CN104892720B - 4,4-二甲基石胆酸-2,3-骈n-芳基吡唑衍生物及其制备方法和应用 - Google Patents
4,4-二甲基石胆酸-2,3-骈n-芳基吡唑衍生物及其制备方法和应用 Download PDFInfo
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- CN104892720B CN104892720B CN201410084085.6A CN201410084085A CN104892720B CN 104892720 B CN104892720 B CN 104892720B CN 201410084085 A CN201410084085 A CN 201410084085A CN 104892720 B CN104892720 B CN 104892720B
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- lithocholic acid
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Abstract
本发明属于医药技术领域,具体公开了一种4,4‑二甲基石胆酸‑2,3‑骈N‑芳基吡唑衍生物,其结构如式(I)所示。本发明还公开了4,4‑二甲基石胆酸‑2,3‑骈N‑芳基吡唑衍生物的制备方法,包括方法一:以化合物II为原料,在氮气保护下,以乙醇为溶剂,与化合物a经环化反应得到化合物III,其在氢氧化锂存在下经水解反应制备得到化合物Ia;或方法二:以相同方法得到化合物III,在丙酮溶剂中,冰醋酸、N‑羟基邻苯二甲酰亚胺存在条件下,利用重铬酸钠经氧化得到化合物IV;其经硼氢化钠还原得到化合物V,再在氢氧化锂存在下经水解反应制备得到化合物Ib。本发明4,4‑二甲基石胆酸‑2,3‑骈N‑芳基吡唑衍生物对PTPlB酶具有较好的抑制活性,适用于制备糖尿病和肥胖症等疾病的治疗药物。
Description
技术领域
本发明属于医药技术领域,具体涉及一种4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物及其制备方法和应用、以及其作为蛋白酪氨酸磷酸酯酶1B(简称PTPlB)抑制剂用于制备治疗糖尿病和肥胖症药物中的应用。
背景技术
糖尿病和肥胖症是严重危害人们身体健康的内分泌紊乱性代谢类疾病,常伴随着胰岛素敏感组织中的胰岛素敏感性降低即胰岛素抵抗,从而引起肌肉、肝脏、脂肪组织中的糖脂代谢平衡失调。人体内无法产生胰岛素被称为I型糖尿病,体内可以产生胰岛素但无法有效利用被称为II型糖尿病,又称胰岛素抵抗。
近年来对II型糖尿病发病机理的研究发现了很多新的药物靶点,其中蛋白酪氨酸磷酸酯酶1B(简称PTPlB)在人体糖代谢中有非常重要的作用。PTPlB是PTPs酶家族中的一种,人类PTP家族非常庞大,有100多位成员,在信号转导途径及人类健康和疾病的发生、发展中起着关键作用。胰岛素信号通路中一个重要的调控机制是对胰岛素受体、胰岛素受体底物以及其它下游分子的蛋白质酪氨酸磷酸化进行可逆调节。蛋白酪氨酸磷酸化是一种重要的调节信号转导的翻译后修饰方式,在体内酪氨酸的磷酸化是可逆的动态过程,其磷酸化和去磷酸化分别由蛋白酪氨酸激酶(protein tyrosine kinases,PTKs)和蛋白酪氨酸磷酸酯酶(protein tyrosine phosphatases,PTPs)来调节。PTPlB可对胰岛素受体以及信号通路中下游分子进行脱磷酸化作用,这被认为是调节胰岛素受体活性的一个重要调控者(Jacqueline Montalibet et al.DrugDiscovery Today,2005,2,129)。PTPlB还可使瘦素受体相关激酶JAK2去磷酸化而失活,无法对瘦素产生应答,从而引起瘦素抵抗(Elchebly,M.et al.Science,1999,283,1544)。
动物试验表明,PTPlB缺失的老鼠由于增加或延长了在肌肉与肝脏组织中胰岛素受体的磷酸化水平,而使其对胰岛素的敏感性增强,明显降低体内甘油三酯的水平;同时相关的研究表明PTPlB缺失的老鼠由于对瘦素敏感性的增强,能量消耗增加,所以对高脂食物引起的肥胖有着良好的抵抗作用(Klaman,L.D.Et al.Mol.Cell.Biol.2000,20,5479)。因此,PTPlB是治疗糖尿病和肥胖症的潜在靶点。
