CN115583890B - 一种治疗血脂异常的药物及其用途 - Google Patents
一种治疗血脂异常的药物及其用途 Download PDFInfo
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/78—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07C217/80—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C217/82—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring
- C07C217/84—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton having amino groups and etherified hydroxy groups bound to carbon atoms of non-condensed six-membered aromatic rings of the same non-condensed six-membered aromatic ring the oxygen atom of at least one of the etherified hydroxy groups being further bound to an acyclic carbon atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
本发明提供了一种治疗血脂异常的药物及其用途。本发明所述的药物由羟基酪醇类多酚化合物进行结构修饰得到，具有很强的降低血脂的作用，并可预防肝损伤和氧化应激损伤，是一种有效的治疗血脂异常的药物。
Description
技术领域
本发明涉及药物领域，具体而言，本发明涉及一种治疗血脂异常的药物及其用途。
背景技术
血脂异常是脂质代谢性疾病，主要包括总胆固醇(TC)、甘油三酯(TG)、和低密度脂蛋白胆固醇(LDL-C)升高和/或高密度脂蛋白胆固醇(HDL-C)降低等在内的各种情况。目前，我国成人血脂异常发病率高达40.40％，美国成人单项低密度脂蛋白胆固醇(LDL-C)异常者超1亿，发病率逐年上升且呈低龄化趋势。血脂异常与脂肪肝、动脉粥样硬化、高血压、冠心病、糖尿病和脑卒中等多种疾病密切相关，现已发展为全球性公共卫生问题，严重威胁人类生命健康。
以LDL-C或TC升高为特点的高脂血症是动脉粥样硬化性心血管疾病(atherosclerotic cardiovascular disease,ASCVD)重要的危险因素；降低LDL-C水平，可显著减少ASCVD的发病及死亡危险。降低血脂的途径主要有以下几个方面：一是提高脂蛋白脂肪酶和卵磷脂胆固醇酰基转移酶的活性，增加HDL含量，从而促进脂质分解代谢，抑制脂质合成转运及在动脉壁上的沉积；二是抑制胆固醇的生物合成途径中一个或几个环节；三是与胆固醇或其转化物胆酸结合，从而抑制其在肠内的吸收，促进降解和排泄；四是通过抗氧化来降血脂。
天然产物降脂剂是重要的降脂活性化合物，其包括以下几类：一、多糖类化合物，能提高超氧化物歧化酶、谷胱甘肽过氧化物酶等的活性、降低脂质过氧化物含量，还能通过增加肠道蠕动、增加对脂类的吸附、促进TC向胆酸的转化与排泄；一、多酚类化合物，主要是通过清除自由基和抗脂质过氧化而实现调节血脂作用；三、黄酮类化合物，可在肠道内与TC形成络合物，而降低TC在体内的吸收，或通过抗氧化和清除自由基起到调节血脂的作用；四、植物甾醇类化合物，可与TC竞争酯化酶，使TC不能酯化，从而减少TC的吸收；五、不饱和脂肪酸类化合物，可与TC结合，促进TC在体内的运转和代谢，并能改善和保护血管壁功能；六、蒽醌类化合物，可促进胃肠蠕动，减少脂类在肠道的停留时间及吸收量；七、皂苷类化合物，能够与TC相结合，阻断肠循环，减少人体对TC的吸收，也作用于低密度脂蛋白受体(LDL-R)；八、生物碱类化合物，可提高HDL-C含量、抑制脂质过氧化和增强抗氧化酶活性；九、蛋白质类化合物，可影响体内激素水平，达到调节血脂的作用。
发明内容
本发明从羟基酪醇类多酚化合物出发，将其作为先导化合物，对其结构进行合理的改造和优化，从而构建了一种新型生物活性分子，提高了化合物的生物活性。
本发明提供一种式I所示的化合物或其药学上可接受的盐、前药、溶剂化物：
其中，R1选自H、羟基、C1-C6的烷氧基、C1-C4烷氧基C1-C4烷氧基；
