CN115175892A - 消退素e2的稳定等效物 - Google Patents
消退素e2的稳定等效物 Download PDFInfo
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- CN115175892A CN115175892A CN202180014981.3A CN202180014981A CN115175892A CN 115175892 A CN115175892 A CN 115175892A CN 202180014981 A CN202180014981 A CN 202180014981A CN 115175892 A CN115175892 A CN 115175892A
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- KPRHYAOSTOHNQA-NNQKPOSRSA-N resolvin E2 Chemical compound CC[C@@H](O)\C=C\C=C/C\C=C/C\C=C/C=C/[C@@H](O)CCCC(O)=O KPRHYAOSTOHNQA-NNQKPOSRSA-N 0.000 title description 39
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Abstract
Description
技术领域
本发明涉及一种具有与消退素E2相同的抗炎作用且比消退素E2更稳定的化合物,和以该化合物为有效成分的抗炎剂。
背景技术
消退素(Rvs)是ω-3多不饱和脂肪酸的代谢物,具有很强的抗炎作用(非专利文献1),近年来作为新型抗炎剂的引领者备受关注。Rvs通过抑制中性粒细胞浸润和以显著低剂量促进巨噬细胞的吞噬作用,积极促进炎症消散。其中,消退素E2(RvE2:(5S,6E,8Z,11Z,14Z,16E,18R)-5,18-dihydroxyicosa-6,8,11,14,16-pentaenoic acid)是一种脂质介质,具有极强的炎症收敛作用。然而,由于其多不饱和结构,Rvs在化学和代谢上都不稳定。因此,需要开发出在维持强效的抗炎活性的同时更加稳定的物质。
作为RvE2的稳定等效化合物,已报道有例如RvE2的环丙烷同系物(congener)(CP-RvE2)(非专利文献2)。RvE2的跳跃二烯(skipped diene)部分的两个双烯丙基C10和C13的位置容易被氧化。CP-RvE2是用cis-环丙烷取代C11-C12的cis-烯烃的化合物。
现有技术文献
非专利文献
非专利文献1:Serhan and Petasis,Chemical Reviews,2011,vol.111(10),p.5922-5943.
非专利文献2:Fukuda et al.,Organic Letters,2016,vol.18(24),p.6224-6227.
非专利文献3:Deyama et al.,Psychopharmacology,2018,vol.235,p.329-336.
非专利文献4:Ningzhang Zhou et al.,Org.Lett.,2008,10,14,3001-3004
非专利文献5:Jean-Martial L’Helgoual’ch et al.,Chem.Commun.,2008,5375-5377
非专利文献6:Gotz,K.,Liermann et al.,Org.Biomol.Chem.,2010,8,2123
非专利文献7:Corey,E.J.et al.,J.Am.Chem.Soc.,1997,119,11769
非专利文献8:Boer,R.E.et al.,Org.Lett.,2018,20,4020
发明内容
发明所要解决的课题
CP-RvE2是一种强效的抗炎剂,与RvE2相比,对氧的稳定性有所改善,但代谢稳定性不足。此外,合成CP-RvE2需要相当长的反应步骤,其结果是存在总产率低的问题。
也就是说,本发明的目的在于提供一种RvE2的稳定等效物,该RvE2的稳定等效物克服了阻碍RvE2药物应用的两个问题,也即化学及代谢上的不稳定性和化学合成繁琐。
用于解决课题的手段
本发明者们发现通过用苯环取代RvE2的跳跃二烯部分得到的RvE2的苯同系物(BZ-RvE2)在与RvE2同样表现出抗炎活性的同时,化学及代谢上的稳定性更高,且相对容易合成,籍此完成了本发明。
也即,本发明提供了以下等化合物。
[1]由下述通式(1)或(1′)表示的化合物:
[化学式1]
式中,R1和R2分别独立为氢原子或羟基;R3为碳数为1-6的烷基;R4为卤素原子或烷基;m为R4的数目,且为0-4的整数;当m为2以上时,多个R4可以相同也可以不同;n为1-6的整数;n’为1-4的整数。
[2]根据[1]所述的化合物,其由下述通式(1-o)或通式(1-m)表示:
[化学式2]
式中,R1、R2、R3、R4、m以及n与所述通式(1)相同。
[3]根据[2]所述的化合物,其由下述通式(1-o-1)、(1-o-2)、(1-m-1)或(1-m-2)表示:
[化学式3]
式中,R3、R4、m以及n与所述通式(1)相同。
[4]根据[1]-[3]中任一项所述的化合物,其中,所述卤素原子为氟原子、氯原子、溴原子或碘原子,所述烷基为甲基。
[5]根据[1]-[4]中任一项所述的化合物,其中,所述卤素原子为溴原子。
[6]根据[1]-[5]中任一项所述的化合物,其中,所述通式(1)中或(1′)中,m为0或1。
[7]根据[2]-[6]中任一项所述的化合物,其中,所述通式(1-o)、(1-m)中,R4在具有羧酸基团的取代基的间位或对位取代。
[8]根据[1]所述的化合物,其中,所述通式(1′)中,具有R2和R3的取代基在具有内酯环的取代基的邻位或间位取代。
[9]根据[8]所述的化合物,其中,所述通式(1′)中,R4在具有内酯环的取代基的间位或对位取代。
[10]根据[1]所述的化合物,其中,所述通式(1′)为下述通式(1′-1)或(1′-2)。
[化学式4]
[11]一种中性粒细胞浸润抑制剂,其以[1]-[10]中任一项所述的化合物作为有效成分。
[12]一种抗炎剂,其以[1]-[10]中任一项所述的化合物作为有效成分。
[13]一种抗抑郁剂,其以[1]-[10]中任一项所述的化合物作为有效成分。
[14]一种药物组合物,以[1]-[10]中任一项所述的化合物作为有效成分。
[15]根据[14]所述的药物组合物,其用于治疗炎症。
[16]根据[14]所述的药物组合物,其用于治疗抑郁症。
发明效果
本发明提供的化合物在与RvE2同样表现出抗炎活性的同时,化学及代谢上的稳定性更高,且相对容易合成。因此,该化合物与RvE2一样,作为药物组合物的有效成分,在用于治疗炎症性疾病等方面作用重大。
附图说明
图1是示出了实施例1中进行了RvE2、o-BZ-RvE2、m-BZ-RvE2、以及p-BZ-RvE2的抗炎性评价试验的结果的图。图1(a)是示出了将300pg的RvE2、o-BZ-RvE2、m-BZ-RvE2、p-BZ-RvE2或仅溶剂,对急性炎症模型小鼠进行腹腔内给药,收集腹膜渗出液并对中性粒细胞进行计数的结果的图。图1(b)是示出了将300fg、300pg或300ng的RvE2、o-BZ-RvE2或仅溶剂,对急性炎症模型小鼠进行腹腔内给药,收集腹膜渗出液并对中性粒细胞进行计数的结果的图;
图2是示出了实施例1中进行了RvE2、o-BZ-RvE2、m-BZ-RvE2、以及p-BZ-RvE2的对人肝微粒体代谢稳定性评价试验的结果的图;
图3是示出了实施例2中进行了RvE2、o-BZ-RvE2、17-deoxy-o-BZ-RvE2、5-deoxy-o-BZ-RvE2、以及5,17-dideoxy-o-BZ-RvE2的抗炎性评价试验的结果的图;
图4是示出了实施例2中进行了RvE2、o-BZ-RvE2、17-deoxy-o-BZ-RvE2、5-deoxy-o-BZ-RvE2、以及5,17-dideoxy-o-BZ-RvE2的对人肝微粒体代谢稳定性评价试验的结果的图。
具体实施方式
在本发明和本申请说明书中,“Cy-z(y和z为满足y<z的正整数)”表示碳数在y以上且z以下。
在本发明和本申请说明书中,“用式(X)表示的化合物”有时用“化合物(X)”表示。
本发明提供的化合物是由下述通式(1)或(1′)表示的化合物(以下有时称为“化合物(1)”或“化合物(1′)”)。化合物(1)和(1′)为BZ-RvE2及其同系物,其中RvE2的跳跃二烯部分被苯环取代。化合物(1)和(1′)将稳定性较低的二烯部分取代为稳定性较高的苯环,因此在化学上和代谢上都是稳定的。
<化合物(1)>
[化学式5]
式中,R1和R2分别独立为氢原子或羟基;R3为碳数为1-6的烷基;R4为卤素原子或烷基;m为R4的数目,且为0-4的整数;当m为2以上时,多个R4可以相同或不同;n为1-6的整数。
在通式(1)中,m优选为0-2的整数,更优选为0或1。在通式(1)中,优选为当m为1以上时,R4为氟原子、氯原子、溴原子、碘原子或甲基,更优选为当m为1时,R4为溴原子。在后述式(1-o)、(1-m)中,优选R4在具有羧酸基团的取代基的间位或对位取代。
化合物(1)包括化合物(1-o)、化合物(1-m)和化合物(1-p)。
[化学式6]
在通式(1)、(1-o)、(1-m)和(1-p)中,R1和R2分别独立为氢原子或羟基。作为化合物(1)、化合物(1-o)、化合物(1-m)和化合物(1-p),优选R1为羟基且R2为氢原子的化合物或R1和R2均为羟基的化合物,特别优选R1为羟基且R2为氢原子的化合物。
在通式(1)、(1-o)、(1-m)和(1-p)中,R3为碳数1-6的烷基(C1-6烷基)。C1-6烷基可以是直链状,也可以是支链状。作为该C1-6烷基可以举出甲基、乙基、丙基、异丙基、丁基、异丁基、sec-丁基、tert-丁基、戊基、异戊基、新戊基、tert-戊基、己基等。作为化合物(1)、化合物(1-o)、化合物(1-m)和化合物(1-p),优选R3为C1-4烷基的化合物,更优选R3为直链C1-4烷基的化合物,进一步优选R3为甲基、乙基或丙基的化合物,特别优选R3为乙基的化合物。