目前研究发现的小分子PTPlB抑制剂大多数为酪氨酸磷酸酯类似物,如二氟亚甲基磷酸盐,N-草酰胺苯甲酸,取代苯乙酮,水杨酸,取代丙二酸酪氨酸,氨基磺酸,这些化合物是 竞争性的抑制剂,且电荷密度高,因此脂溶性、透膜性较差,生物利用度低,对PTP家族其他同源性酶选择性不好。
石胆酸是人体肠内经细菌代谢产生的甾体化合物,基于石胆酸进行结构改造得到的衍生物表现了较好的PTPlB抑制活性(IC50=1.62μM)(Hai-Bing He et al.BioorganicδMedicinal Chemistry Letters,2012,22,7237)。本发明对现有PTPlB抑制剂进行改进,提出一种结构新颖、PTPlB抑制活性显著提高的新抑制剂。
发明内容
本发明的目的是提供一种新的4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物及其制备方法。
本发明4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物,其结构如以下式(I)所示:
其中,R1为4-甲氧基,4-氯,4-甲基,4-溴,4-氟,3-甲基,2-甲基,3-氯,2-氯,2,4-二甲基,3,4-二甲基,3,4-二氯或2,4-二氯;R2为氢或羟基取代。
本发明的另一个目的在于提供4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物的制备方法,包括以下:
方法一:
以化合物II为原料,在氮气保护条件下,以乙醇为溶剂,与化合物a经环化反应得到化合物III;所述化合物III在氢氧化锂存在下经水解反应制备得到化合物Ia;
或者
方法二:
以化合物II为原料,在氮气保护条件下,以乙醇为溶剂,与化合物a经环化反应得到化合物III;所述化合物III在丙酮溶剂中,冰醋酸、N-羟基邻苯二甲酰亚胺存在条件下,利用重铬酸钠经氧化得到化合物IV;所述化合物IV经硼氢化钠还原得到化合物V,再在氢氧化锂存在下经水解反应制备得到化合物Ib。
所述方法如以下反应式(A)所示:
式中R1为:4-甲氧基,4-氯,4-甲基,4-溴,4-氟,3-甲基,2-甲基,3-氯,2-氯,2,4-二甲基,3,4-二甲基,3,4-二氯或2,4-二氯。
本发明中,化合物a包括4-甲氧基苯肼盐酸盐、4-氯苯肼盐酸盐、4-甲基苯肼盐酸盐、4-溴苯肼盐酸盐、4-氟苯肼盐酸盐、3-甲基苯肼盐酸盐、2-甲基苯肼盐酸盐、3-氯苯肼盐酸盐、2-氯苯肼盐酸盐、2,4-二甲基苯肼盐酸盐、3,4-二甲基苯肼盐酸盐、3,4-二氯苯肼盐酸盐、2,4-二氯苯肼盐酸盐。
根据上述反应式,以化合物II为原料,在氮气保护条件下,以乙醇为溶剂,与化合物a环化反应,反应时间为2~5小时,反应温度为50℃~75℃,产物经硅胶柱层析纯化,得到化合物III,产率50%~80%。III在氢氧化锂存在下进行水解,反应时间24~36小时,溶剂为甲醇,得到化合物Ia,收率80%~95%;化合物III在丙酮溶剂中,冰醋酸、N-羟基邻苯二甲酰亚胺(NHPI)存在条件下,利用重铬酸钠进行氧化,反应温度为40℃~50℃,反应36~48小时,产物经硅胶柱层析纯化,得到化合物IV,产率45%~55%。化合物IV经硼氢化钠还原得到化合物V,溶剂为甲醇,反应时间4小时,化合物V经水解反应得到化合物Ib,溶剂为甲醇,所用碱为氢氧化锂,还原水解两步反应收率60%~70%。
本发明的另一目的在于提供本发明4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物在制备治 疗糖尿病和肥胖症药物方面的应用。通过对PTPlB酶抑制活性的筛选,发现上述方法得到的本发明4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物对PTPlB酶具有较好的抑制活性,其中化合物MSW-159的IC50达到0.42μM,明显优于阳性对照化合物齐墩果酸(IC50=2.8μM)。
