CN115806580A - 12-o-脂肪酸酯齐墩果酸类化合物及其制备方法和用途 - Google Patents
12-o-脂肪酸酯齐墩果酸类化合物及其制备方法和用途 Download PDFInfo
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- CN115806580A CN115806580A CN202111071546.2A CN202111071546A CN115806580A CN 115806580 A CN115806580 A CN 115806580A CN 202111071546 A CN202111071546 A CN 202111071546A CN 115806580 A CN115806580 A CN 115806580A
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Abstract
本发明属于医药技术领域。涉及一种作用于法尼酯X受体(FXR)的12‑O‑脂肪酸酯齐墩果酸类化合物及其制备方法和用途。具体是,提供了如式(I)所示化合物及其药学上可接受的盐、非对映异构体,这些化合物的制备方法,以及这些化合物调节FXR活性,用于治疗和/或预防FXR介导的糖尿病、高血脂症、非酒精性脂肪性肝炎等代谢性疾病的应用。
Description
技术领域
本发明属于医药技术领域。具体地,本发明涉及一种作用于法尼酯X受体(FXR)的齐墩果酸类衍生物及其制备方法和用途。更具体地,本发明涉及12-O-脂肪酸酯齐墩果酸类化合物及其制备方法和用途,以及它们在药学上可接受的盐、非对映异构体,这些化合物的制备方法,以及这些化合物在调节FXR活性、用于治疗和/或预防FXR介导的疾病的药物中的应用。这些FXR介导的疾病包括但不限于糖尿病、高脂血症、动脉粥样硬化等代谢性疾病和胆汁淤积、非酒精性脂肪性肝炎等肝胆疾病。
背景技术
法尼酯X受体(FXR)在1995年作为一种孤儿核受体被发现。1999年发现胆汁酸在生理浓度下能激活FXR。作为胆汁酸的受体,FXR通过调控参与胆汁酸代谢的基因表达来维持胆汁酸在体内的平衡。此外,FXR还参与脂质和糖类的代谢过程。FXR作为一个药物靶标,有望为糖尿病、高脂血症、非酒精性脂肪性肝炎,甚至肿瘤、感染性疾病等提供新的治疗选择。
生理浓度的多种初级和次级胆汁酸可激活FXR,其中鹅去氧胆酸(chenodexycholic acid,CDCA)激动作用最强。不过,直接将CDCA用于相关的生物学调控并产生疾病治疗作用,受其自身溶解性差且毒性较高的限制。在甾体结构的基础上,发现了FXR激动剂6-乙基鹅去氧胆酸(6-ECDCA)。6-ECDCA又称奥贝胆酸(OCA),在2016年被FDA批准用于治疗原发性胆汁性肝硬化,是第一个被批准的以FXR为靶的新药。此外,非甾体类结构的FXR激动剂代表性化合物,有早期发现的GW4064以及处于临床试验的Tropifexor,Nidufexor等。由于在临床实验中的强效FXR激动剂可导致高密度脂蛋白上升、瘙痒等副作用,近来对于FXR部分激动剂乃至拮抗剂的研究增多。
已有的研究表明,由于FXR下游基因众多,选择性调节其中与某种疾病密切相关的部分基因,可治疗疾病并减轻副作用。因此,作用于FXR并具有选择性调节作用的小分子化合物,又被称为选择性胆酸受体调节剂(SBARM),可用于开发治疗代谢性疾病和肝胆疾病的分子。
含有齐墩果酸(OA)的植物在传统医药中可用于治疗肝病,而OA也在中国被批准用于保肝和辅助性治疗病毒性肝炎(通过降低谷丙转氨酶等机制)。近年来OA还被发现对FXR具有选择性调节作用【Liu W,Wong C.Phytotherapy Research2010,24:369-373.】,并可通过对FXR的拮抗减轻模型动物的胆汁淤积症状。但是OA活性不强,因而我们以这类五环三萜的结构为基础,经过修饰发展了12位取代的OA类似物,对FXR的作用明显增强且对下游基因具有选择性调控作用。本发明所公开的是与FXR作用的12-O-脂肪酸酯齐墩果酸类化合物,及其制备方法和对FXR相关疾病的应用。
发明内容
本发明提供式(I)所示的一类化合物,以及它们在药学上可接受的盐、非对映异构体,它们的制备方法以及用于治疗或预防各种FXR相关疾病方面的应用。
本发明是通过如下技术方案来实现的。
首先,本发明提供一种式(I)所示的含有12-O-脂肪酸酯齐墩果酸类化合物,其特征在于,取代基R选自氢、未取代和取代C1-7烷基。其中所述的C1-7烷基优选C1-6烷基或C1-5烷基,更优选自甲基、乙基、正丙基、正丁基、正戊基、正己基、正庚基。
取代C1-7烷基中的取代基优选自氢、甲酰基、C1-5烷酰基、C1-5烷酰氧基、羟基、C1-5烷氧基、C2-5烯氧基、羧基、C1-5烷氧羰基、C3-5烯氧羰基。
所述的C1-5烷酰基优选自乙酰基、丙酰基、丁酰基、戊酰基、己酰基;所述的C1-5烷酰氧基选自甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰烷氧基;所述的C1-5烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基、戊烷氧基;所述的C2-5烯氧基选自丙烯氧基、丁烯氧基、戊烯氧基;所述的C1-5烷氧羰基选自甲氧羰基、乙氧羰基、丙氧羰基、丁氧羰基、戊烷氧羰基;所述的C3-5烯氧羰基选自丙烯氧羰基、丁烯氧羰基、戊烯氧羰基。
