CN109394764A - 一种n-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物在药物制备中的应用 - Google Patents
一种n-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物在药物制备中的应用 Download PDFInfo
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Abstract
本发明公开了一种N‑(噻唑‑2‑基)‑3‑(哌嗪‑1‑基)丙酰胺类化合物在药物制备中的应用,所述的化合物用于制备抗炎药物。试验结果表明该类化合物具有抗炎活性,尤其是能用于治疗由TNF‑α和/或IL‑6超出正常量表达和释放而导致的急性肺损伤。
Description
技术领域
本发明属于医药技术领域,具体涉及式(I)的化合物(代号LM9)或其药学上可接受的盐在制备用于治疗或预防炎症疾病病的药物中的用途。
背景技术
炎症作为一种重要的病理过程,是人类机体对于外来的或者异体的刺激的一种自身免疫应答。而当这种应答失调或者过分应答从而导致机体自损伤时,就逐步演变成了炎症。在炎症发生过程中,炎症因子会直接或间接造成组织和细胞的破坏。
急性肺损伤(Acute Lung Inflammation,ALI)是由各种间接或者直接致伤因素导致的肺泡上皮细胞及毛细血管内皮细胞损伤,造成弥漫性肺间质及肺泡水肿,导致急性低氧性呼吸功能不全。该疾病的死亡率可以超过30。然而目前临床上还没有有效的治疗手段。ALI的发病机制十分复杂,这是由于机体常遭受内源性或外源性致病微生物及其代谢产物的侵袭,以及中毒、休克、急性胰腺炎等均可引发机体组织细胞炎症反应,继而引发感染、脓毒血症等,并进一步诱发机体产生大量的炎性细胞因子主要有IL-6、TNF-α、IL-1β和IL-12等。多项临床研究表明,由炎症因子和趋化因子形成的复杂的网络在介导、放大和延续急性肺损伤的过程中起重要作用。因此抑制炎症因子的释放成为了治疗急性肺损伤的重要手段。
本发明人在多年的工作基础上,发现了式(I)的化合物(LM9)能治疗炎症引起的急性肺损伤的研究报道,后续生物实验发现该化合物具有抗炎活性,尤其是能用于治疗由TNF-α和/或IL-6超出正常量表达和释放而导致的急性肺损伤。
发明内容
本发明的目的在于提供了一种N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物的新的用途。
一种N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物在药物制备中的应用,所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物用于制备抗炎药物;
所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物选自以下化合物中的一种:
作为优选,所述抗炎药物用于预防或者治疗炎症以及与炎症相关的疾病。
作为优选,其中所述抗炎药物是能够通过抑制巨噬细胞释放炎症因子的释放而治疗的炎症;
所述巨噬细胞释放炎症因子为TNF-α和/或IL-6。
本发明涉及一类具有急性肺损伤治疗作用的一类以取代哌啶酮为母核结构的单羰基姜黄素类似物及与炎症相关疾病的治疗药物,所述疾病的病因至少部分地是由炎症引起,所述疾病包括但不限于以下疾病:缓解类风湿关节炎、骨关节炎、脊柱关节病、痛风性关节炎、风湿性关节炎、各种慢性关节炎的急性发作期或持续性的关节肿痛症状;治疗非关节性的各种软组织风湿性疼痛,如肩痛、腱鞘炎、滑囊炎、肌痛及运动后损伤性疼痛;急性的轻、中度疼痛,如,手术后、创伤后、劳损后、原发性痛经、牙痛、头痛;缺血性再灌注,如,脑缺血再灌注、心肌缺血再灌注;动脉粥样硬化;肝炎;淋巴炎;肺炎;痢疾;阑尾炎。
作为优选,化合物选自如下化合物之任一:
作为最优选,本发明的化合物为:
作为优先,所述的抗炎药物用于缓解或治疗急性肺损伤。
本发明还提供了一种用于治疗炎症的药物组合物,含有治疗有效量的权利要求1所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其可药用盐和药用辅料。
作为优选,所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其可药用盐作为唯一的活性成分。
作为优选,所述药物组合物的制剂形式选自注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂和纳米制剂。
附图说明
图1中为活性化合物抑制LPS刺激原代巨噬细胞释放IL-6的量效关系;