本发明的优点是通过在石胆酸A环骈N-芳基吡唑,在结构上拉长了化合物分子,可能是改善了与PTPlB酶的结合而显著提高了该类化合物对PTPlB酶的抑制活性,为进一步的治疗糖尿病和肥胖症的药物研发奠定了基础。与现有化合物相比较,本发明的4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物对PTPlB酶的抑制活性提高达四倍。
具体实施方式
结合以下具体实施例,对本发明作进一步的详细说明,本发明的保护内容不局限于以下实施例。在不背离发明构思的精神和范围下,本领域技术人员能够想到的变化和优点都被包括在本发明中,并且以所附的权利要求书为保护范围。实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。
实施例1制备本发明化合物Ia-1(R1=4-CH3O,R2=H)
化合物II(0.50g,1.1mmol)溶解于20ml乙醇中,加入1g的4-甲氧基苯肼盐酸盐,氮气保护下加热至70℃,反应2小时后冷却至室温,反应液浓缩,加入30ml的水,乙酸乙酯萃取(30ml×3),收集有机相,10ml水洗涤,饱和食盐水10ml洗涤,无水硫酸钠干燥,减压蒸馏浓缩有机溶剂后硅胶柱色谱(石油醚:乙酸乙酯=10:1)分离纯化,得0.35g化合物III(Ri=4-CH3O,R2=H)。
0.35g化合物III(Ri=4-CH3O,R2=H)溶解于10ml甲醇中,加入1ml水,0.3g一水合氢氧化锂,室温反应36小时,向反应液中滴加1M的盐酸调至pH=5,减压蒸馏浓缩反应液,加入10ml水,乙酸乙酯萃取(10ml×3),收集有机相,10ml饱和食盐水洗涤,无水硫酸钠干燥,有机溶剂浓缩后硅胶柱色谱分离(二氯甲烷:甲醇=40:1),得0.30g化合物Ia-1,产率60%; 1H-NMR(CDCl3/MeOD,400MHz):δ=7.32(s,1H),7.30(d,2H),7.00(d,2H),5.73(dd,1H),3.87(s,3H),2.79(d,1H),2.35~0.63(m,35H),其中1.3l(s,3H),1.17(s,3H),0.98(d,3H),0.95(s,3H),0.75(s,3H);HRMS(ESI):Calcd for C34H47N2O3[M+H]+,531.3581;Found:[M+H]+=531.3548,[M+Na]+=553.3342.
实施例2制备本发明化合物Ia-2(R1=4-C1,R2=H)MSW-134的制备
制备方法类似于实施例1,不同之处是以4-氯苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.28g化合物Ia-2,产率56%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.39(d,2H),7.28(m, 3H),5.63(dd,1H),2.69(d,1H),2.34~0.64(m,35H),其中1.22(s,3H),1.09(s,3H),0.88(d,3H),0.86(s,3H),0.64(s,3H);HRMS(ESI):Calcd for C33H44ClN2O2[M+H]+,535.3086;Found:[M+H]+=535.3133,[M+Na]+=557.2945.
实施例3制备本发明化合物Ia-3(R1=4-CH3,R2=H)MSW-142的制备
制备方法类似于实施例1,不同之处是以4-甲基苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.38g化合物Ia-3,产率76%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.18(m,5H),5.62(dd,1H),2.69(d,1H),2.36(s,3H),2.35~0.64(m,35H),其中1.22(s,3H),1.07(s,3H),0.87(d,3H),0.86(s,3H),0.64(s,3H);HRMS(ESI):Calcd for C34H47N2O2[M+H]+,515.3632;Found:[M+H]+=515.3683.
