物对VDR受体有较强亲和力，对正常细胞毒性较低，且能在体内及体外有效抑制纤维化的形成，并且其升血钙的能力非常弱，可以用于治疗多种纤维化及相关性疾病。
本发明的另一目是提供一种上述双苯环类化合物的制备方法。
本发明的第三个目的是提供一种上述双苯环类化合物在医药方面的用途。
本发明的目的可以通过以下措施达到：
式I所示的双苯环类化合物或其药学上可接受的盐，
其中，
R1或R2分别独立地代表氢、C1～5烷基、C1～5卤代烷基或R1、R2一起形成取代或非取代的3至8元杂脂环基；
L代表-(CH2)n-、-O(CH2)n-或-NH(CH2)n-基团；
n代表0-8的整数；
R3代表氢、羟基、羧基、取代或非取代的C1～8烷基、
p代表0～3的整数；
R5代表氢、羟基、C1～6烷基、C1～6烷氧基、苯基取代的C1～4烷基或者取代或非取代的苯基；
R6、R7或R8分别独立代表氢、C1～6烷基、苯基取代的C1～6烷基、羟基取代的C1～6烷基、C1～6烷氧基、C3～6环烷基或者取代或非取代的苯基；
M代表-(CH2)m-、-O(CH2)m-或-NH(CH2)m-基团；
m代表0-8的整数；
R4代表氢、羟基、羧基、取代或非取代的C1～8烷基、
q代表0～3的整数；
R9代表氢、羟基、C1～6烷基、C1～6烷氧基、苯基取代的C1～4烷基或者取代或非取代的苯基；
R10、R11或R12分别独立代表氢、C1～6烷基、苯基取代的C1～6烷基、羟基取代的C1～6烷基、C1～6烷氧基、C3～6环烷基或者取代或非取代的苯基；
所述取代或非取代的C1～8烷基或取代或非取代的苯基中的取代基，分别独立的选自羟基、卤素、C1～6烷基、C1～6烷氧基或硝基中的一种或多种。
在一种方案中，R1或R2分别独立地代表C1～3烷基，优选代表甲基、乙基、正丙基或异丙基。
在一种方案中，L代表-O(CH2)n-基团，n代表0-7的整数，优选地，n代表0-6的整数。
在另一种方案中，R3代表氢、羟基、羧基、C1～6烷基、
优选地，R3代表氢、羟基、羧基、C1～5烷基、
进一步的，p代表0～2的整数，p优选代表0或1；C1～5烷基优选代表甲基、乙基、正丙基，正丁基或叔丁基，更优选地，C1～5烷基代表正丁基或叔丁基。
更一步的，R5代表C1～4烷基、C1～4烷氧基、苯基或者取代苯基，其取代基选自卤素、C1～4烷基或硝基中的一种或多种。
再一步的，R5优选代表C1～3烷基、苯基或者取代苯基，其取代基选自卤素、C1～3烷基或硝基中的一种或多种。
更一步的，R5更优选代表C1～3烷基、苯基、C1～3烷基取代的苯基。
在一种方案中，R6代表C1～6烷基、C1～6烷氧基、苯基或取代的苯基，其取代基选自卤素、C1～4烷基或硝基中的一种或多种。
在一种优选方案中，R6代表C1～5烷基、C1～4烷氧基或苯基。
在一种更优选方案中，R6代表正丁基、叔丁基、甲氧基、乙氧基或苯基。
在一种方案中，R7或R8分别独立代表氢、C1～6烷基或苯基。
在一种优选方案中，R7或R8优选分别独立代表氢或C1～5烷基。
在一种更优选方案中，R7代表氢，R8代表C1～5烷基。
在一种方案中，M代表-O(CH2)m-基团；m代表0-7的整数。
在另一种方案中，R4代表氢、羟基、羧基、C1～6烷基、
R4优选代表氢、羟基、羧基、
q代表0～3的整数；q优选代表0～2的整数，q更优选代表0或1。
进一步的，R9代表C1～6烷基、苯基或取代的苯基，其取代基选自卤素、C1～4烷基或硝基中的一种或多种。
更一步的，R9优选代表苯基或取代的苯基，其取代基选自卤素、C1～4烷基或硝基中的一种或多种。
再一步的，R9更优选代表苯基或取代的苯基，其取代基选自甲基、乙基、叔丁基或硝基中的一种或多种。
在一种方案中，R10代表C1～6烷基、C1～5烷氧基、苯基或者取代的苯基，其取代基选自卤素、C1～4烷基或硝基中的一种或多种。
在一种优选方案中，R10代表C1～6烷基或C1～4烷氧基。
在一种更优选方案中，R10代表甲基、乙基、叔丁基或C1～4烷氧基。
在一种方案中，R11或R12分别独立代表氢、C1～6烷基、羟基取代的C1～6烷基或苯基。
在一种优选方案中，R11或R12优选分别独立代表氢、C1～5烷基或羟基取代的C1～5烷基。
在一种更优选方案中，R11代表氢，R12代表C1～5烷基或羟基取代的C1～4烷基。
在一种方案中，R1或R2分别独立地代表甲基、乙基或正丙基。
在一种方案中，L代表-O(CH2)n-基团，n代表0-7的整数，优选代表0-6的整数；M代表-O(CH2)m-基团；m代表0-7的整数。
在另一种方案中，R3代表氢、羟基、羧基、C1～5烷基、
p代表0～2的整数，p优选代表0或1。
进一步的，R5代表C1～3烷基或苯基；优选地，R5代表甲基、乙基或苯基；R5更优选代表甲基或苯基。
在一种方案中，R6代表C1～5烷基、C1～4烷氧基或苯基。
在一种优选方案中，R6代表C1～4烷基或C1～3烷氧基。
在一种更优选方案中，R6代表甲基、乙基或叔丁基。
在一种方案中，R7代表氢。
在一种方案中，R8代表C1～5烷基。
在一种优选方案中，R8代表甲基、乙基或叔丁基。
在另一种方案中，R4代表氢、羟基、羧基、q代表0～3的整数。
优选地，q代表0～2的整数。q更优选代表0或1。
进一步地，R9代表苯基或取代的苯基，其取代基选自C1～4烷基或硝基中的一种或多种；优选地，R9代表苯基或取代的苯基，其取代基选自甲基、乙基、叔丁基或硝基中的一种或多种；更优选地，R9代表苯基或取代的苯基，其取代基选自甲基、乙基或硝基中的一种或多种。
更进一步，R10代表C1～6烷基或C1～4烷氧基；优选地，R10代表C1～6烷基或C1～3烷氧基。
在一种方案中，R11代表氢。
在一种方案中，R12代表C1～5烷基或羟基取代的C1～4烷基。
在一种优选方案中，R12代表C1～5烷基或羟基取代的C1～2烷基。
进一步地，在通式I所述化合物或其药学上可接受的盐中，所述化合物优选下列化合物：
本发明公开了一种通式I所示化合物的制备方法，制备方法包括步骤1)或步骤2)：
1)通式I化合物，合成路线如下：
2)通式I化合物，合成路线如下：
基团说明：
烷基：表示1-20个碳原子的饱和的脂烃基，包括直链和支链基团。“1-20”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括20个碳原子。优选地，烷基是有1-10个碳原子的中等大小的烷基，即C1～10烷基，例如甲基、乙基、丙基、2-丙基(或异丙基)、正丁基、异丁基、叔丁基、正戊基、正己基、正庚基等。更优选的，烷基是C1～8烷基、C1～7烷基、C1～6烷基、C1～5烷基、C1～4烷基或C1～3烷基，本申请书中提到的数字范围，例如“1-5”，是指该基团，此时为烷基，可以含1个碳原子、2个碳原子、3个碳原子等，直至包括5个碳原子。
取代烷基：表示烷基中的一个或多个氢被其他基团所取代的烷基。
卤素：表示氟、氯、溴或碘，优选为氟或氯。
0-8的整数：是指0、1、2、3、4、5、6、7或8。相应的，0～3的整数是指0、1、2或3。
卤代烷基：是指该基团，此时为烷基，被卤代取代，可以是一个或多个取代。相应的，氟烷基是指烷基中的一个或多个氢被氟取代的烷基。
羟基：表示-OH基团。
羧基：表示-COOH或
团。
硝基：表示-NO2基团。
烷氧基：表示-O-(未取代的烷基)和-O-(未取代的环烷基)。代表性实例包括但不限于甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基等。
杂脂环基：表示单环或稠合环基团，在环中具有5到9个环原子，其中一个或两个环原子是选自N、O或S(O)m(其中m是0至2的整数)的杂原子，其余环原子是C。这些环可以具有一条或多条双键，但这些环不具有完全共轭的π电子系统。未取代的杂脂环基的非限制性实例有吡咯烷基、哌啶子基、哌嗪子基、吗啉代基等。
苯基：表示基团。
取代苯基：表示苯基被取代，取代基优可以一个或多个。
羟基取代的烷基：是指该基团，此时为烷基，一个或多个氢被-OH所取代。
本发明中的化合物的化学结构式中出现
是指与OH所连接的碳原子为手性碳原子。
药学上可接受的盐：表示保留母体化合物的生物有效性和性质的那些盐，这类盐包括：
(1)与酸成盐，通过母体化合物的游离碱与无机酸或有机酸的反应而得，无机酸包括盐酸、氢溴酸、硝酸、磷酸、偏磷酸、硫酸、亚硫酸和高氯酸等，有机酸包括乙酸、三氟乙酸、丙酸、丙烯酸、己酸、环戊烷丙酸、羟乙酸、丙酮酸、草酸、(D)或(L)苹果酸、富马酸、马来酸、抗坏血酸、樟脑酸、苯甲酸、羟基苯甲酸、γ-羟基丁酸、甲氧基苯甲酸、邻苯二甲酸、甲磺酸、乙磺酸、萘-1-磺酸、萘-2-磺酸、对甲苯磺酸、水杨酸、酒石酸、柠檬酸、乳酸、肉桂酸、十二烷基硫酸、葡糖酸、谷氨酸、天冬氨酸、硬脂酸、扁桃酸、琥珀酸、戊二酸或丙二酸等。
(2)存在于母体化合物中的酸性质子被金属离子代替或者与有机碱配位化合所生成的盐，金属例子例如碱金属离子、碱土金属离子或铝离子，有机碱例如乙醇胺、二乙醇胺、三乙醇胺、氨丁三醇、N-甲基葡糖胺、奎宁等。
药物组合物：指将本发明中的化合物中的一个或多个或其药学上可接受的盐、溶剂化物、水合物或前药与别的化学成分，例如药学上可接受的载体，混合。药物组合物的目的是促进给药给动物的过程。
