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CN108358811B - 苯乙酮类化合物、其制备方法及其在调血脂方面的应用 - Google Patents

苯乙酮类化合物、其制备方法及其在调血脂方面的应用 Download PDF

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CN108358811B
CN108358811B CN201810203556.9A CN201810203556A CN108358811B CN 108358811 B CN108358811 B CN 108358811B CN 201810203556 A CN201810203556 A CN 201810203556A CN 108358811 B CN108358811 B CN 108358811B
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董玉琼
刘全海
沈俞
蔡文韬
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Shanghai Bai Ao Najib Medical Technology Co Ltd
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Abstract

本发明公开了如式I所示化合物或其药学上可接受的盐及其制备方法，

Description

苯乙酮类化合物、其制备方法及其在调血脂方面的应用
技术领域
本发明属于新药设计与合成领域，具体涉及一种新型的氨基苯乙酮类化合物、其制备方法及其调血脂方面的应用。
背景技术
脂肪代谢或转运异常会引起血浆一种或多种脂质高于正常值，称为高血脂症。高血脂症是一种全身性疾病，表现为血中总胆固醇(TC)和/或甘油三酯(TG)过高或高密度脂蛋白胆固醇 (HDL-C)过低，现代医学或称之为血脂异常。脂质不溶或微溶于水，必须与蛋白质结合以脂蛋白形式存在，因此，高血脂症通常也称为高脂蛋白血症。
我国现有超过1.6亿高血脂症患者。高血脂症危害严重，其身体的损害是隐匿、逐渐、进行性和全身性的。高血脂症往往加速全身动脉粥样硬化，而全身的重要器官都要依靠动脉供血、供氧，一旦动脉被粥样斑块堵塞，就会导致严重后果，例如动脉硬化引起的肾功能衰竭等都与高血脂症密切相关。大量研究资料表明，高血脂症是脑卒中、冠心病、心肌梗死、心脏猝死独立而重要的危险因素。我国每年有260万人死于心血管疾病，平均每12秒就有1 人被心血管病夺去生命，每年新发中风患者超过200万，其中三分之二致死或致残。许多高血脂病人常常是在不知不觉中突发心肌梗死、脑中卒、猝死，因此高血脂也被称作是人类健康的“无声杀手”。
此外，高血脂症也是促进高血压、糖耐量异常、糖尿病的一个重要危险因素。高血脂症还可导致脂肪肝、肝硬化、胆石症、胰腺炎、眼底出血、失明、周围血管疾病、跛行、高尿酸血症。有些原发性和家族性高血脂症患者还可出现腱状、结节状、掌平面及眼眶周围黄色瘤、青年角膜弓等。
鉴于高血脂症对人体的危害，特别是其直接相关的心脑血管疾病的威胁，调血脂类药物一直是当今新药研究的一个重要领域。大量的临床研究表明，一些降脂药物可以减少动脉粥状硬化和冠心病的发生，降低冠心病所致的死亡率和心肌梗死发生率。而且通过降脂药物的治疗也可以减少粥样硬化斑块内脂质的含量，加固纤维质而稳定斑块，从而减少斑块破裂而引发的心肌梗死和脑梗等严重病患。此外，调血脂药还可恢复受损血管内皮细胞的功能，防止血栓生成，并且延缓人的动脉粥样硬化的进展、消退已形成的斑块。因此，积极使用调血脂药物治疗是减轻动脉粥样硬化和减少冠心病的发生的重要措施。