实施例4制备本发明化合物Ia-4(R1=4-Br,R2=H)MSW-157的制备
制备方法类似于实施例1,不同之处是以4-溴苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.41g化合物Ia-4,产率82%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.63(d,2H),7.57(s,1H),7.32(d,2H),5.68(dd,1H),2.78(d,1H),2.40~0.65(m,35H),其中1.26(s,3H),1.12(s,3H),0.88(d,3H),0.86(s,3H),0.65(s,3H);HRMS(ESI):Calcd for C33H44BrN2O2[M+H]+,579.2581;Found:[M+H]+=579.2582.
实施例5制备本发明化合物Ia-5(R1=4-F,R2=H)MSW-159的制备
制备方法类似于实施例1,不同之处是以4-氟苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.31g化合物Ia-5,产率62%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.39~7.42(m,2H),7.35(s,1H),7.20(m,2H),5.73(dd,1H),2.79(d,1H),2.40~0.74(m,35H),其中1.31(s,3H),1.17(s,3H),0.98(d,3H),0.95(s,3H),0.74(s,3H);HRMS(ESI):Calcd for C33H44FN2O2[M+H]+,519.3381;Found:[M+H]+=519.3346.
实施例6制备本发明化合物Ia-6(R1=3-CH3,R2=H)MSW-163的制备
制备方法类似于实施例1,不同之处是以3-甲基苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.26g化合物Ia-6,产率52%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.36~7.24(m,3H),7.19(m,2H),5.69(dd,1H),2.76(d,1H),2.40(s,3H),2.37~0.71(m,35H),其中1.30(s,3H),1.15(s,3H),0.97(d,3H),0.94(s,3H),0.71(s,3H);HRMS(ESI):Calcd for C34H47N2O2[M+H]+,515.3632;Found:[M+H]+=515.3661。
实施例7制备本发明化合物Ia-7(R1=2-CH3,R2=H)MSW-165的制备
制备方法类似于实施例1,不同之处是以2-甲基苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.27g化合物Ia-7,产率54%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.45~7.25(m,5H),5.70(dd,1H),2.78(d,1H),2.42~0.72(m,38H),其中1.96(s,3H),1.36(s,3H),1.00(s,3H),0.97(d,3H),0.93(s,3H),0.72(s,3H);HRMS(ESI):Calcd for C34H47N2O2[M+H]+,515.3632;Found:[M+H]+=515.3655.
实施例8制备本发明化合物Ia-8(R1=3-Cl,R2=H)MSW-167的制备
制备方法类似于实施例1,不同之处是以3-氯苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.31g化合物Ia-8,产率62%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.52~7.28(m,5H),5.72(dd,1H),2.78(d,1H),2.40~0.73(m,35H),其中1.32(s,3H),1.18(s,3H),0.97(d,3H),0.95(s,3H),0.73(s,3H);HRMS(ESI):Calcd for C33H44ClN2O2[M+H]+,535.3086;Found:[M+H]+=535.3131,[M+Na]+=557.2945.