在通式(1)、(1-o)、(1-m)和(1-p)中,n为1-6的整数。作为化合物(1)、化合物(1-o)、化合物(1-m)和化合物(1-p),优选n为2-5的整数的化合物,更优选n为2-4的整数的化合物,特别优选n为3的化合物。
在通式(1-o)、(1-m)中,R4和m与前述通式(1)相同。
由于在生物体内的代谢稳定性更好,化合物(1)优选为化合物(1-o)或化合物(1-m),更优选为化合物(1-o)。作为化合物(1-o)可以举出化合物(1-o-1)~化合物(1-o-4),作为化合物(1-m)可以举出化合物(1-m-1)~化合物(1-m-4)。由于包括中性粒细胞浸润抑制作用在内的抗炎作用更好,化合物(1)优选为由下述通式(1-o-1)、(1-o-2)、(1-m-1)或(1-m-2)表示的化合物,更优选为由下述通式(1-o-2)或(1-m-2)表示的化合物,进一步优选为由下述通式(1-o-2)表示的化合物。
[化学式7]
在通式(1-o-1)~(1-o-4)、(1-m-1)~(1-m-4)中,R3、R4、m以及n与前述通式(1)相同。作为由这些通式表示的化合物优选R3为直链C1-4烷基,n为2-4的整数的化合物,更优选R3为甲基、乙基或丙基,n为2-4整数的化合物。
<化合物(1′)>
[化学式8]
在通式(1′)中,R2、R3、R4以及m与前述通式(1)相同。n’为1-4的整数,优选为3。在通式(1′)中,优选为具有R2和R3的取代基在具有内酯环的取代基的邻位或间位取代。此时,优选R4在具有内酯环的取代基的间位或对位取代。
化合物(1′)优选为由下述式(1′-1)或(1′-2)表示的化合物。
[化学式9]
化合物(1)可以形成盐。作为形成该盐的碱基可以举出钠、钾等碱金属;钙、镁等碱土金属等。此外,化合物(1)和(1′)可以是水合物等的形态。例如,化合物(1)中的羧基可以形成如钠、钾等的碱金属盐。
化合物(1)和(1′)可以像例如后述实施例所示那样,通过Stille偶联反应等将RvE2的ω-端链部分和羧酸链部分连接至苯环来进行合成。由于是以稳定的苯化合物为原料,可以在相对温和的反应条件下进行合成反应,化合物(1)和(1′)与RvE2和CP-RvE2相比更易于化学合成。
化合物(1)和(1′)是RvE2的稳定等效物,具有与RvE2相同的药理作用。例如,化合物(1)和(1′)与RvE2一样具有炎症收敛作用。因此,化合物(1),(1′)及其盐作为药物组合物的有效成分,在用于治疗通过炎症收敛作用预期具有治疗或预防效果的疾病治疗方面作用重大,特别是适合作为药物组合物的有效成分,用于治疗或预防炎症和炎症性疾病。作为炎症性疾病可以举出如溃疡性结肠炎、克罗恩病等炎症性肠病,如过敏性皮炎、哮喘、过敏性鼻炎等过敏性疾病,如类风湿性关节炎、胶原病、系统性红斑狼疮、多发性肌炎/皮肌炎、干燥综合征等自身免疫性疾病等。此外,化合物(1)和(1’)与RvE2一样(非专利文献3)可用作药物组合物的有效成分,用于治疗或预防抑郁症。
化合物(1)、(1′)或其盐为低分子化合物,因此不存在免疫原性等问题。此外,也可以口服给药,给药途径也不受太大限制。因此,化合物(1)、(1′)或其盐特别地可以用作包括人类在内的哺乳动物的药物的有效成分。
当药物组合物中含有化合物(1)、(1′)或其盐时,可以根据需要与药物上允许的载体配合,并根据预防或治疗目的采用各种给药形式。作为该形式例如可以举出:口服剂、注射剂、栓剂、软膏剂、贴剂等,但优选为口服剂。这些给药形式可以通过本领域技术人员公知惯用的制剂方法来制造。
作为药学上允许的载体可以举出:固体制剂中的赋形剂、粘合剂、崩解剂、润滑剂、着色剂;液体制剂中的溶剂、溶解辅助剂、混悬剂、等渗剂、缓冲剂、无痛剂等。必要时也可使用防腐剂、抗氧化剂、着色剂、甜味剂、稳定剂等制剂添加剂。
制备口服固体制剂时,可以在化合物(1)或(1′)中加入赋形剂,必要时加入粘结剂、崩解剂、润滑剂、着色剂、除味/除臭剂等之后,按常规方法制造片剂、包覆片剂、颗粒剂、散剂、胶囊剂等。
制备口服液体制剂时,可以在化合物(1)或(1′)中加入矫味剂、缓冲剂、稳定剂、矫臭剂等,然后按常规方法制造口服液体剂、糖浆剂、助氧剂等。
制备注射剂时,可以在化合物(1)或(1′)中加入pH调节剂、缓冲剂、稳定剂、等渗剂、局部麻醉剂等,然后按常规方法制造皮下、肌内和静脉用注射剂。
制备栓剂时,可以在化合物(1)或(1′)中加入本行业已知的例如聚乙二醇、羊毛脂、可可脂、脂肪酸甘油三酯等制剂载体,然后按常规方法进行制造。
制备软膏剂时,将在化合物(1)或(1′)中常规使用的基剂、稳定剂、润湿剂、防腐剂等根据需要配制,并按常规方法进行混合和制剂。
制备贴剂时,将上述软膏、乳膏、凝胶、膏状物等按常规方法涂在常规的支撑物上即可。
虽然前述各制剂中化合物(1)或(1′)的含量根据患者的症状和剂型等不是固定的,但通常口服制剂约为0.05-1000mg,注射剂约为0.01-500mg,栓剂约为1-1000mg。
此外,虽然这些制剂的每日的给药量根据患者的症状、体重、年龄、性别等不同不能一概而论,但普通成人(体重60kg)每日的化合物(1)或(1′)约为0.05-5000mg左右,优选为0.1-1000mg,且优选每日1次或分为2-3次左右进行给药。
被以化合物(1)或(1′)为有效成分的中性粒细胞浸润抑制剂、抗炎剂和药物组合物进行给药的动物不受特别限制,可以是人,也可以是非人动物。作为非人动物可以举出:牛、猪、马、羊、山羊、猴、狗、猫、兔、小鼠、大鼠、仓鼠、豚鼠等哺乳动物和鸡、鹌鹑、鸭等鸟类。
实施例
下面示出实施例更详细地说明本发明,但本发明不限于以下的实施例。
<化合物的分析方法>
使用NMR装置JEOL ECX400P(400MHz)、JEOL EXP400(400MHz)以及JEOL ECA500(500MHz)(均为日本电子公司制造)进行NMR光谱测量。化学位移是以相对于四甲基硅烷(TMS)的δ尺度作为内部标准,已报道的有:相对于1H(CDCl3)为0.00ppm,残留CHCl3(相对于1H为7.26ppm,相对于13C为77.16ppm),CH3OH(相对于1H为3.31ppm,相对于13C为49.0ppm)。
使用质谱装置JEOL JMS-HX110、JEOL JMS-T100GCV、JEOL JMS-T100LCP、以及JEOLJMS-700TZ(ESI)(均为日本电子公司制造)进行质谱(MS)测量。
旋光度使用旋光计DIP-1030(日本分光公司制造)测量。
硅胶柱色谱法(silica gel column chromatography)和快速柱色谱法(flashcolumn chromatography)分别使用Wakogel 60N(和光纯药工业公司生产,中性,63-212μm)和硅胶60N(关东化学公司生产,球状,中性,40-50m)进行测定。
如无特别说明,所有的反应均在氩气环境下,使用直火或烤箱干燥的玻璃器具进行,并使用分析TLC(TLC硅胶60F254,Merck公司制造)进行监测。
<动物实验>
所有动物程序均按照日本北海道大学动物伦理委员会执行。
<抗炎性评价试验>
使用将痤疮丙酸杆菌移植到腹腔内诱发的小鼠急性炎症模型,对各化合物的抗炎作用的强度进行了评价。
小鼠急性炎症模型使用雄性BALB/c小鼠(6-7周,从Japan SLC公司获得)制作。首先,将热杀菌后的痤疮丙酸杆菌(Propionibacterium acnes,P.acnes;每小鼠500μg)注射到小鼠的腹腔内,制作急性炎症模型小鼠。在痤疮丙酸杆菌注射8或12小时后,对急性炎症模型小鼠进行受试化合物的腹腔内给药。然后,在痤疮丙酸杆菌注射24小时后,收集腹膜渗出液并计数中性粒细胞数。
<代谢稳定性评价>
从作为评价对象的合成化合物的乙醇溶液(1mg/1mL)中分取60μL,并除去溶剂。将0.1M的PBS缓冲液(435μL,pH7.4)、CH3CN(10μL)、NADPH再生系统A溶液(25μL)、以及NADPH再生系统B溶液(5μL)添加到各化合物中,并用涡流搅拌机搅拌。将所得到的反应液在37℃下温育5分钟后,加入人肝微粒体(Corning(注册商标)UltraPool(注册商标)HLM 150)(25μL),每隔1小时(添加后0、1、2、3、6小时)分取80μL的溶液。分取的溶液通过加入CH3CN(80μL)进行淬灭后,在室温下离心(10000rpm)3分钟。收集上清液,使用HPLC(COSMOSIL 5C18-MS-II,4.6mm×250mm,CH3CN/H2O/TFA=35/65/0.01,1.0mL/分,检测254nm)进行分析。
实施例1
将2-碘苯甲醇通过Stille偶联与乙烯基烷依次连接,经过脱保护、水解后合成o-BZ-RvE2[通式(1-o-1)中,R3为乙基,m为0,n为3的化合物]。通过从相同途径使用相应的碘苯甲醇,还合成了m-BZ-RvE2[通式(1-m-1)中,R3为乙基,m为0,n为3的化合物]和p-BZ-RvE2[通式(1-p)中,R1和R2为羟基,R3为乙基,m为0,n为3的化合物]。
[化学式10]
[化学式11]
<Methyl(S,E)-5-hydroxy-7-(tributylstannyl)hept-6-enoate(S2)>
向Cy3PH·BF4(88.0mg,0.24mmol)和i-Pr2NEt(84μL,0.48mmol)的CH2Cl2(60mL)溶液中在室温下加入Pd2(dba)3(55mg,60μmol)。将所得到的溶液在相同温度下搅拌10分钟。在反应混合物中,加入含有化合物S1(1.87g,12.0mmol,>99%ee)和Bu3SnH(3.9mL,14.4mmol)的CH2Cl2溶液0℃后,将该混合物在相同温度下搅拌一夜浓缩。将所得到的残渣用硅胶柱色谱法(K2CO3-SiO2=1:9,AcOEt-己烷=1:8)纯化,得到无色油状的化合物S2(3.5g,7.83mmol,65%)。化合物S2的分析结果如下所示,这与以往报道的结果一致。
1H NMR(400MHz,CDCl3)δ6.15(dd,J=19.2,1.0Hz,1H),5.99(dd,J=19.2,5.2Hz,1H),4.08(m,1H),3.67(s,3H),2.36(t,J=7.6Hz,2H),1.78-1.65(m,2H),1.61-1.54(m,2H),1.53-1.45(m,6H),1.30(sextuplet,J=7.2Hz,6H),0.91-0.87(m,15H).
