CN103483282B - 苯基取代的***酰胺类化合物及用途 - Google Patents
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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,本发明涉及具有通式I的对糖尿病有治疗作用的一类含***酰胺结构化合物作为过氧化物酶体增殖物激活性受体(PPAR)激动剂,其制备方法以及在治疗糖尿病方面的应用。
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类含***酰胺骨架的过氧化物酶体增殖物激活性受体(PPAR)激动剂,其制备方法以及含有它们的药物组合物。
背景技术
糖尿病是患者控制血糖能力受损的疾病,患者已经不同程度地丧失了对胰岛素作用做出适当反应的能力。糖尿病中大部分是II型糖尿病(即非胰岛素依赖型糖尿病),约占80%-90%,研究发现,外周组织(包括骨骼肌、肝脏和脂肪组织等)的胰岛素抵抗在II型糖尿病的发生、发展中起着极为重要的作用。目前已经引入了一类使患者对自身胰岛素恢复敏感的一类药物,即胰岛素致敏剂,以使胰岛素和甘油三酯恢复到正常。在研究糖尿病的治疗中过氧化物酶体增殖物激活性受体(PPARs)成为理想的靶标,它是核受体超家族成员之一,能同时调控多种基因表达,参与了脂肪细胞分化、脂类代谢调节和增加胰岛素敏感性等生理过程。PPAR家族有三种类型:PPARα、PPARβ(也叫PPARδ)和PPARγ。PPARα涉及刺激脂肪酸的β-氧化,还涉及控制HDL胆固醇水平,在肝脏脂类代谢中发挥着重要作用,而PPARγ受体涉及脂肪细胞分化程序得激活,能改善胰岛素抵抗和提高胰岛素敏感性(杨俊,邹秀兰,PPARα/γ双重激动机与2型糖尿病,医学综述,2008,14(16):2492-2496)。PPARγ被认为是格列酮类胰岛素致敏剂的主要分子靶标,尽管格列酮类化合物是治疗II型糖尿病的有效药物,但是该类化合物的副作用非常明显,例如严重的肝脏毒型、体重增加和贫血,这主要是格列酮类是PPARγ的主要或完全激动剂(N·阿杰,D·罗彻,S·伊冯,CN101098865A)。因此,PPARα和PPARγ的双重激动剂就能减轻甚至消除格列酮类PPARγ激动剂的副作用,除了使血糖和胰岛素正常化之外,还具有降低血脂和抑制心血管并发症的作用。
本发明公开了一类***酰胺类化合物作为PPARα和PPARγ的双重激动剂,这些抑制剂可以用于制备治疗糖尿病的药物,特别是非胰岛素依赖型糖尿病的药物打下了基础。
发明内容
本发明的一个目的是克服现有技术的缺点和不足,提供一种具有良好活性,具有通式I的化合物。
本发明的另一个目的是提供制备具有通式I的化合物及其盐和酯的方法。
本发明的再一个目的是提供含有通式I的化合物在治疗糖尿病方面的应用。
现结合本发明的目的对本发明内容进行具体描述。
本发明具有通式I的化合物具有下述结构式:
其中,
R1选自H、甲基、乙基;
R2选自H、C1-C5的烷基。
优选以下通式I化合物,
R1选自H、甲基、乙基;
R2选自H、C1-C3的烷基。
更优选的本发明具有通式I的化合物如下所示:
本发明所述通式I化合物通过以下步骤合成:
化合物A与B在无机碱存在下反应,得到化合物C;化合物C用PBr3处理得到化合物D,D与E在碱存在下反应得到化合物I。
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。
本发明所述通式I化合物具有PPARα和PPARγ的双重激动作用,可作为有效成分用于制备糖尿病方面的治疗药物并能减轻体重增加和抑制心血管并发症疾病。本发明所述通式I化合物的活性是通过体内降血糖和降血液胆固醇和甘油三酯模型来验证的。
本发明的通式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20mg-400mg/人范围内,分为一次或数次给药。实际服用本发明通式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
1.37g(10mmol)化合物A-1与1.24g(10mmol)化合物B-1溶于10mL DMF中,加入4.15g(30mmol)K2CO3,而后在120℃氮气保护下搅拌过夜。反应混合物稍冷后倾入100mL冰水中,搅拌,用浓盐酸调节pH=3-4,用50mL×3的二氯甲烷萃取,合并萃取相,盐水洗涤一次,无水硫酸钠干燥,在旋转蒸发仪蒸去溶剂得到一残余物,而后柱层析纯化,得到C-1的纯品,ESl-MS,m/z=199([M+NH4]+)。
1.45g(8mmol)化合物C-1溶于10mL干燥的甲苯中,冰水浴冷却下慢慢搅拌,慢慢滴加2.71g(10mmol)PBr3溶于2mL干燥的二氯甲烷制成的溶液,滴加完毕后反应混合物在室温下搅拌半小时后倾入100mL冰水中,搅拌,用50mL×3的二氯甲烷萃取,合并萃取相,盐水洗涤一次,无水硫酸钠干燥,在旋转蒸发仪蒸去溶剂得到一残余物,而后柱层析纯化,得到D-1的纯品,ESI-MS,m/z=258([M+NH4]+)。
1.22g(5mmol)化合物D-1和0.96g(5mmol)E-1溶于5mL MeCN中,搅拌,加入2.07g(15mmol)K2CO3,室温下继续搅拌直到原料消耗完毕(12-24小时)。反应混合物倾入100mL冰水中,搅拌,用浓盐酸调节pH=3-4,用50mL×3的二氯甲烷萃取,合并萃取相,盐水洗涤一次,无水硫酸钠干燥,在旋转蒸发仪蒸去溶剂得到一残余物,而后柱层析纯化,得到I-1的纯品,淡黄色固体,熔点183-186℃;ESI-MS,m/z=369([M+NH4]+)。
实施例2-6
参照实施例1的方法,制备了下表所示的通式为I的化合物。
实施例7
样品以1%羧甲基纤维素钠配制成5mg/mL浓度的混悬液,给药体积为0.4mL/20g体重,相当于100mg/kg剂量。
健康ICR小鼠,雌雄各半,体重20-24g,符合一级标准。动物禁食16小时,灌胃给予待测化合物15分钟后腹腔注射2g/kg的葡萄糖盐水溶液,于造模后0.5h、1h、1.5h和2h定时取用毛细管自小鼠球后静脉丛取血,离心分离血清,用葡萄糖氧化酶法测定各时间点血清葡萄糖含量。空白小鼠既不给予葡萄糖也不给予待测化合物,模型小鼠只给予葡萄糖不给予待测化合物。
从上表格中数据可以看出,各给药均能显著增强葡萄糖引起的小鼠血糖耐受量。
实施例8
样品以1%羧甲基纤维素钠配制成5mg/mL浓度的混悬液,给药容量为0.4mL/20g体重,相当于100mg/kg剂量。
健康Wister大鼠,雌雄各半,体重300g左右,符合一级标准。动物以高脂饲料喂养30天,测定血清中胆固醇和甘油三酯含量,以胆固醇和甘油三酯含量为标准随机分组,动物分组后连续灌胃给予待测化合物7天,末次给药前禁食12小时,药后1h用毛细管自大鼠球后静脉丛取血,离心分离血清,用胆固醇和甘油三酯试剂盒测定血清胆固醇和甘油三酯含量。
胆固醇含量(g/dl)
甘油三酯含量(g/dl)
上述两个表的数据说明,本发明的化合物能有效降低胆固醇和甘油三酯。
Claims (2)
1.下式化合物:
2.权利要求1所述化合物在制备治疗糖尿病药物方面的用途。
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