药用载体：指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性和性质的药物组合物中的非活性成分，例如但不限于：碳酸钙、磷酸钙、各种糖(例如乳糖、甘露醇等)、淀粉、环糊精、硬脂酸镁、纤维素、碳酸镁、丙烯酸聚合物或甲基丙烯酸聚合物、凝胶、水、聚乙二醇、丙二醇、乙二醇、蓖麻油或氢化蓖麻油或多乙氧基氢化蓖麻油、芝麻油、玉米油、花生油等。
本发明提供了一种药物组合物，它以本发明的化合物或其药学上可接受的盐为活性成分或主要活性成分，辅以药学上可接受的载体。
本发明的化合物或其药学上可接受的盐可应用于制备与抗纤维化有关疾病的药物方面。
本发明化合物或其药学上可接受的盐可通过添加药学上可接受的载体制成各种制剂。在临床用于口服、注射、局部用药等。
本发明的化合物临床所用剂量为0.001mg～1000mg/天，也可根据病情的轻重或剂型的不同偏离此范围。
药效学实验证明：本发明的化合物对VDR受体有较强亲和力，对正常细胞毒性较低，且能在体内及体外有效抑制纤维化的形成，并且其升血钙的能力非常弱。因此，本发明的化合物可以用于治疗多种纤维化及相关性疾病。
附图说明
图1是本发明的化合物激动VDR的相对荧光强度；
图2是本发明的化合物对LTC-14胞内COL1α1和α-SMA蛋白相对表达量的影响；
图3是本发明的化合物对LTC-14细胞中COL1α1和α-SMA的mRNA含量的影响；
图4是本发明的化合物DK-3对大鼠胰腺炎组织纤维化程度的影响；
图5是本发明的化合物DK-3体内对血钙浓度的影响；
图6是本发明的化合物DK-3对小鼠体重的影响。
具体实施方式
通过以下实施例对本发明进一步解释，但这些实施例不对本发明构成任何限制。
实施例1：
(1)制备化合物2，化学结构式如下：
将4-羟基-3-甲基苯甲酸(100.0g,0.64mol)溶解于300mL甲醇中，于搅拌状态下缓慢加入100mL浓硫酸，加完后升温至回流反应12h。反应结束后冷却至室温，然后将反应液倾入5L冰水中。将析出的固体过滤并用冷水洗，烘干得粉红色固体101g，收率：93％。熔点：67-78℃；1H NMR(300MHz,CDCl3)δ(ppm)7.60(s,1H),7.55(d,J＝8.28Hz,1H),6.62(d,1H,J＝8.28Hz),3.68(s,1H),2.06(s,1H).MS(TOF)m/z:189.1[M+Na]+.
(2)制备化合物3，化学结构式如下：
将化合物2(50g,300.89mmol)溶解于200mL丙酮中，依次加入碳酸钾(49.90g,361.06mmol)和对甲基苯磺酰氯(68.83g,361.06mmol)，回流反应12h。反应结束后冷却至室温，滤去不溶物，滤液减压蒸馏除去大部分溶剂，得黄色油状物，用200mL石油醚重结晶，得类白色固体90.0g，收率93％。熔点：87-93℃；1H NMR(300MHz,CDCl3)δ(ppm)7.83(s,1H),7.79(d,J＝8.68Hz,1H),7.72(s,1H),7.69(s,1H).7.23(s,1H),7.29(s,1H),7.08(d,J＝8.68Hz,1H),3.87(s,3H),2.44(s,3H),2.07(s,3H).MS(TOF)m/z:343.1[M+Na]+.
(3)制备化合物4，化学结构式如下：
按照常规方法制备乙基格氏试剂。在0℃下，将化合物3(20g,62.43mmol)的乙醚溶液(100mL)缓慢滴入格氏试剂/乙醚溶液中(100mL,156.08mmol)，于30min内滴完，升温至25℃反应5h。反应结束后，置于0℃中，缓慢滴加饱和氯化铵水溶液至无气泡放出。加入乙酸乙酯，震荡后分层，取有机层，用饱和食盐水洗涤，取有机层，使用无水硫酸钠干燥，浓缩，得无色油状物17.2g，收率79％。1H NMR(300MHz,CDCl3)δ(ppm)7.71(s,1H),7.68(s,1H),7.30(s,1H).7.27(s,1H),7.15(d,J＝2.12Hz,1H),7.08(dd,J＝8.58Hz,2.12Hz,1H),6.97(d,J＝8.58Hz,1H),2.43(s,3H),2.02(s,3H),1.77(qd,J＝7.42Hz,J＝3.45Hz,4H),0.71(t,J＝7.42Hz,6H).MS(TOF)m/z:371.2[M+Na]+.
(4)制备化合物5，化学结构式如下：
将化合物4(1.5g,4.30mmol)与邻苯二酚(0.56g,5.17mmol)溶解于10mL二氯甲烷中，于0℃下滴加2mL三氟化硼乙醚，滴加结束后搅拌反应3h。反应结束后，加入饱和碳酸氢钠水溶液10mL，震荡后分层，取有机相，用饱和食盐水洗涤，取有机相，无水硫酸钠干燥，浓缩，得无色油状物，经柱层析纯化(二氯甲烷：甲醇＝15:1)得无色油状物1.62g，收率85％。1H NMR(300MHz,CDCl3)δ(ppm)7.72(s,1H),7.69(s,1H),7.31(s,1H).7.28(s,1H),6.91-6.90(m,1H),6.89(s,1H),6.74(d,J＝7.86Hz,1H),6.61-6.57(m,2H),2.44(s,3H),1.98(s,3H),1.97(q,J＝7.25Hz,4H),0.57(t,J＝7.25Hz,6H).MS(TOF)m/z:463.2[M+Na]+.
(5)制备化合物6，化学结构式如下：
将化合物5(5.7g,12.94mmol)溶解于50mL丙酮中，依次加入碳酸钾(4.47g,32.35mmol)、碘化钾(0.21g,1.29mmol)和一氯频呐酮(4.35g,32.35mmol)，回流搅拌12h。反应结束后，过滤除去不溶物，滤液浓缩除去大部分溶剂得淡黄色油状物，经柱层析纯化(石油醚：乙酸乙酯＝30:1)，得白色固体7.01g，收率85％。熔点：77-79℃；1H NMR(500MHz,CDCl3)δ(ppm)7.70(s,1H),7.69(s,1H),7.29(s,1H),7.27(s,1H),6.88(s,1H),6.86(s,2H),6.71-6.67(m,2H),6.51(s,1H),4.92(s,2H),4.87(s,2H),2.42(s,3H),1.98(s,3H),1.94(q,J＝7.33Hz,4H),1.20(s,9H),1.11(s,9H),0.54(t,J＝7.33Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)147.65,147.16,146.52,146.07,145.12,142.42,133.26,131.02,130.30,129.63,128.28,126.54,126.41,121.77,121.26,117.07,114.89,70.83,70.80,70.58,70.56,70.41,49.20,42.82,29.29,26.25,26.16,26.06,21.59,16.41,8.28.ESI-HRMS calcd for C37H48O7S[M+Na]+659.3121,found 659.3030.
(6)制备化合物7，化学结构式如下：
将化合物6(1.3g,2.04mmol)溶解于10mL甲醇，置于0℃中，缓慢分批加入硼氢化钠(0.77g,20.4mmol)，置于室温反应2h。反应结束后，加入10mL水，浓缩除去大部分甲醇，用乙酸乙酯萃取，分出有机层，用饱和食盐水洗涤，取有机层，无水硫酸钠干燥，浓缩，得黄色油状物，经柱层析纯化(石油醚：乙酸乙酯＝30:1)得白色固体1.07g，收率81％。熔点：74-77℃；1H NMR(500MHz,CDCl3)δ(ppm)7.72(s,1H),7.71(s,1H),7.30(s,1H),7.28(s,1H),6.92-6.91(m,3H),6.82(dd,J＝8.42Hz,3.75Hz,1H),6.75(dt,J＝8.42Hz,1.85Hz,1H),6.70(dd,J＝7.05Hz,2.0Hz,1H),4.18-4.12(m,1H),4.10-4.01(m,1H),3.89-3.81(m,1H),3.82-3.71(m,1H),3.68-3.63(m,1H),3.62-3.54(m,1H),2.44(s,3H),2.00(s,3H),2.00(q,J＝7.20Hz,4H),0.98(d,J＝1.25Hz,9H),0.94(d,J＝5.2Hz,9H),0.59(t,J＝7.20Hz,6H).13CNMR(125MHz,CDCl3)δ(ppm)147.29,146.14,145.12,142.41,142.35,133.40,131.04,130.39,129.65,128.34,126.55,122.28,122.18,121.34,117.39,117.26,114.52,114.39,77.39,77.22,76.95,76.79,49.25,33.49,33.45,33.37,33.34,29.36,29.30,26.14,26.10,26.08,26.02,21.66,16.51,8.35.ESI-HRMS calcd for C37H48O7S[M+Na]+663.3434,found 663.3336.
