CN110669012A - 一类氟取代的苯并咪唑衍生物及其制备方法与医药领域的应用 - Google Patents
一类氟取代的苯并咪唑衍生物及其制备方法与医药领域的应用 Download PDFInfo
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Abstract
Description
技术领域
本发明涉及一类氟取代的苯并咪唑衍生物及其制备方法与医药领域的应用。该类化合物可用于高血压等心脑肾血管疾病的防治。
背景技术
血管紧张素II受体拮抗剂(Angiotensin II receptor antagonist,ARB),是一类作用于肾素-血管紧张素系统的药物。1970年Marshall等人合成了第一个血管紧张素II(Angiotensin II,AII)受体拮抗剂--肽类化合物沙拉新(Saralasin,Sarl-Ala8-AngII),它与血管紧张素II的结构十分相似,对离体组织有专属性拮抗作用。但在临床实际应用中,由于口服无效、代谢不稳定且会使部分AII产生激动作用而受到限制。1982年,日本武田制药公司在研究咪唑乙酸类化合物的利尿降压作用时,发现S-8307能够抑制AII诱发的兔动脉收缩和升压效应,虽然活性较弱,但属于AII受体专一性拮抗剂,且没有沙拉新的激动效应。80年代末期,Dupont公司(Med.Rev.,1992,12:149-158)和Smithkline Beecham公司(Drugs of the future,1992,17:575-593)的研究人员,将AII的C-末端区域与S-8307排列比较,对S-8307进行了系列的结构修饰,结果分别得到了两种不同结构类型、都具有较高活性的化合物Dup-753(Losartan,氯沙坦)和SK&F-108566(Eprosartan,伊普沙坦)。氯沙坦于1994年在瑞典上市(Drugs ofthe Future,1997,22:1079-1085),伊普沙坦于1997年在德国上市(Drugs ofthe future,1996,21(8):794-798)。ARB主要应用于治疗高血压,特别适用于同时患有心脏衰竭、心肌梗塞恢复、糖尿病肾病、蛋白尿、左心室肥厚、心房颤动、代谢综合征、对ACEI不耐受的患者,而且这类药物并不抑制缓激肽或其他激肽的分解,也很少引起ACEI治疗中常有的干咳或血管性水肿等副作用。ARB的降压效果好且副作用小,常用的有氯沙坦、缬沙坦、替米沙坦、坎地沙坦等。目前用于降高血压的6大类单体药物中,ARB已经成为降高血压的一线主流药物,降压显著、耐受性好,与其他药物相比,各种常见咳嗽等副作用的发生率明显要低,故在临床应用上具有广泛的前景。
氯沙坦(Losartan)于1994年在瑞典上市,成为第一个用于临床的ARB类药物。对氯沙坦的构效关系的研究表明:在苄基对位引入1个苯环,构成联苯结构,生物活性提高;引人的苯环邻位有一酸性官能团,酸性越强与血管紧张素II受体亲和力越大,例如:-CN、-COOMe、-CF3、-CONH2等均能达到和羧酸相似的亲和力。末端苯环上的酸性取代基位置十分重要,2’、6’-双取代使联苯不在同一平面并且使旋转障碍增加,会导致与受体结合的亲合力下降一个数量级;咪唑环的2位取代基团是长度为3-4个碳原子的亲脂性侧链,如正烷烃;而支链烷烃、环烷烃和芳香取代基均会降低亲合力;咪唑环4位最好是1个亲脂性的基团;咪唑环5位取代基为能形成氢键的小基团,如醇、醛、酸等。氯沙坦的发现为AngII受体拮抗剂的研究提供了分子模型,之后多家制药公司和科研机构参与了非肽类ARB的研究工作,发现了多个活性高、选择性好的化合物AT1受体拮抗剂。参考Wexler等的分类方法,可以将这方面的工作分为四种,即不同的中心杂环的取代、联苯骨架的改造、酸性基团或多个部位共同进行结构修饰与变换。血管紧张素II受体拮抗剂大多从氯沙坦结构改造而来,如Candesartan(J.Med.Chem.,1993,36,15:2182-2195)、Pomisartan(中国药科大学学报,2005,36,2:99-101)、TAK-536(J.Med.Chem.,1996,39,26:5228-5235)是将氯沙坦的咪唑结构用苯并咪唑结构代替。对苯并咪唑类化合物的研究,主要集中在对苯并咪唑6位(Pomisartan、Telmisartan等)和7位(如Candesartan等)的修饰,而对于苯并咪唑2位的烷基链修饰与改造较少,一般以正丙基和乙氧基为主。
将氟原子引入到药物分子中是改善药物活性的重要策略之一,有助于改善其物理化学特性。随着对氟化学的研究进展,含氟药物在临床治疗中所占的比重也是越来越大。比如近些年由美国FDA批准上市的含氟心血管药物有:替格瑞洛、利奥西呱、硫酸沃拉帕沙等。本团队参考以上研究结果,在苯并咪唑的2-位的烷基链中引入氟原子,以期待获得具有更好生物活性的AT1受体拮抗剂。
为寻找制备方便,并具有更佳AT1受体拮抗效果的降压新药,本发明以已上市的洛沙坦为先导化合物,将氯沙坦的咪唑结构用苯并咪唑结构进行替换,在苯并咪唑的2-位的烷基链中引入氟原子并在苯并咪唑的6位上引入不同的杂环基团和酰胺基团。设计合成了一类氟取代的苯并咪唑衍生物(I,II):