R2、R3各自独立地选自H、C1-C6的烷基、C1-C4烷氧基C1-C4烷基；
L选自C1-6的亚烷基；
R4选自H、C1-C6的烷基。
本发明提供的化合物在下文中称为“本发明化合物”。本发明化合物包括任何形式的化合物，例如游离形式、盐形式、溶剂化物形式以及盐和溶剂化物形式。
本发明提供了盐形式的本发明化合物。这类盐优选地包括药学上可接受的盐，但是也包括不可药用的盐，例如用于制备/分离/纯化目的的盐。
本发明化合物的药学上可接受的盐包括其碱加成盐和酸加成盐。优选地，所述碱加成盐选自钠盐、钾盐、钙盐、锂盐、镁盐、锌盐、铵盐、四甲基铵盐、四乙基铵盐、三乙胺盐、三甲基铵盐、乙胺盐、二乙醇胺盐、精氨酸盐或赖氨酸盐；所述酸加成盐，选自乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、乳酸盐、苹果酸盐、三氟乙酸盐、马来酸盐等有机酸盐，以及盐酸盐、氢溴酸盐、硫酸氢盐、硝酸盐、磷酸盐等无机酸盐。游离形式的本发明化合物可以被转化为盐形式的相应化合物；并且反之亦然。游离形式或盐形式和溶剂化物形式的本发明化合物可以被转化为非溶剂化物形式的游离形式或盐形式的相应化合物；并且反之亦然。
本发明化合物可作为前体药物形式被给予。因此，自身可能具有很少药理学活性或不具有药理学活性的某些衍生物当被给予到体内或体上时，通过例如水解裂解而转化为具有所需活性的本发明的化合物。这种衍生物被称为“前体药物”。关于前体药物的使用的详细信息可参见Pro-drugs as Novel Delivery Systems,Vol.14,ACS Symposium Series(T.Higuchi和W.Stella)以及Bioreversible Carriers in Drug Design，PergamonPress，1987(编辑：E.B.Roche,American Pharmaceutical Association)。
本发明化合物还包含其溶剂化物形式，其是指一个或多个溶剂分子与本发明化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
在本发明的一个实施方案中，R1选自H、羟基、甲氧基，优选为H、羟基。
在本发明的一个实施方案中，R2和R3选自H、甲基，优选为H。
在本发明的一个实施方案中，L选自C1-C4的亚烷基，优选为-CH2-、-CH2CH2-、-CH2CH2CH2-。
在本发明的一个实施方案中，R4选自H、C1-4烷基，优选为H、甲基、乙基、正丙基、异丙基、异丁基、仲丁基。
在本发明的一个实施方案中，式I化合物选自：
本发明的另一个方面提供了一种药物组合物，其包含式I所示的化合物或其药学上可接受的盐、前药、溶剂化物中的一种或多种。
本发明中，所述“药物组合物”指的是：含有用药学上可接受的载体配制的一种或多种本发明所述的式I所示的化合物或其药学上可接受的盐、前药、溶剂化物的组合物。因此，本发明所述药物组合物还可包含药学上可接受的载体。典型的本发明药物组合物为：散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、贴剂等。
如本文所用的术语“药学上可接受的载体”包括任何和所有的溶剂、分散介质、包衣材料、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、崩解剂、润滑剂、染料等和其组合，这是本领域技术人员所熟知的(例如参见Remington’s Pharmaceutical Sciences,18th Ed.Mack PrintingCompany,1990,pp.1289-1329)。除了与活性成分不相容的载体外，在治疗或药物组合物中考虑使用任何常规载体。
在本发明药物组合物中，式I所示的化合物或其药学上可接受的盐、前药、溶剂化物一般配方成为单位剂型的形式。对于每日一次或数次的给药，每个单位剂量是0.5～500mg，有利地是5～200mg，优选是5～100mg。
本发明化合物可与其他药物联用并用于预防和治疗血脂异常相关的疾病，所述药物的实例包括但不限于：HMG-CoA还原酶抑制剂、烟酸及其衍生物、贝特类药物、具有降脂作用的各类天然产物及其衍生物(例如多糖类、多酚类、黄酮类、植物甾醇类、不饱和脂肪酸类、蒽醌类、皂苷类、生物碱类、蛋白质类化合物)。因此，在本发明药物组合物中还可包含选自以下中的一种或多种的活性化合物：HMG-CoA还原酶抑制剂、烟酸及其衍生物、贝特类药物、具有降脂作用的各类天然产物及其衍生物。
