CN108558847A - 一种酯类衍生物及其在防治心脑血管疾病中的应用 - Google Patents
一种酯类衍生物及其在防治心脑血管疾病中的应用 Download PDFInfo
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- CN108558847A CN108558847A CN201810551984.0A CN201810551984A CN108558847A CN 108558847 A CN108558847 A CN 108558847A CN 201810551984 A CN201810551984 A CN 201810551984A CN 108558847 A CN108558847 A CN 108558847A
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- 239000002245 particle Substances 0.000 description 1
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- 239000002953 phosphate buffered saline Substances 0.000 description 1
- 229940075930 picrate Drugs 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-M picrate anion Chemical compound [O-]C1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-M 0.000 description 1
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- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 235000011056 potassium acetate Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
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- 238000005956 quaternization reaction Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
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- 229910002027 silica gel Inorganic materials 0.000 description 1
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 235000003702 sterols Nutrition 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 1
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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Abstract
本发明公开了一种酯类衍生物及其在防治心脑血管疾病中的应用，其中：R1、R2、R3各自独立的选自H、F或CH3。体外LCAT激活实验说明本发明化合物具有LCAT激活作用，体内药效实验说明本发明化合物能够提高HDL水平，推断本发明化合物可以用于预防或治疗脑血管疾病、冠心病、动脉硬化、动脉硬化性心脏病、周围性血管疾病、血脂障碍、低HDL胆固醇血症、高LDL胆固醇血症等。
Description
技术领域
本发明属于化学医药领域，涉及一种酯类衍生物及其在防治心脑血管疾病中的应用。
背景技术