(7)制备化合物8，化学结构式如下：
将化合物7(2.2g,3.43mmol)溶解于30mL乙醇中，室温下加入氢氧化钠(1.37g,34.33mmol)水溶液5mL，回流反应24h。反应结束后，浓缩除去大部分乙醇，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得无色透明油状物，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得白色固体1.43g，收率86％。熔点：63-68℃；1H NMR(500MHz,CDCl3)δ(ppm)6.87(s,1H),6.83(dd,J＝8.3Hz,2.15Hz,1H),6.81-6.78(m,2H),6.75(dd,J＝7.0Hz,1.65Hz,1H),6.64(d,J＝8.3Hz,1H),4.17-4.12(m,1H),4.10-4.03(m,1H),3.89-3.81(m,1H),3.81-3.72(m,1H),3.68-3.64(m,1H),3.61-3.53(m,1H),2.18(s,3H),2.00(q,J＝7.25Hz,4H),0.98(s,9H),0.94(d,J＝4.80Hz,9H),0.59(t,J＝7.25Hz,6H).MS(TOF)m/z:509.3[M+Na]+.
(8)制备化合物9a，化学结构式如下：
将化合物8(0.56g,1.15mmol)溶解于20mL丙酮中，依次加入2-溴乙酸乙酯(0.23g,1.38mmol)和碳酸钾(0.32g,2.30mmol)，回流反应8h，反应结束后，浓缩除去大部分丙酮，加入20mL水，加入乙酸乙酯萃取，取有机相，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色透明油状物0.51g，收率77％。1H NMR(500MHz,CDCl3)δ(ppm)6.91-6.90(m,2H),6.80(q,J＝8.4Hz,2H),6.76-6.75(m,1H),6.58(d,J＝9.2Hz,2H),4.59(s,2H),4.25(q,J＝7.2Hz,2H),4.16(d,J＝9.4Hz,1H),4.09(d,J＝9.4Hz,1H),3.80(t,J＝9.3Hz,1H),3.73(t,J＝9.3Hz,1H),3.67(d,J＝9.4Hz,1H),3.59(d,J＝9.4Hz,1H),2.22(s,3H),2.01(q,J＝7.3Hz,4H),1.28(t,J＝7.2,3H),0.98(s,9H),0.94(s,9H),0.59(t,J＝7.3Hz,6H).MS(TOF)m/z:572.37[M+Na]+.
(9)制备化合物9b，化学结构式如下：
用4-溴丁酸乙酯(1.38mmol)代替2-溴乙酸乙酯，以与化合物9a相同的方法合成化合物9b。1H NMR(500MHz,CDCl3)δ(ppm)6.92(dd,J＝8.5Hz,2.3Hz,1H),6.87(s,1H),6.82-6.80(m,2H),6.76(dd,J＝6.9Hz,1.7Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.14(m,1H),4.14(q,J＝7.1Hz,2H),4.11-4.03(m,1H),3.97(t,J＝6.0Hz,2H),3.87(t,J＝10.4Hz,1H),3.83-3.72(m,1H),3.65(td,J＝10.4Hz,J＝2.1Hz,1H),3.60-3.53(m,1H),2.52(t,J＝7.4Hz,2H),2.15(s,3H),2.14-2.08(m,2H),2.01(q,J＝7.3Hz,4H),1.25(t,J＝7.1Hz,2H),0.98(s,9H),0.94(d,J＝5.1Hz,9H),0.61(t,J＝7.3Hz,6H).MS(TOF)m/z:623.4[M+Na]+.
(10)制备化合物9c，化学结构式如下：
用5-溴戊酸乙酯(1.38mmol)代替2-溴乙酸乙酯，以与化合物9a相同的方法合成化合物9c。1H NMR(500MHz,CDCl3)δ(ppm)6.92(d,J＝8.4Hz,1H),6.87(s,1H),6.83-6.80(m,2H),6.76(d,J＝7.0Hz,1H),6.67(d,J＝8.4Hz,1H),4.17-4.13(m,1H),4.13(q,J＝7.2Hz,2H),4.10-4.03(m,1H),3.94(t,J＝5.4Hz,2H),3.87(t,J＝10.3Hz,1H),3.82-3.72(m,1H),3.65(t,J＝10.3Hz,1H),3.60-3.52(m,1H),2.38(t,J＝6.8Hz,2H),2.15(s,3H),2.03-1.97(m,4H),1.85-1.82(m,4H),1.25(t,J＝7.2Hz,3H),0.98(s,9H),0.94(d,J＝5.1Hz,9H),0.61(t,J＝7.3Hz,6H).MS(TOF)m/z:637.5[M+Na]+.
(11)制备化合物9d，化学结构式如下：
用6-溴己酸乙酯(1.38mmol)代替2-溴乙酸乙酯，以与化合物9a相同的方法合成化合物9d。1H NMR(500MHz,CDCl3)δ(ppm)6.91(d,J＝8.5Hz,1H),6.87(s,1H),6.83-6.78(m,2H),6.76(d,J＝6.8Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.14(m,1H),4.13(q,J＝7.1Hz,2H),4.10-4.03(m,1H),3.92(t,J＝6.2Hz,2H),3.89-3.80(m,1H),3.78-3.72(m,1H),3.68-3.63(m,1H),3.60-3.53(m,1H),2.33(t,J＝7.4Hz,2H),2.15(s,3H),2.05-1.97(m,4H),1.83-1.77(m,2H),1.74-1.68(m,2H),1.55-1.49(m,2H),1.25(t,J＝7.1Hz,3H),0.98(s,9H),0.94(d,J＝4.6Hz,9H),0.61(t,J＝7.2Hz,6H).MS(TOF)m/z:651.4[M+Na]+.
(12)制备化合物9e，化学结构式如下：
用7-溴庚酸乙酯(1.38mmol)代替2-溴乙酸乙酯，以与化合物9a相同的方法合成化合物9e。1H NMR(500MHz,CDCl3)δ(ppm)6.91(dd,J＝8.5Hz,2.2Hz,1H),6.87(d,J＝2.2Hz,1H),6.82-6.78(m,2H),6.76(dd,J＝7.1Hz,1.7Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.14(m,1H),4.12(q,J＝7.2Hz,2H),4.10-4.03(m,1H),3.92(t,J＝6.3Hz,2H),3.89-3.84(m,1H),3.84-3.72(m,1H),3.68-3.63(m,1H),3.60-3.52(m,1H),2.30(t,J＝7.4Hz,2H),2.15(s,3H),2.04-1.98(m,4H),1.81-1.75(m,2H),1.69-1.63(m,2H),1.53-1.47(m,2H),1.43-1.37(m,2H),1.25(t,J＝7.2Hz,3H),0.98(s,9H),0.94(d,J＝5.7Hz,9H),0.61(t,J＝7.2Hz,6H).MS(TOF)m/z:665.5[M+Na]+.
(13)制备化合物10，化学结构式如下：
将化合物5(1.2g,2.72mmol)溶解于20mL丙酮中，依次加入碳酸钾(1.13g,8.17mmol)和对溴化苄(1.02g,5.99mmol)，回流反应6h。反应结束后冷却至室温，滤去不溶物，滤液减压蒸馏除去大部分溶剂，得无色油状物，经柱层析纯化(石油醚：乙酸乙酯＝50:1)得无色透明油状物1.55g，收率92％。1H NMR(300MHz,CDCl3)δ(ppm)7.71(s,1H),7.68(s,1H),7.46-7.43(m,2H),7.38-7.34(m,2H),7.33-7.24(m,8H),6.87-6.82(m,3H),6.82-6.80(m,1H),6.68(dd,J＝8.5Hz,2.2Hz,1H),6.58(d,J＝2.2Hz,1H),5.11(s,2H),5.03(s,2H),2.41(s,3H),1.95(s,3H),1.92(q,J＝7.2Hz,4H),0.51(t,J＝7.2Hz,6H).MS(TOF)m/z:643.2[M+Na]+.
(14)制备化合物11，化学结构式如下：
将化合物10(1.00g,1.61mmol)溶解于30mL乙醇中，室温下加入氢氧化钠(0.32g,8.05mmol)水溶液5mL，回流反应24h。反应结束后，浓缩除去大部分乙醇，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得无色透明油状物，经柱层析纯化(石油醚：乙酸乙酯＝30:1)得无色油状物0.63g，收率84％。1H NMR(300MHz,CDCl3)δ(ppm)7.46-7.43(m,2H),7.38-7.35(m,1H),7.35-7.32(m,2H),7.32-7.31(m,2H),7.29-7.25(m,3H),6.82-6.80(m,3H),6.73-6.69(m,1H),6.68-6.67(m,1H),6.63-6.60(m,1H),5.11(s,2H),5.04(s,2H),2.16(s,3H),1.93(q,J＝7.2Hz,4H),0.53(t,J＝7.2Hz,6H).MS(TOF)m/z:465.3[M-H]-.
(15)制备化合物12，化学结构式如下：
用化合物11(1.27mmol)代替化合物5，以与化合物6相同的方法合成化合物12。1HNMR(300MHz,CDCl3)δ(ppm)7.45-7.42(m,2H),7.37-7.31(m,5H),7.28-7.24(m,3H),6.85-6.79(m,3H),6.71-6.68(m,2H),6.47(d,J＝9.2Hz,1H),5.10(s,2H),5.03(s,2H),4.82(s,2H),2.21(s,3H),1.94(q,J＝7.2Hz,4H),1.25(s,9H),0.53(t,J＝7.2Hz,6H).
(16)制备化合物13，化学结构式如下：
将化合物12(0.74g,1.31mmol)溶解于10mL甲醇中，加入10％钯碳(0.1g)，室温下通入氢气，反应24h。反应结束后，抽滤除去钯碳，浓缩以除去大部分甲醇，加入水，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，浓缩得无色透明油状物，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色油状物0.41g，收率82％。1H NMR(300MHz,CDCl3)δ(ppm)6.90-6.87(m,2H),6.74-6.71(m,1H),6.64-6.59(m,2H),6.47(d,J＝8.4Hz,1H),4.84(s,2H),2.21(s,3H),1.97(q,J＝7.3Hz,4H),1.25(s,9H),0.58(t,J＝7.3Hz,6H).