具有式(I)结构的化合物,进一步优选为12-正戊酰、正己酰、乙酰丙酰、乙酰丁酰、(3-羧基)丙酰、(3-羧基)丁酰、甲氧羰乙酰、甲氧羰丙酰、甲氧羰丁酰取代的12β-O-羟基-13H-齐墩果烷-3β-羟基-28-羧酸。
其次,本发明所述的12-O-脂肪酸酯齐墩果酸类化合物可以采用下述流程中描述的方法和/或本领域普通技术人员已知的其他技术来合成,但不仅限于以下方法。
反应步骤为:
1.将原料OA溶于有机溶剂(如四氢呋喃、乙醚),在碱(如碳酸钾、碳酸铯、三乙胺、三丁胺、吡啶)的水溶液存在下,与苄基卤化物(如溴苄、氯苄)反应,形成中间体1所示的化合物。
2.将中间体1溶于有机溶剂中(如二氯甲烷、N,N-二甲基甲酰胺),在碱(如三乙胺、咪唑)和硅烷化试剂(如三氟甲磺酸叔丁基二甲基硅烷酯、叔丁基二甲基氯硅烷)存在下,形成中间体2所示的化合物。
3.将中间体2溶于有机溶剂(如氯仿),加入氧化剂(如间氯过氧苯甲酸、叔丁基过氧化氢),经后处理形成中间体3所示的化合物。
4.将中间体3溶于有机溶剂(如四氢呋喃、乙醚),加入还原剂(如硼氢化钠、硼氢化锂),形成中间体4所示的化合物。
5.将中间体4溶于有机溶剂(如二氯甲烷、甲苯、四氢呋喃、乙醚),与适当的酰化试剂进行反应,形成中间体5所示的化合物。
6.将中间体5溶于有机溶剂(如二氯甲烷、乙腈),在含氟试剂(如氢氟酸-吡啶、四丁基氟化铵)或酸(盐酸、三氟化硼-乙醚)存在下,形成如中间体6所示的化合物。
7.将中间体6溶于有机溶剂(如甲醇、乙醇、四氢呋喃、乙醚)的混合溶剂中,加入催化剂(如Pd/C)和氢供体(如氢气、1,4-环己二烯),形成如式(I)所示的化合物。
以上反应式中的R如前文所定义。
本发明还涉及式(I)化合物的有机或无机盐。
本发明还涉及这些化合物单一光学异构体和/或非对映异构体及其所有比例的混合物。
再次,本发明提供一种式(I)所述的化合物,以及它们在药学上可接受的盐、非对映异构体,通过调节FXR的作用,用于预防或治疗由FXR介导的疾病的一个或多个症状的方法。其中调节FXR的作用包括但不限于对FXR激动剂的拮抗作用。
本发明涉及的FXR介导的疾病,包括但不限于高胆固醇血症、高脂蛋白血症、高甘油三酯血症、血脂异常、脂肪代谢障碍、高血糖、糖尿病、胰岛素耐受、动脉粥样硬化等代谢性疾病,以及非酒精性脂肪性肝炎、肝纤维化、肝细胞性肝癌、胆汁淤积症、胆石症等肝胆疾病。
与现有技术相比,本发明具有如下显著效果:
本发明发现了一系列结构新颖的作用于FXR的齐墩果酸类似物。如实施例中所示,部分化合物可强烈拮抗FXR激动剂CDCA的激动作用,IC50值达到100nM,对FXR下游基因具有选择性调节作用。
附图说明
图1是实施例8改善KKay小鼠的葡萄糖平衡。KKay小鼠在喂食和不喂食OCA(10mg/kg,qd)或实施例8(100mg/kg和200mg/kg,qd)的情况下高脂饮食(HFD)喂养6周。(A)在5周治疗期间的小鼠体重。(B)食物摄取曲线。(C)禁食血糖水平。(D)随机血糖水平。(E)糖化血红蛋白HbA1c水平。(F)OGTT结果。(E)ITT结果。数据结果以平均值±SD(n=9)表示(*P<0.05,**P<0.01和***P<0.001)。
具体实施方式
本发明由以下的实施例来更进一步阐明。这些实施例并非用来限制上文所定义的或要求保护的本发明的范围。
实施例1
齐墩果烷-28-苄基酯的制备
齐墩果酸21.6mg用0.35ml四氢呋喃溶解,室温加入碳酸钾12.9mg、溴苄13μl和水8μl,4小时后停止反应。反应液用硅藻土过滤,滤液浓缩后用硅胶柱层析,石油醚:丙酮=9:1洗脱,得产物25.7mg,产率99%。1HNMR(400MHz,CDCl3):δ7.56-7.26(m,5H),5.32(brs,1H),5.12(ABq,2H),3.24(m,1H),2.93(d,J=13Hz,1H),1.18(s,1H),1.03(s,3H),0.97(s,3H),0.94(s,6H),0.92(s,3H),0.80(s,3H),0.66(s,3H).
实施例2
3β-叔丁基二甲基硅烷基齐墩果烷-28-苄基酯的制备
将齐墩果烷-28-苄基酯(12.5g)溶解在CH2Cl2(241mL)中,加入咪唑(8.50g)。室温下缓慢加入叔丁基二甲基硅三氟甲磺酸酯(16.6g)并搅拌过夜。反应混合物用水(240mL)洗涤。水相用CH2Cl2(2×240mL)萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,并减压浓缩。残余物通过闪蒸柱层析纯化(2%乙酸乙酯/石油醚),得到产物3β-叔丁基二甲基硅烷基齐墩果烷-28-苄基酯,产率81%。1H NMR(400MHz,CDCl3):7.29-7.30(m,5H),5.24(s,1H),5.04(d,J=12.4Hz,1H),4.99(d,J=12.4Hz,1H),3.11-3.14(m,1H),2.84-2.87(m,1H),1.07(s,3H),0.87(s,6H),0.85(s,3H),0.84(s,9H),0.82(s,3H),0.69(s,3H),0.50(s,3H),-0.02(s,6H).