目前临床使用的调血脂的药物品种较多，主要有胆酸螯合剂(如考来烯胺、考来替泊等)、 3-羟基-3-甲基戊二酰辅酶A(HMG—CoA)还原酶抑制剂(如洛伐他汀、普伐他汀、阿伐他汀等他汀类)、烟酸及其衍生物(如烟酸、阿昔莫司等)、苯氧芳酸类(如氯贝特、环丙贝特、非诺贝特、吉非罗齐等)四大类，其它有降脂作用的药物或保健品还包括普罗布考、泛硫乙胺、弹性蛋白酶、欧米伽-3脂肪酸等。
近年来这些调血脂药物在降低血液中胆固醇水平和低密度脂蛋白(LDL-C)水平方面有显著作用，达到了预防和减少动脉粥样硬化和冠心病等严重临床事件的发生。然而，现有调血脂类药物还存在着一些副作用，以目前使用最为广泛的他汀类药物为例，长期服用除了有上腹不适等消化系统症状外，相当部分病人会产生肝功能损害，转氨酶升高，肌肉疼痛，肌酸激酶升高等不良反应。因此，希望设计新的化学结构，研发得到效果更好、副作用小的新型降脂药。
发明内容
本发明的目的在于提供了一种在体内发挥调血脂作用的新颖氨基苯乙酮类化合物。试验表明，该类化合物可降低高脂模型动物血液中的胆固醇和低密度脂蛋白，具有良好的降低血脂的作用。
具体地，本发明的第一方面是提供一类如式I所示化合物或其药学上可接受的盐，
X选自氧或-NH；
R1选自H或羟基；
R2选自经取代的以下基团：苯基、具有1到2个独立选自氮、氧的杂原子的5到6元单环杂芳基，或：
R3独立选自单取代的苯基或二取代的苯基，其中苯基的取代基为卤素、羟基、C1-C6的烷基、C1-C6的烷氧基、C3-C6的环烷基、C5-C10的芳基取代的C1-C6的烷基、C5-C10的芳基、含有1-3个独立选自氮、氧或硫的杂原子的3-7元的杂环基、含有1到4个独立选自氮、氧或硫的杂原子的5到7元杂芳环基、取代的C1-C6的烷基、取代的C3-C6的环烷基或取代的甲酰基；
n为0-5整数；
根据本发明一个优选的实施方式，式I所示化合物或其药学上可接受的盐，其特征在于，
R2选自经取代的以下基团：苯基、具有1到2个独立选自氮原子的6元单环杂芳基，或：
R3独立选自单取代的苯基或二取代的苯基，其中苯基的取代基为卤素、羟基、C1-C6的烷基、C1-C6的烷氧基、C3-C6的环烷基、C5-C10的芳基取代的C1-C6的烷基、C5-C10的芳基、含有1-3个独立选自氮、氧或硫的杂原子的3-7元的杂环基、含有1到4个独立选自氮、氧或硫的杂原子的5到7元杂芳环基、取代的C1-C6的烷基、取代的C3-C6的环烷基或取代的甲酰基；
n为0-5整数。
根据本发明一个更优选的实施方式，式I所示化合物或其药学上可接受的盐，其特征在于：
R2选自以下经取代的基团：苯基、具有1到2个独立选自氮原子的6元单环杂芳基，或：
R3独立选自单取代的苯基或二取代的苯基，其中苯基的取代基为卤素、羟基、C1-C3的烷基、C1-C3的烷氧基、C3-C6的环烷基、取代的C1-C3的烷基、取代的C3-C6的环烷基；
n为0-5整数。
根据本发明一个更优选的实施方式，式I所示化合物或其药学上可接受的盐，其特征在于：
R2选自经取代的以下基团：苯基、具有1到2个独立选自氮原子的6元单环杂芳基，或：
其中，R3独立选自单取代的苯基或二取代的苯基，其中苯基的取代基为卤素、C1-C3的烷基；
n为0-3整数。
根据本发明的一个特别优选的实施方式，R2为吡啶-3-基；
根据本发明的一个特别优选的实施方式，R3为2,5-二甲基苯基。
根据本发明的一个特别优选的实施方式，n为3。
根据本发明特别优选的实施方式，本发明式I化合物为如下化合物：
01：
02：
03：
04：
05
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
本发明中使用的术语“杂芳基”表示各环中可高达6个原子的稳定单环或者二环，其中至少一个环是芳香环并且含有1-4个选自O、N、和S的杂原子。在此定义范围内的杂芳基包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。“杂芳基”还应当理解为包括任何含氮杂芳基的N-氧化物衍生物。在其中杂芳基取代基是二环取代基并且一个环是非芳香环或者不包含杂原子的情况下，可以理解，连接分别通过芳环或者通过包含杂原子的环进行。
