CN101244057A - 具有降血脂作用的3-取代氧基-3’,4’-二甲氧基黄酮类化合物 - Google Patents
具有降血脂作用的3-取代氧基-3’,4’-二甲氧基黄酮类化合物 Download PDFInfo
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- CN101244057A CN101244057A CNA2008100344460A CN200810034446A CN101244057A CN 101244057 A CN101244057 A CN 101244057A CN A2008100344460 A CNA2008100344460 A CN A2008100344460A CN 200810034446 A CN200810034446 A CN 200810034446A CN 101244057 A CN101244057 A CN 101244057A
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- benzoyl
- dimethoxy flavone
- dimethoxy
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Landscapes
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Abstract
本发明涉及医药技术领域,是一种具有具有降血脂作用的3-取代氧基-3’,4’-二甲氧基黄酮化合物,化学结构如通式I,其中R表示:H,烷基,酰基等。动物实验表明本发明合物具降低血清甘油三脂,胆固醇和LDL胆固醇水平,因此可制备治疗和预防高血脂症、冠心病、动脉粥样硬化等心血管疾病的药物或保健食品。
Description
技术领域:
本发明涉及医药技术领域,是一类具有降血脂作用的3-取代氧基-3’,4’-二甲氧基黄酮类化合物及其制备方法和用途。
背景技术:
高脂血症是一种常见的心血管疾病,主要是由于血脂代谢紊乱引起的,在临床上分为原发性高脂血症和继发性高脂血症,常表现为高胆固醇血症(TC升高),高甘油三脂血症(TG升高)或二者兼有。其与动脉硬化以及心血管疾病的发生发展有紧密地联系。由血脂异常,如高低密度脂蛋白胆固醇血症、高甘油三脂血症、尤其低高密度脂蛋白胆固醇血症引起的血管疾病,如外周血管疾病、冠心病、中风疾病、血管再狭窄等血管疾病,成为严重威胁人类健康的危险因素。高脂血症最初认为是体内过量的甘油三酯所致。后来研究发现高血浆甘油三脂只是形成此类疾病的一个重要原因,并非主要病因。其主要病因是高血清总胆固醇或高低密度脂蛋白胆固醇。因此降低血清总胆固醇或低密度脂蛋白胆固醇是治疗和预防高脂血症的一种重要方法。
3-羟基-3’,4’-二甲氧基黄酮、3-乙酰氧基-3’,4’-二甲氧基黄酮和3,3’,4’-三甲氧基黄酮是3-取代氧基-3’,4’-二甲氧基黄酮类化合物,结构通式如通式I所示,其中R基分别表示H、乙酰基和甲基。文献报道了当R为H时的化合物:3-羟基-3’,4’-二甲氧基黄酮具有抗氧化(Journal of CardiovascularPharmacology 2005,46(3),302-309)、细胞毒和抗菌作用(Archiv der Pharmazie2000,333(7),205-210;Arzneimittel Forschung 1986,36(8),1249-53),未见其具有降血脂活性的报道。当R为乙酰基的化合物:3-乙酰氧基-3’,4’-二甲氧基黄酮和R为甲基的化合物:3,3’,4’-三甲氧基黄酮也未见具有降血脂作用的报道。
发明内容:
本发明的目的是提供一类具有降血脂活性的3-取代氧基-3’,4’-二甲氧基黄酮类化合物(通式I)。实验证明,除了上述提及的3-羟基-3’,4’-二甲氧基黄酮和3-乙酰氧基-3’,4’-二甲氧基黄酮具有降血脂活性外,将R基团置换为本发明所示的相应基团后,均显示出较好的降血脂活性。
本发明化合物的化学结构如通式I所示:
其中R基表示:
(1)H;
(2)烷基是指包括甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,优选甲基、乙基和丙基在内的1~6个碳原子的直链或支链烷基;
(3)酰基是指乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、甲烷磺酰基、苯甲酰基、对氟苯甲酰基、对氯苯甲酰基、对溴苯甲酰基、对碘苯甲酰基、对硝基苯甲酰基、对甲基苯甲酰基、对乙基苯甲酰基、对丙基苯甲酰基、对甲氧基苯甲酰基、对乙氧基苯甲酰基;
(4)-COCH2CH2COOH,-COCH2CH2CH2COOH;
(5)通过糖的1位羟基形成糖苷键葡萄糖基,鼠李糖等六碳糖;
本发明新的3-取代氧基-3’,4’-二甲氧基黄酮类化合物是以3-羟基-3’,4’-二甲氧基黄酮(化合物1)为原料制备,根据R基的不同,选用相应的试剂与其反应制得相应的化合物。合成路线举例如下:
R=丙酰基(化合物3)
R=丁酰基(化合物4)
R=COCH2CH2COOH
(化合物5)
R=1-D-葡萄糖基(化合物15)
3-羟基-3’,4’-二甲氧基黄酮(化合物1)的制备方法详见Yakugaku Zasshi 1951,71:1178-83.,CA 1952,46:35907。
当R=酰基和当时,由化合物3-羟基-3’,4’-二甲氧基黄酮(化合物1)与乙酸酐、丙酸酐或者丁酸酐在浓硫酸的作用下于0~50℃反应可制得相应的3-乙酰氧基-3’,4’-二甲氧基黄酮(化合物2)或3-丙酰氧基-3’,4’-二甲氧基黄酮(化合物3)或3-丁酰氧基-3’,4’-二甲氧基黄酮(化合物4)。
也可用3-羟基-3’,4’-二甲氧基黄酮(化合物1)的氢氧化钠或钾、碳酸钠或钾、碳酸氢钠或钾的水溶液在-15~5℃低温条件下与丁酰氯、苯甲酰氯、取代苯甲酰氯、三氯氧磷反应制得相应的3-丁酰氧基-3’,4’-二甲氧基黄酮(化合物3)、3-取代苯甲酰氧基-3’,4’-二甲氧基黄酮(化合物11~14)或3’,4’-二甲氧基黄酮醇磷酸酯(化合物7)。
3’,4’-二甲氧基黄酮醇硫酸酯(化合物9)采用3-羟基-3’,4’-二甲氧基黄酮与浓硫酸在10~80℃下反应制得。
3’,4’-二甲氧基黄酮醇磷酸酯二钠(化合物8)和3’,4’-二甲氧基黄酮醇硫酸酯一钠盐(化合物12)采用与等量的氢氧化钠的水溶液反应制得。
3’,4’-二甲氧基黄酮醇琥珀酸单酯(化合物5)可采用3-羟基-3’,4’-二甲氧基黄酮与琥珀酸酐在DMAP催化下反应制备。相应的3’,4’-二甲氧基黄酮醇琥珀酸单酯钠盐(化合物6)可以将3’,4’-二甲氧基黄酮醇琥珀酸单酯与等量的氢氧化钠在水中反应制备。
3’,4’-二甲氧基黄酮醇-D-葡萄糖苷(化合物15)的合成采用相转移催化法由3’,4’-二甲氧基黄酮醇和溴代四乙酰葡萄糖反应制备。
3,3’,4’-三甲氧基黄酮(化合物16)参考文献方法(Indian J.Chem.Sect.B;1981;20(6);511-512)采用3’,4’-二甲氧基黄酮醇为原料与碘甲烷在乙醇中回流制备。
动物实验:
本发明采用如下方法测试了11种化合物的降血脂活性。将清洁级小鼠按体重随机分为空白组、阳性对照组、高脂模型组和实验组(每组9只)。阳性对照组按10mg/kg给予辛伐他汀的CMC-Na混悬液,实验组按照10mg/kg给予本发明化合物的CMC-Na混悬液,空白组及高脂模型组给予相同体积的CMC-Na溶液,1次/天,连续给药7天,于第7天给药后禁食,但是不禁水,末次用药2小时后,除空白组腹腔注射等体积的生理盐水外,其余各组均腹腔注射75%蛋黄乳液,0.5ml/只,造成实验性高血脂症。注射20小时后,从小鼠眼眶静脉丛取血,检测各组小鼠血清指标,降血脂作用的实验结果见表1。
表1本发明的11种化合物的降血脂作用实验结果
GROUP | N | TC | TG | LDL-C |
