CN104478861B - 一种硝基金刚烷四氮唑化合物、其制备方法和用途 - Google Patents
一种硝基金刚烷四氮唑化合物、其制备方法和用途 Download PDFInfo
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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Abstract
本发明涉及与糖尿病相关的药物领域。具体而言，本发明涉及一种含硝基金刚烷和四氮唑类结构的二肽基肽酶‑IV抑制剂及其制备方法，及其在制备糖尿病药物方面的应用。
Description
技术领域
本发明涉及与糖尿病相关的药物领域。具体而言，本发明涉及对糖尿病有治疗作用的一种硝基金刚烷四氮唑类结构的二肽基肽酶-IV抑制剂及其制备方法、含有它们的药物组合物和在治疗糖尿病方面的药物。
背景技术
根据统计，2007年全球糖尿病患者大约有2.5亿左右，其中绝大数为II型(即非胰岛素依赖型)糖尿病患者。目前在临床使用的抗糖尿病药物主要有磺酰脲类、二甲双胍类和胰岛素类药物，近年来上市的还有胰岛素增敏剂类药物和α-葡糖苷酶抑制剂等。这些药物具有良好的治疗效果，但普遍存在低血糖等严重副作用，而且长期治疗存在安全性问题，如肝毒性和体重增加等诸多问题。
二肽基肽酶IV(dipeptidylpeptidaseIV,DPP-IV)能有效并能快速地降解胰高血糖素样肽1(GLP-1),GLP-1是胰岛素生产和分泌最有效的刺激剂之一，因此抑制DPP-IV能加强内源性GLP-1的作用，从而提高血液中胰岛素的水平。目前医学已经证实DPP-IV抑制剂是一种新型的抗糖尿病治疗药物，目前已经有多个药物上市销售。临床结果显示该类药物具有良好的降糖效果，同时未发现其他糖尿病药物所产生的常见体重增加和低血糖等不良反应物。
现有DPP-IV抑制剂的主要结构类型有：从化学结构类型划分主要分为哌嗪并三唑类、2-氰基-吡咯烷类、噻唑烷类、嘧啶酮类，以及其他类型结构药物。
本发明公开了一种硝基金刚烷四氮唑类结构的DPP-IV抑制剂，这些化合物可以用于制备治疗糖尿病的药物。
发明内容
本发明的一个目的是提供一种具有良好活性，具有式I结构的化合物及其药学上可接受的盐。
本发明的另一个目的是提供制备具有式I结构的化合物及其盐的方法。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有式I结构的化合物具有下述结构式：
本发明所述式I化合物通过以下步骤合成：
化合物II与溴乙酰溴III在碱存在下反应得到化合物IV，后者与2H-四氮唑-5-甲酸V在碱存在下反应得到化合物VI，化合物VI与在缩合剂存在下与VII反应，得到化合物I；上述缩合剂包括N,N'-二环己基碳化二亚胺(DCC)、N-乙基-N'-(3-二甲氨基丙基)碳化二亚胺盐酸盐(EDC)和羰基二咪唑(CDI)等，这些缩合剂可以与有机碱联合使用，如三乙胺、二异丙基乙基胺(DIPEA)和4-二甲氨基吡啶(DMAP)等。
本发明所述式I化合物的药学上可接受的盐包括，但不限于与各种无机酸，例如，盐酸、硫酸、硝酸、磷酸等，或有机酸，例如甲酸、乙酸、柠檬酸、草酸、富马酸、马来酸、氨基酸等所生成的药学上可接受的盐。
本发明式I所示的化合物或其盐具有DPP-IV的抑制作用，可作为有效成分用于制备治疗糖尿病药物中；优选地，所述糖尿病为非胰岛素依赖型糖尿病。本发明化合物的活性是通过体外对DPP-IV酶的抑制作用来验证的。
本发明所述式I化合物或其盐具有DPP-IV的抑制作用，可作为有效成分用于制备糖尿病方面的治疗药物。本发明所述式I化合物的活性是通过体内降糖模型验证的。
本发明的式I化合物在相当宽的剂量范围内是有效的。例如每天服用的剂量约在1mg-1000mg/人范围内，分为一次或数次给药。实际服用本发明式I化合物的剂量可由医生根据有关的情况来决定。这些情况包括：被治疗者的身体状态、给药途径、年龄、体重、对药物的个体反应，症状的严重程度等。
具体实施方式
下面结合实施例对本发明作进一步的说明。需要说明的是，下述实施例仅是用于说明，而并非用于限制本发明。本领域技术人员根据本发明的教导所做出的各种变化均应在本申请权利要求所要求的保护范围之内。
