CN104693264B - 一种化合物及其制备方法和应用 - Google Patents
一种化合物及其制备方法和应用 Download PDFInfo
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- CN104693264B CN104693264B CN201510067773.6A CN201510067773A CN104693264B CN 104693264 B CN104693264 B CN 104693264B CN 201510067773 A CN201510067773 A CN 201510067773A CN 104693264 B CN104693264 B CN 104693264B
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Abstract
本发明涉及一种化合物及其制备方法和应用，该化合物具有式I所示结构或其药学上可接受的盐或酯；该化合物为一类新型的胆酸缀合吡咯酰胺类糖原磷酸化酶抑制剂，可有效作用于肝脏的糖原磷酸化酶，是2型糖尿病患者控制血糖的优选药物。该类化合物可用于制备抗糖尿病及其并发症药物、抗心血管疾病药物、减肥药物、治疗代谢综合征药物。
Description
技术领域
本发明涉及药物化学领域，具体涉及一类新型的胆酸缀合吡咯酰胺类糖原磷酸化酶抑制剂。还涉及他们的制备方法及含有它们的药物组合物。该类化合物可用于制备抗糖尿病及其并发症药物、抗心血管疾病药物、减肥药物、治疗代谢综合征药物。
背景技术
目前我国有糖尿病患者9200多万，成为全球第一糖尿病大国，其中约97％患者属于2型糖尿病。目前，对于2型糖尿病的治疗，根据药物药理作用机制的不同，分为胰岛素及其同类药物、胰岛素增敏剂、胰岛素促泌剂、减少碳水化合物调节剂等。但这些药物的降糖效果有限。随着人们对糖尿病发病机制认识的不断深入，许多治疗糖尿病的新型作用靶点被发现，新型药物不断问世。
糖原磷酸化酶(GP)为糖代谢途径中的重要酶，催化糖原降解的关键酶。抑制该酶的活性，可以减少糖原的降解，达到减少肝脏葡萄糖的生成，从而降低血糖的目的。近年来，GP抑制剂作为潜在的降血糖药物已受到广泛关注。其特点在于在降低血糖的同时，对缺血性心肌损伤有显著的保护作用，这一点对患有缺血性心血管并发症的糖尿病患者是尤其重要的。
US6297269和EP0832066报道了作为GP抑制剂的取代的N-(吲哚-2-羰基)酰胺和衍生物。US6107329和US6277877报道了作为GP抑制剂的取代的N-(吲哚-2-羰基)甘氨酰胺和衍生物。US6399601报道了双环吡咯酰胺类GP抑制剂。US5952322公开了GP抑制剂用于降低非心脏缺血性组织损伤的方法。
目前Pfizer的CP-368296(1)和OSI公司的氮杂吲哚酰胺衍生物PSN-357已进入临床研究阶段。另外，也有一些天然的五环三萜类化合物具有通过抑制肝脏葡萄糖的生成达到降血糖的目的，分子模拟手段证实了这些五环三萜类化合物具有与GP可能的相互作用位点。
总之，GP与过量肝脏葡糖糖生成的调节相关，其抑制剂的降血糖作用将对联合治疗及其相关的心血管疾病的治疗是非常有利的。
肝脏是糖代谢的主要器官，肝靶向前药是以肝脏为作用部位的一类药物，其设计思路是将现有药物或先导化合物与特殊的肝靶向载体经化学键连接或包裹，从而定向输送到肝脏，以达到减毒增效的目的。目前，肝靶向前药还是主要应用于肝癌、肝炎、肝硬化等疾病的治疗，而在糖尿病的治疗中应用较少，其应用潜力尚待开发。