空白组高脂模型组阳性对照组化合物1化合物2化合物3化合物4化合物5化合物6化合物7化合物8化合物9化合物10化合物15 | 99999999999999 | 1.81±0.14*4.54±0.613.66±0.65*3.69±0.42*3.56±0.99*3.68±0.67*3.43±0.62*3.32±1.13*3.47±0.73*3.21±0.69*3.16±0.34*3.26±0.57*3.37±1.36*3.43±0.68* | 1.46±0.37*4.62±1.363.99±1.344.79±1.364.22±1.904.41±1.854.64±0.884.25±1.274.24±1.163.12±1.05*3.32±1.26*3.12±0.79*3.01±0.82*4.34±1.63 | 0.66±0.16*1.72±0.261.66±0.291.57±0.451.34±0.21*1.26±0.43*1.15±0.26*1.14±0.95*1.25±1.12*1.32±0.31*1.22±0.51*1.25±0.38*1.15±0.75*1.30±1.26* |
*同模型组比较p<0.05;
从表1可以看出,所测试的化合物均有明显的降低血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)的作用,作用优于或与辛伐他汀相当。部分化合物降低甘油三酯(TG)的作用甚至优于辛伐他汀。
对化合物1,2,3,4,5,7,9,15进行了进一步的急性毒性试验,一次性给小鼠灌胃相应化合物(2g/kg),小鼠无明显反应,1个月后小鼠没有死亡,说明本发明化合物毒性小。
因此,本发明化合物及其生理上可以接受的盐和/或水合物可用于制备降血脂,治疗和预防高脂血症、脂肪肝和动脉粥样硬化的药物或保健品。
具体实施方式
现结合实施例,对本发明化合物的制备方法作详细描述。
实施例1 3-乙酰氧基-3’,4’-二甲氧基黄酮(化合物2)的制备(通式I中R=乙酰基)
取化合物1 100mg,乙酸酐10ml,浓硫酸1滴,室温搅拌反应3h。然后向反应液中加入水100ml,继续搅拌过夜。过滤,固体烘干后用异丙醇重结晶,得到化合物2略带黄色固体,熔点106~108℃,收率70%。
1HNMR(CDCl3)δ,ppm:2.37(3H,s,-CH3),3.95,3.97(6H,d,-OCH3),6.98~7.01(1H,d,2’-H),7.41~7.43(2H,m,5’,6’-H),7.52~7.58(2H,m,6,8-H),7.69~7.74(1H,m,7-H),8.25~8.26(1H,m,5-H).
MS(ESI)M+=341
实施例2 3-丙酰氧基-3’,4’-二甲氧基黄酮(化合物3)的制备(通式I中R=丙酰基)
取化合物1 100mg,丙酸酐10ml,按实施例1方法制得化合物3淡黄色固体,熔点148~150℃,收率60%。
1HNMR(CDCl3)δ,ppm:1.26~1.30(3H,t,-CH3),2.68~2.70(2H,m,-CH2-),3.96,3.977(6H,d,-OCH3),6.98~7.01(1H,d,2’-H),7.42~7.47(2H,m,5’,6’-H),7.52~7.58(2H,m,6,8-H),7.69~7.72(1H,m,7-H),8.25~8.27(1H,m,5-H).
MS(ESI)M+=355
实施例3 3-丁酰氧基-3’,4’-二甲氧基黄酮(化合物4)的制备(通式I中R=丁酰基)
取化合物1 100mg,NaOH 65mg,水5ml,THF 5ml.5℃以下加入含1ml丁酰氯的5ml THF溶液,滴毕,继续保持该温度反应1h,然后将反应液倒入50ml水中,析出固体过滤,用异丙醇重结晶,得化合物4淡黄色固体,熔点113~116℃。
1HNMR(CDCl3)δ,ppm:1.01~1.06(3H,t,-CH3),1.77~1.84(2H,m,-CH2-),2.60~2.65(2H,t,-OCH2-),3.96~3.99(6H,d,-OCH3)6.98~7.01(1H,d,2’-H),7.41~7.44(2H,m,5’,6’-H),7.52~7.58(2H,m,6,8-H),7.69~7.75(1H,m,7-H),8.25~8.28(1H,m,5-H).
