CN106749210B - 一种烟酸酯类化合物及其制备方法与应用 - Google Patents
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Abstract
本发明涉及一种烟酸酯类化合物及其制备方法与应用，该化合物为2‑羟基‑3‑(癸酸脂基)‑6‑(4,4‘‑二甲基‑二氢苯并噻喃基‑6‑乙炔基)烟酸酯，以2‑羟基‑3‑(癸酸脂基)‑6‑(4,4‘‑二甲基‑二氢苯并噻喃基‑6‑乙炔基)烟酸应用二环己基碳二亚胺(DCC)与2‑羟基‑3‑(癸酸脂基)醇进行缩合反应得到；是制备选择性结合二种维A酸受体(RAR‑β；RAR‑γ)，但不与维A酸X受体(RXR)结合的药物的重要中间体，是预防和治疗银屑病性关节炎,关节病性银屑病,银屑病关节炎药物的关键组成部分；其制备方法原料便宜易得，合成方法简单，是一种合成烟酸酯类化合物的全新方法，适合规模化工业生产的需要。
Description
技术领域
本发明涉及化合物生产领域，尤其是一种烟酸酯类化合物及其制备方法与应用。
背景技术
烟酸酯类化合物现阶段主要有甘露醇烟酸酯和肌醇烟酸酯。
甘露醇烟酸酯主要具有扩张血管与降低血脂作用，对降低舒张压效果明显。肌醇烟酸酯具有降低胆固醇及扩张末梢血管作用，用于高胆固醇血症及动脉粥样硬化症。
发明内容
本发明所要解决的技术问题在于提供一种烟酸酯类化合物。
本发明所要解决的另一技术问题在于提供上述烟酸酯类化合物的制备方法。
本发明所要解决的另一技术问题在于提供上述烟酸酯类化合物的应用。
为解决上述技术问题，本发明的技术方案是：
一种烟酸酯类化合物，2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯，其结构式为(Ⅰ)所示，
优选的，上述烟酸酯类化合物，2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯的核磁共振氢谱数据为0.799(s,3H),1.126-1.183(b，20H)，1.574-1.539(t,2H),1.897-1.867(t,2H),2.283(t,2H),2.977-2.962(d,2H),4.191(s,3H),4.382(s,2H)，7.017-6.997(d,1H),7.198-7.174(d,1H),7.502-7.481(d,1H),7.549(s,1H),8.203-8.178(dd,1H),9.117(s,1H)。
上述烟酸酯类化合物的制备方法，通过1步反应得到目标化合物，具体步骤如下：二环己基碳二亚胺(DCC)与2-羟基-3-(癸酸脂基)醇进行缩合反应得到2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯。
上述烟酸酯类化合物的制备方法的具体反应方程式如下：
上述烟酸酯类化合物在制备预防和治疗银屑病性关节炎的药物方面的应用。
本发明的有益效果是：
上述烟酸酯类化合物2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯是制备选择性结合二种维A酸受体(RAR-β；RAR-γ)，但不与维A酸X受体(RXR)结合的药物的重要中间体，是预防和治疗银屑病性关节炎,关节病性银屑病,银屑病关节炎药物的关键组成部分；其制备方法原料便宜易得，合成方法简单，是一种合成烟酸酯类化合物的全新方法，适合规模化工业生产的需要。
附图说明
图1为2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯的HNMR谱图。其氢谱数据为：0.799(s,3H),1.126-1.183(b，20H)，1.574-1.539(t,2H),1.897-1.867(t,2H),2.283(t,2H),2.977-2.962(d,2H),4.191(s,3H),4.382(s,2H)，7.017-6.997(d,1H),7.198-7.174(d,1H),7.502-7.481(d,1H),7.549(s,1H),8.203-8.178(dd,1H),9.117(s,1H)。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯的制备方法，具体步骤如下：
将化合物1，100mg，化合物2，76mg，1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)120mg，1-羟基苯并三氮唑(HOBt)42mg溶解于2mlTHF，反应物混合并置换三次氮气，后室温搅拌1小时。TLC检测(DCM:MeOH＝5:1)，原料有剩余，将体系直接浓缩干并刮大板(DCM:MeOH＝10:1)得到51mg淡黄色油状物。如图1所示，2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯的HNMR谱图(CDCl3)，其氢谱数据为：0.799(s,3H),1.126-1.183(b，20H)，1.574-1.539(t,2H),1.897-1.867(t,2H),2.283(t,2H),2.977-2.962(d,2H),4.191(s,3H),4.382(s,2H)，7.017-6.997(d,1H),7.198-7.174(d,1H),7.502-7.481(d,1H),7.549(s,1H),8.203-8.178(dd,1H),9.117(s,1H)。
上述具体反应方程式如下：
应用试验例
参考Zenz R,Eferl R,Kenner L,et al.Psoriasis2like skin disease andarthritis caused by inducible epidermal deletion of Jun proteins[J].Nat.2005,437:369–375方法建立小鼠银屑病动物模型。选择位于PSORS6的JunB基因,通过基因敲除并联合药物干扰制备银屑病动物模型，联合敲除JunB和c2Jun基因后再给予他莫昔芬处理,18d后受试小鼠全身均出现特征性皮肤改变,在毛发稀疏的部位(耳朵、脚掌、尾巴)症状尤其明显,且该模型可见明显足部畸形、掌趾关节处炎性细胞浸润、骨组织破坏等银屑病样关节炎改变,与人类银屑病颇为相似。
将实施例1中目标化合物以0.2mg/kg剂量对20只模型小鼠肌肉注射3天，采用PsARC标准进行初次评价；而后0.4mg/kg剂量继续肌肉注射3天，采用ARC20标准进行二次评价。结果显示：PsARC有效率为60％，ARC20有效率为40％。
上述参照具体实施方式对该一种烟酸酯类化合物及其制备方法与应用进行的详细描述，是说明性的而不是限定性的，可按照所限定范围列举出若干个实施例，因此在不脱离本发明总体构思下的变化和修改，应属本发明的保护范围之内。
Claims (2)
1.烟酸酯类化合物在制备预防和治疗银屑病性关节炎的药物方面的应用，其特征在于：所述烟酸酯类化合物为2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯，其结构式为(Ⅰ)所示，
2.权利要求1中所述烟酸酯类化合物的制备方法，其特征在于：通过1步反应得到目标化合物，具体步骤如下：二环己基碳二亚胺(DCC)与2-羟基-3-(癸酸脂基)醇进行缩合反应得到2-羟基-3-(癸酸脂基)-6-(4,4‘-二甲基-二氢苯并噻喃基-6-乙炔基)烟酸酯。
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