本发明的另一个方面为本发明式I所示的化合物或其药学上可接受的盐、前药、溶剂化物或本发明药物组合物在制备药物中的用途，所述药物用于为需要的受试者治疗血脂异常以及相关疾病。
本发明中，所述血脂异常以及相关疾病尤其包括高脂血症、动脉粥样硬化、高胆固醇血症、高脂蛋白血症以及高甘油三酯血症等。
本发明还提供使用本发明的化合物或药物组合物的用途和方法。例如，本发明的一个实施方式为用于治疗有需要治疗的受试者的血脂异常以及相关疾病的用途和方法，包括给予所述受试者治疗有效量的任何的本发明化合物或药用组合物。
合成方法
本发明提供按照传统有机合成方法、以及矩阵合成方法或组合合成方法制备已公开的化合物的方法。下列方案描述了所提出的合成路线。使用这些方案、下述指导原则和实施例，本领域技术人员可开发出类似或相近的用于制备本发明范围内的化合物的方法。
本领域技术人员应理解本发明化合物的合成可通过购买描述于本文所公开的任何方案中的中间体或经保护的中间体化合物而加快进度。本领域技术人员还应理解在任何本发明化合物的制备过程中，需要和/或期望保护任何所关心的分子上的敏感性或反应性基团。这可通过常规保护基团的手段达成，所述保护基团为诸如那些描述于“ProtectiveGroups in Organic Synthesis”，JohnWiley&Sons出版社，1999。这些保护基团可使用本领域的已知方法在合适的阶段移除。
本发明所述式I所示的化合物可通过以下方法制备：
式a所示的化合物与卤代试剂反应得到式b所示的化合物，然后在碱存在下与式c所示的化合物反应生成式I所示的化合物；
其中，X选自氯或溴；R1-R4、L如本文所述。
可选的，R4为C1-C6烷基的式I所示的化合物也可由R1为H的式I所示的化合物经酯化反应得到。
优选的，所述卤代试剂包括氯化亚砜、三氯化磷、五氯化磷、NBS、Br2等。
优选的，所述碱可为氢氧化物，例如氢氧化钠、氢氧化钾；碳酸盐，例如碳酸钠、碳酸钾、碳酸铯；碳酸氢盐，例如碳酸氢钠、碳酸氢钾。碱优选为碳酸盐，更优选为碳酸铯。
有益效果
本发明提供了一种用于治疗血脂异常的药物，其由羟基酪醇类多酚化合物进行结构修饰得到，具有很强的降低血清中TC、TG、LDL-C以及升高血清HDL-C的作用，并可预防肝损伤和氧化应激损伤，与阳性药物非诺贝特相比，效果相当或者甚至更好。因此，本发明化合物是一种有效的治疗血脂异常的药物。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
下面实施例中的实验方法，如无特殊说明，均为常规方法。实施例中未注明具体技术或条件者，按照本领域内的文献所描述的技术或条件，或者按照产品说明书进行。
实施例1：化合物1的合成
在氩气氛围下，将5mmol的化合物a-1溶于无水CH2Cl2中，搅拌下缓慢滴加0.5mL的氯化亚砜(6.67mmol)，30℃下反应10h，减压蒸除溶剂和未反应的氯化亚砜，真空干燥过夜得到中间体b-1。将其溶于20ml的DMF中，加入15mmol的碳酸铯和7.5mmol的化合物c-1，搅拌下于85℃中加热反应。反应结束后冷却至室温，抽滤除去碳酸铯，滤饼用少量乙酸乙酯淋洗，合并滤液后再加入40ml的乙酸乙酯，用2N盐酸洗涤2次，有机相用无水硫酸镁干燥，减压蒸除溶剂；将残余物重新溶解于30ml的甲醇中，用盐酸调节体系pH＝3，用乙酸乙酯萃取3次，合并有机相后用无水硫酸镁干燥，减压蒸除溶剂，得到浅黄色油状物，用200-300目硅胶对其进行柱层析分离，洗脱体系为石油醚：乙酸乙酯＝4：1，得到白色固体的化合物1，收率75.3％。
HRESI-MS：354.1328[M+Na]+(理论值354.1317)
元素分析：C18H21NO5；理论值C,65.24；H,6.39；N,4.23；O,24.14；实测值C,65.28；H,6.40；N,4.27；O,24.05
1H NMR(400MHz,CDCl3)δ10.03(s,1H),6.87(d,J＝8.0Hz,2H),6.72(d,J＝8.9Hz,1H),6.62–6.54(m,4H),6.53(s,1H),6.24(s,1H),5.83(br,1H),3.56(q,J＝5.0Hz,2H),2.82(t,J＝5.0Hz,2H),1.54(s,6H)。
实施例2：化合物2的合成
按照实施例1相同的方法进行，区别在于将化合物a-1替换为等量的化合物a-2，得到白色固体的化合物2，收率72.1％。
HRESI-MS：370.1260[M+Na]+(理论值370.1267)