<Methyl(S,E)-5-((tert-butyldimethylsilyl)oxy)-7-(tributylstannyl)hept-6-enoate(8)>
将化合物S2(3.5g,7.83mmol)的DMF(52mL)溶液搅拌后,在室温下加入咪唑(2.13g,31.3mmol)和TBSCl(2.36g,15.7mmol)。将所得到的混合物在相同温度下搅拌12小时,通过添加水淬灭后,用AcOEt/己烷(1:4)萃取。将所得到的有机萃取物全部混合,用盐水洗净,并用硫酸钠(Na2SO4)干燥浓缩。将所得到的残渣用快速硅胶柱色谱法(K2CO3-SiO2=1:9,AcOEt-己烷=1:8)纯化,得到无色油状的化合物(8)(4.0g,7.12mmol,91%)。化合物(8)的分析结果如下所示,这与以往报道的结果一致。
1H NMR(400MHz,CDCl3)δ6.04(d,J=19.2Hz,1H),5.89(dd,J=19.2,6.0Hz,1H),4.04(dt,J=6.0,6.0Hz,1H),3.66(s,3H),2.32(t,J=7.4Hz,2H),1.72-1.59(m,2H),1.55-1.40(m,8H),1.30(sextuplet,J=7.6Hz,6H),0.90-0.85(m,24H),0.04(s,3H),0.02(s,3H).
[化学式12]
<(R,E)-1-(Tributylstannyl)pent-1-en-3-ol(3)>
将化合物(2)(2.0g,5.4mmol,95%ee)的DMF(52mL)溶液搅拌后,在室温下加入咪唑(1.47g,21.6mmol)和TBSCl(1.62g,10.8mmol)。将所得到的混合物在相同温度下搅拌12小时,通过添加水淬灭,并用AcOEt/己烷(1:4)萃取。将所得到的有机萃取物全部混合,用盐水洗净,并用硫酸钠干燥浓缩。将所得到的残渣用快速硅胶柱色谱法(K2CO3-SiO2=1:9,AcOEt-己烷=1:10)纯化,得到无色油状的化合物(3)(2.1g,4.28mmol,79%)。化合物(3)的分析结果如下所示。
[α]15 D+19.2(c 1.00,CHCl3);
1H NMR(500MHz,CDCl3)δ6.01(dd,J=19.3,0.8Hz,1H),5.91(dd,J=19.3,5.5Hz,1H),3.96(dt,J=5.5,5.5Hz,1H),1.54-1.40(m,8H),1.30(tq,J=7.5,7.5Hz,6H),0.94-0.81(m,27H),0.05(s,3H),0.04(s,3H);
13C NMR(100MHz,CDCl3)δ151.8,126.6,78.2,31.0,29.3,27.4,26.1,18.5,13.9,10.0,9.6;
LRMS(ESI)m/z 513.25[(M+Na)+];
HRMS(EI)calcd for C19H41OSSn:433.1949[(M-Bu)+],found:433.1951.
<(R,E)-(2-(3-((Tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)methanol(5a)>
将化合物(3)(510mg,1.04mmol)以及o-碘苯甲醇(4a)(268mg,1.14mmol)的甲苯(10mL)溶液进行搅拌后,在室温下加入Pd(PPh3)4(60mg,50μmol)。将得到的混合物回流一晚,通过添加饱和NH4Cl水溶液进行淬灭,并用AcOEt萃取。将所得到的有机萃取物全部混合,用盐水洗净,并用硫酸钠干燥浓缩。将所得到的残渣用快速硅胶柱色谱法(K2CO3-SiO2=1:9,AcOEt-己烷=1:4)纯化,得到无色油状的化合物(5a)(191mg,0.623mmol,60%)。化合物(5a)的分析结果如下所示。
[α]24 D+31.6(c 1.00,CHCl3);
1H NMR(500MHz,CDCl3)δ7.47(m,1H),7.37(m,1H),7.30-7.23(m,2H),6.81(d,J=15.6Hz,1H),6.11(dd,J=16.0,6.0Hz,1H),4.75(d,J=3.6Hz,2H),4.23(dt,J=6.4,5.2Hz,1H),1.65-1.55(m,3H),0.93(s,9H),0.93(t,J=7.4Hz,3H),0.10(s,3H),0.07(s,3H);
13C NMR(100MHz,CDCl3)δ137.6,136.3,136.2,128.3,128.2,127.6,126.4,125.7,74.8,63.6,31.3,26.0,18.4,9.8,-4.2,-4.6;
LRMS(ESI)m/z 329.15[(M+Na)+];
HRMS(ESI)calcd for C18H30NaO2Si:329.1913[(M+Na)+],found:329.1922.
<(R,E)-(3-(3-((Tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)methanol(5b)>
与化合物(5a)的合成类似,化合物(5b)是由3-碘苯甲醇(4b)以61%的产率制备的。化合物(5b)的分析结果如下所示。
[α]23 D+37.7(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3)δ7.38-7.30(m,3H),7.22(s,1H),6.50(d,J=16.0Hz,1H),6.20(dd,J=16.0,6.4Hz,1H),4.69(s,2H),4.20(dt,J=6.0,6.0Hz,1H),1.70-1.56(m,3H),1.08-0.76(m,12H),0.08(s,3H),0.05(s,3H);
13C NMR(100MHz,CDCl3)δ141.3,137.7,133.9,128.9,128.9,126.0,125.8,125.0,74.8,65.5,31.4,26.1,18.5,9.8,-4.1,-4.6;
LRMS(ESI)m/z 329.15[(M+Na)+];
HRMS(ESI)calcd for calcd for C18H30NaO2Si:329.1913[(M+Na)+],found:329.1910.
<(R,E)-(4-(3-((Tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)methanol(5c)>
与化合物(5a)的合成类似,化合物(5c)是由4-碘苯甲醇(4c)以46%的产率制备的。化合物(5c)的分析结果如下所示。
[α]25 D+44.3(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3)δ7.37(d,J=8.4Hz,2H),7.31(d,J=8.4Hz,2H),6.49(d,J=16.0Hz,1H),6.17(dd,J=16.0,6.4Hz,1H),4.68(d,J=4.0Hz,2H),4.20(dt,J=6.0,6.0Hz,1H),1.64-1.56(m,2H),0.92(s,9H),0.92(t,J=7.6Hz,3H),0.08(s,3H),0.05(s,3H);
13C NMR(100MHz,CDCl3)δ140.0,136.9,133.6,128.7,127.4,126.7,74.9,65.3,31.4,26.1,18.5,9.8,-4.1,-4.6;
LRMS(ESI)m/z 329.10[(M+Na)+];
HRMS(ESI)calcd for C18H30NaO2Si:329.1913[(M+Na)+],found:329.1915.