MS(ESI)M+=369
实施例4 3’,4’-二甲氧基黄酮醇琥珀酸单酯(化合物5)的制备(通式I中R=-COCH2CH2COOH)
取化合物1 100mg,吡啶2ml,K2CO3 2g,DMAP少许,DMF 10ml,琥珀酸酐220mg,加热回流反应24h。然后将反应液缓慢地加入到100ml的冰水中,并在0~5℃下搅拌滴加3N HCl至溶液pH 1~5。过滤析出的沉淀,用乙醇重结晶,得到化合物5淡黄色固体,熔点159~163℃,收率53%。
1HNMR(CDCl3)δ,ppm:2.67~2.74(2H,t,-CH2-),2.79~2.85(2H,t,-CH2-),3.97~4.00(6H,d,-OCH3),6.98~7.01(1H,d,2’-H),7.42~7.47(2H,m,5’,6’-H),7.52~7.58(2H,m,6,8-H),7.69~7.73(1H,m,7-H),8.25~8.28(1H,m,5-H).
MS(ESI)M+=399
实施例5 3’,4’-二甲氧基黄酮醇琥珀酸单酯钠(化合物6)的制备(通式I中R=-COCH2CH2COONa)
精密称量NaOH 10mg,加入到10ml乙醇中,搅拌使之溶解。取化合物5100mg,加入到上面的溶液中,搅拌3h。然后减压蒸除乙醇,向剩余固体中加入5ml水,滤除不溶物,然后减压蒸干溶液,将得到的固体用葡聚糖凝聚LH-20层析,得到化合物6黄色粉末,熔点>250℃,收率55%。
MS(ESI)M+=443(M+Na+)
实施例6 3’,4’-二甲氧基黄酮醇磷酸酯(化合物7)(通式I中R=-PO(OH)2)
取化合物1 100mg,NaOH 65mg,水5ml,THF或者二氧六环5ml.5℃以下加入含3ml三氯氧磷的5ml二氧六环溶液,滴毕,继续保持该温度反应1h,然后将反应液倒入50ml水中,析出固体过滤,用乙醇重结晶,得化合物7淡黄色固体,熔点198~200℃。
1HNMR(DMSO-d6)δ,ppm:3.85(6H,d,-OCH3),7.13~7.16(1H,d,2’-H),7.49~7.54(1H,m,5’-H),7.71~7.75(1H,m,6’-H),7.78~7.85(3H,m,6,7,8-H),8.07(1H,m,5-H).
MS(ESI)M+=401(M+Na+)
实施例7 3’,4’-二甲氧基黄酮醇磷酸酯二钠盐(化合物8)(通式I中R=-POOHNa)
取化合物7 100mg,NaOH 22mg,方法同实施例5,得化合物8黄色固体,熔点>250℃,收率80%。
MS(ESI)M+=446(M+Na+)
实施例8 3’,4’-二甲氧基黄酮醇硫酸酯(化合物9)(通式I中R=-SO2OH)
取化合物8 100mg,在10~30℃下搅拌滴加2ml浓硫酸,然后室温搅拌反应6h。向反应液中加入15ml水,析出固体,抽滤,干燥。用乙醇重结晶或者用葡聚糖凝聚LH-20层析纯化,得化合物9黄色固体,熔点201~204℃。
1HNMR(DMSO-d6)δ,ppm:3.84(6H,d,-OCH3),7.13~7.16(1H,d,2’-H),7.49~7.54(1H,m,5’-H),7.71~7.75(1H,m,6’-H),7.78~7.86(3H,m,6,7,8-H),8.07~8.09(1H,m,5-H).