实施例9制备本发明化合物Ia-9(R1=2-C1,R2=H)MSW-169的制备
制备方法类似于实施例1,不同之处是以2-氯苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.30g化合物Ia-9,产率60%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.52~7.38(m,4H),7.34(s,1H),5.70(dd,1H),2.78(d,1H),2.42~0.72(m,35H),其中1.33(s,3H),1.08(s,3H),0.97(d,3H),0.95(s,3H),0.72(s,3H);HRMS(ESI):Calcd for C33H44ClN2O2[M+H]+,535.3086;Found:[M+H]+=535.3135。
实施例10制备本发明化合物Ia-10(R1=2,4-二甲基,R2=H)MSW-172的制备
制备方法类似于实施例1,不同之处是以2,4-二甲基苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.33g化合物Ia-10,产率66%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.31(m,1H),7.16(m,1H),7.03(m,2H),5.64(dd,1H),2.71(d,1H),2.31(s,3H),2.25~0.64(m,38H),其中1.83(s,3H),1.27(s,3H),1.08(s,3H),0.93(d,3H),0.91(s,3H),0.64(s,3H).HRMS(ESI):Calcd for C35H49N2O2[M+H]+,529.3832;Found:[M+H]+=529.3825
实施例11制备本发明化合物Ia-11(R1=3,4-二甲基,R2=H)MSW-174的制备
制备方法类似于实施例1,不同之处是以3,4-,二甲基苯肼盐酸盐代替4-甲氧基苯肼盐 酸盐,得0.31g化合物Ia-11,产率62%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.23(s,1H),7.11(m,1H),7.02(m,2H),5.61(dd,1H),2.68(d,1H),2.50~0.64(m,41H),其中2.25(s,3H),2.22(s,3H),1.22(s,3H),1.07(s,3H),0.89(d,3H),0.86(s,3H),0.64(s,3H);HRMS(ESI):Calcd for C35H49N2O2[M+H]+,529.3832;Found:[M+H]+=529.3849.
实施例12制备本发明化合物Ia-12(R1=3,4-二氯,R4=H)MSW-176的制备
制备方法类似于实施例1,不同之处是以3,4-二氯苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.35g化合物Ia-12,产率70%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.55~7.45(m,2H),7.29(s,1H),7.22(d,1H),5.65(dd,1H),2.68(d,1H),2.50~0.64(m,35H),其中1.23(s,3H),1.12(s,3H),0.88(d,3H),0.85(s,3H),0.64(s,3H);HRMS(ESI):Calcd for C33H43Cl2N2O2[M+H]+,569.2696;Found:[M+H]+=569.2727。
实施例13制备本发明化合物Ia-13(R1=2,4-二氯,R2=H)MSW-178的制备
制备方法类似于实施例1,不同之处是以2,4-二氯苯肼盐酸盐代替4-甲氧基苯肼盐酸盐,得0.34g化合物Ia-13,产率68%;1H-NMR(CDCl3/MeOD,400MHz):δ=7.55~7.25(m,4H),5.63(dd,1H),2.68(d,1H),2.50~0.64(m,35H),其中1.23(s,3H),1.01(s,3H),0.89(d,3H),0.86(s,3H),0.64(s,3H);HRMS(ESI):Calcd for C33H43Cl2N2O2[M+H]+,569.2696;Found:[M+H]+=569.2743.
实施例14制备本发明化合物Ib-1(R1=2-CH3,R2=OH)
0.50g的化合物II溶解于20ml乙醇中,加入1g的2-甲基苯肼盐酸盐,氮气保护下加热至70℃,反应2小时后冷却至室温,反应液浓缩,加入30ml的水,乙酸乙酯萃取(30ml×3),收集有机相,10ml水洗涤,饱和食盐水10ml洗涤,无水硫酸钠干燥,减压蒸馏浓缩有机溶剂后硅胶柱色谱(石油醚:乙酸乙酯=10:1)分离纯化,得0.35g化合物III-1(R1=2-CH3,R2=OH)。