心脑血管疾病(cardiovascular and cerebrovascular diseases，CCVd)是心脏血管和脑血管疾病的统称，泛指由于高脂血症、血液黏稠、动脉粥样硬化、高血压等所导致的心脏、大脑及全身组织发生的缺血性或出血性疾病。流行病学研究表明冠心病(CoronaryHeart Disease，CHD)的发病率呈逐渐升高趋势，严重影响人群健康，已成为威胁人类健康的一大杀手，越来越多的人因CHD而致残致死。
卵磷脂胆固醇脂酰基转移酶(lecithin-cholesterolacyltransferase，LCAT)由肝合成释放入血液，以游离或与脂蛋白结合的形式存在，是一种在血浆中起催化作用的酶，其作用是将HDL的卵磷脂的C2位不饱和脂肪酸转移给游离胆固醇，生成溶血卵磷脂和胆固醇酯。血浆胆固醇几乎70％-80％是胆固醇酯，均是LCAT催化生成所致。LCAT常与HDL结合在一起，在HDL颗粒表面活性很高并起催化作用，对VLDL和LDL的颗粒几乎不起作用。LCAT在人类血浆胆固醇代谢及HDL代谢中扮演着重要角色，对于心脏血管和脑血管疾病防治具有重要意义。
发明内容
本发明公开了一种酯类衍生物式Ⅰ，其结构为：
其中：R1、R2、R3各自独立的选自H、F或CH3。本发明还涉及所述酯类衍生物式Ⅰ的药学上可接受的盐或溶剂化物。
进一步地，一些优选的方案中所述酯类衍生物式Ⅰ为
本发明的另一目的公开了所述的酯类衍生物式Ⅰ的合成路线为：
具体合成方法为：
1)化合物1与环戊酮在强碱性条件下发生反应生成4-(环戊-1-烯-1-基)-1H-吡咯-2-甲酸(化合物2)；
2)化合物2在Pd(OH)2/C作为催化剂、1:1的THF-MeOH作为溶剂的作用下发生氢化反应，生成4-环戊基-1H-吡咯-2-甲酸(化合物3)；
3)化合物3中的羧基在亚硫酰氯、乙醇的作用下发生酯化反应，生成4-环戊基-1H-吡咯-2-甲酸-(4-甲基环己基)酯(化合物4)；
4)化合物4在溴化试剂的作用下发生取代反应生成5-溴-4-环戊基-1H-吡咯-2-甲酸-(4-甲基环己基)酯(化合物5)；
5)在碱性条件下，化合物5与相对应的硼酸发生反应，生成最终产物。
进一步地，所述步骤1)中的强碱可以是碱金属氢氧化物、碱金属醇盐或者碱金属在溶剂中的氢化物，优选碱金属醇盐，最优选甲醇钠。
进一步地，所述步骤4)中合适的溴化试剂包括元素溴，N-溴代琥珀酰亚胺，三溴化吡啶，二溴乙内酰脲和相应的碘代衍生物，优选三溴化吡啶。
进一步地，所述步骤5)中的碱可以是碳酸钠，碳酸钾或者醋酸钾等，优选碳酸钠。
本发明的另一目的公开了所述酯类衍生物式Ⅰ作为卵磷脂胆固醇脂酰基转移酶激活剂的应用。
本发明的另一目的公开了所述酯类衍生物式Ⅰ在制备心脑血管疾病的药物中的应用。
进一步地，所述酯类衍生物式Ⅰ用于预防或治疗脑血管疾病(包括中风和脑梗塞)、冠心病(包括心力衰竭、心肌梗塞、心绞痛、心肌缺血、心血管障碍和血管生成性再狭窄)、动脉硬化、动脉硬化性心脏病、周围性血管疾病(包括糖尿病血管并发症)、血脂障碍、低HDL胆固醇血症、高LDL胆固醇血症等。
本发明所述的药学上可接受的盐是指本发明化合物的有机盐和无机盐。药学上可接受的无毒的酸形成的盐包括，但并不限于，无机酸盐，如盐酸盐，氢溴酸盐，磷酸盐，硫酸盐，高氯酸盐；有机酸盐，如乙酸盐，草酸盐，马来酸盐，酒石酸盐，柠檬酸盐，琥珀酸盐，丙二酸盐；或通过书籍文献上所记载的其他方法如离子交换法来得到这些盐。其他药学上可接受的盐包括，己二酸盐，藻酸盐，抗坏血酸盐，天冬氨酸盐，苯磺酸盐，苯甲酸盐，重硫酸盐，硼酸盐，丁酸盐，樟脑酸盐，樟脑磺酸盐，环戊基丙酸盐，二葡萄糖酸盐，十二烷基硫酸盐，乙磺酸盐，甲酸盐，反丁烯二酸盐，葡庚糖酸盐，甘油磷酸盐，葡萄糖酸盐，半硫酸盐，庚酸盐，己酸盐，氢碘酸盐，2-羟基-乙磺酸盐，乳糖醛酸盐，乳酸盐，月桂酸盐，月桂基硫酸盐，苹果酸盐，甲磺酸盐，2-萘磺酸盐，烟酸盐，硝酸盐，油酸盐，棕榈酸盐，扑酸盐，果胶酸盐，过硫酸盐，3-苯基丙酸盐，苦味酸盐，特戊酸盐，丙酸盐，硬脂酸盐，硫氰酸盐，对甲苯磺酸盐，十一酸盐，戊酸盐，等等。通过与适当的碱反应得到的盐包括碱金属，碱土金属，铵和N+(C1-4烷基)4的盐。水溶性或油溶性或分散产物可以通过季铵化作用得到。可以形成盐的碱金属或碱土金属包括钠，锂，钾，钙，镁，等等。药学上可接受的盐进一步包括适当的、无毒的铵，季铵盐和抗平衡离子形成的胺阳离子，如卤化物，氢氧化物，羧化物，硫酸化物，磷酸化物，硝酸化物，C1-8磺酸化物和芳香磺酸化物。