胆酸是目前唯一口服有效的小分子肝靶向载体，其胆酸-药物复合体可被内源性的胆酸转运系统识别而进入肝脏，且胆酸为人体内自身分泌的物质之一，几无毒副作用，是优良的药物肝靶向载体。如Jacobson等以胆酸为肝靶向载体，将糖皮质激素受体拮抗剂米非司酮与胆酸偶联，制备成肝靶向偶合物A-348441，该化合物能够选择性的作用于肝脏，产生特异性的降糖作用，而没有皮质激素类受体拮抗剂常见的恶心、呕吐及衰竭等副作用。
在靶向载体与小分子药物(母药)中间的间隔基团是靶向前药结构中的关键成分之一。因为大多数靶向载体与小分子药物不能通过化学键直接连接，或两者直接相连所形成的化学键难以进一步解离，释放出小分子药物。所以，在靶向载体和小分子药物之间需要引入新的基团，这就是间隔基团。它需要保持药物在血液循环中的稳定性以避免药物释放对正常组织产生伤害，而在靶细胞中须使药物有效释放产生活性。合适的间隔基团应该具备：可以发生化学解离，或者在特定的酶作用下释放出药物，能够控制药物释放速率和药物释放部位。
低分子乙二醇聚合链是中性、无毒且具有独特理化性质和良好生物相容性的聚合物，当乙二醇链与药物分子偶联时，可以将其优良性质赋予修饰后的药物分子，如改变药物的溶解性，增加生物相容性、改善组织分布、降低毒性、延长循环半衰期和增强疗效等，因此小分子乙二醇链可作为间隔基团用于靶向的前药设计中。如：Eriksson等将环西多福韦通过乙烯乙二醇与氨基酸L-Val或L-Phe相连得到氨基酸轭合物，其活性都获得提高等。
发明内容
本发明首次公开了式(I)所示的具有药用价值的胆酸缀合的吡咯酰胺类糖原磷酸化酶抑制剂、制备方法及医药用途。包括在制备抗糖尿病及其并发症药物、抗心血管疾病药物、减肥药物、治疗代谢综合征药物方面的用途。此外，本发明还提供一种含有式(I)所示化合物的药物制剂。
本发明涉及式(I)所示的化合物及其药学上可接受的盐或酯：
其中：
X1、X2、X3和X4全为C或者X1、X2、X3和X4之一为N而其他的必须为C；
R1代表H、卤素、羟基、氰基、C1-4的直链或支链烷基，C1-4的直链或支链烷氧基，三氟甲基、乙烯基、乙炔基；
n代表1-6。
上述化合物中优选的化合物为：
X1、X2、X3和X4全为C或者X1、X2、X3和X4之一为N而其他的必须为C；
R1代表H、卤素、羟基、氰基；
n代表1-6。
本发明中，术语“C1-6的烷基”指含有1-6个碳原子的直链或支链烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、新戊基、叔戊基、己基等。术语“C1-6的烷氧基”指含有1-6个碳原子的直链或支链烷氧基，如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、异戊氧基、新戊氧基、叔戊氧基、己氧基等。
本发明中，n表示：1、2、3、4、5、6的整数。
更为优选的化合物是：
本发明所述的化合物可采用已报道的合成方法制备，也可采用下述方法制备获得：1)胆酸甲酯(II)在碱性催化剂下用甲磺酰氯活化得到甲磺酰胆酸甲酯(III)，碱性催化剂可采用无机碱如碳酸钾、碳酸钠、碳酸氢钠、氢化钠，有机碱如三乙胺、吡啶、4-二甲氨基吡啶等；2)将(III)与不同分子量的聚乙二醇(IV)缩合得化合物(V)，可适当添加吡啶、4-二甲氨基吡啶等催化剂；3)对甲基苯磺酰氯与化合物(V)反应得化合物(VI)；4)碱性催化剂下，化合物(VI)与预先制备好的吡咯酰胺片段(VII)缩合再经碱催化水解得得化合物(I)，其中，与吡咯酰胺片段的缩合可采用无机碱如碳酸钾、碳酸钠、碳酸氢钠、氢化钠，有机碱如三乙胺、吡啶、4-二甲氨基吡啶等，碱催化水解一步中所用的碱可用氢氧化钠、氢氧化锂等，吡咯酰胺片段的合成可参考CN200480021117.2，其合成路线如下：