0.35g化合物III-1(R1=2-CH3,R2=OH)溶解于20ml丙酮中,加入0.2g的NHPI和0.2ml的冰醋酸,待底物溶解后加入0.2g的重铬酸钠,升温至50℃,反应48小时,冷却至室温,抽滤,收集滤液,浓缩后加入30ml二氯甲烷,依次用30ml水洗涤,饱和碳酸氢钠溶液洗涤(30ml×3),20ml饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩后硅胶柱色谱(石油醚:乙酸乙酯=5:1)分离纯化,得到0.27g化合物Ⅳ-1(R1=2-CH3,R2=OH),产率77%。
0.27g的化合物Ⅳ-1(R1=2-CH3,R2=OH)溶解于20ml甲醇中,加入80mg的硼氢化钠,室温反应6小时,向体系中逐滴加入冰水淬灭反应,浓缩反应液,加入20ml水,乙酸乙酯 (20ml×3)萃取,收集有机相,20ml饱和食盐水洗涤,无水硫酸钠干燥,过滤得滤液,减压蒸馏除去溶剂得化合物V-1(R1=2-CH3,R2=OH)粗品0.19g,产率70%,直接投下一步。
0.19g的化合物V-1(R1=2-CH3,R2=OH)粗品溶解于甲醇,加入1ml的水,0.16g一水合氢氧化锂,室温反应36小时,向反应液中滴加1M的盐酸调至pH=5,减压蒸馏浓缩反应液,加入10ml水,乙酸乙酯萃取(10ml×3),收集有机相,10ml饱和食盐水洗涤,无水硫酸钠干燥,有机溶剂浓缩后硅胶柱色谱分离(二氯甲烷:甲醇=30:1),得0.14g化合物Ib-1。收率74%。 1H-NMR(CDCl3/MeOD,400MHz):δ=7.55~7.30(m,5H),5.62(dd,1H),3.86(m,1H),2.86(d,1H),2.50~0.76(m,36H),其中1.91(s,3H),1.40(s,3H),1.18(s,3H),1.07(d,3H),1.00(s,3H),0.76(s,3H);HRMS(ESI):Calcd for C34H46NaN2O3[M+Na]+,553.3401;Found:[M+Na]+=553.3455。
实施例15:制备本发明化合物Ib-2(R1=4-CH3O,R2=OH)的制备
制备方法类似于实施例14,不同之处是以4-甲氧基苯肼盐酸盐代替2-甲基苯肼盐酸盐,得0.13g化合物Ib-2。总收率26%。
实施例16:4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物对PTPlB酶抑制活性测试
材料和仪器:生物活性测试中使用PTPlB酶为大肠杆菌表达系统得到的GST融合蛋白,酶底物为对硝基苯磷酸盐(pNPP);使用的自动加样系统为Beckman生产的Biomek2000和Robbins Scientific生产的Hydra96;使用的96-孔聚丙烯酶标板和96孔板紫外/可见分光光度计SpectraMAX340及Flexstation II384分别购自Greiner和Molecular Devices。
原理:底物pNPP经PTPlB水解得到的游离产物在405nm处有很强的光吸收。采用光吸收检测法,在96孔平底透明微孔板中检测酶活性。通过酶标仪监测405nm处光吸收强度的变化,计算得到反应初速度。实验中采用的对照化合物为齐墩果酸(OA)。
方法:样品用DMSO溶解,低温保存,DMSO在最终体系中的浓度控制在不影响检测活性的范围之内。初筛选择单浓度(20μg/ml)条件下,对样品的活性进行测试,对于在此浓度条件下表现出活性的样品(抑制率%Inhibition大于50),测试活性剂量依赖关系,即ICS0值,通过样品活性对样品浓度进行非线性拟和得到,计算所用软件为Graphpad Prism4,拟合所使用的模型为sigmoidal dose-response(varible slope),对于大多数抑制剂筛选模型,将拟合曲线底部和顶部设定为0和100。一股情况下,每个样品在测试中均设置复孔(n≥2),在结果中以标准偏差(Standard Deviation,SD)或者标准误差(Standard Error,SE)表示。
部分4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物对PTPlB酶抑制活性测试结果如表1所 示:
表1表 1
化合物编号 | IC50(μM) |
Ia-1 | 2.66 |
Ia-2 | 1.12 |
Ia-3 | 0.81 |
Ia-4 | 2.35 |
Ia-5 | 0.42 |
Ia-6 | 0.93 |
Ia-7 | 1.17 |
Ia-8 | 1.24 |
Ia-9 | 0.86 |
Ia-10 | 1.34 |
Ia-11 | 0.73 |
Ia-12 | 1.03 |
Ia-13 | 1.18 |
齐墩果酸(OA) | 2.8 |