本发明所述的溶剂化物是指一个或多个溶剂分子与本发明的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，乙酸和氨基乙醇。
具体的实施方案
实施例1：4-环戊基-5-(4-氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
1-1、4-(环戊-1-烯-1-基)-1H-吡咯-2-甲酸的合成
在250mL的圆底烧瓶中配备回流冷凝器和机械搅拌器，并且整个系统用氮气净化。将1H-吡咯-2-羧酸(1.21g，10.86mmol)加入到烧瓶中，然后加入MeOH(15.5mL)。在室温下搅拌10分钟后，加入环戊酮(2.88mL，32.58mmol)。在10分钟内分批加入甲醇/甲醇钠(25％w/w，15.15mL，66.25mmol)。然后将该混合物回流24小时。冷却至室温后，加入水(23.31mL)并减压除去甲醇。用浓HCl(约7mL)将残留的水相酸化至pH＝1。过滤收集得到的淡黄色沉淀物，用水洗涤并在50℃下真空干燥。得到所需的米色固体4-(环戊-1-烯-1-基)-1H-吡咯-2-羧酸(化合物2)，1.91g，产率99％。1H-NMR(400MHz,CDCl3)δ:1.82(m,2H),2.31(m,2H),2.53(t,2H),5.75(t,1H),7.02(s,1H),7.05(s,1H),9.03(s,1H).13C-NMR(125MHz,CDCl3)δ:28.64,31.87,32.20,114.52,116.02,123.12,124.28,128.48,141.40,160.97.LC-MS(ESI,pos,ion)m/z:178[M+H].
1-2、4-环戊基-1H-吡咯-2-甲酸的合成
将上述得到的不饱和化合物2(1.91g，10.75mmol)置于50psi氢气压力下进行氢化20个小时，使用20％Pd(OH)2/C作为催化剂、1:1的THF-MeOH作为溶剂。过滤催化剂后，减压除去挥发物，剩余物用己烷打浆。过滤收集米色固体，用己烷洗涤并真空干燥，得到4-环戊基-1H-吡咯-2-羧酸(化合物3)，1.50g，产率78％。1H-NMR(400MHz,CDCl3)δ:1.66(m,4H),1.76(m,2H),1.92(m,2H),3.11(m,1H),7.05(s,1H),7.18(s,1H),8.87(s,1H).13C-NMR(125MHz,CDCl3)δ:26.10,34.25,36.55,117.72,118.97,126.68,128.71,160.97.LC-MS(ESI,pos,ion)m/z:180[M+H].
1-3、4-环戊基-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
在100mL的三颈烧瓶中配备回流冷凝器和机械搅拌器，并且整个系统用氮气净化。将化合物3(1.50g，8.37mmol)加入烧瓶中并悬浮于乙醇(13.58mL)中。逐滴加入亚硫酰氯(1mL，0.42mmol)并将混合物回流24小时。减压除去挥发物，剩余物用己烷打浆，用己烷洗涤并真空干燥后得到黄色固体4-环戊基-1H-吡咯-2-甲酸-(4-甲基环己基)酯(化合物4)，1.89g，产率82％。1H-NMR(400MHz,CDCl3)δ:0.88-0.96(m,5H),1.20-1.33(m,3H),1.66-1.94(m,12H),3.07(m,1H),4.51(m,1H),6.89(s,1H),7.10(s,1H),8.82(s,1H).13C-NMR(125MHz,CDCl3)δ:21.89,26.1,29.2,32.28,32.54,34.25,36.55,74.54,114.65,118.97,125.43,128.71,162.47.LC-MS(ESI,pos,ion)m/z:276[M+H].