本发明化合物可在预防和治疗糖尿病及其并发症、高血脂症、高血压及其并发症、动脉粥样硬化症、肥胖、代谢综合症的药物中应用。
本发明还包括药物组合物，包含作为活性剂的式(I)化合物或其药用盐、酯或药学上可接受的载体。
上述药学上可接受的载体是指药学领域常规的药物载体，是指一种或几种惰性的、非毒性的固体或液体填充物、稀释剂、助剂等，他们不逆向与活性化合物或病人发生作用。
本发明组合物的剂型可以是片剂、胶囊、丸剂、栓剂、软胶囊、口服液、混悬液、注射液等药剂学上常用的剂型。
口服用药片和胶囊含有传统的赋形剂如填充物、稀释剂、润滑剂、分散剂以及粘合剂。本发明药物组合物的各种剂型可以按照药学领域中熟知的方法制备。以上活性剂的剂量因配方而异。
与现有技术相比，本发明具有如下优点：
(1)本发明化合物具有较好的GP抑制活性，由表1可见：1)随着乙二醇链的延长，其GP酶抑活性先增强后逐渐降低，其中化合物I2的活性最好；2)本专利中采用乙二醇链为连接基团，连接基团通过胆酸3位羟基与胆酸相连这种方式优于其他连接基团与胆酸24位羧基相连，本专利采用的连接基团和连接方式更有利于活性保持。
(2)本发明化合物为一类新型的胆酸缀合吡咯酰胺类糖原磷酸化酶抑制剂，可有效作用于肝脏的糖原磷酸化酶，是2型糖尿病患者控制血糖的优选药物。该类化合物可用于制备抗糖尿病及其并发症药物、抗心血管疾病药物、减肥药物、治疗代谢综合征药物。
具体实施方式
下面通过实施例具体说明本发明的内容。在本发明中，以下所述的实例是为了更好的阐述本发明，而不是限制本发明的范围，对于未特别注明的工艺参数，可参照常规技术进行。
实施例1
化合物I1的制备
3α-甲磺酰氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(III)
冰浴下，将胆酸甲酯(0.19g，0.66mol)溶于吡啶(10mL)中，搅拌下加入对甲苯磺酰氯(97mg，0.79mmol)和DMAP(97mg，0.79mmol)，室温搅拌过夜。次日，减压浓缩，残渣加入乙酸乙酯稀释后，饱和食盐水洗涤，无水Na2SO4干燥，减压蒸去溶剂，快速柱层析(石油醚/乙酸乙酯1/1，V/V)得白色固体(1.09g，95％)。ESI-MS:500.5[M+H]+；1H NMR(400MHz,CDCl3)δ:0.66(s,3H),0.87(s,3H),0.94(d,J＝6.3Hz,3H),2.38-1.25(m,25H),2.56-2.52(m,1H),2.48(s,3H),3.68(s,3H),3.84(s,1H),7.32(d,J＝8.0Hz,2H),7.79(d,J＝8.4Hz,2H).
3α-羟基乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(V1)
将3α-甲磺酰氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(0.19g，0.66mol)溶于吡啶(10mL)中，搅拌下加入乙二醇(97mg，0.79mmol)，80℃搅拌过夜。次日，减压浓缩，残渣加入乙酸乙酯稀释后，饱和食盐水洗涤，无水Na2SO4干燥，减压蒸去溶剂，快速柱层析(二氯甲烷:甲醇30/1，V/V)得白色固体(0.32g，34％)。ESI-MS:484.4([M+18])+；1H NMR(400MHz,CDCl3)δ:0.63(s,3H),0.85(s,3H),0.91(d,J＝5.2Hz,3H),1.84-1.03(m,23H),2.38-2.02(m,5H),3.42-3.39(m,2H),3.53(s,3H),3.59(s,3H),3.65-3.63(m,2H).