结果与评价:本发明制备的4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物均对PTPlB酶有较好的抑制活性,尤其是化合物MSW-159,IC50达到0.42uM,与对照文件(Bioorganic Medicinal Chemistry Letters2012,22,7237)相比,活性提高4倍左右。因此,本发明4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物适用于制备以PTPlB为靶点的治疗糖尿病和肥胖症的药物。
综上所述,本发明提出的4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物作为PTPlB酶抑制剂在治疗糖尿病和肥胖症方面有着潜在的药物研究价值,为寻找新型的治疗糖尿病和肥胖症药物提供了新思路。
Claims (13)
1.一种4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物,其特征在于,其结构如以下式(I)所示:
其中,R1为4-甲氧基,4-氯,4-甲基,4-溴,4-氟,3-甲基,2-甲基,3-氯,2-氯,2,4-二甲基,3,4-二甲基,3,4-二氯或2,4-二氯;R2为氢或羟基。
2.一种4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物的制备方法,其特征在于,包括以下
以化合物II为原料,在氮气保护条件下,以乙醇为溶剂,与化合物a经环化反应得到化合物III;所述化合物III在丙酮溶剂中,冰醋酸、N-羟基邻苯二甲酰亚胺存在条件下,利用重铬酸钠经氧化得到化合物IV;所述化合物IV经硼氢化钠还原得到化合物V,再在氢氧化锂存在下经水解反应制备得到化合物Ib;
所述方法如以下反应式(A)所示:
其中,R1为4-甲氧基,4-氯,4-甲基,4-溴,4-氟,3-甲基,2-甲基,3-氯,2-氯,2,4-二甲基,3,4-二甲基,3,4-二氯或2,4-二氯。
3.如权利要求2所述的制备方法,其特征在于,以化合物II制备化合物III的过程中,环化反应时间为2~5小时,反应温度为50℃~75℃。
4.如权利要求2所述的制备方法,其特征在于,以化合物II制备化合物III的过程中,经硅胶柱层析纯化制备得到所述化合物III。
5.如权利要求2所述的制备方法,其特征在于,所述化合物III的产率为50%~80%。
6.如权利要求2所述的制备方法,其特征在于,以化合物III制备化合物IV的过程中,氧化反应时间为36~48小时,反应温度为40℃~50℃。
7.如权利要求2所述的制备方法,其特征在于,以化合物III制备化合物IV的过程中,经硅胶柱层析纯化制备得到所述化合物IV。
8.如权利要求2所述的制备方法,其特征在于,所述化合物IV的产率为45%~55%。
9.如权利要求2所述的制备方法,其特征在于,以化合物IV制备化合物V的过程中,还原反应时间为4小时,溶剂为甲醇。
10.如权利要求2所述的制备方法,其特征在于,所述化合物V的产率为60%~70%。
11.如权利要求2所述的制备方法,其特征在于,以化合物V制备化合物Ib的过程中,溶剂为甲醇。
12.如权利要求1所述式(I)所示4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物制备PTP1B抑制剂中的应用。
13.如权利要求1所述式(I)所示4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物在制备治疗II型糖尿病药物中的应用,其特征在于,式(I)所示4,4-二甲基石胆酸-2,3-骈N-芳基吡唑衍生物抑制PTP1B的活性。
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4,4-二甲基豆甾醇衍生物的分子设计、合成及其PTP1B抑制活性研究及一些FBP酶抑制剂的合成;龚雪萍;《中国优秀硕士学位论文全文数据库(医药卫生科技辑)》;20121231;第24页倒数第2段,第27页Scheme 2-5 * |
Synthesis and biological evaluation of 4,4-dimethyl lithocholic acid derivatives as novel inhibitors of protein tyrosine phosphatase 1B;Hai-Bing He etal;《Bioorganic & Medicinal Chemistry Letters》;20120921;第22卷;第7237页摘要、第7239页Scheme 2、第7240页Table 1 * |
齐墩果酸的结构修饰与生物活性研究进展;唐初等;《有机化学》;20131231;第33卷;第52页左栏第1段、第53页右栏第1段 * |
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