MS(ESI)M+=401(M+Na)
实施例9 3’,4’-二甲氧基黄酮醇硫酸酯一钠盐(化合物10)(通式I中R=-SO2ONa)
取化合物9 100mg,NaOH 11mg,方法同实施例5,得化合物10黄色固体,熔点>250℃
MS(ESI)M+=423(M+Na)
实施例10 3-苯甲酰氧基-3’,4’-二甲氧基黄酮(化合物11)(通式I中R=苯甲酰基)
以苯甲酰氯0.5ml和化合物1 100mg为原料,方法同实施例3。得化合物11淡黄色固体,熔点160~163℃,收率81%。
1HNMR(CDCl3)δ,ppm:3.77(3H,s,-OCH3),3.93(3H,s,-OCH3),6.94~6.97(1H,d,2’-H),7.43~7.54(4H,m,3”,5”,5’,6,-H),7.59~7.66(4H,m,6,7,8,),7.72~7.75(1H,m,4”-H),8.23~8.26(2H,m,2”,6”-H),8.27~8.31(1H,m,5-H).
MS(ESI)M+=403
实施例11 3-对甲基苯甲酰氧基-3’,4’-二甲氧基黄酮(化合物12)(通式I中R=对甲基苯甲酰基)
以对甲基苯甲酰氯0.6ml和化合物1 100mg为原料,方法同实施例3。得化合物12淡黄色固体,熔点143~145℃,收率52%。
1HNMR(CDCl3)δ,ppm:2.45(3H,s,-CH3),3.77(3H,s,-OCH3),3.92(3H,s,-OCH3),6.93~6.96(1H,d,2’-H),7.29~7.32((2H,dd,3”,5”-H),7.42~7.48(2H,m,,5’,6,-H),7.60(2H,m,6,7,-H),7.72(1H,d,8-H),8.11~8.14(2H,dd,2”,6”-H),8.27~8.30(1H,m,5-H).
MS(ESI)M+=417
实施例12 3-对氯苯甲酰氧基-3’,4’-二甲氧基黄酮(化合物13)(通式I中R=对氯苯甲酰基)
以对氯苯甲酰氯0.6ml和化合物1 100mg为原料,方法同实施例3。得化合物13淡黄色固体,熔点158~160℃,收率62%。
1HNMR(CDCl3)δ,ppm:3.78(3H,s,-OCH3),3.93(3H,s,-OCH3),6.96(1H,d,2’-H),7.406~7.59(4H,m,3”,5”,5’,6,-H),7.59~7.63(3H,m,6,7,8,-H),8.13(2H,dd,2”,6”-H),8.29(1H,m,5-H).
MS(ESI)M+=437
实施例13 3-对甲氧基苯甲酰氧基-3’,4’-二甲氧基黄酮(化合物14)(通式I中R=对甲氧基苯甲酰基)
以对甲氧基苯甲酰氯0.6ml和化合物1100mg为原料,方法同例3。得化合物14淡黄色固体,熔点169.5~~171.5℃,收率47%。
1HNMR(CDCl3)δ,ppm:3.74(3H,s,4”-OCH3),3.93(3H,s,3’-OCH3),4.01(3H,s,4’-OCH3),6.92~6.94(1H,d,2’-H),6.97~7.01(2H,dd,3”,5”-H),7.42~7.49(2H,m,5’,6,-H),7.59~7.63(2H,m,6,7-H),7.71~7.77(1H,m,8-H),8.17~8.19(2H,dd,2”,6”-H),8.20~8.21(1H,d,,5-H).
MS(ESI)M+=433
实施例14 3’,4’-二甲氧基黄酮醇-D-葡萄糖苷(化合物15)(通式I中R=1-D-葡萄糖基)
取10ml水和10ml氯仿,加入0.5g TEBA,化合物1 200mg,NaOH 130mg搅拌,使基本溶解。然后加入溴代四乙酰葡萄糖400mg,加热至60℃搅拌反应8h,然后分出氯仿层,水层用氯仿提取三次,每次10ml。合并氯仿液,硫酸钠干燥后减压蒸去氯仿,剩余固体用乙醇重结晶。得到3’,4’-二甲氧基黄酮醇-D-四乙酰基葡萄糖苷,黄色固体,熔点117~119℃,收率41%。
1HNMR(CDCl3)δ,ppm:1.25~1.28(1H,d,1”-H),1.88(3H,s,-COCH3),1.94~1.96(3H,d,-COCH3),2.02~2.07(3H,d,-COCH3),2.12(3H,s,-COCH3),3.64~3.69(1H,m,4”-CH-),3.86~3.92(1H,m,2”-CH-),3.99(6H,d,-OCH3),4.01(1H,s,-OCH3),5.05~5.11(1H,t,6”-CH2),5.18~5.24(1H,s,5”-H),5.27~5.33(1H,s,3”-H),6.96~6.99(1H,m,2’-H),7.39~7.43(1H,t,5’-H),7.52~7.55(1H,d,6’-H),7.66~7.76(3H,m,6,7,8-H),8.20~8.23(1H,m,5-H).