除非另有定义，否则，本发明中使用的术语“取代的”所指的取代基包括:卤素、羟基、 C1-C6的烷基、C1-C6的烷氧基、C1-C6的卤代烷氧基、C1-C6的卤代烷基、C3-C6的环烷基、 C5-C10的芳基取代的C1-C6的烷基、C5-C10的芳基、含有1-3个独立选自氮、氧或硫的杂原子的3-7元的杂环基、含有1到4个独立选自氮、氧或硫的杂原子的5到7元杂芳环基、C1-C6的酯基或氰基。
本发明中，所述的药学上可接受的盐较佳的为本发明化合物与药学上可接受的酸进行反应制得的酸加成盐，或者其中具有酸性基团的化合物和碱性化合物反应生成的盐。其中，所述的酸较佳的选自无机酸(如盐酸、硫酸、磷酸或氢溴酸等)和有机酸(如草酸、马来酸、富马酸、苹果酸、酒石酸、柠檬酸或苯甲酸等)；所述的碱性化合物较佳的选自氢氧化钠、氢氧化钾、氢氧化钙、碳酸钠或碳酸氢钾等。上述药学上可接受的盐容易分离，可采用常规分离方法提纯，如溶剂萃取、稀释、重结晶、柱色谱和制备薄层色谱等。
本发明的第二方面是提供上述如式I所示的化合物或其药学上可接受的盐的制备方法。
一般来说，式I化合物可通过下列流程制备。
此流程提供式I所示化合物的两种制备方法。
方法一，包括将酸和化合物在缩合剂和溶剂存在下直接缩合的步骤。
根据本发明的一个优选的实施方式，所述的缩合剂为常用的酰胺缩合剂，如2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、N,N’-羰基二咪唑、二环己基碳二亚胺、二异丙基碳二亚胺等。
根据本发明的一个优选的实施方式，所述的溶剂选自酰胺类溶剂，如N,N-二甲基甲酰胺、 N,N’-二甲基乙酰胺、N-甲基吡咯烷酮等；卤代烃如二氯甲烷、二氯乙烷、氯仿等；酯类溶剂如乙酸乙酯、乙酸异丙酯等；环醚类溶剂如四氢呋喃、二氧六环等。
根据本发明的一个优选的实施方式，所述反应中可加入含氮类催化剂，如N,N-二甲氨基吡啶，以加快反应速度。
方法二包括如下步骤：酰氯与化合物在溶剂中进行缩合；其中，酰氯是通过酸和氯化试剂反应制得的。
根据本发明的一个优选的实施方式，所述的卤化试剂包括草酰氯、二氯亚砜、三氯化磷、五氯化磷、二溴亚砜、三溴化磷等。
根据本发明的一个优选的实施方式，所述的溶剂选自酰胺类溶剂，如N,N-二甲基甲酰胺、 N,N’-二甲基乙酰胺、N-甲基吡咯烷酮等；卤代烃如二氯甲烷、二氯乙烷、氯仿等；酯类溶剂如乙酸乙酯、乙酸异丙酯等；环醚类溶剂如四氢呋喃、二氧六环等。
根据本发明的一个优选的实施方式，在缩合反应中可加入无机碱或有机碱来加快反应速度，无机碱如氢氧化钠、氢氧化钾、碳酸钠、碳酸钾等；有机碱如三乙胺、吡啶，二异丙基乙基胺等。
本发明的第三方面是提供一类药物组合物，含有式I所示化合物或其药学上可接受的盐和药学上可接受的添加剂。
本发明的化合物可与药学上各种常用添加剂(如稀释剂和赋形剂等)制成药物组合物。根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、溶液、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液、羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基硫酸钠、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基硫酸钠等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。如果需要的话，还可以用通常的涂渍材料使片剂作为糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋性剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液和悬浮液消毒，并最好加入适量的氯化钠，葡萄糖或甘油等，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。根据需要，在治疗精神分裂症期间，也可加入着色剂、防腐剂、香料、调味剂、香化剂和其它药物等。