其中R1为:-COOH、R2为:-n-CH2CF3、-n-(CH2)2CF3、-n-(CH2)3CF3、-n-CH2CH2F、-n-(CH2)2CH2F、-n-(CH2)3CH2F;R3为:-CO-N(CH3)2、-CO-N(CH2CH3)2、-CO-NH(CH2)2(C6H5)。
氟取代苯并咪唑衍生物(I,II)具体包括如下化合物:
4'-((6-(二甲基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ia);
4'-((6-(二乙基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ib);
4'-((6-(苯乙基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ic)。
4'-((1,7'-二甲基-2'-(2,2,2-三氟乙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIa);
4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIb);
4'-((1,7'-二甲基-2'-(4,4,4-三氟丁基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIc);
3’-((2’-(1H-四氮唑-5-基)-[1,1’-联苯]-4-基)甲基)-1,7’-二甲基-2’-(3,3,3-三氟丙基)-1H,3’H-2,5’-联苯并[d]咪唑(化合物IId);
3-(4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3'-H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯]-2-基)-1,2,4-噁二唑-5(4H)-酮(化合物IIe);
4'-((1,7'-二甲基-2'-(2-氟乙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIf);
4'-((1,7'-二甲基-2'-(3-氟丙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIg);
4'-((1,7'-二甲基-2'-(4-氟丁基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIh);
3’-((2’-(1H-四唑-5-基)-[1,1’-联苯]-4-基)甲基)-2’-(3-氟丙基)-1,7’-二甲基-1H,3’H-2,5’-联苯并[d]咪唑(化合物IIi);
3-(4'-((2'-(3-氟丙基)-1,7'-二甲基-1H,3'-H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯]-2-基)-1,2,4-噁二唑-5(4H)-酮(化合物IIj)。
氟取代苯并咪唑衍生物(I)可以通过下述方法制备:
氟取代苯并咪唑衍生物(II)可以通过下述方法制备:
其中R1为-COOH、R2为:-n-CH2CF3、-n-(CH2)2CF3、-n-(CH2)3CF3、-n-CH2CH2F、-n-(CH2)2CH2F、-n-(CH2)3CH2F;R3为:-CO-N(CH3)2、-CO-N(CH2CH3)2、-CO-NH(CH2)2(C6H5)。
在有机溶剂中化合物III和IV通过N-烷基化反应得到化合物V;然后V在有机溶剂中经过水解或加成等反应得到氟取代的苯并咪唑衍生物(Ia–c)。
在有机溶剂中化合物VI和IV通过N-烷基化反应得到化合物VII;然后VII在有机溶剂中经过水解或加成等反应得到氟取代的苯并咪唑衍生物(IIa–j)。
本领域技术人员根据以上描述的方法可以合成该类化合物。经进一步的研究发现,上述化合物对高血压、冠心病、心脑肾血管疾病、偏头痛、肺动脉高压、糖尿病等疾病具有较好的预防或治疗作用。因此,本发明的化合物可用于制备预防或治疗高血压等疾病的药物。
具体实施方式
[实施例1]
4'-((6-(二甲基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ia)的制备方法具体步骤:
将化合物(III1,150mg,0.5mmol)溶于50mLN,N-二甲基甲酰胺中,再加入钠氢(48mg,2mmol)于室温下搅拌30min,缓慢加入化合物IV(217mg,0.7mmol)。滴加完毕后,混合液于室温下继续搅拌反应约2h,TLC监测至反应完全。补加2M的氢氧化钠溶液5mL,加热回流搅拌反应约6h。待反应完全后,用2M稀盐酸调节pH值至5-6,向反应液中加入200mL二氯甲烷和200mL水,分取有机相;水相用二氯甲烷(150mL×3)萃取三次,合并有机相;有机相用饱和食盐水(300mL×4)洗涤四次,无水硫酸镁干燥,过滤;将滤液减压浓缩,得到黄褐色固体。将该固体重结晶得到灰白色固体(化合物Ia)约123mg,收率为48.3%。