实施例3
3β-叔丁基二甲基硅烷基-12-氧代-齐墩果烷-28-苄基酯的制备
将3β-叔丁基二甲基硅烷基齐墩果烷-28-苄基酯(12.5g)溶于二氯甲烷(248mL)中,加入85%的间氯过氧苯甲酸(11.5g),室温反应约9h,反应完全后,用饱和亚硫酸氢钠水溶液(248mL)淬灭,分离有机相,用乙酸乙酯(2×248mL)萃取水相,合并有机相减压浓缩,浓缩物分别用饱和碳酸钠溶液和饱和食盐水溶液洗涤,有机相用无水硫酸钠干燥,过滤后蒸干溶剂,通过硅胶柱色谱法(5%乙酸乙酯/石油醚)纯化得到产物3β-叔丁基二甲基硅烷基-12-氧代-齐墩果烷-28-苄基酯,产率63%。1H NMR(400MHz,CDCl3):7.31-7.33(m,5H),5.05-5.21(m,2H),3.12-3.15(m,1H),2.77-2.80(m,1H),2.42-2.45(m,1H),2.17-2.19(m,1H),1.12(s,3H),0.92(s,3H),0.90(s,3H),0.88(s,3H),0.87(s,12H),0.77(s,3H),0.61(s,3H),0.03(s,6H).
实施例4
3β-叔丁基二甲基硅烷基-12-羟基-齐墩果烷-28-苄基酯的制备
3β-叔丁基二甲基硅烷基-12-氧代-齐墩果烷-28-苄基酯24.3mg,溶于0.54ml四氢呋喃中,加入硼氢化钠4.1mg,水54μl,室温反应11小时后结束反应。反应液用饱和氯化铵水溶液调节pH值至中性,有机层依次用3×10ml水和10ml饱和氯化钠水溶液洗涤,水层用3×10ml二氯甲烷萃取,合并有机层并用无水硫酸钠干燥。有机层浓缩后用硅胶柱层析,石油醚:丙酮=50:1洗脱,得3β-叔丁基二甲基硅烷基-12α-羟基-齐墩果烷-28-苄基酯8.6mg,产率35%;3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯15.7mg,产率64%。
3β-叔丁基二甲基硅烷基-12α-羟基-齐墩果烷-28-苄基酯:1HNMR(400MHz,CDCl3):δ7.24-7.39(m,5H),5.13(ABq,2H),3.99(brs,1H),3.17(dd,J=6.4Hz,1H),2.49(d,J=12Hz,1H),0.97(s,3H),0.96(s,3H),0.88(s,12H),0.83(s,3H),0.79(s,3H),0.71(s,3H),0.60(s,3H),0.02(s,6H).
3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯:1HNMR(400MHz,CDCl3):δ7.29-7.42(m,5H),5.15(ABq,2H),3.67(m,1H),3.14(dd,J=6.8Hz,1H),2.74(m,1H),0.92(s,6H),0.89(s,12H),0.85(s,3H),0.77(s,3H),0.70(s,3H),0.60(s,3H),0.02(s,6H).
实施例5
3β-羟基-12β-正戊酰氧-齐墩果烷-28-羧酸(7a)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯100mg溶于3mL无水二氯甲烷中,随后依次加入4-二甲氨基吡啶183mg、正戊酸76μL和N,N'-二异丙基碳二亚胺115μL,反应混合物在室温下反应12h,TLC监测,反应完全后,将反应混合物减压浓缩,然后用30mL乙酸乙酯稀释,用2×10mL水和10mL饱和食盐水洗涤,有机相用无水硫酸钠干燥,在真空下除去溶剂,通过硅胶柱色谱法(二氯甲烷:甲醇=200:1)得到产物3β-叔丁基二甲基硅氧基-12β-正戊酰氧-齐墩果烷-28-苄基酯。(2)该产物(191mg)溶于5.6mL无水二氯甲烷中,在0℃氩气保护的条件下,缓慢加入三氟化硼乙醚1.4mL,在0℃下反应约2.5h,TLC监测,反应完全后,反应混合物用25mL二氯甲烷稀释,用10mL水饱和2×10mL食盐水洗涤,用无水硫酸钠干燥有机相,减压浓缩除去有机溶剂,通过硅胶柱色谱法(石油醚:丙酮=5:1)纯化得到产物3β-羟基-12β-正戊酰氧-齐墩果烷-28-苄基酯。(3)该产物(80mg)溶于1mL四氢呋喃和1mL甲醇中,并向反应混合物中加入10%钯碳45mg,在室温下在氢气存在的条件下反应约12h,TLC监测,反应完全后,将反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用3×12mL的6%甲醇/二氯甲烷洗涤,减压浓缩有机层,通过快速硅胶柱色谱法(石油醚:丙酮=3:1)纯化得到产物3β-羟基-12β-正戊酰氧-齐墩果烷-28-羧酸(7a),三步合计产率71%。
1H NMR(400MHz,CDCl3):δ4.95-5.00(m,1H),3.48(s,4H),3.19(dd,J=4.8Hz,11.2Hz,1H),2.51-2.54(m,1H),2.27-2.31(m,2H),2.07(dd,J=4.8Hz,11.6Hz,1H),1.06-1.92(m,25H),1.01(s,3H),0.96(s,3H),0.91(s,3H),0.89(s,3H),0.82(s,3H),0.81(s,3H),0.74(s,3H);13C NMR(100MHz,CDCl3):δ183.8,173.7,78.8,77.3,71.4,55.2,48.8,47.3,41.5,40.7,40.0,38.9,38.6,37.1,36.0,34.3,33.3,33.2,32.5,31.4,30.5,28.8,28.1,27.4,27.2,27.1,23.3,22.9,22.5,18.3,17.8,16.5,15.9,15.4,13.8.HRMS(ESI-TOF)m/z calcd.for C35H58O5[M+Na]+:581.4176,found 581.4174.