(17)制备化合物14，化学结构式如下：
用化合物13(0.86mmol)代替化合物6，以与化合物7相同的方法合成化合物14。1HNMR(300MHz,CDCl3)δ(ppm)6.95(dd,J＝8.5Hz,2.1Hz,1H),6.89-6.88(m,1H),6.70(dd,J＝15.0Hz,8.4Hz,2H),6.63-6.60(m,2H),4.08(dd,J＝9.0Hz,2.5Hz,1H),3.86(t,J＝9.0Hz,1H),3.71(dd,J＝8.5Hz,2.5Hz,1H),2.14(s,3H),1.99(q,J＝7.3Hz,4H),1.00(s,9H),0.59(t,J＝7.3Hz,6H).
实施例2
合成DK-1，化学结构式如下：
将化合物8(0.2g,0.41mmol)溶解于50mL DMF中，置于0℃，缓慢分批加入氢化钠(11.83mg,0.49mmol)，置于室温搅拌1h，加入缩水甘油(45.66mg,0.62mmol)，加热至90℃反应12h。反应结束后，加入10mL水，用乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色透明油状物0.17g，收率74％。1H NMR(500MHz,CDCl3)δ(ppm)6.93(dd,J＝8.4Hz,2.2Hz,1H),6.87(d,J＝2.2Hz,1H),6.81-6.76(m,2H),6.73(dd,J＝8.0Hz,1.6Hz,1H),6.68(d,J＝8.4Hz,1H),4.16-4.11(m,1H),4.09-4.02(m,2H),4.0(d,J＝5.4Hz,2H),3.86-3.84(m,1H),3.83-3.81(m,1H),3.74-3.72(m,1H),3.67-3.65(m,1H),3.57-3.51(m,1H),2.14(s,3H),2.04-1.98(m,4H),0.97(s,9H),0.94(d,J＝6.4Hz,9H),0.61(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.25,147.95,147.13,143.08,140.78,130.56,126.15,125.56,122.00,116.97,114.02,110.24,77.21,77.18,76.96,76.68,72.77,72.42,71.80,71.55,70.57,69.13,63.89,48.84,33.38,29.42,25.98,16.44,8.40.ESI-HRMS calcd for C33H52O7[M+Na]+583.3713,found 583.3627.
实施例3
合成DK-2，化学结构式如下：
用2-溴乙醇(0.62mmol)代替缩水甘油，以与化合物DK-1相同的方法合成化合物DK-2。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.4Hz,2.2Hz,1H),6.89(d,J＝2.2Hz,1H),6.83-6.78(m,2H),6.76(dd,J＝7.0Hz,1.9Hz,1H),6.70(d,J＝8.4Hz,1H),4.17-4.12(m,1H),4.12-4.03(m,1H),4.06(t,J＝4.6Hz,2H),3.95(t,J＝4.5Hz,2H),3.89-3.82(m,1H),3.80-3.72(m,1H),3.68-3.63(m,1H),3.60-3.53(m,1H),2.18(s,3H),2.05-1.99(m,4H),0.98(s,9H),0.94(d,J＝5.0Hz,9H),0.61(t,J＝7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.43,148.12,147.25,143.30,140.69,130.61,126.16,125.71,122.29,117.50,114.47,110.38,77.32,69.26,61.69,48.87,33.45,33.32,29.47,29.40,26.14,26.10,26.07,26.01,16.47,8.44.ESI-HRMS calcd for C32H50O6[M+Na]+553.3607,found 553.3503.
实施例4
合成DK-3，化学结构式如下：
用3-溴丙醇(0.62mmol)代替缩水甘油，以与化合物DK-1相同的方法合成化合物DK-3。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.4Hz,2.2Hz,1H),6.88(d,J＝2.2Hz,1H),6.82-6.78(m,2H),6.75(dd,J＝7.1Hz,1.9Hz,1H),6.71(d,J＝8.4Hz,1H),4.17-4.11(m,1H),4.09(t,J＝5.8Hz,2H),4.09-4.03(m,1H),3.87(t,J＝6.0Hz,2H),3.87-3.84(m,1H),3.82-3.72(m,1H),3.68-3.63(m,1H),3.60-3.52(m,1H),2.15(s,3H),2.07-2.05(m,2H),2.04-1.98(m,4H),0.98(s,9H),0.94(d,J＝5.1Hz,9H),0.61(t,J＝7.4Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.63,147.98,147.26,143.28,140.34,130.49,126.12,125.45,122.20,117.39,114.32,109.93,77.30,77.21,76.95,76.70,72.68,71.75,65.99,60.95,48.86,33.36,32.15,29.48,26.14,26.10,26.07,26.01,16.54,8.44.ESI-HRMS calcd forC33H52O6[M+H]+545.3764,found 545.3847.
实施例5
合成DK-4,化学结构式如下：
将化合物9b(0.2g,0.33mmol)溶解于20mL四氢呋喃，在0℃下加入四氢铝锂(31.58mg,0.83mmol)，置于室温反应4h。反应结束后，浓缩除去大部分四氢呋喃，加入10mL水，用乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色透明油状物0.13g，收率70％。1H NMR(500MHz,CDCl3)δ(ppm)6.92(dd,J＝8.4Hz,1.9Hz,1H),6.87(d,J＝1.9Hz,1H),6.82-6.78(m,2H),6.75(d,J＝7.0Hz,1H),6.68(d,J＝8.4Hz,1H),4.17-4.12(m,1H),4.11-4.03(m,1H),3.97(t,J＝6.0Hz,2H),3.89-3.82(m,1H),3.80-3.74(m,1H),3.72(t,J＝6.3Hz,2H),3.68-3.64(m,1H),3.60-3.52(m,1H),2.16(s,3H),2.06-1.97(m,4H),1.91-1.85(m,2H),1.79-1.74(m,2H),0.98(s,9H),0.94(d,J＝5.0Hz,9H),0.61(t,J＝7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.78,148.06,147.18,143.38,140.03,130.44,126.03,125.60,122.27,117.44,114.40,110.00,77.26,76.95,76.68,73.02,71.99,67.66,62.60,48.84,33.44,29.68,26.13,26.10,26.06,26.01,25.99,16.49,8.44.ESI-HRMS calcd forC34H54O6[M+Na]+581.3920,found 581.3826.
实施例6
合成DK-5，化学结构式如下：
用化合物9c代替9b，以与化合物DK-4相同的方法合成化合物DK-5。1H NMR(500MHz,CDCl3)δ(ppm)6.92(dd,J＝8.4Hz,2.1Hz,1H),6.87(d,J＝2.1Hz,1H),6.83-6.78(m,2H),6.76(d,J＝1.8Hz,1H),6.67(d,J＝8.4Hz,1H),4.16(dd,J＝9.2Hz,J＝2.2Hz,1H),4.10(dd,J＝9.5Hz,2.2Hz,1H),3.94(t,J＝6.3Hz,2H),3.80(t,J＝9.2Hz,1H),3.73(t,J＝9.5Hz,1H),3.67(t,J＝6.4Hz,2H),3.67-3.65(m,1H),3.59(dd,J＝9.4Hz,2.2Hz,1H),2.15(s,3H),2.04-2.01(m,4H),1.85-1.79(m,2H),1.68-1.62(m,2H),1.59-1.53(m,2H),0.98(s,9H),0.94(s,9H),0.61(t,J＝7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.93,148.09,147.20,143.47,139.87,130.40,126.00,125.65,122.33,117.56,114.47,109.96,77.31,73.10,72.04,67.67,62.86,48.84,33.45,33.33,32.47,29.23,26.15,26.08,22.48,16.49,8.46.ESI-HRMS calcd for C35H56O6[M+Na]+595.4077,found 595.3981.
实施例7
合成DK-6，化学结构式如下：
用化合物9d代替9b，以与化合物DK-4相同的方法合成化合物DK-6。1H NMR(500MHz,CDCl3)δ(ppm)6.90(dd,J＝8.5Hz,2.1Hz,1H),6.87(d,J＝2.1Hz,1H),6.83-6.78(m,2H),6.75(dd,J＝7.0Hz,1.6Hz,1H),6.67(d,J＝8.4Hz,1H),4.17-4.12(m,1H),4.11-4.03(m,1H),3.93(t,J＝6.3Hz,2H),3.89-3.80(m,1H),3.80-3.71(m,1H),3.69-3.63(m,1H),3.65(t,J＝6.5Hz,2H),3.60-3.52(m,1H),2.15(s,3H),2.04-1.98(m,4H),1.82-1.77(m,2H),1.63-1.58(m,2H),1.54-1.48(m,2H),1.47-1.42(m,2H),0.98(s,9H),0.94(d,J＝4.8Hz,9H),0.61(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.97,148.09,147.20,143.48,139.82,130.39,126.00,125.65,122.32,117.57,114.47,109.96,77.31,73.09,72.04,67.72,62.91,48.84,33.45,33.32,32.72,29.50,29.42,26.15,26.11,26.08,26.03,25.55,16.47,8.46.ESI-HRMS calcd for C36H58O6[M+Na]+609.4233,found609.4138.
实施例8
合成DK-7，化学结构式如下：
用化合物9e代替9b，以与化合物DK-4相同的方法合成化合物DK-7。1H NMR(500MHz,CDCl3)δ(ppm)6.91(dd,J＝8.5Hz,2.0Hz,1H),6.87(d,J＝2.0Hz,1H),6.82-6.78(m,2H),6.75(d,J＝7.0Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.11(m,1H),4.11-4.03(m,1H),3.92(t,J＝6.4Hz,2H),3.89-3.80(m,1H),3.80-3.71(m,1H),3.67-3.62(m,1H),3.64(t,J＝6.6Hz,2H),3.60-3.52(m,1H),2.15(s,3H),2.03-1.98(m,4H),1.81-1.75(m,2H),1.59-1.56(m,2H),1.50-1.47(m,2H),1.40-1.38(m,4H),0.98(s,9H),0.94(d,J＝4.9Hz,9H),0.61(t,J＝7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)154.99,148.07,147.18,143.47,139.78,130.37,125.98,125.65,122.29,117.52,114.43,109.94,77.21,76.69,73.06,72.02,67.80,62.96,48.83,33.44,32.70,29.50,29.38,29.19,26.17,26.14,26.11,26.07,26.01,25.70,16.47,8.46.ESI-HRMS calcd for C37H60O6[M+Na]+623.4390,found 623.4287.