1HNMR(400MHz,CDCl3)δ8.24(dd,J=7.1,2.0Hz,1H),7.93(d,J=1.5Hz,1H),7.80(td,J=7.4,2.0Hz,1H),7.72–7.64(m,3H),7.53–7.47(m,2H),7.29–7.23(m,2H),5.34(d,J=1.2Hz,2H),3.03(s,6H),2.53(t,J=5.9Hz,2H),2.48(s,3H),2.14(qt,J=9.1,5.9Hz,2H).13C NMR(101MHz,CDCl3)δ170.73,169.33,157.20,156.96,149.98,142.71,137.42,134.63,133.90,131.73,130.28,129.57,129.38,129.34,129.14,129.11,128.56,127.33,127.24,126.87,125.19,112.47,46.76,37.23,35.52,35.31,24.11,24.02,18.56.MS(ESI)m/z:543.28[M+H]+。
[实施例2]
4'-((6-(二乙基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ib)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ7.96(dd,J=7.4,2.0Hz,1H),7.87(d,J=1.5Hz,1H),7.80(td,J=7.4,2.0Hz,1H),7.73–7.62(m,2H),7.58(d,J=1.5Hz,1H),7.55–7.49(m,2H),7.23(dt,J=7.6,1.1Hz,2H),5.34(d,J=1.2Hz,2H),3.72(q,J=8.0Hz,4H),2.53(t,J=8.6Hz,2H),2.47(s,3H),2.14(h,J=8.8Hz,2H),1.23(t,J=8.0Hz,6H).13C NMR(101MHz,CDCl3)δ170.03,169.33,150.14,142.71,137.42,134.63,133.90,132.24,130.28,129.57,129.38,129.35,128.72,128.56,128.49,127.24,126.87,112.87,46.76,41.37,35.52,35.31,24.11,24.02,18.56,13.45.MS(ESI)m/z:538.2[M+H]+。
[实施例3]
4'-((6-(苯乙基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ic)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ8.06(d,J=1.5Hz,1H),7.92(dd,J=7.5,2.0Hz,1H),7.84–7.71(m,2H),7.58(td,J=7.5,2.1Hz,1H),7.54–7.48(m,2H),7.44(d,J=1.7Hz,1H),7.31–7.16(m,7H),6.38(s,1H),5.34(d,J=1.5Hz,2H),3.47(t,J=5.2Hz,2H),2.86(t,J=5.2Hz,2H),2.53(t,J=5.8Hz,2H),2.43(s,3H),2.14(qt,J=9.0,5.7Hz,2H).13C NMR(101MHz,CDCl3)δ169.33,166.93,149.87,142.71,138.55,137.42,134.63,133.90,130.28,130.23,129.93,129.57,129.38,128.76,128.73,128.56,127.54,127.42,127.24,126.87,126.22,114.28,46.76,41.68,35.52,35.31,34.89,24.11,24.02,18.56.MS(ESI)m/z:586.2[M+H]+。
[实施例4]
4'-((1,7'-二甲基-2'-(2,2,2-三氟乙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIa)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ8.27–6.77(m,14H),5.34(d,J=1.2Hz,2H),3.89(s,3H),3.07(q,J=9.0Hz,2H),2.49(s,3H).13C NMR(101MHz,CDCl3)δ169.33,152.90,152.43,142.71,141.47,137.42,136.46,135.57,134.63,133.90,132.79,130.28,129.57,129.38,128.56,128.06,127.24,126.87,126.78,122.70,122.30,119.60,111.15,109.52,46.76,34.97,34.76,31.40,18.56.MS(ESI)m/z:555.2[M+H]+。
[实施例5]