元素分析：C18H21NO6；理论值C,62.24；H,6.09；N,4.03；O,27.63；实测值C,62.25；H,6.12；N,4.05；O,27.59
1H NMR(400MHz,CDCl3)δ10.03(s,1H),7.05(s,2H),6.87(d,J＝8.0Hz,2H),6.59(d,J＝8.0Hz,2H),6.55(s,1H),6.25(s,2H),5.83(br,1H),3.58(q,J＝5.0Hz,2H),2.77(t,J＝5.0Hz,2H),1.54(s,6H)。
实施例3：化合物3的合成
氮气保护下，将化合物1(2mmol)以及DMAP(0.4mmol)溶于10ml的CH2Cl2中，再加入4ml化合物d-3的异丁醇，冰浴下搅拌至温度恒定，将EDCl(3.0mmol)加入到上述混合物中，保持在0℃下反应1.5h，随后升至室温反应过夜；加入10ml水以淬灭反应，减压蒸除低沸点溶剂后用CH2Cl2萃取3次，合并有机相，用饱和氯化钠溶液洗涤、无水硫酸镁干燥，减压蒸除溶剂，残余物用乙醇重结晶，得到灰白色固体的化合物3，收率91.2％。
HRESI-MS：410.1932[M+Na]+(理论值410.1943)
元素分析：C22H29NO5；理论值C,68.20；H,7.54；N,3.61；O,20.65；实测值C,68.23；H,7.52；N,3.55；O,20.69
1H NMR(400MHz,CDCl3)δ6.87(d,J＝8.0Hz,2H),6.72(d,J＝8.9Hz,1H),6.62–6.54(m,4H),6.53(s,1H),6.24(s,1H),5.83(br,1H),3.90(d,J＝11.0,2H),3.56(q,J＝5.0Hz,2H),2.82(t,J＝5.1Hz,2H),1.96(m,1H),1.54(s,6H),0.95(d,J＝7.4Hz,6H)。
实施例4：化合物4的合成
按照实施例3相同的方法进行，区别在于将化合物1替换为等量的化合物2，得到白色固体的化合物4，收率88.4％。
HRESI-MS：426.1877[M+Na]+(理论值426.1893)
元素分析：C22H29NO6；理论值C,65.49；H,7.25；N,3.47；O,23.79；实测值C,65.53；H,7.25；N,3.49；O,23.71
1H NMR(400MHz,CDCl3)δ7.05(s,2H),6.87(d,J＝8.0Hz,2H),6.59(d,J＝8.0Hz,2H),6.55(s,1H),6.25(s,2H),5.83(br,1H),3.90(d,J＝11.0,2H),3.58(q,J＝5.0Hz,2H),2.77(t,J＝5.1Hz,2H),1.96(m,1H),1.54(s,6H),0.95(d,J＝7.4Hz,6H)。
药效试验例：
随机选取70只雄性昆明种小鼠(20±2g)，按20mL/kg每天灌胃给予高脂乳剂(由猪油15g、胆固醇6g、胆酸钠2g、丙硫氧嘧啶0.2g、4mL吐温-80，加蒸馏水定容至100mL，制成脂乳剂)。造模第21d，随机抽取7只小鼠，取血，检测血清TG、TC、LDL-C含量，三者均显著升高视为造模成功。取造模成功后的60只小鼠随机分为模型组、阳性对照组、给药组(化合物1-4组)，每组10只。另设置10只未进行造模处理的小鼠作为空白组，每天灌胃等量生理盐水。
分组后，模型组与阳性对照组、各给药组每天上午继续给予高脂乳剂，阳性对照组和各给药组每天下午灌胃给药，阳性对照组给予非诺贝特20mg/kg，各给药组给予相应药物20mg/kg；模型组每天下午每天灌胃等量生理盐水；空白组每天上午、下午各灌胃生理盐水一次。每组均连续干预21d。小鼠禁食不禁水12h，测量空腹体质量，末次给药2h后，用戊巴比妥钠腹腔注射进行麻醉，眼底静脉丛取血，3000r/min离心10min，分离血清备用。应用全自动生化仪检测血清TG、TC、HDL-C、LDL-C、AST和ALT，按照试剂盒说明书操作。采血后，处死各组小鼠，分离其肝脏，取肝组织于液氮中冻存。取冻存的肝组织适量，按照试剂盒说明书方法操作，用酶标仪测定各组小鼠肝组织中SOD、MDA的含量。其中，各试剂盒为：TG测定试剂盒[单试剂甘油磷酸氧化酶(GPO)-过氧化物酶(PAP)法]、TC测定试剂盒(单试剂GPO-PAP法)、HDL-C测定试剂盒(双试剂直接法)、LDL-C测定试剂盒(双试剂直接法)、天冬氨酸转氨酶(AST)测试盒(微板法)、丙氨酸转氨酶(ALT)测试盒(赖氏法)、超氧化物歧化酶(SOD)测定试剂盒[水溶性四氮唑-1(WST-1)法]、丙二醛(MDA)测定试剂盒[硫代巴比妥酸(TBA法)]，中生北控生物科技股份有限公司。