<(R,E)-((1-(2-(Bromomethyl)phenyl)pent-1-en-3-yl)oxy)(tert-butyl)dimethylsilane(7a)>
对化合物(5a)(6.0mg,20μmol)和Et3N(3.0μL,22μmol)的CH2Cl2(0.2mL)溶液进行搅拌,并在0℃下加入MsCl(2.0μL,22μmol)。将所得到的混合物在相同温度下搅拌1小时,通过添加盐水淬灭,并用AcOEt萃取。将所得到的有机萃取物全部混合,并用硫酸钠干燥浓缩,得到粗化合物(6a)。
对粗化合物(6a)的丙酮(0.2mL)溶液进行搅拌,在室温下加入NaBr(6.0mg,58μmol)。将得到的混合物回流12小时,通过添加盐水进行淬灭,并用AcOEt萃取。将所得到的有机萃取物全部混合,并用硫酸钠干燥浓缩。将所得到的残渣用硅胶柱色谱法(AcOEt-己烷=1:20)纯化,得到无色油状的化合物(7a)(6.0mg,16μmol,通过两步至83%)。化合物(7a)的分析结果如下所示。
[α]21 D+20.6(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3)δ7.46(d,J=8.0Hz 1H),7.30(m,2H),7.21(m,1H),6.86(dJ=15.6Hz,1H),6.16(dd,J=16.0,6.0Hz,1H),4.55(d,J=2.8Hz,2H),4.27(dt,J=6.0,6.0Hz,1H),1.62(m,2H),0.95(t,J=7.2Hz,3H),0.95(s,9H),0.11(s,3H),0.10(s,3H);
13C NMR(100MHz,CDCl3)δ137.2,136.8,134.7,130.4,129.2,127.7,126.9,125.3,74.6,31.9,31.3,26.1,18.4,9.7,-4.1,-4.6;
LRMS(ESI)m/z 369.35[(M+H)+];
HRMS(EI)calcd for calcd for C16H24BrOSi:339.0780[(M-Et)+],found:339.0779.
<(R,E)-((1-(3-(Bromomethyl)phenyl)pent-1-en-3-yl)oxy)(tert-butyl)dimethylsilane(7b)>
与化合物(7a)的合成类似,化合物(7b)是由化合物(5b)以68%的产率制备的。化合物(7b)的分析结果如下所示。
[α]23D+32.9(c 1.25,CHCl3);
1H NMR(400MHz,CDCl3)δ7.37(s,1H),7.31-7.20(m,3H),6.48(d,J=16.4Hz,1H),6.20(dd,J=16.0,6.0Hz,1H),4.49(s,2H),4.20(dt,J=6.0,6.0Hz,1H),1.59(m,2H),0.95-0.89(m,12H),0.08(s,3H),0.06(s,3H);
13C NMR(100MHz,CDCl3)δ138.5,138.4,134.6,129.5,128.8,128.3,127.4,126.9,75.0,34.0,31.7,26.4,18.8,10.1,-3.8,-4.3;
LRMS(ESI)m/z 369.15[(M+H)+];
HRMS(EI)calcd for calcd for C18H29BrOSi:368.1171(M+),found:368.1173.
<(R,E)-((1-(4-(Bromomethyl)phenyl)pent-1-en-3-yl)oxy)(tert-butyl)dimethylsilane(7c)>
与化合物(7a)的合成类似,化合物(7c)是由化合物(5c)以75%的产率制备的。化合物(7c)的分析结果如下所示。
[α]23 D+43.1(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3),δ7.43(s,4H),6.48(dd,J=16.0,1.6Hz,1H),6.19(dd,J=16.0,6.4Hz,1H),4.50(s,2H),4.20(m,1H),1.63-1.55(m,2H),0.92(m,12H),0.08(s,3H),0.05(s,3H);
13C NMR(100MHz,CDCl3)δ137.7,136.8,134.4,129.4,128.4,126.9,74.8,33.7,31.3,26.1,18.5,9.8,-4.2,-4.6;
LRMS(ESI)m/z 391.20[(M+Na)+];
HRMS(EI)calcd for calcd for C18H29BrOSi:368.1171(M+),found:368.1167.
<Methyl(S,E)-5-((tert-butyldimethylsilyl)oxy)-8-(2-((R,E)-3-((tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)oct-6-enoate(9a)>
搅拌含有化合物(7a)(60mg,0.162mmol)和化合物(8)(148mg,0.243mmol)的DMF(1.8mL)溶液,在室温下加入Pd(PPh3)4(9.0mg,8.0μmol)。将得到的混合物在90℃保持一晚,通过添加盐水进行淬灭,并用Et2O萃取。将所得到的有机萃取物全部混合,并用硫酸钠干燥浓缩。将所得到的残渣用硅胶柱色谱法(K2CO3-SiO2=1:9,AcOEt-己烷=1:8)以及EPCLC(条件:Yamazen Ultrapack Si-40A,己烷:AcOEt=97:3,流速10mL/分,检测UV 254nm)纯化,得到无色油状的化合物(9a)(45mg,80μmol,50%)。化合物(9a)的分析结果如下所示。
[α]19 D+7.21(c 0.80,CHCl3);
1H NMR(400MHz,CDCl3)δ7.42(m,1H),7.19-7.15(m,2H),7.11(m,1H),6.71(d,J=16.0Hz,1H),6.03(dd,J=16.0,6.4Hz,1H),5.70(dt,J=15.2,6.4Hz,1H),5.38(dd,J=15.6,6.8Hz,1H),4.20(dt,J=6.0,6.0Hz,1H),4.07(dt,J=6.0,6.0Hz,1H),3.66(s,3H),3.38(d,J=6.4Hz,2H),2.29(t,J=7.6Hz,2H),1.70-1.55(m,4H),1.51-1.41(m,2H),0.92(t,J=7.6Hz,3H),0.92(s,9H),0.86(s,9H),0.09(s,3H),0.06(s,3H),0.01(s,3H),-0.03(s,3H);
13C NMR(100MHz,CDCl3)δ174.2,137.5,136.3,135.4,134.9,129.6,128.6,127.5,126.7,126.6,126.3,75.0,73.2,51.6,37.8,35.8,34.1,31.4,26.1,26.0,21.0,18.4,18.3,9.9,-4.1,-4.1,-4.6,-4.7;
LRMS(ESI)m/z 583.35[(M+Na)+];
HRMS(ESI)calcd for C32H56NaO4Si2:583.3615[(M+Na)+],found:583.3636.
<Methyl(S,E)-5-((tert-butyldimethylsilyl)oxy)-8-(3-((R,E)-3-((tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)oct-6-enoate(9b)>
与化合物(7a)的合成类似,化合物(9b)是由化合物(7b)以58%的产率制备的。化合物(9b)的分析结果如下所示。
[α]19 D+16.9(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3)δ7.26-7.16(m,3H),7.03(d,J=6.8Hz,1H),6.45(d,J=16.0Hz,1H),6.15(dd,J=16.0,6.4Hz,1H),5.69(dt,J=15.2,6.8Hz,1H),5.48(dd,J=15.2,6.4Hz,1H),4.19(dt,J=6.0,6.0Hz,1H),4.10(dt,J=6.4,6.4Hz,1H),3.66(s,3H),3.34(d,J=6.4Hz,2H),2.31(t,J=7.6Hz,2H),1.68-1.47(m,6H),0.92-0.87(m,21H),0.08(s,3H),0.05(s,3H),0.03(s,3H),0.01(s,3H);
13C NMR(100MHz,CDCl3)δ174.2,140.7,137.5,135.1,133.4,129.2,129.1,128.7,127.7,126.7,124.3,75.0,73.2,51.6,38.7,37.9,34.2,31.4,26.1,26.0,21.0,18.5,18.4,9.8,0.14,-4.0,-4.1,-4.6,-4.6;
LRMS(ESI)m/z 583.35[(M+Na)+];
HRMS(ESI)calcd for C32H56NaO4Si2:583.3615[(M+Na)+],found:583.3631.
<Methyl(S,E)-5-((tert-butyldimethylsilyl)oxy)-8-(4-((R,E)-3-((tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)oct-6-enoate(9c)>
与化合物(7a)的合成类似,化合物(9c)是由化合物(7c)以66%的产率制备的。化合物(9c)的分析结果如下所示。
[α]18 D+29.0(c 1.10,CHCl3);
1H NMR(500MHz,CDCl3)δ7.29(d,J=8.0Hz,2H),7.11(d,J=8.0Hz,2H),6.45(d,J=16.0Hz,1H),6.13(dd,J=16.0,6.3Hz,1H),5.67(dt,J=15.0,6.5Hz,1H),5.46(dd,J=15.0,6.5Hz,1H),4.18(dt,J=6.0,6.0Hz,1H),4.09(dt,J=6.0,6.0Hz,1H),3.66(s,3H),3.33(d,J=6.5Hz,2H),2.31(t,J=7.3Hz,2H),1.70-1.44(m,6H),0.95-0.79(m,21H),0.08(s,3H),0.05(s,3H),0.03(s,3H),0.01(s,3H);
13C NMR(100MHz,CDCl3)δ174.3,139.6,135.2,135.0,132.8,129.0,128.9,128.9,126.5,75.0,73.2,51.6,38.4,37.8,34.2,31.4,26.1,26.0,21.0,18.5,18.4,9.9,-4.0,-4.1,-4.6,-4.6;
LRMS(ESI)m/z 583.35[(M+Na)+];
HRMS(ESI)calcd for C32H56NaO4Si2:583.3615[(M+Na)+],found:583.3629.