实施例6
3β-羟基-12β-正己酰氧-齐墩果烷-28-羧酸(7b)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯(300mg)和己酸(137mg)溶解在甲苯(8.90ml)中,随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(677mg)和4-二甲氨基吡啶(108mg)。反应混合物在氩气下60℃搅拌3h,反应混合物浓缩在真空中,然后用二氯甲烷(18.0mL)稀释,用H2O(2×9.00mL)和盐水(9.00mL)洗涤。有机相用无水Na2SO4干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(2)该产物粗品用CH2Cl2(5.65mL)稀释,在0℃氩气下缓慢加入BF3Et2O(1.97mL),在0℃下搅拌3h,反应混合物用CH2Cl2(12.0mL)稀释,用H2O(6.00mL)和盐水(2×16.0mL)洗涤。有机层在无水Na2SO4上干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(3)该产物粗品溶于THF(10.8mL)和乙醇(10.8mL)中,在反应混合物中加入10%Pd/C19mg。在氢气,30℃下搅拌5h。反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用6%甲醇/CH2Cl2(3×12.0mL)洗涤。有机层真空浓缩,剩余物经闪蒸柱层析纯化(6%MeOH/CH2Cl2),得到产物(7b)。三步反应合计产率65%。
1H NMR(500MHz,CD3OD):δ5.00(td,J=10.8,5.6Hz,1H),3.15(dd,J=10.6,5.4Hz,1H),2.57(d,J=13.7Hz,1H),2.31(hept,J=7.9,7.4Hz,2H),2.15(dd,J=11.8,4.8Hz,1H),1.06(s,3H),0.97(s,3H),0.96(s,3H),0.91(s,3H),0.86(s,3H),0.84(s,3H),0.76(s,3H),0.74(d,J=11.3Hz,1H);13C NMR(125MHz,CD3OD):δ181.90,175.34,79.43,72.97,56.60,50.08,48.21,42.67,41.82,41.20,39.92,39.82,38.16,37.38,35.45,35.38,34.47,33.87,33.68,32.81,32.60,31.47,29.93,28.65,28.52,27.91,25.75,24.08,23.96,23.40,19.40,18.30,16.94,16.42,16.12,14.30;HRMS(ESI)calculated forC36H60O5[M+Na]+:595.4333,found 595.4324.
实施例7
3β-羟基-12β-乙酰丙酰氧-齐墩果烷-28-羧酸(7c)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯100mg溶于3mL无水二氯甲烷中,随后依次加入4-二甲氨基吡啶183mg、4甲基-4氧代丁酸76μL和N,N'-二异丙基碳二亚胺115μL,反应混合物在室温下反应12h,TLC监测,反应完全后,将反应混合物减压浓缩,然后用30mL乙酸乙酯稀释,用2×10mL水和10mL饱和食盐水洗涤,有机相用无水硫酸钠干燥,在真空下除去溶剂,通过硅胶柱色谱法(二氯甲烷:甲醇=200:1)得到产物3β-叔丁基二甲基硅氧基-12β-乙酰丙酰氧-齐墩果烷-28-苄基酯。该产物(191mg)溶于5.6mL无水二氯甲烷中,在0℃氩气保护的条件下,缓慢加入三氟化硼乙醚1.4mL,在0℃下反应约2.5h,TLC监测,反应完全后,反应混合物用25mL二氯甲烷稀释,用10mL水和饱和2×10mL食盐水洗涤,用无水硫酸钠干燥有机相,减压浓缩除去有机溶剂,通过硅胶柱色谱法(石油醚:丙酮=5:1)纯化得到产物3β-羟基-12β-乙酰丙酰氧-齐墩果烷-28-苄基酯。(3)该产物(80mg)溶于1mL四氢呋喃和1mL甲醇中,并向反应混合物中加入10%钯碳45mg,在室温下在氢气存在的条件下反应约12h,TLC监测,反应完全后,将反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用3×12mL的6%甲醇/二氯甲烷洗涤,减压浓缩有机层,通过快速硅胶柱色谱法(石油醚:丙酮=3:1)纯化得到产物3β-羟基-12β-乙酰丙酰氧-齐墩果烷-28-羧酸(7c),三步合计产率65%。
1H-NMR(400MHz,CDCl3):δ4.93-4.98(m,1H),3.17-3.21(m,1H),2.71-2.75(m,2H),2.50-2.59(m,3H),2.19(s,3H),2.08(dd,J=4.8Hz,11.6Hz,1H),1.05-1.91(m,22H),0.99(s,3H),0.96(s,3H),0.90(s,6H),0.85(s,3H),0.81(s,3H),0.74(s,3H).13C-NMR(100MHz,CDCl3):δ206.7,184.2,172.5,78.8,72.2,55.2,48.8,47.3,41.4,40.6,39.9,38.8,38.6,37.9,37.1,36.0,34.3,33.3,33.2,32.4,31.3,30.5,29.9,28.8,28.3,28.0,27.3,27.2,23.2,22.9,18.2,17.7,16.5,15.9,15.4.HRMS(ESI-TOF)m/zcalcd.for C35H56O6[M+Na]+:595.3969,found 595.3966.