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采用SPSS 22.0软件进行统计分析。计量资料以“χ±s”表示，两组间比较采用t检验，多组间比较采用单因素方差分析。以P＜0.05为差异有统计学意义。
结果：
1.与空白组比较，各组小鼠6周后的体重均有升高趋势，模型组小鼠给药6周后的体重显著升高(P＜0.01)。与模型组比较，阳性对照组和各给药组小鼠的体重均显著降低(P＜0.05或P＜0.01)。
与空白组比较，模型组小鼠血清中TC、TG、LDL-C含量均显著升高(P＜0.01)，HDL-C含量显著降低(P＜0.01)，表现出典型的高脂血症症状。与模型组比较，阳性对照组和各给药组小鼠血清中TC、TG、LDL-C含量均显著降低(P＜0.01)，HDL-C含量均显著升高(P＜0.01)，提示本发明化合物具有较佳的降血脂能力，能预防和治疗高脂血症；同时，与阳性对照组相比，本发明化合物1和2甚至具有更佳的降低TG、TC和LDL-C的效果(P＜0.05)。具体结果见表1。
表1：
注：与空白组比较**P<0.01；与模型组比较#P<0.05，##P<0.01；与阳性对照组比较，&P<0.05
2.与空白组比较，模型组小鼠血清中AST、ALT含量均显著升高(P＜0.01)，说明高脂血症模型小鼠存在一定程度的肝损伤。与模型组比较，阳性对照组和各给药组小鼠血清中AST、ALT含量均显著降低(P＜0.01)，表明本发明化合物可预防高脂血症模型小鼠的肝损伤。具体结果见表2。
表2：
注：与空白组比较**P<0.01；与模型组比较##P<0.01；与阳性对照组比较，&P<0.05
3.与空白组比较，模型组小鼠肝组织中MDA含量显著升高(P＜0.01)，SOD含量显著降低(P＜0.05)，表明高脂血症模型小鼠存在一定程度的氧化应激损伤。与模型组比较，阳性对照组和各给药组小鼠肝组织中MDA含量均显著降低(P＜0.01)，SOD含量均显著升高(P＜0.05或P＜0.01)，表明本发明化合物可预防高脂血症模型小鼠的氧化应激损伤。具体结果见表3。
表3：
注：与空白组比较**P<0.01；与模型组比较#P<0.05，##P<0.01
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (7)
1.一种式I所示的化合物或其药学上可接受的盐：
其中，R1选自H、羟基；
R2、R3各自独立地选自H；
L选自-CH2CH2-；
R4选自H、C1-C4的烷基。
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，R4选自H、甲基、乙基、正丙基、异丙基、异丁基、仲丁基。
3.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，式I化合物选自：
4.一种药物组合物，其包含根据权利要求1-3任一项所述的式I所示的化合物或其药学上可接受的盐中的一种或多种。
5.根据权利要求1-3任一项所述的式I所示的化合物或其药学上可接受的盐或根据权利要求4所述的药物组合物在制备药物中的用途，所述药物用于为需要的受试者治疗血脂异常以及相关疾病，所述血脂异常以及相关疾病包括高脂血症、动脉粥样硬化。
6.根据权利要求1-3任一项所述的式I所示的化合物或其药学上可接受的盐或根据权利要求4所述的药物组合物在制备药物中的用途，所述药物用于为需要的受试者治疗血脂异常以及相关疾病，所述血脂异常以及相关疾病包括高胆固醇血症、高脂蛋白血症以及高甘油三酯血症。
7.权利要求1中所述的式I所示的化合物的制备方法，包括：
式a所示的化合物与卤代试剂反应得到式b所示的化合物，然后在碱存在下与式c所示的化合物反应生成式I所示的化合物；
其中，X选自氯或溴；R1-R4、L如权利要求1中所述。
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| US8034966B1 (en) * | 2008-02-20 | 2011-10-11 | Cell Viable Corporation | Phenoxyisobutyric acid compounds and methods for synthesis |
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