4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIb)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ8.39–7.00(m,14H),5.34(d,J=1.2Hz,2H),3.84(s,3H),2.67–2.34(m,5H),2.14(h,J=8.8Hz,2H).13C NMR(101MHz,CDCl3)δ169.33,152.90,152.43,142.71,141.47,137.42,136.46,135.57,134.63,133.90,132.79,130.28,129.57,129.38,128.56,128.06,127.24,126.87,126.78,122.70,122.30,119.60,111.15,109.52,46.76,35.52,35.31,31.40,24.11,24.02,18.56.MS(ESI)m/z:569.2[M+H]+。
[实施例6]
4'-((1,7'-二甲基-2'-(4,4,4-三氟丁基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIc)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ1H NMR(400MHz,CDCl3)δ8.06–6.98(m,14H),5.34(d,J=1.2Hz,2H),3.83(s,3H),2.67–2.38(m,5H),1.79(h,J=8.7Hz,2H),1.64–1.42(m,2H).13CNMR(101MHz,CDCl3)δ169.33,158.44,152.90,152.43,142.71,141.47,137.42,136.46,135.57,134.63,133.90,132.79,130.28,129.57,129.38,128.56,128.06,127.24,126.87,126.78,122.70,122.30,119.60,111.15,109.52,46.76,35.00,34.78,31.40,30.29,19.53,19.45,18.56.MS(ESI)m/z:583.2[M+H]+。
[实施例7]
3’-((2’-(1H-四氮唑-5-基)-[1,1’-联苯]-4-基)甲基)-1,7’-二甲基-2’-(3,3,3-三氟丙基)-1H,3’H-2,5’-联苯并[d]咪唑(化合物IId)的制备:
步骤一:4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3'H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯基]-2-甲腈(化合物VII2)的制备:
将化合物VI1(500mg,1.39mmol)溶于100mLN,N-二甲基甲酰胺中,再加入钠氢(120mg,5mmol)于室温下搅拌30min。缓慢加入化合物IV(379mg,1.39mmol)中。滴加完毕后,混合液于室温下继续搅拌反应约2h,TLC监测至反应完全。用二氯甲烷(150mL×3)萃取水相三次,合并有机相。有机相用饱和食盐水(300mL×4)洗涤四次,无水硫酸镁干燥,过滤;将滤液减压浓缩,得到黄褐色固体。将该固体重结晶得到灰白色固体化合物VII2约456mg,收率为59.8%。1H NMR(400MHz,CDCl3)δ8.03–7.38(m,10H),7.38–7.16(m,4H),5.34(d,J=1.2Hz,2H),3.79(s,3H),2.60–2.37(m,5H),2.14(qt,J=8.9,5.6Hz,2H).MS(ESI)m/z:550.2[M+H]+。
步骤二:3’-((2’-(1H-四氮唑-5-基)-[1,1’-联苯]-4-基)甲基)-1,7’-二甲基-2’-(3,3,3-三氟丙基)-1H,3’H-2,5’-联苯并[d]咪唑(化合物IId)的制备:
将化合物(VII2,150mg,0.27mmol),叠氮化钠(102mg,1.57mmol)和三丁基氯化锡(0.4mL,1.57mmol)溶于50mLN,N-二甲基甲酰胺中,在氮气保护下加热回流搅拌10h。待反应完全后,反应液冷却至室温,将反应液倒入100mL的冰水中,用2M稀盐酸调节pH值至5-6,向反应液中加入200mL二氯甲烷和200mL水,分取有机相;水相用二氯甲烷(150mL×3)萃取三次,合并有机相。有机相用饱和食盐水(300mL×4)洗涤四次,无水硫酸镁干燥,过滤。将滤液减压浓缩,得到黄褐色固体。将该固体重结晶得到灰白色固体化合物IId约76mg,收率为47.5%。1HNMR(400MHz,CDCl3)δ7.75–7.61(m,4H),7.61–7.50(m,3H),7.46(d,J=1.5Hz,1H),7.37–7.27(m,4H),7.07–7.01(m,2H),5.34(s,1H),3.91(s,3H),2.53(t,J=8.6Hz,2H),2.50(s,3H),2.14(q,J=8.9Hz,2H).13C NMR(101MHz,CDCl3)δ154.61,152.90,152.43,141.47,138.26,136.46,135.79,135.57,134.63,132.79,130.55,130.50,129.33,129.21,128.06,127.71,126.87,126.78,123.33,122.70,122.30,119.60,111.15,109.52,46.76,35.52,35.31,31.40,24.11,24.02,18.56.MS(ESI)m/z:593.2[M+H]+。