实施例8
3β-羟基基-12β-乙酰丁酰氧-齐墩果烷-28-羧酸(7d)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯(300mg)和5-甲基-5氧代戊酸(153mg)溶解在甲苯(8.90ml)中,随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(677mg)和4-二甲氨基吡啶(108mg)。反应混合物在氩气下60℃搅拌3h,反应混合物浓缩在真空中,然后用二氯甲烷(18.0mL)稀释,用H2O(2×9.00mL)和盐水(9.00mL)洗涤。有机相用无水Na2SO4干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(2)该产物粗品用CH2Cl2(5.65mL)稀释,在0℃氩气下缓慢加入BF3Et2O(1.97mL),在0℃下搅拌3h,反应混合物用CH2Cl2(12.0mL)稀释,用H2O(6.00mL)和盐水(2×16.0mL)洗涤。有机层在无水Na2SO4上干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(3)该产物粗品溶于THF(10.8mL)和乙醇(10.8mL)中,在反应混合物中加入10%Pd/C 19mg。在氢气,30℃下搅拌5h。反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用6%甲醇/CH2Cl2(3×12.0mL)洗涤。有机层真空浓缩,剩余物经闪蒸柱层析纯化(6%MeOH/CH2Cl2)或液相色谱(5%MeOH/CH2Cl2)纯化,得到产物(7d),三步反应合计产率62%。
1H NMR(500MHz,CD3OD):δ5.08–5.00(m,1H),3.17(dt,J=10.9,4.5Hz,1H),2.65–2.53(m,3H),2.37(t,J=6.9Hz,2H),2.16(s,4H),1.07(s,3H),0.99(s,3H),0.98(s,3H),0.93(s,3H),0.88(s,3H),0.87(s,3H),0.78(s,3H),0.75(d,J=10.6Hz,1H);13C NMR(125MHz,CD3OD):δ210.88,181.86,174.79,79.46,73.17,56.63,50.11,48.23,43.30,42.69,41.83,41.23,39.93,39.81,38.17,37.40,35.35,34.48,33.80,33.66,32.87,31.46,29.93,29.84,28.62,28.53,27.93,24.05,23.97,20.03,19.39,18.22,16.92,16.39,16.09;HRMS(ESI)calculated for C36H58O6[M+Na]+:609.4126,found609.4104.
实施例9
3β-羟基-12β-(3-羧基)丙酰氧-齐墩果烷-28-羧酸(7e)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯100mg溶于3mL无水二氯甲烷中,随后依次加入4-二甲氨基吡啶183mg、3-羧基丙酸76μL和N,N'-二异丙基碳二亚胺115μL,反应混合物在室温下反应12h,TLC监测,反应完全后,将反应混合物减压浓缩,然后用30mL乙酸乙酯稀释,用2×10mL水和10mL饱和食盐水洗涤,有机相用无水硫酸钠干燥,在真空下除去溶剂,通过硅胶柱色谱法(二氯甲烷:甲醇=200:1)得到产物3β-叔丁基二甲基硅氧基-12β-(3-羧基)丙酰氧-齐墩果烷-28-苄基酯。该产物(191mg)溶于5.6mL无水二氯甲烷中,在0℃氩气保护的条件下,缓慢加入三氟化硼乙醚1.4mL,在0℃下反应约2.5h,TLC监测,反应完全后,反应混合物用25mL二氯甲烷稀释,用10mL水和2×10mL饱和食盐水洗涤,用无水硫酸钠干燥有机相,减压浓缩除去有机溶剂,通过硅胶柱色谱法(石油醚:丙酮=5:1)纯化得到产物3β-羟基-12β-(3-羧基)丙酰氧-齐墩果烷-28-苄基酯。(3)该产物(80mg)溶于1mL四氢呋喃和1mL甲醇中,并向反应混合物中加入10%钯碳45mg,在室温下在氢气存在的条件下反应约12h,TLC监测,反应完全后,将反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用3×12mL的6%甲醇/二氯甲烷洗涤,减压浓缩有机层,通过快速硅胶柱色谱法(石油醚:丙酮=3:1)纯化得到产物3β-羟基-12β-(3-羧基)丙酰氧-齐墩果烷-28-羧酸(7e),三步合计产率65%。
1H-NMR(400MHz,CDCl3):δ8.19(s,1H),4.97-4.98(m,1H),3.22-3.24(m,1H),2.49-2.69(m,5H),2.07-2.11(m,1H),1.06-1.96(m,22H),0.99(s,3H),0.96(s,3H),0.91(s,3H),0.88(s,3H),0.83(s,3H),0.81(s,3H),0.75(s,3H).13C-NMR(100MHz,CDCl3):δ184.3,178.1,171.9,78.8,72.5,55.1,48.7,47.2,41.4,40.6,39.9,38.9,38.6,37.1,34.3,33.3,32.4,31.9,31.3,30.5,29.3,28.0,26.9,23.1,22.7,22.6,20.2,19.2,18.3,17.8,16.4,15.9,15.6,14.1.HRMS(ESI-TOF)m/z calcd.for C34H54O7[M+Na]+:597.3762,found597.3763.