<o-BZ-RvE2(1a)>
对化合物(9a)(5.0mg,8.9μmol)的THF(18μL)溶液进行搅拌,并在室温下添加TBAF(THF中,1.0M,54μL,54μmol)。将所得到的混合物在相同温度下搅拌24小时。反应完成后,在反应混合物中加入磷酸缓冲液(pH6),并用AcOEt萃取。将所得到的有机萃取物全部混合,用盐水洗净,并用硫酸钠干燥浓缩。将所得到的残渣用快速硅胶柱色谱法(MeOH-CHCl3=1:30)纯化,得到无色油状的o-BZ-RvE2(1a)(2.7mg,8.5μmol,95%)。o-BZ-RvE2的分析结果如下所示。
[α]19 D+1.45(c 0.25,MeOH);
1H NMR(400MHz,CD3OD)δ7.46(m,1H),7.16(m,3H),6.83(d,J=16.0Hz,1H),6.08(dd,J=16.0,6.4Hz,1H),5.79(dt,J=15.6,6.0Hz,1H),5.37(dd,J=15.6,6.8Hz,1H),4.14(dt,J=6.8,6.8Hz,1H),4.00(dt,J=6.4,6.4Hz,1H),3.44(d,J=6.0Hz,2H),2.24(t,J=7.2Hz,2H),1.68-1.44(m,6H),0.98(t,J=7.6Hz,3H);
13C NMR(100MHz,CD3OD)δ180.2,138.7,137.4,135.5,135.3,130.9,130.7,128.8,128.6,127.6,127.0,75.1,73.2,38.0,36.9,31.3,23.0,10.3;
LRMS(ESI)m/z 316.95[(M-H)-];
HRMS(ESI)calcd for C19H25O4:317.1753[(M-H)-],found:317.1749;
HPLC purity>99%(COSMOSIL 5C18-MS-II 4.6mm x 250mm,CH3CN/H2O/TFA=35/65/0.01,1.0mL/min,tR=11.7min,detection 254nm)
<m-BZ-RvE2(1b)>
与o-BZ-RvE2的合成类似,m-BZ-RvE2(1b)是由化合物(9b)以72%的产率制备的。m-BZ-RvE2(1b)的分析结果如下所示。
[α]19 D-1.31(c 0.18,MeOH);
1H NMR(400MHz,CD3OD)δ7.23(m,3H),7.07(m,1H),6.54(d,J=16.0Hz,1H),6.20(dd,J=16.0,6.8Hz,1H),5.79(dt,J=15.2,6.8Hz,1H),5.52(dd,J=15.6,6.8Hz,1H),4.11(dt,J=6.8,6.8Hz,1H),4.11(dt,J=6.8,6.8Hz,1H),3.36(d,J=6.8Hz,2H),2.30(t,J=7.2Hz,2H),1.66-1.50(m,6H),0.96(t,J=7.2Hz,3H);
13C NMR(100MHz,CD3OD)δ177.9,142.1,138.8,135.7,133.7,131.5,131.5,129.9,129.1,127.9,125.4,75.3,73.3,39.7,38.0,35.1,31.5,22.5,10.5;
LRMS(ESI)m/z 316.90[(M-Na)-];
HRMS(ESI)calcd for C19H25O4:317.1753[(M-H)-],found:317.1746;
HPLC purity>99%(COSMOSIL 5C18-MS-II 4.6mm x 250mm,CH3CN/H2O/TFA=35/65/0.01,1.0mL/min,tR=11.5min,detection 254nm)
<p-BZ-RvE2(1c)>
与o-BZ-RvE2的合成类似,p-BZ-RvE2(1c)是由化合物(9c)以76%的产率制备的。p-BZ-RvE2的分析结果如下所示。
[α]18 D+1.77(c 0.43,MeOH);
1H NMR(500MHz,CD3OD)δ7.31(d,J=8.0Hz,2H),7.13(d,J=8.0Hz,2H),6.52(d,J=16.0Hz,1H),6.16(dd,J=16.0,6.5Hz,1H),5.77(dt,J=15.5,6.5Hz,1H),5.49(dd,J=15.5,7.0Hz,1H),4.09(dt,J=6.5,6.5Hz,1H),4.02(dt,J=7.0,7.0Hz,1H),3.34(d,J=6.5Hz,2H),2.29(t,J=7.5Hz,2H),1.70-1.46(m,6H),0.96(t,J=7.5Hz,3H);
13C NMR(100MHz,CD3OD)δ177.7,141.0,136.4,135.5,132.8,131.2,131.1,129.8,127.5,75.1,73.1,39.3,37.8,34.9,31.3,22.3,10.3;
LRMS(ESI)m/z 316.90[(M-Na)-];
HRMS(ESI)calcd for C19H25O4:317.1753[(M-H)-],found:317.1749;
HPLC purity 98%(COSMOSIL 5C18-MS-II 4.6mm x 250mm,CH3CN/H2O/TFA=35/65/0.01,1.0mL/min,tR=11.0min,detection 254nm)
<抗炎性评价试验>
将300pg的RvE2、o-BZ-RvE2、m-BZ-RvE2、p-BZ-RvE2或仅溶剂,对注射痤疮丙酸杆菌12小时后的急性炎症模型小鼠进行腹腔内给药(n=4)。然后,在痤疮丙酸杆菌注射24小时后,收集腹膜渗出液并计数中性粒细胞数。结果如图1(a)所示。
将300fg、300pg或300ng的RvE2、o-BZ-RvE2或仅溶剂,独立地对注射痤疮丙酸杆菌12小时后的急性炎症模型小鼠进行腹腔内给药(n=3或4)。然后,在痤疮丙酸杆菌注射24小时后,收集腹膜渗出液并计数中性粒细胞数。结果如图1(b)所示。
如图1(a)所示,o-BZ-RvE2、m-BZ-RvE2以及p-BZ-RvE2的中性粒细胞的数量均比仅给药了溶剂的模型小鼠少,向作为炎症部位的腹腔内的中性粒细胞浸润被明显抑制。结果表明,o-BZ-RvE2、m-BZ-RvE2以及p-BZ-RvE2均与RvE2一样,具有炎症收敛作用,可以用作抗炎剂。特别地,o-BZ-RvE2比RvE2具有更好的抗炎作用(图1(a)和(b))。
<代谢稳定性评价>
对RvE2、o-BZ-RvE2、m-BZ-RvE2、以及p-BZ-RvE2的对人肝微粒体代谢稳定性进行了研究。具体地,将RvE2、o-BZ-RvE2、m-BZ-RvE2以及p-BZ-RvE2分别与人肝微粒体混合,并研究了随时间推移残留的RvE2等的比例。结果如图2所示。如图2所示,p-BZ-RvE2与RvE2一样容易被人肝微粒体分解。与此相对,o-BZ-RvE2以及m-BZ-RvE2与人肝微粒体混合6小时后,残留率仍在90%以上。特别是o-BZ-RvE2具有非常优异的代谢稳定性。
实施例2
RvE类共通地具有羧酸和ω-3位的羟基,此外在RvE1和RvE2中共通地具有5位的羟基。针对在实施例1中抗炎活性最强的o-BZ-RvE2合成脱氧衍生物,并研究了其对生物活性的影响。5-deoxy-o-BZ-RvE2是通式(1-o-3)中R3为乙基、m为0、n为3的化合物,17-deoxy-o-BZ-RvE2是通式(1-o-2)中R3为乙基、m为0、n为3的化合物,5,17-deoxy-o-BZ-RvE2是通式(1-o-4)中R3为乙基、m为0、n为3的化合物。
[化学式13]
[化学式14]
<(E)-Tributyl(pent-1-en-1-yl)stannane(10)>
化合物(10)(2.7g,7.52mmol,75%)是由1-戊炔(994μL,10.0mmol)以与化合物(S2)类似的方式合成。化合物(10)的分析结果如下所示。
1H NMR(500MHz,CDCl3)δ5.95(dt,J=19.0,6.0Hz,1H),5.86(d,J=19.0Hz,1H),2.11(dt,J=6.5,6.5Hz,2H),1.54-1.26(m,15H),1.00-0.75(m,19H);
13C NMR(100MHz,CDCl3)δ149.8,127.3,40.2,29.3,27.4,22.2,13.9,13.8,9.5;
LRMS(EI)m/z 303.10(M+);
HRMS(EI)calcd for calcd for C13H27Sn:303.1135(M+),found:303.1134.
<methyl hept-6-ynoate(12)>
在氩气环境下,向6-庚炔酸(630μL,5.0mmol)的二氯甲烷溶液(5mL)中加入对甲苯磺酸(10mg,36.5mmol)和甲醇(900μL),并加热回流一晚。接着,将该反应液用碳酸氢钠饱和水溶液淬灭,并用二氯甲烷萃取。用饱和盐水清洗有机层后,用硫酸钠干燥。干燥后的反应物经棉塞过滤后,在减压下馏去溶剂,所得残渣用硅胶色谱(己烷:乙酸乙酯=4:1)纯化,得到黄色油状物的化合物(12)(530mg,3.78mmol,76%)。化合物(12)的分析结果如下所示,这与以往报道的结果一致。
1H NMR(400MHz,CDCl3)δ3.68(s,3H),2.35(t,J=7.6Hz,2H),2.22(dt,J=7.2,2.8Hz,2H),1.96(t,J=2.8Hz,1H),1.74(m,2H),1.57(m,2H).
<Methyl(E)-7-(tributylstannyl)hept-6-enoate(11)>
在氩气环境下,将三(二亚苄基丙酮)二钯(0)(4.6mg、5μmol、0.5mol%)、三环己基四氟硼酸盐(7.4mg、20μmol、2mol%)、二异丙基乙胺(7μL、40μmol、4mol%)的二氯甲烷溶液(10mL)在室温下搅拌。10分钟后,将该反应液置于0℃后,加入化合物(12)(140mg,1.0mmol)及三丁基氢化锡(320μL,1.2mmol,1.2eq.),再搅拌一晚。然后,从该反应液中减压馏去溶剂,用硅胶柱色谱法(10%w/w K2CO3-SiOH,己烷:乙酸乙酯=10:1)纯化,得到化合物(11)(295mg)的粗产物。化合物(11)直接用于合成化合物(16e)和化合物(16f)。
[化学式15]
<(E)-(2-(Pent-1-en-1-yl)phenyl)methanol(13d)>
在氩气环境下,将化合物(10)(1.08g,3.0mmol)、2-碘苯甲醇(4a,702mg,3.0mmol,1.0eq.)、四(三苯基膦)钯(173mg,0.15mmol,5mol%)的甲苯溶液(20mL)冷冻脱气,并在加热回流下搅拌一晚。在得到的反应液中加入饱和氯化铵水溶液停止反应,并用乙酸乙酯萃取。用饱和盐水清洗得到的有机层,并加入无水硫酸钠干燥。然后,在减压下馏去溶剂,用快速硅胶柱色谱法(10%w/w K2CO3-SiOH,己烷:乙酸乙酯=10:1)纯化,得到化合物(13d)(323mg,0.65mmol,63%)。化合物(13d)的分析结果如下,这与以前报道的结果一致。
1H NMR(400MHz,CDCl3)δ7.64(d,J=7.2Hz,1H),7.33(d,J=7.2Hz,1H),7.28-7.19(m,2H),6.68(d,J=15.6Hz,1H),6.15(dt,J=16.0,6.8Hz,1H),4.73(d,J=6.0Hz,2H),2.22(dt,J=6.8,6.8Hz,2H),1.64(m,1H),1.51(tq,J=7.4,7.4Hz,2H),0.96(t,J=7.4Hz,3H).