3α-对甲苯磺酰氧乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(VI1)
参照3α-甲磺酰氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯的制备方法，得白色固体(4.8g，68％)。ESI-MS:638.4[M+18]+；1H NMR(400MHz,CDCl3)δ:0.69(s,3H),0.88(s,3H),0.98(d,J＝5.6Hz,3H),1.97-1.05(m,22H),2.44-2.02(m,4H),2.45(s,3H),3.50(s,1H),3.56-3.53(m,2H),3.66(s,3H),3.84(s,1H),7.33(d,J＝8.0Hz,2H),7.80(d,J＝8.0Hz,2H).
(3α-氧乙氧-胆酸-基)-{1-[2-(5-氯-1H-吡咯并[2,3-c]吡啶-2-甲酰胺)-3-(4-氟苯基)丙酰基]-哌啶-4-基}醚(I1)
将5-氯-1H-吡咯并[2,3-c]吡啶-2-甲酸[1-(S)-(4-氟苄基)-2-(-羟基哌啶-1-基)-2-氧代乙基]酰胺(2.60g，5.85mmol)溶解于DMF(30mL)，向其中加入NaH(1.56g，60％，39.02mmol)，冰浴下搅拌30min，缓慢加入3α-对甲苯磺酰氧乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(4.35g，7.02mmol)，升温至60℃搅拌4h。向反应液中加入30mL水破坏过量的NaH，得到的混合物以乙酸乙酯提取3次，合并有机层，饱和食盐水洗涤，无水Na2SO4干燥。蒸去溶剂，得白色固体(3.9g，74％)，此粗品无需纯化可直接进行下一步反应。将上述固体(3.9g，4.4mmol)溶于四氢呋喃(50mL)中，冰浴下，滴加一水合氢氧化锂(0.37g，8.8mmol)的水溶液，滴毕室温搅拌3h。减压蒸干溶剂，残渣用水稀释，以1N盐酸水溶液酸化至pH＝2，乙酸乙酯萃取，无水硫酸钠干燥过滤除去干燥剂，浓缩，残渣应用反相HPLC分离(73mg，1.9％)。ESI-MS:896.4[M+18]+；1H NMR(400MHz,CD3OD)δ:0.68(d,J＝34.8Hz,3H),0.89(d,J＝23.6Hz,3H),0.96-1.06(m,3H),2.79-2.84(m,1H),3.18-3.23(m,1H),3.35-3.51(m,2H),3.53-3.76(m,4H),3.80-3.88(m,5H),4.81-5.06(m,1H),5.34(dd,J＝14.8,7.2Hz,1H),7.04(td,J＝8.8,2.0Hz,2H),7.21(d,J＝4.8Hz,1H),7.31-7.36(m,2H),7.76(s,1H),8.63(d,J＝4.4Hz,1H).
实施例2
化合物I2的制备
3α-(羟基乙氧基)乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(V2)
参照3α-羟基乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯的制备方法，得白色固体(174mg，41％)。ESI-MS:511.4[M+H]+；1H NMR(400MHz,CDCl3)δ:0.62(s,3H),0.85(s,3H),0.91(d,J＝6.4Hz,3H),1.97-1.03(m,21H),2.18-2.03(m,5H),3.47-3.45(m,2H),3.65-3.54(m,10H).
3α-(磺酰氧基乙氧基)乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(VI2)
参照3α-甲磺酰氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯的制备方法，得白色固体(159mg，51％)。ESI-MS:682.5[M+18]+；1H NMR(400MHz,CDCl3)δ:0.62(s,3H),0.84(s,3H),0.91(d,J＝6.0Hz,3H),1.96-1.05(m,22H),2.35-2.03(m,4H),2.37(s,3H),3.65-3.36(m,10H),3.79(s,1H),7.27(d,J＝8.0Hz,2H),7.74(d,J＝8.0Hz,2H).