实施例1化合物I的制备
2.10g(10mmol)化合物II和3.04g(30mmol)三乙胺溶于20mL干燥的二氯甲烷中，冰水浴冷却下搅拌，而后慢慢滴加2.42g(12mmol)化合物III溶于5mL干燥的二氯甲烷中制成的溶液。滴加完毕后，反应混合物在室温下继续搅拌1小时。反应混合物倾倒到200mL冰水中，搅拌，用50mL×3二氯甲烷萃取，合并萃取相用食盐水洗涤，无水硫酸钠干燥，而后在旋转蒸发仪上蒸干，得到的残余物柱层析纯化，得到IV的纯品，白色固体，ESI-MS,m/z＝330和332([M+H]+)。
1.97g(6mmol)化合物IV0.68g(6mmol)化合物V、1.00g(6mmol)固体碘化钾和4.15g(30mmol)固体碳酸钾在20mL干燥的DMF中120℃氮气下搅拌过夜。反应混合物稍冷后倾倒到200mL冰水中，搅拌，用50mL×3二氯甲烷萃取，合并萃取相用食盐水洗涤，无水硫酸钠干燥，而后在旋转蒸发仪上蒸干，得到的残余物柱层析纯化，得到VI的纯品，白色固体，ESI-MS,m/z＝364([M+H]+)。
1.09g(3mmol)化合物VI、0.29g(mmol)化合物VII和0.62g(3mmol)DCC在6mL干燥的THF中室温下搅拌过夜。抽滤除去反应混合物中的固体，滤液在旋转蒸发仪上蒸干，残余物柱层析纯化得到产物I的纯品，白色固体，ESI-MS,m/z＝442([M+H]+)。
实施例2参比化合物D的制备
为充分说明本发明化合物的有益效果，申请人记载了实验过程中发现的下式化合物D(未公开)，作为药效参比化合物。
其制备方法如下：
1.65g(10mmol)化合物II-1和3.04g(30mmol)三乙胺溶于20mL干燥的二氯甲烷中，冰水浴冷却下搅拌，而后慢慢滴加2.42g(12mmol)化合物III溶于5mL干燥的二氯甲烷中制成的溶液。滴加完毕后，反应混合物在室温下继续搅拌1小时。反应混合物倾倒到200mL冰水中，搅拌，用50mL×3二氯甲烷萃取，合并萃取相用食盐水洗涤，无水硫酸钠干燥，而后在旋转蒸发仪上蒸干，得到的残余物柱层析纯化，得到IV-1的纯品。ESI-MS,m/z＝286和288([M+H]+)。
1.72g(6mmol)化合物IV-1、0.68g(6mmol)化合物V、1.00g(6mmol)固体碘化钾和4.15g(30mmol)固体碳酸钾在20mL干燥的DMF中120℃氮气下搅拌过夜。反应混合物稍冷后倾倒到200mL冰水中，搅拌，用50mL×3二氯甲烷萃取，合并萃取相用食盐水洗涤，无水硫酸钠干燥，而后在旋转蒸发仪上蒸干，得到的残余物柱层析纯化，得到VI-1的纯品。ESI-MS,m/z＝320([M+H]+)。
0.96g(3mmol)化合物VI-1、0.29g(mmol)化合物VII和0.62g(3mmol)DCC在6mL干燥的THF中室温下搅拌过夜。抽滤除去反应混合物中的固体，滤液在旋转蒸发仪上蒸干，残余物柱层析纯化得到产物D的纯品，ESI-MS,m/z＝398([M+H]+)。
实施例3化合物对DPP-IV酶的抑制作用测定
使用BPS生物科学公司的荧光DPP4活性检测试剂盒，测定本发明的化合物对DPP-IV酶的抑制活性。
将样品依次按梯度稀释浓度分别为：5、10、30、100和200ng/kg，荧光反应96孔板，按下表加入样品：
22℃水浴，放置10min，SpectraMaxM5型荧光检测器激发光350nm，以450nm荧光测定吸收值。根据浓度-荧光强度曲线计算IC50值，结果见下表：
化合物对DPP-IV酶的抑制的IC50值
从上表可以看出，本发明的化合物对DPP-IV酶具有很强的抑制作用。
Claims (3)
1.式I化合物或其药学上可接受的盐：
2.合成权利要求1所述化合物或其药学上可接受的盐的方法，包括以下步骤：
化合物II与溴乙酰溴III在碱存在下反应得到化合物IV，化合物IV与2H-四氮唑-5-甲酸V在碱存在下反应得到化合物VI，化合物VI在缩合剂存在下与VII反应，得到化合物I。
3.权利要求1所述化合物或其药学上可接受的盐在制备治疗糖尿病药物方面的应用。
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