[实施例8]
3-(4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3'-H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯]-2-基)-1,2,4-噁二唑-5(4H)-酮(化合物IIe)的制备:
将化合物VII2(200mg,0.54mmol),盐酸羟胺(136mg,2.7mmol)和二异丙基乙胺(252mL,2.7mmol)溶于50mL乙醇溶液中,加热回流搅拌12h。待反应完全后,反应液冷却至室温,减压蒸出乙醇。加入200mL二氯甲烷和200mL水,分取有机相;水相用二氯甲烷(150mL×3)萃取三次,合并有机相。有机相用饱和食盐水(300mL×4)洗涤四次,无水硫酸镁干燥,过滤。将滤液减压浓缩,得到油状化合物。然后加入100mL二氧六环溶液,DBU(112mg,0.74mmol)和CDI(118mg,0.72mmol)。加热回流24h,待反应完全后,反应液冷却至室温,减压蒸出二氧六环,加入200mL二氯甲烷和200mL水,分取有机相;水相用二氯甲烷(150mL×3)萃取三次,合并有机相。用饱和食盐水(300mL×4)洗涤有机相四次,无水硫酸镁干燥,过滤;将滤液减压浓缩,所得残留物柱层析纯化得到白色固体化合物IIe约136mg,收率为41.3%。1HNMR(400MHz,CDCl3)δ7.89(d,J=1.7Hz,1H),7.84–7.73(m,4H),7.67–7.54(m,5H),7.36–7.26(m,5H),5.34(s,1H),3.96(s,3H),2.53(t,J=8.6Hz,2H),2.50(s,3H),2.14(q,J=8.9Hz,2H).13C NMR(101MHz,CDCl3)δ159.22,153.03,152.90,152.43,141.47,140.72,139.45,136.46,135.57,134.63,132.79,129.89,129.60,129.33,129.21,128.82,128.06,127.36,127.33,126.87,126.78,122.70,122.30,119.60,111.15,109.52,46.76,35.52,35.31,31.40,24.11,24.02,18.56.MS(ESI)m/z:609.2[M+H]+。
[实施例9]
4'-((1,7'-二甲基-2'-(2-氟乙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIf)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ8.12–7.13(m,14H),5.34(d,J=1.2Hz,2H),4.42(dt,J=46.3,3.7Hz,2H),3.79(s,3H),2.75(dt,J=25.1,3.7Hz,2H),2.48(s,3H).13C NMR(101MHz,CDCl3)δ169.33,152.90,152.43,142.71,141.47,137.42,136.46,135.57,134.63,133.90,132.79,130.28,129.57,129.38,128.56,128.06,127.24,126.87,126.78,122.70,122.30,119.60,111.15,109.52,85.12,82.97,46.76,31.40,27.52,27.30,18.56.MS(ESI)m/z:519.2[M+H]+。
[实施例10]
4'-((1,7'-二甲基-2'-(3-氟丙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIg)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ8.42–6.99(m,14H),5.34(d,J=1.2Hz,2H),4.22–3.82(m,5H),2.62–2.43(m,5H),1.82(dp,J=25.2,7.8Hz,2H).13C NMR(101MHz,CDCl3)δ169.33,152.90,152.43,142.71,141.47,137.42,136.46,135.57,134.63,133.90,132.79,130.28,129.57,129.38,128.56,128.06,127.24,126.87,126.78,122.70,122.30,119.60,111.15,109.52,85.27,83.13,46.76,31.40,30.11,30.03,26.83,26.62,18.56.MS(ESI)m/z:533.2[M+H]+。
[实施例11]