实施例9
合成DK-2，化学结构式如下：
将化合物9a(0.2g,0.35mmol)溶解于20mL乙醇中，加入氢氧化钠(139.66mg,3.49mmol)的水溶液2mL，回流反应24h。反应结束后，浓缩以除去大部分乙醇，加入10mL水，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝5:1)得无色透明油状物0.14g，收率74％。1H NMR(500MHz,CDCl3)δ(ppm)6.93-6.91(m,2H),6.81(dd,J＝8.4Hz,3.2Hz,1H),6.78(dd,J＝8.4Hz,1.8Hz,1H),6.73(dd,J＝7.3Hz,1.8Hz,1H),6.61(d,J＝8.3Hz,1H),4.63(s,2H),4.17-4.12(m,1H),4.10-4.02(m,1H),3.89-3.81(m,1H),3.81-3.72(m,1H),3.69-3.65(m,1H),3.61-3.53(m,1H),2.22(s,3H),2.04-1.98(m,4H),0.98(s,9H),0.94(d,J＝5.7Hz,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)172.58,153.59,148.14,147.27,143.14,141.75,130.90,126.19,126.13,122.28,117.46,114.47,110.56,77.43,77.33,72.99,71.91,65.36,48.93,33.36,29.44,26.14,26.11,26.07,26.02,16.43,8.43.ESI-HRMScalcd for C32H48O7[M+Na]+567.3400,found 567.3299.
实施例10
合成DK-9，化学结构式如下：
用化合物9b代替9a，以与化合物DK-8相同的方法合成化合物DK-9。1H NMR(500MHz,CDCl3)δ(ppm)6.92(dd,J＝8.5Hz,1.8Hz,1H),6.88(s,1H),6.82-6.78(m,2H),6.75(dd,J＝6.8Hz,1.8Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.12(m,1H),4.09-4.03(m,1H),3.98(t,J＝6.0Hz,2H),3.89-3.83(m,1H),3.83-3.72(m,1H),3.68-3.65(m,1H),3.61-3.53(m,1H),2.58(t,J＝7.3Hz,2H),2.15(s,3H),2.13-2.11(m,2H),2.04-1.98(m,4H),0.98(s,9H),0.94(d,J＝5.5Hz,9H),0.60(t,J＝7.2Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)178.32,154.60,148.08,147.19,143.37,140.17,130.48,126.03,125.66,122.29,117.46,114.45,109.88,77.33,66.43,48.85,33.33,30.61,29.42,26.14,26.11,26.07,26.01,24.63,16.42,8.45.ESI-HRMS calcd for C34H52O7[M+Na]+595.3713,found 595.3611.
实施例11
合成DK-10，化学结构式如下：
用化合物9c代替9a，以与化合物DK-8相同的方法合成化合物DK-10。1H NMR(500MHz,CDCl3)δ(ppm)6.92(d,J＝8.5Hz,1H),6.87(s,1H),6.83-6.78(m,2H),6.75(d,J＝7.0Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.12(m,1H),4.11-4.03(m,1H),3.95(t,J＝5.3Hz,2H),3.89-3.83(m,1H),3.83-3.72(m,1H),3.68-3.64(m,1H),3.60-3.53(m,1H),2.44(t,J＝6.6Hz,2H),2.15(s,3H),2.03-1.98(m,4H),1.87-1.83(m,4H),0.98(s,9H),0.94(d,J＝5.3Hz,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)178.26,154.79,147.20,143.39,140.00,130.44,126.02,125.67,122.21,117.49,114.46,114.33,109.88,77.35,67.19,48.85,33.50,33.34,29.50,29.42,28.77,26.15,26.11,26.07,26.02,21.58,16.49,8.46.ESI-HRMS calcd for C35H54O7[M+Na]+609.3870,found609.3796.
实施例12
合成DK-11，化学结构式如下：
用化合物9d代替9a，以与化合物DK-8相同的方法合成化合物DK-11。1H NMR(500MHz,CDCl3)δ(ppm)6.92(dd,J＝8.5Hz,2.3Hz,1H),6.87(d,J＝1.7Hz,1H),6.82-6.78(m,2H),6.75(dd,J＝6.5Hz,1.7Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.12(m,1H),4.11-4.03(m,1H),3.93(t,J＝6.3Hz,2H),3.89-3.79(m,1H),3.79-3.72(m,1H),3.68-3.64(m,1H),3.60-3.53(m,1H),2.38(t,J＝7.5Hz,2H),2.15(s,3H),2.04-1.98(m,4H),1.82-1.78(m,2H),1.75-1.69(m,2H),1.57-1.53(m,2H),0.98(s,9H),0.94(d,J＝5.0Hz,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)178.32,154.89,148.08,147.19,143.46,139.90,130.41,126.01,125.66,122.30,117.51,114.45,109.95,77.34,73.02,71.99,67.49,48.85,33.77,33.34,29.10,26.14,26.07,26.02,25.76,24.47,16.46,8.46.ESI-HRMS calcd for C36H56O7[M+Na]+623.4026,found 623.3934.
实施例13
合成DK-12，化学结构式如下：
用化合物9e代替9a，以与化合物DK-8相同的方法合成化合物DK-12。1H NMR(500MHz,CDCl3)δ(ppm)6.91(dd,J＝8.5Hz,2.2Hz,1H),6.87(d,J＝1.7Hz,1H),6.83-6.78(m,2H),6.75(dd,J＝6.8Hz,1.7Hz,1H),6.67(d,J＝8.5Hz,1H),4.17-4.12(m,1H),4.11-4.03(m,1H),3.92(t,J＝6.4Hz,2H),3.87-3.83(m,1H),3.81-3.72(m,1H),3.68-3.64(m,1H),3.60-3.53(m,1H),2.38(t,J＝7.5Hz,2H),2.15(s,3H),2.04-1.99(m,4H),1.81-1.76(m,2H),1.70-1.64(m,2H),1.53-1.47(m,2H),1.45-1.39(m,2H),0.98(s,9H),0.94(d,J＝5.1Hz,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)178.44,154.94,147.97,147.19,143.48,139.83,130.39,126.00,125.66,122.21,117.50,114.46,109.96,77.34,67.67,48.84,33.75,33.34,29.69,29.50,29.43,29.24,28.82,26.15,26.11,26.08,26.02,25.86,24.63,16.47,8.47.ESI-HRMS calcd for C36H56O7[M+Na]+637.4183,found637.4089.
实施例14
合成DK-13，化学结构式如下：
将化合物8(0.2g,0.41mmol)溶解于丙酮中，依次加入碳酸钾(113.59mg,0.82mmol)和甲磺酰氯(70.60mg,0.62mmol)，室温反应8h。反应结束后，浓缩除去大部分丙酮，加入10mL水，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝20:1)得无色透明油状物0.18g，收率78％。1HNMR(500MHz,CDCl3)δ(ppm)7.16(d,J＝8.52Hz,1H),7.04(d,J＝8.75Hz,1H),7.01(d,J＝8.75Hz,1H),6.85-6.75(m,2H),6.65-6.58(m,1H),4.74-4.71(m,1H),4.64-4.61(m,1H),4.26-4.14(m,2H),4.10-3.97(m,2H),3.17(s,3H),2.30(s,3H),2.03(q,J＝7.33Hz,4H),1.07(s,9H),1.01-0.99(m,9H),0.59(t,J＝7.33Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)147.45,147.34,146.18,145.65,142.59,131.31,130.23,126.88,121.83,121.21,115.61,113.60,88.90,88.59,69.26,68.94,49.37,39.06,38.10,34.17,29.68,29.29,26.31,26.27,26.24,26.12,16.87,8.41.ESI-HRMS calcd for C31H48O7S[M+Na]+587.3121,found587.3017.
实施例15
合成DK-14，化学结构式如下：
用苯磺酰氯(0.62mmol)代替甲磺酰氯，以与化合物DK-13相同的方法合成化合物DK-14。1H NMR(500MHz,CDCl3)δ(ppm)7.85(d,J＝1.2Hz,1H),7.83(d,J＝1.2Hz,1H),7.65(t,J＝7.5Hz,1H),7.50(t,J＝7.5Hz,2H),6.91(s,3H),6.82(dd,J＝8.5Hz,3.6Hz,1H),6.74(dt,J＝8.5Hz,2.1Hz,1H),6.69(dd,J＝7.2Hz,2.1Hz,1H),4.17-4.11(m,1H),4.09-4.01(m,1H),3.89-3.82(m,1H),3.80-3.70(m,1H),3.68-3.63(m,1H),3.61-3.53(m,1H),2.00(q,J＝7.3Hz,4H),1.99(s,3H),0.98(s,9H),0.94(d,J＝4.9Hz,9H),0.59(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)148.30,147.52,147.43,146.10,142.37,142.32,136.34,134.05,131.09,130.37,129.06,128.33,126.61,122.28,122.18,121.33,117.40,114.54,77.40,77.23,73.15,72.00,49.27,33.47,29.36,26.15,26.11,26.09,26.03,16.48,8.36.ESI-HRMS calcd for C36H50O7S[M+Na]+649.3277,found 649.3193.
实施例16
合成DK-15，化学结构式如下：
用对硝基苯磺酰氯(0.62mmol)代替甲磺酰氯，以与化合物DK-13相同的方法合成化合物DK-15。1H NMR(500MHz,CDCl3)δ(ppm)8.37(s,1H),8.35(s,1H),8.07(s,1H),8.05(s,1H),6.96-6.94(m,2H),6.90-6.89(m,1H),6.82(dd,J＝8.4Hz,J＝3.6Hz,1H),6.73(dt,J＝8.4Hz,2.1Hz,1H),6.70(dd,J＝6.6Hz，2.1Hz,1H),4.18-4.12(m,1H),4.11-4.02(m,1H),3.89-3.82(m,1H),3.80-3.71(m,1H),3.68-3.64(m,1H),3.62-3.54(m,1H),2.04(s,3H),2.00(q,J＝7.3Hz,4H),0.98(s,9H),0.94(d,J＝4.4Hz,9H),0.59(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ(ppm)148.23,147.67,145.81,142.16,142.12,141.97,131.46,130.15,129.74,126.91,124.28,122.32,122.23,121.02,117.50,117.39,114.58,114.48,77.48,49.32,33.49,33.38,29.71,29.31,29.25,26.17,26.13,26.11,26.05,16.62,8.38.ESI-HRMS calcd for C36H49NO9S[M+Na]+694.3128,found 649.3037.