<(E)-1-(Bromomethyl)-2-(pent-1-en-1-yl)benzene(15d)>
化合物(15d)(313mg,1.3mmol,通过两步至72%)由化合物(13d)(322mg,1.8mmol)以与化合物(7a)类似的方式合成。化合物(15d)的分析结果如下所示。
1H NMR(400MHz,CDCl3)δ7.46(d,J=7.6Hz 1H),7.31-7.24(m,2H),7.19(d,J=7.6Hz,1H),6.72(d,J=16.0Hz,1H),6.21(dt,J=16.0,7.2Hz,1H),4.57(s,2H),2.25(ddd,J=7.6,7.2,1.2Hz,2H),1.53(tq,J=7.6,7.6Hz,2H),0.98(t,J=7.6Hz,3H);
13C NMR(100MHz,CDCl3)δ138.1,134.9,134.5,130.7,129.5,127.7,127.0,126.7,35.9,32.7,22.9,14.2;
HRMS(EI)calcd for calcd for C12H15Br:238.0357(M+),found:238.0354.
<Methyl(S,E)-5-((tert-butyldimethylsilyl)oxy)-8-(2-((E)-pent-1-en-1-yl)phenyl)oct-6-enoate(16d)>
化合物(16d)(51mg,0.118mmol,60%)由化合物(15d)(48mg,0.2mmol)以与化合物(9a)类似的方式合成。化合物(16d)的分析结果如下所示。
[α]19 D-0.95(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3)δ7.43(m,1H),7.20-7.08(m,3H),6.57(d,J=16.0Hz,1H),6.08(dt,J=16.0,7.2Hz,1H),5.69(dt,J=16.0,6.4Hz,1H),5.35(dd,J=15.6,6.8Hz,1H),4.06(ddd,J=6.4,6.4,6.4Hz,1H),3.66(s,3H),3.39(d,J=6.4Hz,2H),2.29(t,J=7.6Hz,2H),2.19(m,2H),1.70-1.59(m,2H),1.54-1.40(m,4H),0.96(t,J=7.2Hz,3H),0.86(s,9H),0.01(s,3H),-0.02(s,3H);
13C NMR(100MHz,CDCl3)δ174.2,137.1,137.0,134.7,132.8,129.6,128.8,127.6,127.0,126.5,126.0,77.4,73.2,51.6,37.8,36.0,35.5,34.1,26.0,22.7,21.0,18.4,13.9,-4.1,-4.7;
LRMS(ESI)m/z 453.20[(M+Na)+];
HRMS(ESI)calcd for C26H42NaO3Si:453.2801[(M+Na)+],found:458.2802.
<Methyl(S,E)-5-hydroxy-8-(2-((R,E)-3-hydroxypent-1-en-1-yl)phenyl)oct-6-enoate(16e)>
化合物(16e)(51mg,0.17mmol,84%)由化合物(15d)(48mg,0.2mmol)和化合物11(170mg,0.3mmol)以与化合物(9a)类似的方式合成。化合物(16e)的分析结果如下所示。
1H NMR(400MHz,CDCl3)δ7.42(m,1H),7.20-7.10(m,3H),6.60(d,J=16.0Hz,1H),6.07(dt,J=16.0,7.2Hz,1H),5.55(dt,J=15.6,6.8Hz,1H),5.38(dt,J=15.6,6.8Hz,1H),3.66(s,3H),3.36(d,J=5.6Hz,2H),2.29(m,2H),2.19(m,2H),2.02(dt,J=7.2,7.2Hz,2H),1.61(m,2H),
1.50(m,2H),1.37(m,2H),0.96(m,3H);
13C NMR(100MHz,CDCl3)δ174.3,137.6,137.0,132.7,131.3,129.5,129.0,127.7,127.1,126.5,125.9,51.6,36.6,35.5,34.1,32.3,29.0,24.6,22.7,13.9;
LRMS(ESI)m/z 323.15[(M+Na)+];
HRMS(ESI)calcd for C20H28NaO2:323.1987[(M+Na)+],found:323.1992.
<17-deoxy-o-BZ-RvE2>
17-deoxy-o-BZ-RvE2(10.0mg,0.033mmol,94%)由化合物(16d)(15mg,0.035mmol)与o-BZ-RvE2类似的方式合成。17-deoxy-o-BZ-RvE2的分析结果如下所示。
[α]19 D+1.66(c 0.33,MeOH);
1H NMR(400MHz,CD3OD)δ7.41(m,1H),7.19-7.10(m,3H),6.64(d,J=16.0Hz,1H),6.09(dt,J=16.0,7.2Hz,1H),5.77(m,1H),5.36(m,1H),4.00(dt,J=6.4,6.4Hz,1H),3.41(d,J=6.0Hz,2H),2.27(t,J=7.2Hz,2H),2.21(ddd,J=14.4,7.2,1.6Hz,2H),1.68-1.40(m,6H),0.98(t,J=7.2Hz,3H);
13C NMR(100MHz,CD3OD)δ177.6,138.2,138.0,135.2,133.4,130.9,130.7,129.0,128.0,127.5,126.9,73.1,37.8,37.0,36.4,34.9,23.7,22.2,14.1;
LRMS(ESI)m/z 301.00[(M-Na)-];
HRMS(ESI)calcd for C19H25O3:301.1804[(M-H)-],found:301.1799;
HPLC purity>99%(COSMOSIL 38020-41,CH3CN/H2O/TFA=50/50/0.01,1.0mL/min,tR=17.6min,detection 254nm).
<5,17-dideoxy-o-BZ-RvE2>
在氩气环境下,向化合物(16e)(15mg,0.050mmol)的THF溶液(100μL)中加入氢氧化锂一水合物(8mg,0.20mmol,4eq.)的水溶液(100μL),并在室温下搅拌一晚。在该反应液中加入磷酸缓冲液(pH6),用乙酸乙酯萃取。用饱和盐水清洗有机层,并用硫酸钠干燥。然后,在减压下馏去溶剂,并将残渣用快速硅胶柱色谱法(氯仿:甲醇=30:1)纯化,得到无色油状物质的5,17-dideoxy-o-BZ-RvE2(11mg,0.038mmol,77%)。
5,17-dideoxy-o-BZ-RvE2的分析结果如下所示。
1H NMR(400MHz,CDCl3)δ11.23(s,1H),7.43(m,1H),7.20-7.10(m,3H),6.60(d,J=16.0Hz,1H),6.08(dt,J=16.0,7.2Hz,1H),5.57(dt,J=15.6,6.4Hz,1H),5.39(dt,J=15.6,6.4Hz,1H),3.37(d,J=6.4Hz,2H),2.34(t,J=7.6Hz,2H),2.20(dt,J=6.8,6.8Hz,2H),1.63(tt,J=7.6,7.6Hz,2H),1.55-1.36(m,5H),0.96(t,J=7.6Hz,3H);
13C NMR(100MHz,CD3OD)δ177.7,138.6,138.2,133.1,132.1,130.6,130.3,129.1,128.0,127.4,126.8,37.4,36.4,34.9,33.2,30.1,25.6,23.7,14.1;
LRMS(ESI)m/z 284.95[(M-H)-];
HRMS(ESI)calcd for C19H25O2:285.1855[(M-H)-],found:285.1856;
HPLC purity 96%(COSMOSIL 38020-41,CH3CN/H2O/TFA=80/20/0.01,1.0mL/min,tR=9.6min,detection 254nm).
[化学式16]
<Methyl(E)-8-(2-((R,E)-3-((tert-butyldimethylsilyl)oxy)pent-1-en-1-yl)phenyl)oct-6-enoate(16f)>
化合物(16f)(67mg,0.155mmol,78%)由化合物(7a)(74mg,0.2mmol)和化合物(11)以与化合物(9a)类似的方式合成。化合物(16f)的分析结果如下所示。
[α]19 D+22.2(c 1.00,CHCl3);
1H NMR(400MHz,CDCl3)δ7.43(m,1H),7.20-7.12(m,3H),6.73(d,J=16.0Hz,1H),6.04(dd,J=16.0,6.4Hz,1H),5.56(dt,J=15.6,6.4Hz,1H),5.37(dt,J=15.6,6.8Hz,1H),4.21(ddd,J=6.4,6.4,6.4Hz,1H),3.66(s,3H),3.37(d,J=5.6Hz,2H),2.29(t,J=7.6Hz,2H),2.01(dt,J=6.8,6.8Hz,2H),1.65-1.56(m,2H),1.50-1.25(m,4H),0.95-0.86(m,12H),0.09(s,3H),0.06(s,3H);
13C NMR(100MHz,CDCl3)δ174.3,138.1,136.3,135.1,131.3,129.6,128.9,127.5,126.7,126.5,126.2,77.4,75.0,51.6,36.5,34.1,32.3,31.4,29.0,26.1,24.7,18.4,9.8,-4.1,-4.6;
LRMS(ESI)m/z 453.20[(M+Na)+];
HRMS(ESI)calcd for C26H42NaO3Si:453.2801[(M+Na)+],found:458.2809.