本发明的如式I所示的化合物及其药学上可接受的盐在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比1-70％，较佳的为质量百分比1-30％。
本发明中，所述的药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂和胶囊是口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液) 混合进行静脉注射，如有必要可以单纯用针剂进行肌肉、皮内、皮下或腹内注射；栓剂为给药到直肠。
本发明中，可以根据服药方法、病人年龄、性别和其它条件以及症状适当地选择用药剂量。通常的给药剂量可为：约0.1～300mg药物活性成分/kg体重/天。一般来说，每个给药单位剂型可含1～200mg的药物活性成分。
本发明的第四方面是提供式I所示化合物或其药学上可接受的盐在制备调节血脂的药物中的应用。
本发明的有益效果是：本发明化合物不仅可以降低高脂模型动物血中甘油三酯的水平，而且还具有良好的降低胆固醇和低密度脂蛋白的作用，本发明提供的化合物的毒性较低，急性毒性显示ID50≥5g/kg。
具体实施方式
实施例1：化合物01的制备
将4.0g5-(2,5-二甲基苯氧基)-2,2-二甲基戊酸溶于40mL二氯甲烷中，冰浴冷却下加入3.0g草酰氯和2滴N,N-二甲基甲酰胺，撤去冰浴升至室温搅拌3小时，蒸干溶剂得相应的酰氯。
将2.2g对氨基苯乙酮溶于30mL吡啶中，冰浴冷却下，滴加上述酰氯的20mL二氯甲烷溶液，滴加完毕后，撤去冰浴升至室温搅拌1小时，蒸干溶剂，残余物加200mL乙酸乙酯溶解，依次100mL3N盐酸、100mL水和100mL饱和食盐水洗涤，蒸干溶剂，硅胶柱层析得到目标化合物5.4g。1H NMR(400MHz,CDCl3)δ7.95–7.89(m,2H),7.62(d,J＝8.8Hz,2H),7.56(s,1H),6.99(d,J ＝7.5Hz,1H),6.66(d,J＝7.5Hz,1H),6.59(s,1H),3.97–3.88(m,2H),2.57(s,3H),2.28(s,3H),2.14(s,3H), 1.82(dd,J＝15.4,2.8Hz,4H),1.35(s,6H)。MS(ESI)m/z:390.2[M+23]+。
实施例02：化合物02的制备
将3.5g1-(3-氨基-4-羟基苯基)乙酮溶于100mL吡啶中，冰浴冷却下，滴加9.3g5-(2,5- 二甲基苯氧基)-2,2-二甲基戊酰氯的20mL二氯甲烷溶液，滴加完毕后，撤去冰浴升至室温搅拌2小时，蒸干溶剂，残余物加200mL乙酸乙酯溶解，依次100mL3N盐酸、60mL水和30mL 饱和食盐水洗涤，蒸干溶剂，以乙酸乙酯为溶剂重结晶得到目标化合物5.1g。1H NMR(400MHz, CDCl3)δ9.99(s,1H),7.82(s,1H),7.71(dt,J＝6.2,2.0Hz,2H),7.04(d,J＝8.3Hz,1H),6.99(d,J＝7.4Hz, 1H),6.65(d,J＝7.5Hz,1H),6.60(s,1H),3.95(t,J＝5.4Hz,2H),2.53(s,3H),2.29(s,3H),2.16(s,3H),1.91– 1.78(m,4H),1.40(s,6H)。MS(ESI)m/z:406.2[M+23]+。
实施例03：化合物03的制备