1-4、5-溴-4-环戊基-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
将化合物4(1.89g，6.87mmol)溶于THF(40mL)和CHCl3(40mL)的混合溶剂中，然后将溶液在冰浴中冷却并加入三溴化吡啶(2.95g，9.23mmol)。在0℃下搅拌1小时后，通过TLC判断反应完成。用CHCl3(100mL)稀释，依次用1mol/L的NaHSO3(2*25mL)，饱和NaHCO3(2*25mL)水溶液和盐水(25mL)洗涤。用Na2SO4干燥后，减压除去溶剂，剩余物从TBME-己烷中结晶。过滤收集后，用己烷洗涤并干燥后，得1.58g红色的5-溴-4-环戊基-1H-吡咯-2-甲酸-(4-甲基环己基)酯固体(化合物5)。蒸发母液后可以得到红色的固体，将其通过快速色谱法纯化(使用15％EtOAc的己烷溶液作为洗脱剂)，得到另外的0.56g化合物5，总产量为2.14g，产率88％。1H-NMR(400MHz,CDCl3)δ:0.86-0.94(m,5H),1.23-1.35(m,3H),1.66-1.94(m,12H),3.04(m,1H),4.52(m,1H),6.73(s,1H),8.63(s,1H).13C-NMR(125MHz,CDCl3)δ:21.89,26.1,29.2,32.28,32.54,34.69,40.95,74.54,109.52,118.92,126.49,132.33,162.62.LC-MS(ESI,pos,ion)m/z:354[M+H].
1-5、4-环戊基-5-(4-氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
将(4-氟噻吩-2-基)硼酸(6.26mmol)，化合物5(2.14g，6.05mmol)，Na2CO3(2.00g，18.78mmol)，DME(10.14mL)和H2O(2.50mL)加入到50mL微波小瓶中。小瓶用N2脱气35分钟，然后加入PdCl2(dppf)CH2Cl2(0.55g，0.75mmol)加合物。通过微波照射将反应混合物在120℃加热1小时。得到的混合物用乙酸乙酯稀释并通过硅藻土过滤，然后真空浓缩。通过快速色谱法纯化，用0-100％乙酸乙酯/庚烷作为洗脱剂，得到类白色固体4-环戊基-5-(4-氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯，1.79g，产率79％。1H-NMR(400MHz,CDCl3)δ:0.88-0.96(m,5H),1.20-1.32(m,3H),1.66-1.94(m,12H),349(m,1H),4.52(m,1H),6.57(s,1H),7.09(d,1H),7.48(dd,1H),9.51(s,1H).13C-NMR(125MHz,CDCl3)δ:21.89,26.1,29.2,32.28,32.54,34.69,40.75,74.54,113.04,118.95,120.05,125.08,127.89,128.49,138.94,161.62,162.62.LC-MS(ESI,pos,ion)m/z:376[M+H]。
实施例2：4-环戊基-5-(5-氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
将(5-氟噻吩-2-基)硼酸(6.26mmol)，化合物5(2.14g，6.05mmol)，Na2CO3(2.00g，18.78mmol)，DME(10.14mL)和H2O(2.50mL)加入到50mL微波小瓶中。小瓶用N2脱气35分钟，然后加入PdCl2(dppf)CH2Cl2(0.55g，0.75mmol)加合物。通过微波照射将反应混合物在120℃加热1小时。得到的混合物用乙酸乙酯稀释并通过硅藻土过滤，然后真空浓缩。通过快速色谱法纯化，用0-100％乙酸乙酯/庚烷作为洗脱剂，得到类白色固体4-环戊基-5-(5-氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯，1.91g，产率84％。LC-MS(ESI,pos,ion)m/z:376[M+H]。