实施例10
3β-羟基-12β-(3-羧基)丁酰氧-齐墩果烷-28-羧酸(7f)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯100mg溶于3mL无水二氯甲烷中,随后依次加入4-二甲氨基吡啶183mg、4-羧基丁酸76μL和N,N'-二异丙基碳二亚胺115μL,反应混合物在室温下反应12h,TLC监测,反应完全后,将反应混合物减压浓缩,然后用30mL乙酸乙酯稀释,用2×10mL水和10mL饱和食盐水洗涤,有机相用无水硫酸钠干燥,在真空下除去溶剂,通过硅胶柱色谱法(二氯甲烷:甲醇=200:1)得到产物3β-叔丁基二甲基硅氧基-12β-(3-羧基)丁酰氧-齐墩果烷-28-苄基酯。(2)该产物(191mg)溶于5.6mL无水二氯甲烷中,在0℃氩气保护的条件下,缓慢加入三氟化硼乙醚1.4mL,在0℃下反应约2.5h,TLC监测,反应完全后,反应混合物用25mL二氯甲烷稀释,用10mL水和2×10mL饱和食盐水洗涤,用无水硫酸钠干燥有机相,减压浓缩除去有机溶剂,通过硅胶柱色谱法(石油醚:丙酮=5:1)纯化得到产物3β-羟基-12β-(3-羧基)丁酰氧-齐墩果烷-28-苄基酯。(3)该产物(80mg)溶于1mL四氢呋喃和1mL甲醇中,并向反应混合物中加入10%钯碳45mg,在室温下在氢气存在的条件下反应约12h,TLC监测,反应完全后,将反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用3×12mL的6%甲醇/二氯甲烷洗涤,减压浓缩有机层,通过快速硅胶柱色谱法(石油醚:丙酮=3:1)纯化得到产物3β-羟基-12β-(3-羧基)丁酰氧-齐墩果烷-28-羧酸(7f),三步合计产率57%。
1H-NMR(400MHz,CDCl3):δ4.96-5.01(m,1H),3.19(dd,J=4.4Hz,J=11.2Hz,1H),2.33-2.57(m,5H),2.07(dd,J=4.8Hz,J=11.6Hz,1H),1.05-1.99(m,24H),1.01(s,3H),0.97(s,3H),0.94(s,3H),0.90(s,3H),0.83(s,3H),0.82(s,3H),0.75(s,3H).13C-NMR(100MHz,CDCl3):δ185.4,179.9,172.5,78.8,72.1,55.2,48.7,47.4,41.5,40.6,40.3,38.9,38.6,37.1,36.1,34.3,34.1,33.6,33.3,32.5,31.3,30.5,28.7,28.0,27.4,27.2,26.9,23.4,22.8,20.0,18.3,17.8,16.5,15.9,15.4.HRMS(ESI-TOF)m/z calcd.forC35H56O7[M+Na]+:611.3918,found 611.3918.
实施例11
3β-羟基-12β-甲氧羰乙酰氧-齐墩果烷-28-羧酸(7g)的制备
(1)3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯100mg溶于3mL无水二氯甲烷中,随后依次加入4-二甲氨基吡啶183mg、3-甲氧基-3-氧代丙酸76μL和N,N'-二异丙基碳二亚胺115μL,反应混合物在室温下反应12h,TLC监测,反应完全后,将反应混合物减压浓缩,然后用30mL乙酸乙酯稀释,用2×10mL水和10mL饱和食盐水洗涤,有机相用无水硫酸钠干燥,在真空下除去溶剂,通过硅胶柱色谱法(二氯甲烷:甲醇=200:1)得到产物3β-叔丁基二甲基硅氧基-12β-甲氧羰乙酰氧-齐墩果烷-28-苄基酯。(2)该产物(191mg)溶于5.6mL无水二氯甲烷中,在0℃氩气保护的条件下,缓慢加入三氟化硼乙醚1.4mL,在0℃下反应约2.5h,TLC监测,反应完全后,反应混合物用25mL二氯甲烷稀释,用10mL水和饱和2×10mL食盐水洗涤,用无水硫酸钠干燥有机相,减压浓缩除去有机溶剂,通过硅胶柱色谱法(石油醚:丙酮=5:1)纯化得到产物3β-羟基-12β-甲氧羰乙酰氧-齐墩果烷-28-苄基酯。(3)该产物(80mg)溶于1mL四氢呋喃和1mL甲醇中,并向反应混合物中加入10%钯碳45mg,在室温下在氢气存在的条件下反应约12h,TLC监测,反应完全后,将反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用3×12mL的6%甲醇/二氯甲烷洗涤,减压浓缩有机层,通过快速硅胶柱色谱法(石油醚:丙酮=3:1)纯化得到产物3β-羟基-12β-甲氧羰乙酰氧-齐墩果烷-28-羧酸(7g),三步合计产率25%。
1H-NMR(400MHz,CDCl3):δ5.14(s,1H),3.75(s,3H),3.33-3.35(m,1H),3.21(dd,J=3.6Hz,10.8Hz,1H),2.41-2.44(m,1H),1.12-2.04(m,24H),1.10(s,3H),0.98(s,3H),0.91(s,3H),0.89(s,3H),0.85(s,3H),0.83(s,3H),0.75(s,3H).13C-NMR(100MHz,CDCl3):δ186.2,169.0,168.3,78.74,75.44,55.2,52.4,48.7,47.2,41.5,41.4,40.6,39.8,38.8,38.5,37.1,36.0,34.3,33.2,33.1,32.3,31.2,30.4,28.8,28.0,27.1,27.0,23.1,22.8,18.2,17.7,16.4,15.8,15.3.HRMS(ESI-TOF)m/z calcd.for C34H54O7[M+Na]+:597.3762,found 597.3765.