<5-deoxy-o-BZ-RvE2>
在氩气环境下,向化合物(16f)(20mg,0.046mmol)的THF溶液(92μL)中加入四丁基氟化铵(1M THF溶液,276μL,0.276mol,6eq.),并在室温下搅拌24小时。接着,向该反应液中加入氢氧化锂一水合物(8mg,0.184mmol,4eq.)的水溶液(92μL),并在室温下搅拌1小时。然后,加入磷酸缓冲液(pH6),并用乙酸乙酯萃取。用饱和盐水清洗有机层,并用无水硫酸钠干燥。在减压下馏去溶剂并将残渣用快速硅胶柱色谱法(氯仿:甲醇=30:1)纯化,得到无色油状物质的5-deoxy-o-BZ-RvE2(11.2mg,0.037μmol,81%)。
5-deoxy-o-BZ-RvE2的分析结果如下所示。
[α]19 D-5.39(c 0.56,MeOH);
1H NMR(400MHz,CD3OD)δ7.45(m,1H),7.18-7.10(m,3H),6.82(d,J=15.2Hz,1H),6.06(dd,J=15.6,6.4Hz,1H),5.57(dt,J=15.2,6.4Hz,1H),5.37(dt,J=15.2,6.8Hz,1H),4.13(dt,J=6.4,6.4Hz,1H),3.38(d,J=4.8Hz,2H),2.26(t,J=7.6Hz,2H),2.02(dt,J=6.8,6.8Hz,2H),1.71-1.54(m,4H),1.38(m,2H),0.97(t,J=7.2Hz,3H);
13C NMR(100MHz,CD3OD)δ177.8,139.2,137.3,135.1,132.3,130.7,128.9,128.6,127.4,127.0,75.2,37.3,34.9,33.2,31.3,30.0,25.6,10.3;
LRMS(ESI)m/z 300.95[(M-Na)-];
HRMS(ESI)calcd for C19H25O3:301.1804[(M-H)-],found:301.1794;
HPLC purity 98%(COSMOSIL 38020-41,CH3CN/H2O/TFA=50/50/0.01,1.0mL/min,tR=13.9min,detection 254nm).
<抗炎性评价试验>
将300pg的RvE2、o-BZ-RvE2、17-deoxy-o-BZ-RvE2、5-deoxy-o-BZ-RvE2、5,17-dideoxy-o-BZ-RvE2、或仅溶剂,对注射痤疮丙酸杆菌8小时后的急性炎症模型小鼠进行腹腔内给药(n=3或4)。然后,在痤疮丙酸杆菌注射24小时后,收集腹膜渗出液并计数中性粒细胞数。结果如图3所示。
如图3所示,作为对照接种了痤疮丙酸杆菌的小鼠中性粒细胞数显著增加,与此相对,使用RvE2、o-BZ-RvE2、17-deoxy-o-BZ-RvE2、5-deoxy-o-BZ-RvE2和5,17-dideoxy-o-BZ-RvE2的小鼠中性粒细胞数显著减少。特别地,给药了17-deoxy-BZ-RvE2的组与给药了RvE2的组以及给药了o-BZ-RvE2的组相比中性粒细胞数减少程度相同,维持了较高的抗炎活性。另一方面,给药了5-deoxy-BZ-RvE2的组和给药了5,17dideoxy-BZ-RvE2的组的抗炎活性与给药了RvE2或o-BZ-RvE2的组相比减弱了。这些结果表明,羧酸δ位的羟基对o-BZ-RvE2具有的抗炎活性的表达是至关重要。
<代谢稳定性评价>
研究了17-deoxy-o-BZ-RvE2和5-deoxy-o-BZ-RvE2对人肝微粒体的代谢稳定性。具体地,用HPLC测定了RvE2、o-BZ-RvE2、17-deoxy-o-BZ-RvE2和5-deoxy-o-BZ-RvE2在37℃下人肝微粒体存在下,在0.1M PBS(pH7.4)中残留率(%)随时间的变化(n=3)。结果如图4所示。
如图4所示,RvE2随时间推残留率降低,而5-deoxy-BZ-RvE2和17deoxy-BZ-RvE2的残留率与RvE2相比缓慢降低,表明其代谢稳定性较高。此外,由于两脱氧体的代谢稳定性差异不大,因此认为5-deoxy-o-BZ-RvE2抗炎活性的减弱并不是由代谢抵抗性引起的。
实施例3
[化学式17]
<Methyl 5-bromo-2-iodobenzotate(17-a)>
在氩气环境下,将5-溴氨基苯甲酸甲酯(200mg,0.869mmol)溶解在盐酸(12M,2.1mL)中,并在0℃下搅拌。15分钟后,加入冰(1.0g),并在0℃下搅拌。10分钟后,将亚硝酸钠(120mg,3.82mmol,2.0eq.)溶解在水(1.5mL)中,并在0℃下搅拌。10分钟后,加入溶解于水(2.9mL)的碘化钾(634mg,3.82mmol,4.4eq.),并在室温下搅拌。1小时后,向反应液中加入饱和硫代硫酸钠水溶液停止反应,并用乙酸乙酯萃取。用饱和盐水清洗有机层,芒硝干燥,并在减压下馏去溶剂。用硅胶柱色谱法(己烷:乙酸乙酯=9:1)纯化,得到黄色晶体状的化合物(17-a)(283mg,0.831mmol,96%)。
1H NMR(400MHz,CDCl3)δ7.94(d,J=2.0Hz,1H),7.84(d,J=8.4,1H),7.28(dd,J=8.4,2.0Hz,1H),3.94(s,3H);将各种仪器光谱数据与非专利文献4中描述的数据进行了比较鉴别。但是,合成法与非专利文献4不同。
<Methyl 4-bromo-2-iodobenzoate(17-b)>
化合物(17-b)(226mg,0.66mmol,76%)是由4-溴氨茴酸甲酯(200mg,0.869mmol)以与化合物(17-a)类似的方式合成的。
1H NMR(400MHz,CDCl3)δ8.18(d,J=2.0Hz,1H),7.70(d,J=8.4,1H),7.54(dd,J=8.4,2.0Hz,1H),3.93(s,3H);将各种仪器光谱数据与非专利文献5中描述的数据进行了比较鉴别。但是,合成法与非专利文献5不同。
<(5-Bromo-2-iodophenyl)methanol(18-a)>
在氩气环境下,将化合物(17-a)(7.93g,23.0mmol)溶解在THF(46mL)中,并在冰冷条件下向该溶液中加入乙醇(5.4mL,92mmol,4.0eq.)和LiBH4(1.00g,46mmol,2.0eq.),搅拌1小时。进一步升温至室温,并搅拌12小时。向反应液中加入饱和氯化铵水溶液停止反应,并用乙酸乙酯萃取。用饱和盐水清洗得到的有机层,并加入无水硫酸钠干燥。在减压下馏去溶剂,用硅胶柱色谱法(己烷:乙酸乙酯=4:1)纯化,得到白色粉末状物质的化合物(18-a)(6.67g,21.3mmol,93%)。
1H NMR(400MHz,CDCl3)δ7.65(d,J=8.4Hz 1H),7.63(d,J=2.4Hz,1H),7.14(dd,J=8.4,2.4Hz,1H),4.64(d,J=6.4Hz,2H),2.00(t,J=6.4Hz,1H);将各种仪器光谱数据与非专利文献4中描述的数据进行了比较鉴别。但是,合成法与非专利文献4不同。
<(4-Bromo-2-iodophenyl)methanol(18-b)>
化合物(18-b)(5.45g,17.4mmol,85%)是由化合物(17-b)(6.97g,20.4mmol)以与化合物(18-a)类似的方式合成的。
1H NMR(400MHz,CDCl3)δ7.97(d,J=2.0Hz 1H),7.51(dd,J=8.0,2.0Hz,1H),7.34(d,J=8.0Hz,1H),4.63(d,J=6.4Hz,2H),1.94(t,J=6.4Hz,1H);13C NMR(100MHz,CDCl3)δ141.6,140.9,131.5,129.3,121.7,97.4,68.6.
[化学式18]
<(E)-(5-bromo-2-(pent-1-en-1-yl)phenyl)methanol(19-a)>
在氩气环境下,将化合物(18-a)(250mg,0.80mmol)和化合物(10)(287mg,0.80mmol,1.0eq.)溶解在甲苯(5.5mL)中,加入四(三苯基膦)钯(46mg,0.04mmol,0.05eq.),并在加热回流下搅拌24小时。向反应液中加入饱和氯化铵水溶液停止反应,并用乙酸乙酯萃取。用饱和盐水清洗得到的有机层,并加入无水硫酸钠干燥。在减压下馏去溶剂,用硅胶柱色谱法(10%w/w K2CO3-SiOH,己烷:乙酸乙酯=19:1至9:1)纯化得到黄色油状物质的化合物(19-a)(130mg,0.51mmol,64%)。
1H NMR(400MHz,CDCl3)δ7.58(d,J=2.0Hz,1H),7.37(dd,J=8.6,2.0Hz,1H),7.31(d,J=8.6Hz,1H),6.54(d,J=16.0Hz,1H),6.14(dt,J=16.0,7.2Hz,1H),4.71(d,J=6.0Hz,2H),2.20(dt,J=7.2,7.2Hz,2H),1.70(m,1H),1.50(tq,J=7.6,7.2Hz,2H),0.96(t,J=7.6Hz,3H);
13C NMR(100MHz,CDCl3)δ140.3,139.0,135.5,134.6,130.8,130.6,127.6,125.5,62.8,35.4,22.4,13.7.