实施例3：4-环戊基-5-(5-甲基噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
将(5-甲基噻吩-2-基)硼酸(6.26mmol)，化合物5(2.14g，6.05mmol)，Na2CO3(2.00g，18.78mmol)，DME(10.14mL)和H2O(2.50mL)加入到50mL微波小瓶中。小瓶用N2脱气35分钟，然后加入PdCl2(dppf)CH2Cl2(0.55g，0.75mmol)加合物。通过微波照射将反应混合物在120℃加热1小时。得到的混合物用乙酸乙酯稀释并通过硅藻土过滤，然后真空浓缩。通过快速色谱法纯化，用0-100％乙酸乙酯/庚烷作为洗脱剂，得到类白色固体4-环戊基-5-(5-甲基噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯，1.84g，产率82％。LC-MS(ESI,pos,ion)m/z:372[M+H]。
实施例4：4-环戊基-5-(4,5-二氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯的合成
将(4,5-二氟噻吩-2-基)硼酸(6.26mmol)，化合物5(2.14g，6.05mmol)，Na2CO3(2.00g，18.78mmol)，DME(10.14mL)和H2O(2.50mL)加入到50mL微波小瓶中。小瓶用N2脱气35分钟，然后加入PdCl2(dppf)CH2Cl2(0.55g，0.75mmol)加合物。通过微波照射将反应混合物在120℃加热1小时。得到的混合物用乙酸乙酯稀释并通过硅藻土过滤，然后真空浓缩。通过快速色谱法纯化，用0-100％乙酸乙酯/庚烷作为洗脱剂，得到类白色固体4-环戊基-5-(4,5-二氟噻吩-2-基)-1H-吡咯-2-甲酸-(4-甲基环己基)酯，2.12g，产率89％。LC-MS(ESI,pos,ion)m/z:394[M+H]。
试验例1：体外LCAT激活实验
一、实验方案
通过密度梯度离心分离从健康的人的血浆获得由HDL3组成的部分(1.125<比重<1.210/mL)。将获得的部分对磷酸盐-缓冲盐水(pH 7.4)渗析并用作LCAT的酶来源和受体。通过溶于二甲基亚砜制备各测试药物。将含有DTNB(Ellman试剂，最终浓度：0.5mM)、巯基乙醇(最终浓度：12.5mM)和0.6％牛血清白蛋白的[14C]胆固醇添加到含有1mg/mLHDL3的磷酸盐-缓冲盐水(pH 7.4)，并进一步向其添加不同浓度的测试药物以将总量调整为80μL。在37℃培养该混合物约16小时。然后，向其添加己烷和异丙醇的混合溶液(混合比＝3:2)以停止反应。搅拌之后，收集己烷层，并蒸发该层至干。向其添加氯仿溶液(浓度：10mg/mL)，并将混合物点染在薄层硅胶板上，且使用己烷、二乙醚和乙酸乙酯的混合溶液(混合比＝85:15:2)展开。使用成像分析仪BAS-2500(Fujifilm Corp.制造)，测量对应于胆固醇油酸酯的部分的放射性。类似地处理和分析未补充测试药物的样品。根据以下给出的表达式，相对于未补充测试药物的样品的LCAT活性，计算LCAT激活的EC50。
方程式：
Y＝底部+(顶部-底部)/(1+10LogEC-X)
其中X代表测试药物的浓度的对数；
Y代表测试药物的响应性(LCAT活性)；
顶部代表最大值(最大平台)；
底部代表最小值(最小平台)；
EC50代表50％有效浓度。
二、实验结果
体外LCAT激活实验结果如下表所示：
由上表可以看出，本发明化合物具有LCAT激活作用，可以作为LCAT激活剂用于预防或治疗脑血管疾病(包括中风和脑梗塞)、冠心病(包括心力衰竭、心肌梗塞、心绞痛、心肌缺血、心血管障碍和血管生成性再狭窄)、动脉硬化、动脉硬化性心脏病、周围性血管疾病(包括糖尿病血管并发症)、血脂障碍、低HDL胆固醇血症、高LDL胆固醇血症等。
试验例2：体内药效实验
一、实验方案
将各测试药物溶于丙二醇:Tween 80＝4/1(v/v)的混合溶液，并对猕猴口服给药该溶液1或7天。在给药期间的第1或第7天，在给药之前和给药之后收集血液，并获得血浆。使用市售可得的分析试剂盒(胆固醇-E Wako，Wako Pure Chemical Industries,Ltd.)测量血浆中的胆固醇含量。通过HPLC分析脂肪蛋白分布(柱：LipopropakXL，Tosoh Corp.制造)。根据以下计算表达式计算HDL胆固醇和非HDL胆固醇含量：