(3α-氧乙氧基乙氧基-胆酸-基)-{1-[2-(5-氯-1H-吡咯并[2,3-c]吡啶-2-甲酰胺)-3-(4-氟苯基)丙酰基]-哌啶-4-基}醚(I2)
参照I1的制备方法，得白色固体(54mg，3.98％)。ESI-MS:923.4[M+H]+；1H-NMR(400MHz,CD3OD)δ:0.65(d,J＝42.0Hz,3H),0.87(d,J＝29.2Hz,3H),0.97-1.05(m,3H),2.76-2.81(m,2H),3.37-3.49(m,10H),3.61(t,J＝4.4Hz,2H),3.78(t,J＝4.8Hz,2H),3.87-3.95(m,1H),4.30-4.38(m,1H),5.33(dd,J＝15.6,7.6Hz,1H),7.03(td,J＝8.8,3.2Hz,2H),7.17(d,J＝6.0Hz,1H),7.31-7.36(m,2H),7.69(s,1H),8.58(d,J＝4.4Hz,1H).
实施例3
化合物I3的制备
3α-[(羟基乙氧基)乙氧基]乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(V3)
参照3α-羟基乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯的制备方法，得白色固体(516mg，24％)。ESI-MS:555.5[M+H]+；1H NMR(400MHz,CDCl3)δ:0.62(s,3H),0.84(s,3H),0.91(d,J＝5.6Hz,3H),1.98-1.01(m,21H),2.30-2.02(m,5H),2.90-2.65(s,1H),3.66-3.44(m,16H).
3α-[(磺酰氧基乙氧基)乙氧基]乙氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯(VI3)
参照3α-甲磺酰氧基-7α,12α-二羟基-5β-胆甾烷-24-羧酸甲酯的制备方法，得白色固体(870mg，27％)。ESI-MS:726.5[M+18]+；1H NMR(400MHz,CDCl3)δ:0.62(s,3H),0.83(s,3H),0.91(d,J＝6.0Hz,3H),1.95-1.05(m,22H),2.35-2.03(m,4H),2.38(s,3H),3.50(s,1H),3.64-3.41(m,14H),3.78(s,1H),7.27(d,J＝8.4Hz,2H),7.73(d,J＝8.4Hz,2H).
(3α-氧乙氧基乙氧基乙氧基-胆酸-基)-{1-[2-(5-氯-1H-吡咯并[2,3-c]吡
啶-2-甲酰胺)-3-(4-氟苯基)丙酰基]-哌啶-4-基}醚(I3)
参照I1的制备方法，得白色固体(98mg，1.6％)。ESI-MS:967.4[M+H]+；1HNMR(400MHz,CD3OD)δ:0.67(d,J＝41.6Hz,3H),0.88(d,J＝28.0Hz,3H),0.99-1.06(m,3H),2.78-2.90(m,2H),3.37-3.50(m,7H),3.61-3.71(m,6H),3.78-3.97(m,5H),4.47(dt,J＝17.6,7.6Hz,1H),4.97-5.04(m,1H),5.34(dd,J＝17.6,7.6Hz,1H),7.04(t,J＝8.8Hz,2H),7.17(d,J＝5.6Hz,1H),7.33(t,J＝6.0Hz,2H),7.69(s,1H),8.60(s,1H).