<(E)-(4-bromo-2-(pent-1-en-1-yl)phenyl)methanol(19-b)>
化合物(19-b)(22mg,0.084mmol,47%)是化合物(18-b)(56mg,0.178mmol)和化合物(10)(64mg,0.178mmol,1.0eq.)以与化合物(19-a)类似的方式合成的。
1H NMR(400MHz,CDCl3)δ7.59(d,J=2.0Hz,1H),7.34(dd,J=8.8,2.0Hz,1H),7.22(d,J=8.8Hz,1H),6.59(d,J=16.0Hz,1H),6.17(dt,J=16.0,7.2Hz,1H),4.69(d,J=6.0Hz,2H),2.22(dt,J=7.2,6.8Hz,2H),1.26(m,1H),1.57-1.46(m,2H),0.96(t,J=7.6Hz,3H);13C NMR(100MHz,CDCl3)δ138.8,135.9,135.3,129.7,129.7,128.9,125.3,122.0,62.9,35.3,22.4,13.7.
<(E)-4-bromo-2-(bromomethyl)-1-(pent-1-en-1-yl)benzene(21-a)>
在氩气环境下,将化合物(19-a)(50mg,0.20mmol)溶解在二氯甲烷(2.0mL)中,并在0℃条件下向该溶液中加入三乙胺(31μL,0.22mmol,1.1eq.)和甲磺酰氯(17μL,0.22mmol,1.1eq.)并搅拌。90分钟后,加入饱和盐水淬灭,并用乙酸乙酯萃取。向得到的有机层加入无水硫酸钠干燥。在减压下馏去溶剂,得到化合物20-a的粗产物。将粗产物溶解在丙酮(2.0mL)中,加入溴化钠(112mg,1.09mmol,6.0eq.),并回流12小时。向反应液中加入饱和盐水停止反应,并用乙酸乙酯萃取。在减压下馏去溶剂,将残渣用硅胶柱色谱法(己烷:乙酸乙酯=9:1)纯化,得到黄色油状物质的化合物(21-a)(48.5mg,0.152mmol,通过两步至76%)。
1H NMR(400MHz,CDCl3)δ7.43(d,J=2.0Hz,1H),7.38-7.36(m,1H),7.32(d,J=8.4Hz,1H),6.62(d,J=16.0Hz,1H),6.20(dt,J=16.0,7.2Hz,1H),4.47(s,2H),2.26-2.20(m,2H),1.56-1.50(m,2H),0.97(t,J=7.2Hz,3H);13C NMR(100MHz,CDCl3)δ136.5,135.8,135.2,132.8,132.0,128.1,125.3,120.4,35.4,30.7,22.3,13.7.
<(E)-4-bromo-1-(bromomethyl)-2-(pent-1-en-1-yl)benzene(21-b)>
化合物(21-b)(16mg,0.052mmol,通过两步至83%)是由化合物(19-b)(16mg,0.062mmol)以与化合物(21-a)类似的方式合成的。
1H NMR(400MHz,CDCl3)δ7.58(d,J=2.0Hz,1H),7.30(dd,J=8.4,2.0Hz,1H),7.15(d,J=8.4Hz,1H),6.63(d,J=15.6Hz,1H),6.22(dt,J=15.6,7.2Hz,1H),4.84(s,2H),2.27-2.22(m,2H),1.26(tq,J=7.6,7.2Hz,2H),0.96(t,J=7.6Hz,3H);13C NMR(100MHz,CDCl3)δ139.5,135.9,133.0,131.6,130.1,129.5,125.1,123.1,35.4,31.0,22.3,13.7.
<(S,E)-8-(5-bromo-2-((E)-pent-1-en-1-yl)phenyl)-5-hydroxyoct-6-enoicacid(23-a)>
在氩气环境下,,将化合物(21-a)(24.3mg,43.3μmol,1.5eq.)和化合物(8)(9.2mg,28.8μmol,1.0eq.)溶解在甲酰二甲胺(1.0mL)中,加入四(三苯基膦)钯(2.1mg,1.81μmol,0.05eq.),并加热回流搅拌18小时。向反应液中加入饱和盐水停止反应,并用乙酸乙酯萃取。用饱和盐水清洗得到的有机层,并加入无水硫酸钠干燥。在减压下馏去溶剂,用快速硅胶柱色谱法(己烷:乙酸乙酯=99:1)纯化,将得到的化合物(22-a)直接用于接下来的反应。将化合物(22-a)溶解于四氢呋喃(100μL)中,加入四丁基氟化铵(1M THF溶液,107μL,107μmol,4eq.),并在室温下搅拌2天。向反应液中加入磷酸缓冲液(pH6),并用乙酸乙酯萃取。用饱和盐水清洗有机层,并用无水硫酸钠干燥。在减压下馏去溶剂,用硅胶柱色谱法(氯仿:甲醇=30:1)纯化,得到无色油状物质的化合物(23-a)(3.6mg,9.43μmol,通过两步至33%)。
1H NMR(400MHz,CDCl3)δ7.29(m,2H),7.24(m,1H),6.47(d,J=16.0Hz,1H),6.08(dt,J=16.0,7.2Hz,1H),5.77(m,1H),5.45(dd,J=15.6,6.8Hz,1H),4.11(m,1H),3.37(d,J=6.0Hz,2H),2.40(t,J=6.8Hz,2H),2.35-2.17(m,2H),2.06-1.44(m,7H),0.95(t,J=7.6Hz,3H)
<(S,E)-8-(4-bromo-2-((E)-pent-1-en-1-yl)phenyl)-5-hydroxyoct-6-enoicacid(23-b)>
化合物(23-b)(1.8mg,4.72mmol,通过两步至8%)是由化合物(21-b)(52.6mg,93.7μmol,1.5eq.)和化合物(8)(20mg,62.9μmol,1.0eq.)以与化合物(23-a)类似的方式合成的。
1H NMR(400MHz,CDCl3)δ7.25(m,1H),6.98(m,2H),6.47(d,J=16.0Hz,1H),6.33(m,1H)5.65(m,1H),5.33(dd,J=15.6,6.4Hz,1H),4.06(m,1H),3.37(d,J=6.0Hz,2H),2.29(t,J=7.6Hz,2H),2.18(m,2H),1.69-1.46(m,7H),0.95(t,J=7.6Hz,3H)。
Claims (16)
4.根据权利要求1-3中任一项所述的化合物,其中,所述卤素原子为氟原子、氯原子、溴原子或碘原子,所述烷基为甲基。
5.根据权利要求1-4中任一项所述的化合物,其中,所述卤素原子为溴原子。
6.根据权利要求1-5中任一项所述的化合物,其中,所述通式(1)中或(1′)中,m为0或1。
7.根据权利要求2-6中任一项所述的化合物,其中,所述通式(1-o)、(1-m)中,R4在具有羧酸基团的取代基的间位或对位取代。
8.根据权利要求1所述的化合物,其中,所述通式(1′)中,具有R2和R3的取代基在具有内酯环的取代基的邻位或间位取代。
9.根据权利要求8所述的化合物,其中,所述通式(1′)中,R4在具有内酯环的取代基的间位或对位取代。
11.一种中性粒细胞浸润抑制剂,其以权利要求1-10中任一项所述的化合物作为有效成分。
12.一种抗炎剂,其以权利要求1-10中任一项所述的化合物作为有效成分。
13.一种抗抑郁剂,其以权利要求1-10中任一项所述的化合物作为有效成分。
14.一种药物组合物,其以权利要求1-10中任一项所述的化合物作为有效成分。
15.根据权利要求14所述的药物组合物,其用于治疗炎症。
16.根据权利要求14所述的药物组合物,其用于治疗抑郁症。
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US20050049227A1 (en) * | 2003-08-28 | 2005-03-03 | Allergan, Inc. | Cyclohexyl prostaglandin analogs as EP4-receptor agonists |
CN101663031A (zh) * | 2007-02-20 | 2010-03-03 | 马泰克生物科学公司 | 来自长链多不饱和脂肪酸的氧脂素及其制备方法和使用方法 |
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US4032656A (en) * | 1975-11-21 | 1977-06-28 | Smithkline Corporation | Aromatic prostaglandin derivatives |
DK2216318T3 (en) * | 2002-08-12 | 2018-12-10 | Brigham & Womens Hospital | Resolvins: Bio templates for therapeutic interventions |
EP2958561B1 (en) * | 2013-02-22 | 2019-12-11 | University Of Southern California | Lipoxin analogs for use in the treatment of ophthalmic diseases and disorders |
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US20050049227A1 (en) * | 2003-08-28 | 2005-03-03 | Allergan, Inc. | Cyclohexyl prostaglandin analogs as EP4-receptor agonists |
CN101663031A (zh) * | 2007-02-20 | 2010-03-03 | 马泰克生物科学公司 | 来自长链多不饱和脂肪酸的氧脂素及其制备方法和使用方法 |
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YUTO MURAKAMI等: "Design and Synthesis of Benzene Congeners of Resolvin E2,a Proresolving Lipid Mediator,as Its Stable Equivalents", ACS MEDICINAL CHEMISTRY LETTERS, vol. 11, pages 479 - 484, XP055849831, DOI: 10.1021/acsmedchemlett.9b00596 * |
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US20230099067A1 (en) | 2023-03-30 |
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EP4091672A1 (en) | 2022-11-23 |
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