实施例17
合成DK-16，化学结构式如下：
将化合物14(0.15g,0.39mmol)溶解于20mL丙酮中，依次加入2-溴乙酸乙酯(0.14g,0.85mmol)和碳酸钾(0.16g,1.16mmol)，回流反应8h，反应结束后，浓缩除去大部分丙酮，加入20mL水，加入乙酸乙酯萃取，取有机相，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝35:1)得无色透明油状物0.17g，收率76％。1H NMR(500MHz,CDCl3)δ(ppm)6.91(dd,J＝8.5Hz,2.0Hz,1H),6.85-6.84(m,1H),6.78-6.74(m,2H),6.69-6.67(m,2H),4.66(s,2H),4.60(s,2H),4.24(d,J＝7.2Hz,2H),4.16(d,J＝7.1Hz,2H),4.07(dd,J＝9.1Hz,2.7Hz,1H),3.84(t,J＝8.9Hz,1H),3.68(dd,J＝8.6Hz,2.5Hz,1H),2.15(s,3H),2.00-1.96(m,4H),1.25-1.20(m,6H),1.00(s,9H),0.57(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ169.15,169.09,154.49,147.16,145.91,143.59,140.52,130.59,126.12,125.63,122.05,116.59,114.44,110.28,77.31,69.34,67.12,66.84,61.14,61.06,48.85,33.59,29.67,29.37,26.05,16.53,14.12,14.10,14.06,8.38.ESI-HRMS calcd for C32H46O8[M+Na]+581.3193,found 581.3096.
实施例18
合成DK-17，化学结构式如下：
用4-溴丁酸乙酯(0.85mmol)代替2-溴乙酸乙酯，以与化合物DK-16相同的方法合成化合物DK-17。1H NMR(500MHz,CDCl3)δ(ppm)6.93(dd,J＝8.6Hz,2.0Hz,1H),6.88(s,1H),6.76-6.75(m,1H),6.72-6.71(m,1H),6.68(d,J＝8.6Hz,1H),6.66-6.65(m,1H),4.12(d,J＝6.9Hz,4H),4.08(dd,J＝9.4Hz,2.5Hz,1H),4.00(t,J＝6.2Hz,2H),3.92(t,J＝6.2Hz,2H),3.85(t,J＝8.9Hz,1H),3.69(dd,J＝8.6Hz,2.5Hz,1H),2.53-2.47(m,4H),2.16(s,3H),2.11-2.08(m,2H),2.02-1.98(m,6H),1.26-1.24(m,6H),1.00(s,9H),0.59(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ173.29,154.41,147.94,146.81,142.18,140.86,130.64,126.15,125.54,121.07,115.69,113.25,113.19,110.21,110.18,69.31,68.47,68.01,66.92,60.50,60.33,60.29,48.83,33.58,30.82,30.80,30.53,29.47,29.43,26.05,24.86,24.83,24.78,24.10,16.55,14.20,14.18,8.45,8.39.ESI-HRMS calcd forC36H54O8[M+Na]+637.3819,found 637.3738.
实施例19
合成DK-18，化学结构式如下：
用5-溴戊酸乙酯(0.85mmol)代替2-溴乙酸乙酯，以与化合物DK-16相同的方法合成化合物DK-18。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.75-6.70(m,2H),6.68(d,J＝8.7Hz,1H),6.63-6.62(m,1H),4.11(qd,J＝7.0Hz,3.0Hz,4H),4.07-4.06(m,1H),3.97(t,J＝5.6Hz,2H),3.88(t,J＝5.6Hz,2H),3.85(t,J＝8.9Hz,1H),3.69(dd,J＝8.6Hz,2.5Hz,1H),2.38(d,J＝6.8Hz,2H),2.35(d,J＝7.1Hz,2H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.83-1.81(m,4H),1.77-1.75(m,4H),1.25-1.22(m,6H),1.00(s,9H),0.59(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ173.50,154.40,147.98,146.87,141.92,140.94,130.65,126.16,125.50,120.78,115.39,112.87,110.19,77.33,69.32,68.96,68.56,64.82,60.20,60.19,48.83,34.02,33.58,29.47,28.83,28.77,26.06,21.74,21.67,16.55,14.23,8.46.ESI-HRMS calcd for C38H58O8[M+Na]+665.4132,found 665.4039.
实施例20
合成DK-19，化学结构式如下：
用6-溴己酸乙酯(0.85mmol)代替2-溴乙酸乙酯，以与化合物DK-16相同的方法合成化合物DK-19。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.75-6.68(m,3H),6.65-6.64(m,1H),4.11(q,J＝7.1Hz,4H),4.09-4.07(m,1H),3.95(t,J＝6.5Hz,2H),3.87(t,J＝6.5Hz,2H),3.85-3.83(m,1H),3.69(dd,J＝8.7Hz,2.5Hz,1H),2.28(q,J＝6.9Hz,4H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.82-1.76(m,2H),1.73-1.70(m,2H),1.66-1.61(m,4H),1.50-1.42(m,4H),1.24(t,J＝7.1Hz,6H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ173.72,154.38,148.06,147.04,141.73,140.99,130.68,126.17,125.48,120.74,115.56,112.92,110.19,77.33,69.40,69.34,68.94,68.92,60.13,48.82,34.28,33.58,29.68,29.51,29.27,29.20,28.92,28.90,26.06,25.76,25.70,24.91,24.89,24.84,16.54,14.23,8.47.ESI-HRMS calcd for C40H62O8[M+Na]+693.4445,found 693.4350..
实施例21
合成DK-20，化学结构式如下：
用7-溴庚酸乙酯(0.85mmol)代替2-溴乙酸乙酯，以与化合物DK-16相同的方法合成化合物DK-20。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.75-6.73(m,1H),6.71-6.68(m,2H),6.64-6.62(m,1H),4.13-4.07(m,6H),4.09-4.06(m,1H),3.95(t,J＝6.5Hz,1H),3.88-3.86(m,2H),3.69(dd,J＝8.7Hz,2.5Hz,1H),2.33-2.27(m,4H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.83-1.77(m,2H),1.74-1.64(m,10H),1.51-1.44(m,4H),1.24(t,J＝7.1Hz,6H),1.00(s,9H),0.59(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.38,148.01,146.94,141.81,140.96,130.66,126.15,125.48,120.74,115.49,112.93,110.18,77.32,69.32,69.19,68.78,67.65,60.23,60.16,48.81,34.28,34.27,34.23,34.13,34.11,33.97,33.58,29.67,29.48,29.10,29.03,28.37,26.05,25.69,25.63,25.28,24.76,24.74,24.53,16.55,16.53,14.22,8.46,8.40.ESI-HRMS calcd forC42H66O8[M+Na]+721.4758,found 721.4669.
实施例22
合成DK-21，化学结构式如下：
将化合物DK-16(0.1g,0.18mmol)溶解于20mL乙醇中，加入氢氧化钠(71.59mg,1.79mmol)的水溶液2mL，回流反应24h。反应结束后，浓缩以除去大部分乙醇，加入10mL水，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝5:1)得无色透明油状物67mg，收率75％。1H NMR(500MHz,CDCl3)δ(ppm)6.90(d,J＝8.1Hz,1H),6.84(s,1H),6.79(d,J＝8.1Hz,1H),6.70(t,J＝8.3Hz,2H),6.58(s,1H),4.55(s,2H),4.48(s,2H),4.10(d,J＝8.1Hz,2H),3.87(t,J＝9.0Hz,1H),3.71(d,J＝9.0Hz,1H),2.15(s,3H),2.01-1.96(m,4H),0.99(s,9H),0.58(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ170.86,161.83,154.57,144.59,140.31,130.55,126.04,125.92,122.22,110.56,77.51,69.29,48.93,33.62,29.68,29.23,29.18,26.04,16.54,8.38.ESI-HRMS calcd for C28H38O8[M+Na]+525.2567,found 525.2453.
实施例23
合成DK-22，化学结构式如下：
用DK-17(0.18mmol)代替DK-16，以与化合物DK-21相同的方法合成化合物DK-22。1H NMR(500MHz,CDCl3)δ(ppm)6.91(d,J＝7.7Hz,1H),6.85(s,1H),6.67-6.61(m,4H),4.06(d,J＝8.3Hz,1H),3.85-3.81(m,5H),3.68(d,J＝8.3Hz,1H),2.51-2.41(m,4H),2.13(s,3H),2.04-1.90(m,8H),0.99(s,9H),0.57(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.41,147.88,146.87,142.05,140.85,130.61,126.09,125.55,121.05,110.20,77.38,69.30,48.77,33.59,29.69,29.41,26.07,16.55,8.46.ESI-HRMS calcd for C32H46O8[M+Na]+581.3193,found 581.3099.
实施例24
合成DK-23，化学结构式如下：
用DK-18(0.18mmol)代替DK-16，以与化合物DK-21相同的方法合成化合物DK-23。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.73(s,2H),6.69(d,J＝8.6Hz,1H),6.62(s,1H),4.08(dd,J＝9.2Hz,2.6Hz,1H),3.95(t,J＝5.1Hz,2H),3.87(t,J＝5.1Hz,2H),3.86-3.84(m,1H),3.70(dd,J＝8.6Hz,2.6Hz,1H),2.43-2.39(m,4H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.84-1.80(m,4H),1.80-1.74(m,4H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.39,147.95,146.84,141.92,140.95,130.67,126.16,125.54,120.71,115.16,112.56,110.20,77.42,69.27,68.99,68.55,48.85,34.12,34.08,33.59,29.69,29.47,28.77,28.69,28.46,26.06,21.90,21.79,16.55,8.47.ESI-HRMS calcd for C34H50O8[M+Na]+609.3506,found 609.3446.