取3’,4’-二甲氧基黄酮醇-D-四乙酰基葡萄糖苷50mg加入到甲醇10ml中,再加入甲醇钠100mg,50℃反应6h。然后减压蒸去甲醇,剩余固体乙醇重结晶,得化合物15淡黄色固体,熔点229~233℃。
1HNMR(DMSO-d6)δ,ppm:3.10~3.11(2H,m,glucose-CH-),3.21~3.25(2H,m,glucose-CH-),3.37~3.43(1H,m,glucose-5”-CH2),3.55~3.57(1H,m,glucose-5”-CH2),3.83(3H,d,-OCH3),3.84(3H,d,-OCH3),4.34~4.36(1H,t,1”-CH-),4.94(1H,d,glucose-OH),5.07(1H,d,glucose-OH),5.39(1H,d,glucose-OH),5.66(1H,d,glucose-OH),7.12~7.13(1H,d,8-H),7.48~7.51(1H,m,6-H),7.67~7.69(1H,m,6’-H),7.74~7.75(1H,m,5’-H),7.81~7.83(1H,m,7-H),7.96(1H,d,2’-H),8.08~8.10(1H,m,5-H).
MS(ESI)M+=461
实施例15 3,3’,4’-三甲氧基黄酮(化合物16)(通式I中R=甲基)
取化合物1 100mg,乙醇10ml,碳酸钾1g,碘甲烷1ml,回流反应6h。然后减压蒸去乙醇,剩余固体加入10ml水,过滤,用乙醇重结晶得化合物16淡黄色固体,收率61%,熔点166~168℃,文献值168~169℃。(Indian J.Chem.Sect.B;1981;20(6);511-512)
Claims (5)
1.一种3-取代氧基-3’,4’-二甲氧基黄酮类化合物及其在生理上可以接受的盐或水合物在制备降血脂、治疗和预防高脂血症、脂肪肝和动脉粥样硬化的药物或保健品中的应用,其特征在于该化合物具有通式I所示的结构:
其中R代表:
(1)H;
(2)烷基是指甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基在内的1~6个碳原子的直链或支链烷基;
(3)酰基是指乙酰基、丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、甲烷磺酰基、苯甲酰基、对氟苯甲酰基、对氯苯甲酰基、对溴苯甲酰基、对碘苯甲酰基、对硝基苯甲酰基、对甲基苯甲酰基、对乙基苯甲酰基、对丙基苯甲酰基、对甲氧基苯甲酰基、对乙氧基苯甲酰基;
(4)-COCH2CH2COOH,-COCH2CH2CH2COOH;
(5)通过糖的1位羟基形成糖苷键的葡萄糖基或鼠李糖六碳糖基;
3.权利要求1所述的3-取代氧基-3’,4’-二甲氧基黄酮类化合物及其在生理上可以接受的盐或水合物,其特征在于通式I中R代表:
(1)烷基是指乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基,在内的2~6个碳原子的直链或支链烷基;
(2)酰基是指丙酰基、丁酰基、异丁酰基、戊酰基、异戊酰基、新戊酰基、甲烷磺酰基、苯甲酰基、对氟苯甲酰基、对氯苯甲酰基、对溴苯甲酰基、对碘苯甲酰基、对硝基苯甲酰基、对甲基苯甲酰基、对乙基苯甲酰基、对丙基苯甲酰基、对甲氧基苯甲酰基、对乙氧基苯甲酰基;
(3)-COCH2CH2COOH,-COCH2CH2CH2COOH;
(4)通过糖的1位羟基形成的糖苷键葡萄糖基或鼠李糖六碳糖;
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