4'-((1,7'-二甲基-2'-(4-氟丁基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIh)的制备:制备方法如实施例1所述。1HNMR(400MHz,CDCl3)δ8.18–7.42(m,10H),7.42–7.11(m,4H),5.34(d,J=1.2Hz,2H),4.07(dt,J=46.4,3.9Hz,2H),3.78(s,3H),2.59–2.39(m,5H),1.73–1.54(m,2H),1.53–1.38(m,2H).13C NMR(101MHz,CDCl3)δ169.33,158.44,152.90,152.43,142.71,141.47,137.42,136.46,135.57,134.63,133.90,132.79,130.28,129.57,129.38,128.56,128.06,127.24,126.87,126.78,122.70,122.30,119.60,111.15,109.52,84.77,82.62,46.76,31.40,30.76,29.51,29.29,27.87,27.78,18.56.MS(ESI)m/z:547.2[M+H]+。
[实施例12]
3’-((2’-(1H-四唑-5-基)-[1,1’-联苯]-4-基)甲基)-2’-(3-氟丙基)-1,7’-二甲基-1H,3’H-2,5’-联苯并[d]咪唑(化合物IIi)的制备:制备方法如实施例7所述。1HNMR(400MHz,CDCl3)δ7.99–7.11(m,12H),7.11–6.86(m,2H),5.34(d,J=1.2Hz,2H),4.21–3.66(m,5H),2.63–2.34(m,5H),1.82(dtd,J=25.1,8.1,4.0Hz,2H).13C NMR(101MHz,CDCl3)δ154.61,152.90,152.43,141.47,138.26,136.46,135.79,135.57,134.63,132.79,130.55,130.50,129.33,129.21,128.06,127.71,126.87,126.78,123.33,122.70,122.30,119.60,111.15,109.52,85.27,83.13,46.76,31.40,30.11,30.03,26.83,26.62,18.56.MS(ESI)m/z:557.2[M+H]+。
[实施例13]
3-(4'-((2'-(3-氟丙基)-1,7'-二甲基-1H,3'-H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯]-2-基)-1,2,4-噁二唑-5(4H)-酮(化合物IIj)的制备:制备方法如实施例8所述。1HNMR(400MHz,CDCl3)δ7.91–7.74(m,4H),7.71–7.46(m,6H),7.38–7.22(m,4H),7.07(s,1H),5.34(d,J=1.2Hz,2H),4.07(dt,J=46.3,7.5Hz,2H),3.86(s,3H),2.75–2.32(m,5H),1.82(dp,J=25.2,7.8Hz,2H).13CNMR(101MHz,DMSO)δ159.22,153.03,152.90,152.43,141.47,139.45,136.46,135.57,134.63,132.79,129.89,129.60,129.33,129.21,128.82,128.06,127.35,126.87,126.78,122.70,122.30,119.60,111.15,109.52,85.27,83.13,46.76,31.40,30.11,30.03,26.83,26.62,18.56.MS(ESI)m/z:573.2[M+H]+。
[实施例14]降压药物活性实验
实验动物:
自发性高血压大鼠(SHR)15只,220-250g,♂,SPF级,购自北京维通利华实验动物技术有限公司,许可证号:SCXK(京)2012-0001。
受试品:新化合物Ia-c与IIa-j,阳性对照药Losartan,选择10mg/kg作为实验剂量。
实验方法:
自发性高血压大鼠,随机分为空白组、Losartan组,新化合物组,采用无创伤血压换能器经载波放大之后连至MPA-HBBS型清醒自由活动动物血压记录分析系统,四肢皮下插入针形电极,连接到交流放大器用于监测标准二导联心电图。无创尾动脉测压法测量清醒大鼠主动脉平均动脉压(MAP),收缩压(SAP),舒张压(DAP),心率(HR)及心电图(ECG)。每组3只大鼠;大鼠休息1周后测试另一组。
试验时将待测化合物及阳性对照药氯沙坦配制成浓度为10mg/kg的混悬液。试验SHR采取无创尾动脉测压法,SHRs连接多道生理信号系统,在线连续检测血压,记录给药前及给药后血压变化。
数据处理:
所有实验数据均以均数±标准差(_x±SD)表示,用药后各组间血压比较用完全随机设计的方差分析,如各组总体均数不等,再用多个样本均数间的多重比较,即q检验进行处理。
实验结果:
以治疗前后血压降低值作为变量,发现与空白组相比,所有新化合物均具有显著的降压作用(见表1),其中化合物IIb降压活性更为显著性,在给药后3h达到最大降压值,10mg/kg剂量下化合物IIb的最大降压值为58.37±2.16mmHg,且化合物进入体内后降压起效快、降压作用平稳持久。该化合物的降压效果优于相同剂量下的Losartan,具有持续降压趋势,24小时仍有显著降压效果与对照组相比,ΔΔp<0.01,与Losartan相比,*p<0.05,**p<0.01。表明化合物IIb具高效、长效、平稳降压活性的特点,值得进一步研究开发。
表1:10mg/kg剂量下新化合物Ia–Ic,IIa–IIj的最大降压值和持续降压时间
与对照组相比,ΔΔp<0.01,与Losartan相比,*p<0.05,**p<0.01。
应当理解,这些实施例的用途仅用于说明本发明而非意欲限制本发明的保护范围。此外,也应理解,在阅读了本发明的技术内容之后,本领域技术人员可以对本发明作各种改动、修改和/或变型,所有的这些等价形式同样落于本申请所附权利要求书所限定的保护范围之内。
Claims (3)
2.根据权利要求1所述的一类新的含氟沙坦衍生物(I)包括:
4'-((6-(二甲基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ia);
4'-((6-(二乙基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ib);
4'-((6-(苯乙基氨基甲酰基)-4-甲基-2-(3,3,3-三氟丙基)-1H-苯并[d]咪唑-1-基)甲基)-[1,1'-联苯]-2-羧酸(化合物Ic)。
3.根据权利要求1所述的一类新的含氟沙坦衍生物(II)包括:
4'-((1,7'-二甲基-2'-(2,2,2-三氟乙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIa);
4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIb);
4'-((1,7'-二甲基-2'-(4,4,4-三氟丁基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIc);
3’-((2’-(1H-四氮唑-5-基)-[1,1’-联苯]-4-基)甲基)-1,7’-二甲基-2’-(3,3,3-三氟丙基)-1H,3’H-2,5’-联苯并[d]咪唑(化合物IId);
3-(4'-((1,7'-二甲基-2'-(3,3,3-三氟丙基)-1H,3'-H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯]-2-基)-1,2,4-噁二唑-5(4H)-酮(化合物IIe);
4'-((1,7'-二甲基-2'-(2-氟乙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIf);
4'-((1,7'-二甲基-2'-(3-氟丙基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIg);
4'-((1,7'-二甲基-2'-(4-氟丁基)-1H,3’H-[2,5'-联苯并[d]咪唑]-3’-基)甲基)-[1,1'-联苯]-2-羧酸(化合物IIh);
3’-((2’-(1H-四唑-5-基)-[1,1’-联苯]-4-基)甲基)-2’-(3-氟丙基)-1,7’-二甲基-1H,3’H-2,5’-联苯并[d]咪唑(化合物IIi);
3-(4'-((2'-(3-氟丙基)-1,7'-二甲基-1H,3'-H-[2,5'-联苯并[d]咪唑]-3'-基)甲基)-[1,1'-联苯]-2-基)-1,2,4-噁二唑-5(4H)-酮(化合物IIj)。
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CN101037414A (zh) * | 2007-04-19 | 2007-09-19 | 北京理工大学 | [(2-n-丙基-4-甲基-1H-苯并咪唑)-6-基]甲酰胺-1-基]甲基联苯类化合物、合成方法及用途 |
WO2008096820A1 (ja) * | 2007-02-07 | 2008-08-14 | Kyowa Hakko Kirin Co., Ltd. | ビフェニル誘導体 |
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US5541229A (en) * | 1989-04-08 | 1996-07-30 | Dr. Karl Thomae Gmbh | Benzimidazoles and medicaments containing these compounds |
WO2008096820A1 (ja) * | 2007-02-07 | 2008-08-14 | Kyowa Hakko Kirin Co., Ltd. | ビフェニル誘導体 |
CN101037414A (zh) * | 2007-04-19 | 2007-09-19 | 北京理工大学 | [(2-n-丙基-4-甲基-1H-苯并咪唑)-6-基]甲酰胺-1-基]甲基联苯类化合物、合成方法及用途 |
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