HDL胆固醇含量＝血浆中的胆固醇含量×(HDL胆固醇峰面积/峰总和)
非HDL胆固醇含量＝血浆中的胆固醇含量×(非HDL胆固醇的峰面积/峰总和)
二、实验结果
本发明实验结果中仅公开10mg/kg单一剂量给药前和给药后24h HDL水平的变化，用以证明本发明化合物升高猕猴血液中HDL的能力，更多实验数据不在本发明中公开。与给药之前相比，10mg/kg单一剂量给药之后HDL水平的增加率(％)由给药之前和给药后24小时的AUC确定。
由上表可以看出，本发明化合物能够提高HDL水平作用，对预防或治疗下列疾病可能具有积极作用，脑血管疾病(包括中风和脑梗塞)、冠心病(包括心力衰竭、心肌梗塞、心绞痛、心肌缺血、心血管障碍和血管生成性再狭窄)、动脉硬化、动脉硬化性心脏病、周围性血管疾病(包括糖尿病血管并发症)、血脂障碍、低HDL胆固醇血症、高LDL胆固醇血症等。
Claims (6)
1.一种通式结构为式Ⅰ的酯类衍生物及其药学上可接受的盐或溶剂化物
其中：R1、R2、R3各自独立的选自H、F或CH3。
2.如权利要求1所述的酯类衍生物式Ⅰ，其特征是，选自以下化合物：
3.如权利要求1或2所述的酯类衍生物式Ⅰ作为卵磷脂胆固醇脂酰基转移酶激活剂的应用。
4.如权利要求1或2所述的酯类衍生物式Ⅰ在制备心脑血管疾病的药物中的应用。
5.如权利要求1或2所述的酯类衍生物式Ⅰ在制备脑血管疾病、冠心病、动脉硬化、动脉硬化性心脏病、周围性血管疾病、血脂障碍、低HDL胆固醇血症、高LDL胆固醇血症的药物中的应用。
6.如权利要求5所述的应用，其特征在于，所述脑血管疾病包括中风和脑梗塞，所述冠心病包括心力衰竭、心肌梗塞、心绞痛、心肌缺血、心血管障碍和血管生成性再狭窄。
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Citations (4)
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|---|---|---|---|---|
| CN1239474A (zh) * | 1996-07-31 | 1999-12-22 | 美国拜尔公司 | 作为抗高胆固醇血、抗高脂蛋白血和抗高血糖剂的取代的吡啶和联苯 |
| CN101679365A (zh) * | 2007-06-08 | 2010-03-24 | 艾德维纳斯医疗私人有限公司 | 作为葡萄糖激酶激活剂的新型吡咯-2-甲酰胺衍生物、它们的制造方法和药学应用 |
| CN105873928A (zh) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-羟基-4-(三氟甲基)吡唑并吡啶衍生物 |
| CN106916143A (zh) * | 2017-03-14 | 2017-07-04 | 哈尔滨医科大学 | 一种预防和治疗冠心病的药物及其应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1239474A (zh) * | 1996-07-31 | 1999-12-22 | 美国拜尔公司 | 作为抗高胆固醇血、抗高脂蛋白血和抗高血糖剂的取代的吡啶和联苯 |
| CN101679365A (zh) * | 2007-06-08 | 2010-03-24 | 艾德维纳斯医疗私人有限公司 | 作为葡萄糖激酶激活剂的新型吡咯-2-甲酰胺衍生物、它们的制造方法和药学应用 |
| CN105873928A (zh) * | 2013-12-13 | 2016-08-17 | 第三共株式会社 | 5-羟基-4-(三氟甲基)吡唑并吡啶衍生物 |
| CN106916143A (zh) * | 2017-03-14 | 2017-07-04 | 哈尔滨医科大学 | 一种预防和治疗冠心病的药物及其应用 |
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