实施例25
合成DK-24，化学结构式如下：
用DK-19(0.18mmol)代替DK-16，以与化合物DK-21相同的方法合成化合物DK-24。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.72(s,2H),6.69(d,J＝8.5Hz,1H),6.61(s,1H),4.08(dd,J＝9.2Hz,2.5Hz,1H),3.94(t,J＝6.2Hz,2H),3.87-3.86(m,1H),3.85(t,J＝6.2Hz,2H),3.86-3.83(m,1H),3.70(dd,J＝8.6Hz,2.5Hz,1H),2.37-2.32(m,4H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.83-1.77(m,2H),1.74-1.70(m,4H),1.69-1.66(m,2H),1.56-1.51(m,2H),1.50-1.47(m,2H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ179.70,154.37,147.91,146.84,141.68,140.99,130.69,126.15,125.51,120.53,115.02,112.39,110.17,77.44,69.25,68.98,68.62,48.84,34.28,34.24,33.59,29.68,29.49,29.15,29.03,28.71,26.06,25.83,25.72,25.44,24.72,24.33,16.53,8.47.ESI-HRMS calcd for C36H54O8[M+Na]+637.3819,found 637.3723.
实施例26
合成DK-25，化学结构式如下：
用DK-20(0.18mmol)代替DK-16，以与化合物DK-21相同的方法合成化合物DK-25。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.90(s,1H),6.74-6.71(m,2H),6.69-6.68(m,1H),6.64(s,1H),4.08(dd,J＝9.1Hz,2.4Hz,1H),3.96(t,J＝6.1Hz,2H),3.87-3.84(m,3H),3.70(dd,J＝8.7Hz,2.4Hz,1H),2.30(dd,J＝6.9Hz,6.4Hz,4H),2.16(s,3H),2.01(q,J＝7.3Hz,4H),1.79-1.74(m,2H),1.73-1.67(m,2H),1.66-1.58(m,4H),1.53-1.43(m,4H),1.42-1.33(m,4H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ179.96,154.37,148.12,147.08,141.71,141.01,130.70,126.17,125.51,120.70,115.47,112.77,110.22,77.41,69.41,69.30,68.89,48.84,34.55,34.50,33.59,29.70,29.52,29.39,29.30,29.01,28.98,26.07,25.98,25.88,24.89,16.55,8.49.ESI-HRMS calcd for C38H58O8[M+Na]+665.4132,found 665.4050.
实施例27
合成DK-26，化学结构式如下：
用化合物14(0.41mmol)代替化合物8，以与化合物DK-3相同的方法合成化合物DK-26。1H NMR(500MHz,CDCl3)δ(ppm)6.93(dd,J＝8.7Hz,2.0Hz,1H),6.88(s,1H),6.78-6.76(m,2H),6.69(d,J＝8.4Hz,1H),6.65-6.64(m,1H),4.28-4.25(m,1H),4.15-4.09(m,2H),4.07-4.02(m,2H),3.87-3.80(m,4H),3.70-3.68(m,2H),2.16(s,3H),2.03-1.96(m,8H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.44,147.52,146.10,142.22,140.79,130.61,126.12,125.58,120.70,113.86,111.82,110.24,77.33,69.33,67.88,67.61,64.97,64.93,61.08,61.05,48.89,33.59,31.85,31.76,31.63,29.66,29.43,26.05,16.55,8.43.ESI-HRMS calcd for C30H46O6[M+Na]+525.3294,found525.3194.
实施例28
合成DK-27，化学结构式如下：
将化合物DK-17(0.2g,0.33mmol)溶解于20mL四氢呋喃，在0℃下加入四氢铝锂(61.53mg,1.63mmol)，置于室温反应4h。反应结束后，浓缩除去大部分四氢呋喃，加入10mL水，用乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝10:1)得无色透明油状物0.13g，收率78％。1H NMR(500MHz,CDCl3)δ(ppm)6.93(dd,J＝8.6Hz,2.0Hz,1H),6.89(s,1H),6.74(s,2H),6.69(d,J＝8.6Hz,1H),6.60(s,1H),4.12(d,J＝6.9Hz,4H),4.09(dd,J＝9.4Hz,2.5Hz,1H),4.00(t,J＝5.7Hz,2H),3.89(t,J＝5.7Hz,2H),3.85(t,J＝9.0Hz,1H),3.72-3.67(m,5H),2.17(s,3H),2.01(t,J＝7.3Hz,4H),1.96-1.91(m,2H),1.89-1.84(m,2H),1.80-1.71(m,4H),1.01(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.43,147.48,146.15,141.77,140.91,130.66,126.16,125.56,120.31,113.53,111.34,110.22,77.36,69.33,68.73,68.56,62.20,48.90,33.61,30.04,29.94,29.69,29.48,26.07,25.92,25.81,16.57,8.47.ESI-HRMS calcd for C32H50O6[M+Na]+553.3607,found 553.3512.
实施例29
合成DK-28，化学结构式如下：
用化合物DK-18(0.33mmol)代替化合物DK-17，以与化合物DK-27相同的方法合成化合物DK-28。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.76-6.72(m,2H),6.69(d,J＝8.5Hz,1H),6.61(s,1H),4.08(dd,J＝9.2Hz,2.2Hz,1H),3.97(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),3.85(t,J＝8.8Hz,1H),3.69(dd,J＝8.6Hz,2.2Hz,1H),3.65(t,J＝6.0Hz,2H),3.61(t,J＝6.2Hz,2H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.85-1.80(m,2H),1.75-1.70(m,2H),1.66-1.60(m,2H),1.60-1.52(m,4H),1.53-1.47(m,2H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.39,147.89,146.85,141.79,141.01,130.69,126.17,125.51,120.53,115.17,112.50,110.21,77.37,69.36,69.21,68.87,62.57,62.55,48.85,33.61,32.35,29.68,29.46,28.99,28.84,26.06,22.56,22.44,16.56,8.48.ESI-HRMS calcd for C34H54O6[M+Na]+581.3920,found581.3830.
实施例30
合成DK-29，化学结构式如下：
用化合物DK-19(0.33mmol)代替化合物DK-17，以与化合物DK-27相同的方法合成化合物DK-29。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.89(s,1H),6.76-6.71(m,2H),6.71-6.68(m,1H),6.63(s,1H),4.08(dd,J＝9.2Hz,2.3Hz,1H),3.96(t,J＝6.2Hz,2H),3.88(t,J＝6.2Hz,2H),3.86-3.83(m,1H),3.69(dd,J＝8.7Hz,2.3Hz,1H),3.65-3.60(m,4H),2.16(s,3H),2.00(q,J＝7.3Hz,4H),1.83-1.69(m,6H),1.62-1.55(m,4H),1.53-1.48(m,2H),1.47-1.41(m,4H),1.41-1.36(m,2H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.38,148.04,147.03,141.75,141.03,130.70,126.17,125.50,120.63,115.53,112.77,110.23,77.37,69.38,68.94,62.81,62.79,48.84,33.60,32.71,32.69,29.69,29.49,29.43,29.32,29.29,26.07,26.01,25.92,25.57,16.55,8.48.ESI-HRMS calcd for C36H58O6[M+Na]+609.4233,found 609.4140.
实施例31
合成DK-30，化学结构式如下：
用化合物DK-20(0.33mmol)代替化合物DK-17，以与化合物DK-27相同的方法合成化合物DK-30。1H NMR(500MHz,CDCl3)δ(ppm)6.94(dd,J＝8.7Hz,2.0Hz,1H),6.90(s,1H),6.76-6.74(m,1H),6.72-6.70(m,1H),6.69(d,J＝8.6Hz,1H),6.65-6.64(m,1H),4.08(dd,J＝9.2Hz,2.6Hz,1H),3.96(t,J＝6.5Hz,2H),3.88(t,J＝6.5Hz,2H),3.85(t,J＝9.0Hz,1H),3.70(dd,J＝8.7Hz,2.6Hz,1H),3.62(dd,J＝6.4Hz,5.6Hz,4H),2.16(s,3H),2.01(q,J＝7.3Hz,4H),1.81-1.76(m,2H),1.74-1.68(m,2H),1.58-1.53(m,4H),1.50-1.46(m,2H),1.45-1.42(m,2H),1.40-1.37(m,4H),1.36-1.34(m,4H),1.00(s,9H),0.60(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.38,148.07,147.08,141.69,141.03,130.71,126.18,125.49,120.67,115.61,112.85,110.22,77.37,69.48,69.36,69.03,62.93,62.91,48.84,33.59,32.71,32.69,29.68,29.52,29.41,29.31,29.24,29.22,26.13,26.06,26.02,25.76,25.73,16.55,8.48.ESI-HRMS calcd for C38H62O6[M+Na]+637.4546,found637.4459.
实施例32
合成DK-31，化学结构式如下：
将化合物14(0.15g,0.39mmol)溶解于丙酮中，依次加入碳酸钾(160.90mg,1.16mmol)和甲磺酰氯(111.13mg,0.97mmol)，室温反应8h。反应结束后，浓缩除去大部分丙酮，加入10mL水，加入乙酸乙酯萃取，取有机层，使用饱和食盐水洗涤，无水硫酸钠干燥，得白色油状物，经柱层析纯化(石油醚：乙酸乙酯＝20:1)得无色透明油状物0.17g，收率82％。1HNMR(500MHz,CDCl3)δ(ppm)7.32(d,J＝8.6Hz,1H),7.28(d,J＝2.0Hz,1H),7.12(dd,J＝8.6Hz,2.0Hz,1H),6.92(dd,J＝8.5Hz,2.3Hz,1H),6.88(d,J＝1.5Hz,1H),6.72(d,J＝8.5Hz,1H),4.09(dd,J＝9.3Hz,2.6Hz,1H),3.86(t,J＝8.9Hz,1H),3.70(dd,J＝8.6Hz,2.6Hz,1H),3.21(s,3H),3.18(s,3H),2.18(s,3H),2.05(q,J＝7.3Hz,4H),1.01(s,9H),0.62(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.90,150.54,140.21,138.96,138.47,130.44,128.15,126.22,126.14,124.11,123.07,110.61,77.31,69.42,49.43,38.43,38.39,33.62,29.47,26.06,16.57,8.33.ESI-HRMS calcd for C26H38O8S2[M+Na]+565.2008,found 565.1906.