将2.7g1-(3-氨基-4-羟基苯基)乙酮溶于50mL吡啶中，冰浴冷却下加入6.4g烟酰氯，撤去冰浴升至室温搅拌2小时，蒸干溶剂，加入50mL水和50mL饱和碳酸钠水溶液，用300mL 二氯甲烷萃取，有机相用100mL饱和食盐水洗涤，蒸干溶剂。残余物溶于100mL甲醇中，加入30mL4N的氢氧化钠水溶液，室温搅拌1小时，加盐酸调节pH值至8～9，过滤收集固体，硅胶柱层析得到目标化合物3.0g。1H NMR(400MHz,DMSO-d6)δ10.82(s,1H),9.24(d,J＝1.5Hz,1H), 8.89(dd,J＝4.8,1.6Hz,1H),8.45(dt,J＝8.0,1.9Hz,1H),7.85–7.74(m,2H),7.67–7.59(m,1H),7.07(d,J＝ 8.4Hz,1H),2.49(s,3H)。MS(ESI)m/z:257.1[M+1]+。
实施例4：化合物04的制备
将7.1g2-(4-氯代苯氧基)-2-甲基丙酸溶于100mL二氯甲烷中，冰浴冷却下加入6.3g 草酰氯和2滴N,N-二甲基甲酰胺，撤去冰浴升至室温搅拌3小时，蒸干溶剂得相应的酰氯。
将4.05g对氨基苯乙酮溶于50mL吡啶中，冰浴冷却下，滴加上述酰氯的50mL二氯甲烷溶液，滴加完毕后，撤去冰浴升至室温搅拌2小时，蒸干溶剂，残余物加300mL水，过滤收集固体，以50mL5:1的石油醚：乙酸乙酯混合溶剂打浆，过滤收集固体，烘干，得到目标化合物8.5g。1H NMR(400MHz,CDCl3)δ8.72(s,1H),7.96(d,J＝8.6Hz,2H),7.69(d,J＝8.6Hz,2H),7.27 (d,J＝9.1Hz,2H),6.93(d,J＝8.7Hz,2H),2.58(s,3H),1.57(s,6H)。MS(ESI)m/z:332.3[M+1]+。
实施例05：化合物05的制备
将0.46g1-(3,4-二羟基苯基)乙酮和0.40g三乙胺溶于25mL二氯甲烷中，冰浴冷却下，加入0.54g烟酰氯，撤去冰浴升至室温搅拌1小时。反应混合物加50mL二氯甲烷冲稀，依次用20mL水和20mL饱和食盐水洗涤，蒸干溶剂。残余物加入10mL饱和碳酸钠水溶液搅拌，30mL 乙酸乙酯萃取两次。水相分离后加1N盐酸调节pH值至7-8，然后用30mL二氯甲烷和甲醇混合液(二氯甲烷：甲醇＝10:1)萃取三次。合并有机相，30mL饱和食盐水洗涤，蒸干溶剂，得目标化合物0.14g。1H NMR(400MHz,DMSO-d6)δ10.81(s,1H),9.24(d,J＝1.6Hz,1H),8.89(dd,J＝ 4.8,1.6Hz,1H),8.45(dt,J＝8.0,1.9Hz,1H),7.86–7.75(m,2H),7.64(dd,J＝7.9,4.9Hz,1H),7.05(t,J＝9.9 Hz,1H),2.48(s,3H)。MS(ESI)m/z:258.2[M+1]+。
药理及生物活性测试实验
1.对SD大鼠高脂血症的治疗作用
脂肪乳剂制备方法：取猪油500g，放在容器里，加热,溶化后，待温度升到100℃时,加入 200g胆固醇,完全溶解,再加入20g丙硫氧嘧啶,充分搅匀,溶解后，然后加入500ml吐温80, 制成油相。同时，取600mL蒸馏水和1,2－丙二醇400mL,水浴中加热至60℃,然后加入40g 脱氧胆酸钠,充分搅拌直到完全溶解,制成水相。水相加入油相,充分混匀,即制成脂肪乳剂。
造模方法：动物适应性喂养3天，根据体重分出5只作为空白对照组(Control)，其余动物每天上午9:00-11:00灌胃脂肪乳，1mL/100g体重，连续灌胃2周,动物禁食12h，眼眶采血1mL,采用日立自动生化分析仪7080测定血清胆固醇(CHO)、甘油三酯(TG)、低密度脂蛋白(LDL-C)和高密度脂蛋白(HDL-C)，取CHO为4-7mmol/L的动物进行实验。