图2式(I)的化合物(LM8,LM9)缓解急性肺损伤大鼠生理学变化效果。
图3式(I)的化合物(LM8,LM9)缓解急性肺损伤中肺组织的病理学变化。
具体实施方式
在下面的非限制性实施例中,对本发明进行更详细的说明。
实施例1活性化合物抑制LPS刺激巨噬细胞释放炎症因子的量效关系
为了测试了活性化合物抑制LPS刺激RAW 264.7巨噬细胞释放IL-6的量效关系。具体方法如下:1.2×106个原代巨噬细胞用DMEM培养液培养于37℃,24小时后更新培养液,并加入受测化合物(终浓度为10μM)预处理2小时,再用0.5μg/mL的LPS继续处理22小时,收集培养液用ELISA法检测IL-6含量;收集细胞检测总蛋白浓度,ELISA结果用相应的总蛋白浓度相除较准,以LPS对照组的IL-6含量定标为100,计算平均值和误差值。实验结果见图1。
实施例2化合物缓解急性肺损伤大鼠生理学变化
用0.5%羧甲基纤维素钠与化合物LM8和LM9制成混悬液用于腹腔给药。各组大鼠乙醚麻醉后暴露气管,除对照组外,其余各组气管内缓慢滴入50μL 5mg/kg LPS,造成大鼠急性肺损伤,对照组以相同的方式滴入等量生理盐水,缝合伤口,建立急性肺损伤模型。动物造模24h后,按照5mL/kg的剂量腹腔注射10%的水合氯醛麻醉老鼠,开胸结扎左肺,右肺用1mL生理盐水进行支气管肺泡灌洗,收集灌洗液,相同操作重复3次。
肺泡灌洗液收集后,4℃1000rpm离心5分钟,取上清液,测肺泡灌洗液的蛋白浓度。肺泡灌洗液离心后,用50μL生理盐水重悬沉淀,混匀后取20ul用细胞计数仪Standard计数肺泡灌洗液中的总细胞数。此外,取右肺上叶,滤纸吸去组织上的水分后称取湿重,放入60℃烘烤48h以上,直到其重量不再发生变化为止,称取干重,计算肺组织湿重/干重比(W/D),判断肺水肿程度。实验数据见图2,两个实验结果均表明化合物在生理学上可有效缓解大鼠急性肺损伤。
图2中,A表示肺泡灌洗液中蛋白总量、B表示湿重/干重比(W/D)、C肺泡灌洗液中IL-6表达量、D肺泡灌洗液中TNF-α表达量、E血清中IL-6表达量、F血清TNF-α表达量。
实施例3化合物缓解急性肺损伤中肺组织的病理学变化试验
实验数据见图3,正常对照组大鼠肺泡腔清晰,结构完整,壁光滑;气管滴注LPS造成急性肺损伤模型后,肺泡壁明显水肿、增厚,炎症细胞浸润增加;给予化合物LM8和LM9治疗后细胞水肿、增厚显著减弱,且炎症细胞浸润明显减少,与正常组差别不大,说明化合物可有效缓解急性肺损伤中肺组织损伤。
Claims (10)
1.一种N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物在药物制备中的应用,其特征在于,所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物用于制备抗炎药物;
所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物选自以下化合物中的一种:
2.根据权利要求1所述的应用,其特征在于,所述抗炎药物用于预防或者治疗炎症以及与炎症相关的疾病。
3.根据权利要求2所述的应用,其特征在于,所述抗炎药物能够通过抑制巨噬细胞释放炎症因子的释放而治疗的炎症;
所述巨噬细胞释放炎症因子为TNF-α和/或IL-6。
4.根据权利要求2所述的应用,其特征在于,所述炎症选自:类风湿关节炎、骨关节炎、脊柱关节病、痛风性关节炎、风湿性关节炎、各种慢性关节炎的急性发作、持续性的关节肿痛、非关节性的软组织风湿性疼痛、和急性的轻、中度疼痛。
5.根据权利要求1所述的应用,其特征在于,所述的非关节性的软组织风湿性疼痛为肩痛、腱鞘炎、滑囊炎、肌痛或运动后损伤性疼痛;
所述的中度疼痛为手术后、创伤后、劳损后、原发性的痛经、牙痛、头痛。
6.根据权利要求1所述的应用,其特征在于,化合物选自如下化合物之任一:
7.根据权利要求1所述的应用,其特征在于,所述的抗炎药物用于缓解或治疗急性肺损伤。
8.一种用于治疗炎症的药物组合物,其特征在于,含有治疗有效量的权利要求1所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其可药用盐和药用辅料。
9.根据权利要求8所述的药物组合物,其特征在于,所述的N-(噻唑-2-基)-3-(哌嗪-1-基)丙酰胺类化合物或其可药用盐作为唯一的活性成分。
10.根据权利要求8所述的药物组合物,其特征在于,所述药物组合物的制剂形式选自注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂和纳米制剂。
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