实施例33
合成DK-32，化学结构式如下：
用对甲苯磺酰氯(0.97mmol)代替甲磺酰氯，以与化合物DK-31相同的方法合成化合物DK-32。1H NMR(500MHz,CDCl3)δ(ppm)7.65(d,J＝8.2Hz,2H),7.55(d,J＝8.2Hz,2H),7.25(d,J＝8.1Hz,2H),7.21(d,J＝8.1Hz,2H),7.12(d,J＝8.9Hz,2H),6.99-6.97(m,2H),6.86(d,J＝8.5Hz,1H),6.77(s,1H),6.71(d,J＝8.5Hz,1H),4.10(dd,J＝9.3Hz,2.2Hz,1H),3.87(t,J＝8.9Hz,1H),3.71(dd,J＝8.5Hz,2.2Hz,1H),2.42(s,3H),2.41(s,3H),2.18(s,3H),1.99-1.90(m,4H),1.01(s,9H),0.56(t,J＝7.3Hz,6H).13C NMR(125MHz,CDCl3)δ154.80,149.68,145.52,145.44,140.58,139.35,138.72,132.41,132.35,130.48,129.60,128.56,127.48,126.08,125.97,123.80,123.27,110.49,77.34,77.06,76.81,69.45,49.18,33.63,29.20,26.07,21.73,21.69,16.59,8.28.ESI-HRMS calcd for C38H46O8S2[M+Na]+717.2634,found 717.2538.
实施例34
下面是本发明部分化合物的药效学试验及结果，化合物代号对应的结构式见实施例。阳性药的结构式：
(1)化合物的VDR亲和力活性试验
实验方法：利用化合物与荧光性VDR配体竞争性结合VDR受体，从而降低荧光强度的原理，测定化合物的VDR亲和力。按照Polarscreen Vitamin D Receptor CompetitorAssay的要求，将化合物稀释到1μM浓度，与荧光性VDR配体和VDR室温避光共孵育3小时，用多功能酶标仪在535nm/590nm条件下检测其偏振光强度，重复测定三次。化合物亲和力以骨化三醇为阳性对照。样品的亲和力比率通过下列公式求得：亲和力比率(％)＝((空白组-给药组)/(空白组-阳性对照组))*100％。实验结果见表1。
表1本发明化合物对VDR的相对亲和力
上述药效试验证明，本发明部分化合物具有较好的VDR亲和力。其中化合物DK-1，DK-3与DK-4的相对亲和力高于先导化合物LG190178。
(2)化合物激动VDR的能力测定
实验方法：将化合物10倍稀释至三个浓度(10nM,100nM,1000nM)，将表达VDR的质粒和含有VDR特异性结合的报告基因质粒共转染到HEK293细胞中，运用Luciferase报告基因系统检测化合物对VDR的激动能力。实验结果见图1。
上述药效实验结果表明，本发明化合物DK-1，DK-3与DK-4具有较好的VDR激动能力。
(3)化合物对正常细胞毒性测定
实验方法：取对数生长期的LTC-14细胞(永生化胰腺星状细胞)，调整细胞密度为1×105个/mL的细胞悬液，接种于96孔细胞板中，每孔接种细胞悬液200μL，置于37℃，5％CO2恒温培养箱内培养。细胞接种24h后，弃去上清，利用IMDM不完全培养液将化合物的DMSO母液稀释成50μM、20μM、10μM、1μM、0.1μM和0.01μM共六个浓度，每孔给予200uL此溶液，每个化合物设3个平行孔；继续培养，48h后弃上清，每孔加入20μL的MTT工作液继续培养4h。弃去上清，每孔加入150μL DMSO于摇床上振动10min，用酶标仪测定波长570nm的吸光值，重复测定三次。用GraphPad Prism 5.0软件计算各化合物的IC50值。实验结果见表2。
表2本发明化合物对LTC-14细胞的毒性
上述药效实验结果证明，本发明化合物对星状细胞LTC-14不具有明显毒性，且IC50值均大于5μM。
(4)化合物体外抗I型胶原合成活性试验
实验方法：1.检测化合物对胞外胶原含量的影响。
采用双抗体夹心ELISA法。取对数生长期的LX-2细胞，调整细胞密度为1×105个/mL的细胞悬液，接种于24孔细胞培养板中，每孔接种细胞悬液500μL，置于37℃，5％CO2恒温培养箱内培养。细胞接种24h后，弃去上清，利用IMDM不完全培养液将配制的0.5μM待测化合物，每孔给予500uL此溶液，每个化合物设3个平行孔；继续培养。细胞与药物共孵育24h后取上清200uL，按照人I型胶原(COL1)酶联免疫吸附测定试剂盒操作说明，进行I型胶原含量的测定。用酶标仪(450nm)测得化合物对应的OD值。化合物抗I型胶原合成活性以卡泊三醇为阳性对照。样品的比率通过下列公式求得:抗I型胶原合成比率(％)＝OD450(空白组-加药组)/OD450(空白组-阳性对照组)×100％。结果见表3：
表3本发明化合物体外抗Ⅰ型胶原合成活性
2.检测化合物对胞内胶原含量的影响。根据已有的化合物抗I型胶原合成能力结果，选取活性较好的化合物(0.5μM)，在给予TGFβ1(5ng/mL)刺激的情况下，通过体外western blot和Q-PCR测试COL1α1和α-SMA的表达含量。结果见图2与图3。
上述药效实验结果表明，本发明化合物具有较好的抗胞外胶原合成能力，其中7，DK-1，DK-2，DK-3，DK-4，DK-5的抗胞外胶原合成活性比先导化合物LG190178更强。且本发明化合物DK-3，DK-4比先导化合物LG190178具有更强的抑制胞内胶原合成能力。
(5)化合物体内抗纤维化活性试验
实验方法：1.模型建立。
雄性C57BL/6小鼠被随机分成4组，每组5只小鼠。小鼠能自由地获取食物和水，饲养在通风且温度为23℃左右的房间中，并保持12h光照和12h黑暗的昼夜交替。实验中使用雨蛙素诱导的小鼠胰腺炎模型，具体操作方法如下:将雨蛙素和玉米油按照1:50混合，每只小鼠按照50μg/kg体重腹腔注射5周，每周注射3天，每天注射6次，每次间隔时间为1h。对照组则按照相同剂量每周腹腔注射玉米油。在给予雨蛙素21天后，通过灌胃给予小鼠卡泊三醇或化合物DK-3，1周5次。在给予最后一次雨蛙素72h后通过眼眶取血，断颈处死小鼠。
2.化合物DK-3对胰腺炎组织的影响。标本处理，将胰腺组织切成4mm×4mm左右的方块，置于4％多聚甲醛中固定24h，连续石蜡切片，做HE染色和Masson染色；取胰腺组织进行羟脯氨酸含量测定，观察组织结构受损及纤维增生期胶原积累情况。HE染色程序，制作石蜡组织切片后，切片脱蜡至水，依照以下流程进行HE染色：二甲苯5min-二甲苯5min-100％乙醇2min-95％乙醇2min-90％乙醇2min-85％乙醇2min-80％乙醇2min-70％乙醇2min-50％乙醇2min-30％乙醇2min-苏木精5min-蒸馏水冲洗5min-弱氨水5s-蒸馏水2min-30％乙醇2min-50％乙醇2min-70％乙醇2min-80％乙醇2min-85％乙醇2min-85％乙醇30min-90％乙醇2min-95％乙醇伊红10min-95％乙醇2min-100％乙醇2min-100％乙醇2min-二甲苯5min-二甲苯5min，稍干后，中性树胶封片，晾干，显微镜下观察胰腺组织结构。马松染色程序，切片脱蜡至水，使用马松试剂盒，依照说明进行操作。马松复合染色液试剂A5min-蒸馏水冲洗-磷钼酸试剂C 5min-甩干-苯胺蓝试剂D 5min-蒸馏水冲洗-分化液试剂B 30-60s，两次-95％乙醇5min-100％乙醇5min-二甲苯透明10min，稍干后，中性树胶封片，晾干，显微镜下观察胰腺组织胶原沉积情况。
体内实验结果见图4。
由图4可见，本发明化合物DK-3具有较好的体内抗胰腺纤维化的活性。
(6)化合物体内升血钙活性试验
实验方法：取得全血后室温静置30min，然后3000rpm离心15分钟，取上清。通过血钙检测试剂盒检测血清中及血液中钙离子的含量。实验结果见图5。
由图5可见，本发明化合物DK-3不具有升高血钙的副作用。
(7)化合物对小鼠体重的影响试验
实验方法：小鼠建模成功后，每三天称重一次，记录体重变化。实验结果见图6。
由图6可见，本发明化合物DK-3不会对小鼠体重产生显著影响。
Claims (6)
1.式I所示的化合物或其药学上可接受的盐，
其中，
n代表整数0或1；
R4代表羟基取代的C1～6烷基、
q代表整数0；
R9代表取代的苯基，其取代基选自C1～4烷基或硝基；
R11代表氢；
R12氢或羟基取代的C1～4烷基。
2.根据权利要求1所述的化合物或其药学上可接受的盐，其中，
R9代表取代的苯基，其取代基选自甲基、乙基或硝基中的一种或多种。
3.根据权利要求1所述的化合物或其药学上可接受的盐，其中，
R12代表羟基取代的C1～2烷基。
4.根据权利要求1所述的化合物或其药学上可接受的盐，其中上述化合物选自：
5.一种权利要求1所述的化合物的制备方法，其特征在于，通式I化合物，合成路线如下：
其中，n代表整数0或1。
6.权利要求1所述的化合物或其药学上可接受的盐在制备与抗纤维化有关疾病的药物方面的应用。
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