实施例12
3β-羟基-12β-甲氧羰丙酰氧-齐墩果烷-28-羧酸(7h)的制备
(1)3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯(300mg)和4-甲氧基-4-氧代丁酸(156mg)溶解在甲苯(8.90ml)中,随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(677mg)和4-二甲氨基吡啶(108mg)。反应混合物在氩气下60℃搅拌3h,反应混合物浓缩在真空中,然后用二氯甲烷(18.0mL)稀释,用H2O(2×9.00mL)和盐水(9.00mL)洗涤。有机相用无水Na2SO4干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(2)该产物粗品用CH2Cl2(5.65mL)稀释,在0℃氩气下缓慢加入BF3Et2O(1.97mL),在0℃下搅拌3h,反应混合物用CH2Cl2(12.0mL)稀释,用H2O(6.00mL)和盐水(2×16.0mL)洗涤。有机层在无水Na2SO4上干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(3)该产物粗品溶于THF(10.8mL)和乙醇(10.8mL)中,在反应混合物中加入10%Pd/C 19mg。在氢气,30℃下搅拌5h。反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用6%甲醇/CH2Cl2(3×12.0mL)洗涤。有机层真空浓缩,剩余物经闪蒸柱层析纯化(6%MeOH/CH2Cl2)或液相色谱(5%MeOH/CH2Cl2)纯化,得到产物(7h),三步反应合计产率24%。
1H NMR(500MHz,CD3OD):δ4.99(td,J=10.6,5.5Hz,1H),3.68(s,3H),3.14(dd,J=10.7,5.4Hz,1H),2.72–2.48(m,5H),2.15(dd,J=11.8,4.9Hz,1H),1.05(s,3H),0.96(d,J=3.5Hz,6H),0.91(s,3H),0.87(s,3H),0.86(s,3H),0.76(s,3H);13C NMR(125MHz,CD3OD):δ181.90,174.42,173.87,79.44,73.59,56.62,52.25,50.13,48.20,42.67,41.84,41.14,39.92,39.81,38.17,37.34,35.41,34.47,33.78,33.66,32.80,31.46,30.28,29.97,29.69,28.63,28.43,27.91,24.08,23.68,19.39,18.25,16.93,16.43,16.10.HRMS(TOF)calculated for C35H56O7[M+Na]+:611.3918,found 611.3896.
实施例13
3β-羟基-12β-甲氧羰丁酰氧-齐墩果烷-28-羧酸(7i)的制备
(1)将3β-叔丁基二甲基硅烷基-12β-羟基-齐墩果烷-28-苄基酯(300mg)和5-甲氧基-5-氧代戊酸(172mg)溶解在甲苯(8.90ml)中,随后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(677mg)和4-二甲氨基吡啶(108mg)。反应混合物在氩气下60℃搅拌3h,反应混合物浓缩在真空中,然后用二氯甲烷(18.0mL)稀释,用H2O(2×9.00mL)和盐水(9.00mL)洗涤。有机相用无水Na2SO4干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(2)该产物粗品用CH2Cl2(5.65mL)稀释,在0℃氩气下缓慢加入BF3Et2O(1.97mL),在0℃下搅拌3h,反应混合物用CH2Cl2(12.0mL)稀释,用H2O(6.00mL)和盐水(2×16.0mL)洗涤。有机层在无水Na2SO4上干燥,真空浓缩。产物不经色谱纯化直接进行下步反应。(3)该产物粗品溶于THF(10.8mL)和乙醇(10.8mL)中,在反应混合物中加入10%Pd/C 19mg。在氢气,30℃下搅拌5h。反应混合物用硅藻土助滤剂过滤,硅藻土助滤剂用6%甲醇/CH2Cl2(3×12.0mL)洗涤。有机层真空浓缩,剩余物经闪蒸柱层析纯化(6%MeOH/CH2Cl2)或液相色谱(5%MeOH/CH2Cl2)纯化,得到产物(7i),三步反应合计产率32%。
1H NMR(500MHz,CDCl3):δ5.12–4.90(m,1H),3.68(s,3H),3.20(dd,J=11.5,4.4Hz,1H),2.58–2.44(m,1H),2.38(dt,J=21.7,7.3Hz,4H),2.08(dd,J=11.7,4.9Hz,1H),1.01(s,3H),0.97(s,3H),0.92(s,3H),0.90(s,3H),0.82(s,6H),0.75(s,3H);13CNMR(100MHz,CDCl3):δ183.24,173.58,172.80,78.92,71.93,55.30,51.76,48.88,47.35,41.57,40.76,40.08,38.98,38.69,37.22,36.19,34.42,33.66,33.41,33.38,33.33,32.53,31.50,30.59,28.93,28.15,27.51,27.33,23.44,23.04,20.26,18.35,17.88,16.59,15.99,15.48;HRMS(TOF)calculated for C36H58O7[M-H]-:601.4110,found601.4114.
