包括马鞭草烯酮衍生物的用于治疗或预防肥胖或肥胖相关肝病的组合物的制作方法

本发明涉及包含马鞭草烯酮衍生物的用于治疗或预防肥胖或肥胖相关肝病的药物组合物，并且更特别地，涉及包含马鞭草烯酮衍生物的用于治疗或预防肥胖或肥胖相关肝病的药物组合物，该药物组合物能够通过抑制高脂饮食诱导的小鼠中的tgf-β/smad3信号传导来治疗或预防肥胖或肥胖相关肝病。

背景技术：

1、肥胖相关非酒精性脂肪性肝病(nafld)是从非酒精性脂肪肝到非酒精性脂肪性肝炎(nash)的连续的慢性肝病，是肝脏相关发病率和死亡率的主要原因。此外，估计nalfd的患病率为约全球总人口的25％，并且其患病率持续上升，从而给公共卫生带来了显著负担[2，3]。

2、越来越多的证据表明，肝脏与内脏脂肪组织(vat)密切相互作用，并且肥胖诱导的发炎的vat在nafld的发展中起着关键作用[1，4-6]。肥胖，尤其是内脏型肥胖，促进代谢健康的vat转化为失调和发炎的vat[5]。失调的vat(作为内分泌和旁分泌器官)分泌促炎症细胞因子诸如白介素-6(il-6)和肿瘤坏死因子-α(tnf-α)，从而增加炎症细胞诸如巨噬细胞的浸润，这导致vat中的炎症进一步加重[4-6]。随后发炎的vat增强促炎症细胞因子的分泌，从而促进全身炎症和胰岛素抵抗，这进一步导致nafld进展加速[1，4-6]。因此，发生在vat中的炎症反应促进了nafld的进展，并将为肥胖相关nafld的适当的治疗靶点[6，7]。

3、先前的几项研究报道了，转化生长因子(tgf)-β/smad3信号传导在vat炎症的病理过程中起着至关重要的作用[8-10]。已知，在tgf-β1与tgf-β1型和2型受体的复合物(tgf-βr1和tgf-βr2)之间的相互作用激活了smad2/3的磷酸化，从而上调了vat炎症(图1a)[10]。此外，先前报道的动物研究结果发现，smad3的遗传切除和用tgf-β功能性封闭抗体的治疗减少肥胖造成的vat炎症[11，12]。因此，tgf-β/smad3信号传导通路可以是发炎的vat的治疗靶点。

4、因此，本发明人付出努力来利用tgf-β/smad3信号传导通路作为用于由上述发炎的vat引起的nafld的治疗靶点，并且结果是，马鞭草烯酮衍生物化合物能够通过抑制高脂饮食诱导的(hfd)小鼠中的tgf-β/smad3信号传导通路来治疗和预防肥胖诱导的内脏脂肪组织(vat)炎症以及后续的肥胖或非酒精性脂肪性肝病(nafld)，从而完成了本发明。

5、[现有技术文件]

6、[非专利文件]

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技术实现思路

1、本发明的目的是提供马鞭草烯酮衍生物用于通过抑制高脂饮食(hfd)诱导的肥胖小鼠中的tgf-β/smad3信号传导通路来治疗和预防肥胖诱导的vat炎症和后续的nafld的新用途。

2、为了实现上述目的，本发明提供了一种用于治疗肥胖的药物组合物，所述药物组合物包括由下式1表示的马鞭草烯酮衍生物或其药学上可接受的盐作为活性成分：

3、[式1]

4、

5、其中，r1、r2、r3、r4和r5各自独立地是氢原子、卤素原子、羟基基团、c1-3烷基基团、c1-3烷氧基基团、氨基基团、c1-3烷基胺基团、c1-3烷基二胺基团、c5-8芳基基团、c5-8环状基团、c5-8杂芳基基团、x、y和z各自独立地是碳原子或n、o或s原子；并且

6、指示双键或单键。

7、本发明还提供了一种用于治疗或预防肥胖相关肝病并且包含活性成分由式1表示的马鞭草烯酮衍生物或其药学上可接受的盐的药物组合物。

8、本发明还提供了一种用于预防或改善肥胖的健康功能性食品，所述健康功能性食品包括由下式1表示的马鞭草烯酮衍生物或其药学上可接受的盐作为活性成分。

9、本发明还提供了一种用于预防或改善肥胖相关肝病的健康功能性食品，所述健康功能性食品包括由下式1表示的马鞭草烯酮衍生物或其药学上可接受的盐作为活性成分。