实施例4
体外GP酶活抑制活性测试：
1)显色剂：钼酸铵5g，500mL1M HCl，搅拌全部溶解后加入孔雀绿190mg，继续搅拌至全部溶解，锡纸避光保存；
2)缓冲液：a)精密称取Hepes 0.5958g，溶于5mL蒸馏水中，用10M的NaOH调pH至7.2，备用；b)精密称取氯化钾0.3728g，溶于5mL蒸馏水中，备用；c)精密称取氯化镁0.0255g，溶于1mL蒸馏水中，备用；d)精密称取EGTA 0.0476g，溶于5mL蒸馏水中，用10M的NaOH调pH至7.0，备用；e)精密称取G-1-P 0.0152g，溶于10mL蒸馏水中，备用；f)精密称取糖原10mg，溶于1mL蒸馏水中，备用。
3)阳性药溶液：精密称取一定量的咖啡因，溶于10mL蒸馏水中，配制成0.5、5、50、500μM的咖啡因溶液；
4)GPa溶液：取1μL的GPa加入到100μL的反应体系中，配制成终浓度为250ng/100μL的GPa溶液；
5)待测试化合物溶液：将待测试化合物溶于DMSO中配制成10mM的贮备液，取适量加入到反应体系中至不同终浓度；
6)实验步骤：(a)96孔板中设计PC(阳性对照)孔，Blank(空白对照)孔，阳性药孔(咖啡因)和待测化合物孔；(b)每孔加反应buffer 52μL；(c)在待测化合物孔加测试化合物至终浓度分别为1μM，5μM，10μM，25μM，50μM，100μM。(d)加酶1μL，终浓度为250ng/100μL。PC(阳性对照)孔只加酶，Blank(空白对照)孔不加酶；(e)加显色液150μL；(6)20-25℃条件下反应20min；(f)在波长655nm条件下比色；(g)结果的初步计算。其结果见表1：
抑制率＝[(PC-B)-(X-B)]/(PC-B)。
表1.化合物的体外GP酶活抑制活性
由上表IC50结果可见：1)随着乙二醇链的延长，其GP酶抑活性先增强后逐渐降低，其中化合物I2的活性最好，其活性较PSN-357略有降低，可能是胆酸部分的引入对整个分子大小、理化性质的影响所致。2)专利CN201310454060.6、CN201310454072.9、CN201310454058.9中报道的化合物也采用了胆酸缀合的方式来制备糖原磷酸化酶抑制剂，与本专利的主要区别在于a)连接基团的不同；b)胆酸上连接基团的不同。将本专利中测试得到的化合物I1-I6的IC50与上述专利中有报道的IC50比较可知，本专利中采用a)乙二醇链为连接基团，b)连接基团通过胆酸3位羟基与胆酸相连这种方式优于其他连接基团与胆酸24位羧基相连，本专利采用的连接基团和连接方式更有利于活性保持。
综上所述，本发明化合物具有较好的GP抑制活性，可以用于制备新型降血糖药物。
Claims (9)
1.一种化合物，其特征在于，该化合物具有式I所示结构或其药学上可接受的盐或酯：
其中：
X1、X2、X3和X4全为CH或者X1、X2、X3和X4之一为N而其他全为CH；
R1为H、卤素、羟基、氰基、C1-6的烷基，C1-6的烷氧基，三氟甲基、乙烯基或乙炔基；
n代表1-6的整数。
2.根据权利要求1所述的化合物，其特征在于，所述R1为C1-4的烷基、C1-4的烷氧基。
3.根据权利要求1所述的化合物，其特征在于，该化合物为下列任一化合物或其药学上可接受的盐或酯：
4.一种胆酸缀合吡咯酰胺类糖原磷酸化酶抑制剂，其特征在于，该抑制剂为权利要求1-3任意一项所述的化合物。
5.权利要求1-3任意一项所述化合物的制备方法，其特征在于，包括如下步骤：
1)胆酸甲酯在碱性催化剂下用甲磺酰氯活化得到甲磺酰胆酸甲酯；
2)将步骤1)的活化产物与不同分子量的聚乙二醇缩合得化合物V，化合物V的结构式如下：
3)对甲基苯磺酰氯与化合物V反应得化合物VI，化合物VI的结构式如下：
4)碱性催化剂下，化合物VI与吡咯酰胺片段缩合，再经碱催化水解得目的化合物。
6.根据权利要求5所述的制备方法，其特征在于，步骤1)、4)所述碱性催化剂为碳酸钾、碳酸钠、碳酸氢钠、氢化钠、三乙胺、吡啶或4-二甲氨基吡啶；步骤4)所述的碱为氢氧化钠或氢氧化锂。
7.根据权利要求5所述的制备方法，其特征在于，步骤2)中还添加催化剂，所述催化剂为吡啶、4-二甲氨基吡啶。
8.权利要求1-3任一项所述的化合物在制备预防和治疗糖尿病及其并发症、高血脂症、高血压及其并发症、动脉粥样硬化症、肥胖、代谢综合症的药物中的应用。
9.一种药物组合物，其特征在于，包含作为活性剂的权利要求1-3任意一项所述化合物。
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