药理实验:
实验例1细胞水平对FXR的作用测试
取对数生长的293T细胞以10,000/孔接种至96孔板。使用无酚红DMEM(70ul/孔)+5%活性炭处理的FBS培养24h。使用表达载体pGAL4-DBD-binding domain pBIND-FXRα(10ng/孔),报告基因载体pGL4.35[luc2P/9X GAL4 UAS/Hygro](50ng/孔),高效转染试剂FuGENE HD Transfection Reagent(0.3μl/孔)进行转染,按照10μL/孔的转染混合物进行瞬时转染。转染24小时后,用含有CDCA(50μM)的0.5%活性炭处理FBS的MEM培养液,然后加入待测化合物的DMSO溶液。继续培养24小时后,根据Dual-Luciferase报告基因说明书检测Luciferase酶活性。以RL酶活性为内参。
表1实施例中化合物的FXR拮抗活性
实验例2实施例8的化合物对2型糖尿病KKAy小鼠血糖的药效学实验
使用自发性2型糖尿病KKAy小鼠,雌性(购于中国医学科学院动物中心)进行动物实验。依据胰岛素耐量实验,按40分钟血糖下降百分数、空腹血糖、体重、血浆甘油三酯和胆固醇水平随机分为两组。
两组KKAy小鼠分别为阴性对照组(Con组),以水灌胃(0.05ml/10g体重);化合物组,灌胃给药(0.05ml/10g体重,剂量为100mg/kg,200mg/kg)。对照组奥贝胆酸(OCA)组,灌胃给药(0.05ml/10g体重,剂量为10mg/kg)每天1次,连续42天。实验期间,定时称量体重,每天记录食水。
于给药第1-5周测定禁食血糖和随机血糖水平。
于给药第3,5周进行胰岛素耐量实验(Insulin tolerance test,ITT)。
于给药第2,4周进行口服葡萄糖耐量实验(Oral glucose tolerance test,OGTT)。
于给药第4,5周进行血HbA1C的测定
于给药第6周停药并处理动物,取肝脏组织,称重。进行多种生化指标的检测,具体结果见图1。
综上,实施例8对KKay小鼠的非禁食血糖、禁食血糖和糖化血红蛋白水平具有降低作用,对胰岛素耐量和口服葡萄糖耐量有改善作用。
Claims (10)
2.根据权利要求1所述的化合物或其药学上可接受的盐,其特征在于,所述的C1-7烷基选自甲基、乙基、正丙基、异丙基、正丁基、异正丁基、正戊基、异戊基、正己基、正庚基。
3.根据权利要求2所述的化合物或其药学上可接受的盐,其特征在于:
所述的C1-5烷酰基选自乙酰基、丙酰基、丁酰基、戊酰基、己酰基;
所述的C1-5烷酰氧基选自甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰烷氧基;
所述的C1-5烷氧基选自甲氧基、乙氧基、丙氧基、丁氧基、戊烷氧基;
所述的C2-5烯氧基选自丙烯氧基、丁烯氧基、戊烯氧基;
所述的C1-5烷氧羰基选自甲氧羰基、乙氧羰基、丙氧羰基、丁氧羰基、戊烷氧羰基;
所述的C3-5烯氧羰基选自丙烯氧羰基、丁烯氧羰基、戊烯氧羰基。
5.权利要求1-4任一项所述化合物的制备方法,其特征在于,包括如下制备步骤:
步骤1:齐墩果酸与苄基卤化物在碱的作用下得到中间体1,所述的苄基卤化物包括溴苄、氯苄,所述的碱包括碳酸钾、碳酸铯、三乙胺、三丁胺、吡啶;
步骤2:中间体1与硅烷化试剂在碱的作用下得到中间体2,所述的碱包括三乙胺或咪唑;所述的硅烷化试剂包括三氟甲磺酸叔丁基二甲基硅烷酯、叔丁基二甲基氯硅烷;
步骤3:中间体2在氧化剂的作用下将12,13-双键氧化得到中间体3,所述的氧化剂包括间氯过氧苯甲酸、叔丁基过氧化氢;
步骤4:中间体3在还原剂作用下将羰基还原得到中间体4,所述的还原剂包括硼氢化钠、硼氢化锂;
步骤5:中间体4与酰化试剂缩合得到中间体5,所使用的为酰化试剂和碱,其中酰化试剂为相应的酰氯或酸酐或羧酸/活化试剂,活化试剂包括N,N’-二环己基碳酰亚胺,N,N’-二异丙基碳二酰亚胺,1-乙基-(3-二甲基氨基丙基)碳酰二亚胺,碱包括吡啶、三乙胺、4-二甲氨基吡啶;
步骤6:中间体5在含氟试剂或酸试剂的作用下脱除28位保护基得到中间体6,所述的含氟试剂包括氢氟酸-吡啶、四丁基氟化铵,酸试剂包括盐酸、三氟化硼-乙醚;
步骤7:中间体6与氢供体在催化剂的作用下脱除3位保护基得到如式(I),所述的催化剂包括Pd/C;制备中间体7所使用的氢供体包括氢气、1,4-环己二烯。
6.一种药物组合物,其特征在于,所述的组合物包括权利要求1-4任意一项所述的化合物或其药学上可接受的盐、非对映异构体,以及药学上可接受的载体或赋形剂。
7.权利要求1-4任一项所述的化合物或其药学上可接受的盐、非对映异构体在制备治疗和/或预防FXR介导的疾病药物中的应用。
8.根据权利要求7的应用,其特征在于,所述的FXR介导的疾病选自高脂蛋白血症、糖尿病、脂肪代谢障碍或动脉粥样硬化。
9.权利要求1-4任一项所述的化合物或其药学上可接受的盐、非对映异构体在制备肝脏保护药物或治疗肝胆疾病药物中的应用。
10.根据权利要求9的应用,其特征在于,所述的肝脏保护包括降低谷草转氨酶、谷丙转氨酶水平产生的保肝作用,所述的肝胆疾病包括非酒精性脂肪性肝炎、肝纤维化、肝细胞性肝癌、胆汁淤积症或胆石症。
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