根据体重将给予脂肪乳剂2周的动物分为模型组(Model)、辛伐他汀组(Sim，10mg/kg)、化合物01组(80mg/kg)、化合物02组(80mg/kg)、化合物03组(80mg/kg)、化合物04组(80mg/kg)、化合物05组(80mg/kg)、化合物A(80mg/kg)。每组5只继续灌胃脂肪乳剂，同时给药组给予相应剂量的药物，模型组给予等体积溶剂。上午灌脂肪乳剂，下午给药。每周一称量体重，观察动物情况。连续给药21天，动物禁食12h，眼眶采血1mL。采用日立自动生化分析仪7080测定血清胆固醇(CHO)、甘油三酯(TG)、低密度脂蛋白(LDL-C)和高密度脂蛋白(HDL-C)。
实验选取的对照品包括化合物A，以及辛伐他汀(Simvastatin,本申请中也简称为Sim)。
化合物A为专利申请号为201110174070.5的中国专利所公开，其结构式如下：
实验结果见表1，降血脂效果计算公式如下：(模型组CHO-给药组CHO)/模型组CHO*100％。根据该公式得到各化合物的降血脂效果如表1，参考胆固醇下降比例，以及各组甘油三酯的水平，各组化合物胆固醇下降比例：化合物01：(10.66-4.29)/10.66*100％＝59.75％；化合物02：(10.66-4.86)/10.66*100％＝54.40％；化合物03：(10.66-4.56)/10.66*100％＝57.22％；化合物04：(10.66-4.90)/10.66*100％＝54.03％；化合物05：(10.66-4.63)/10.66*100％＝56.56％；化合物A：(10.66-6.15)/10.66*100％＝42.30％。本实验的血中胆固醇降低作为主要指标，同时参照甘油三酯的下降，确定我们得到的化合物具有调血脂作用。
表1.样品给药后大鼠血脂水平
注：给药组与模型组比较*P<0.05，**P<0.01；#p<0.05，##p<0.01vs空白
表1显示，化合物01、02、03、04、05均显示了较好的降血脂效果，能够显著降低胆固醇。
2.急性毒性试验
采用单次口服剂量法
动物：ICR小鼠，体重18-20g，每组20只，雌雄各半。
实验药物：化合物01号(5g/kg)、化合物02号(5g/kg)、化合物03号(5g/kg)、化合物04号(5g/kg)、化合物05号(5g/kg)，药物加入0.5％CMC-Na，研磨混匀，备用；
实验方法：给药前禁食16小时，采用口服灌胃单次给药，给受试药物后再禁食3-4小时，给药后密切观察一般征状6小时，观察14天。
实验结果：试验期间所有动物均无死亡，一般状况无异常。
急性毒性：ID50≥5g/kg。

Claims (8)

1.如式I所示化合物或其药学上可接受的盐，
其中，X选自氧或-NH；
R1选自羟基；
R2选自经取代的吡啶基；所述“取代的”所指的取代基选自:卤素、羟基、C1-C6的烷基、C1-C6的烷氧基、C1-C6的卤代烷氧基、C1-C6的卤代烷基、C3-C6的环烷基。
2.根据权利要求1所述的如式I所示化合物或其药学上可接受的盐，其特征在于，R2为吡啶-3-基。
3.根据权利要求1或2所述的如式I所示化合物或其药学上可接受的盐，其特征在于，包括以下具体结构式的化合物：
03：
05:
4.如权利要求1-3任意一项所述的式I所示化合物或其药学上可接受的盐的制备方法，具体如下：
方法一，包括将酸和化合物在缩合剂和溶剂存在下直接缩合的步骤；
或，方法二，包括如下步骤：酰氯与化合物在溶剂中进行缩合；其中，酰氯是通过酸与氯化试剂反应制得的；上述取代基具有对应权利要求1-3任一项所定义的定义。
5.药物组合物，含有如权利要求1-3任一项所述的式I所示化合物或其药学上可接受的盐和药学上可接受的添加剂。
6.如权利要求5所述的药物组合物，其特征在于，其为片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂或针剂形式。
7.如权利要求1-3任意一项所述的式I所示化合物或其药学上可接受的盐在制备调节血脂药物中的应用。
8.权利要求5-6任意一项所述的药物组合物在制备调节血脂药物中的应用。
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