CN103919778B - 一种含哌啶酮结构的姜黄素类似物s1在制备抗炎药物方面的应用 - Google Patents
一种含哌啶酮结构的姜黄素类似物s1在制备抗炎药物方面的应用 Download PDFInfo
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Abstract
本发明属药物化学和药理学领域,具体涉及化合物[(1E,1′E)‑(4‑Oxo‑1‑propionylpiperidine‑3,5‑diylidene)bis(methanylylidene)]bis(2‑me thoxy‑4,1‑phenylene)dipropionate(S1)在制备抗炎或/和抗氧化药物相关疾病的治疗药物中的应用:此哌啶酮类姜黄素类似物S1能够剂量依赖性地抑制TNF‑α、IL‑6等多种炎症因子的表达和释放;也可以明显提高LPS诱导小鼠致死的生存率。并具体良好的安全性和稳定性,此化合物具有开发为炎症或/和氧化应激相关疾病的治疗药物的前景。
Description
技术领域:
本发明属药物化学和药理学领域,具体涉及化合物S1,其化学名称为[(1E,1′E)-(4-Oxo-1-propionylpiperidine-3,5-diylidene)bis(methanylylidene)]bis(2-methoxy-4,1-phenylene)dipropionate在治疗炎症或/和氧化应激所导致疾病中的应用,此化合物通过抑制多种炎症因子的表达和释放从而达到很好的体外和体内抗炎作用,同时它们也具有很好的抗氧化活性,具有开发为炎症或/和氧化应激相关治疗药物的前景。
背景技术:
抗炎药物的现状:
炎症反应是多种重要疾病共有的病理过程,甚至有人提出“炎症是万病之源的说法”。研究已经证实,除了各种典型的炎症和免疫性疾病之外,多种疾病如肿瘤、心血管疾病、动脉粥样硬化、缺血再灌注、糖尿病神经病变和帕金森等的前期阶段,均有局部的炎症反应出现,具体表现为炎症、趋化等因子的增多,并进一步刺激病理反应的过程,如果消除这些疾病的早期炎症反应可以对这些疾病,甚至早期肿瘤也起到治疗作用。
姜黄素是一种天然植物提取物,其主要存在与姜黄属植物如姜黄、郁金等的根茎中,其含量较高,易于提取,成本低廉。姜黄素是一个药理活性强、适应症广的化合物。近年来,药物化学和药理学研究发现姜黄素具有抗炎、抗肿瘤、抗血管生成、抗突变、抗菌、抗病毒、抗氧化和神经保护等多种药理作用,姜黄素在美国已经进入I期临床实验阶段。其抗炎活性包括对巨噬细胞释放多种 炎症因子的释放等。此外,作为一种广泛应用的食品添加剂,姜黄素具有极高的安全性,最新在台湾I期临床实验证明,给予患者8,000mg/d的高剂量服用姜黄素,仍未见明显的毒副作用。正是因为其多种生物活性,以及低分子量、无毒等特点,姜黄素曾被认为是理想的化学治疗药物之一。然而,进一步的研究发现姜黄素在体内的活性偏低、体内吸收少、代谢过快和生物利用度低,极大地限制了它的应用。然而,考虑到它确切的生物活性、相对简单的分子结构,姜黄素仍不失为一种优秀的结构修饰和抗炎药物筛选的先导化合物,目前,以保留其药物安全性、增加抗炎活性和水溶性为目的的姜黄素类似物设计、合成、评估和筛选研究吸引了很多药物研发机构和药物公司。通过大量的文献和专利查阅,我们发现,虽然目前普遍认为姜黄素结构中的活性基团是其酚羟基和β-二酮基团,但在姜黄素类似物的相关研究中,也发现不含β-二酮的单羰基姜黄素类似物有时候也表现出较强的生物活性,这也对β-二酮基团是姜黄素的活性必需基团提出了质疑。而且,β-二酮骨架是姜黄素稳定性较弱的主要原因。据此,我们前期设计了以丙酮、环己酮和环戊酮为中间碳链的稳定的姜黄素单羰基类似物并表征了其抗炎活性(授权专利号:ZL200710066787.1);在本发明中,考虑到中间碳链对于单羰基姜黄素类化合物活性的重要影响,一些杂环化合物在许多药物中也有很好的表现。因此,我们设计了一种硫代吡喃为核心的单羰基姜黄素类似物,并表征了其抗炎活性和作用机制。结果证明这种设计对药理活性的提高起到积极的促进作用。
发明内容:
本发明的目的在于提供一种含哌啶酮结构的姜黄素类化合物[(1E,1′E)-(4-Oxo-1-propionylpiperidine-3,5-diylidene)bis(methanylylidene)]bis(2-me thoxy-4,1-phenylene)dipropionate(S1)在制备抗炎或/和抗氧化药物及与炎症或/ 和氧化应激相关疾病的治疗药物中的应用。
本发明的另一目的是提供一种用于治疗炎症或/和氧化应激所导致的疾病的药物组合物,其含有此化合物与其它单一化合物和/或药用辅料组成的复方。
具体而然,本发明所要保护的杂环化合物为如下所述结构:
就已经报道的有关抗炎活性的文献而言,其抗炎筛选模型一般以对环氧合酶活性的抑制、脂氧合酶活性的抑制、NO释放的抑制、***素PGE2生成的抑制为主,未发现同时选用对TNF-α和IL-6释放的抑制筛选模型。因此,本专利首先用对LPS刺激RAW264.7巨噬细胞释放炎症因子(TNF-α和IL-6)抑制的模型进行了化合物体外抗炎活性的测试(详情见实施例2),结果表明,相比仅有25%抑制率的姜黄素(详见参考文献:Eur.J.Med.Chem.2010,45:5773-5780),此化合物对在10μM浓度下,TNF-α和IL-6的抑制率可以分别达到78.5%和85.2%[图1],并在1、2.5、5.0μM三个浓度下呈剂量依赖关系(图2)。除了测试其活性之外,我们还检测了其对肝细胞HL-7702的毒性和化合物的稳定性,结果表明,此化合物的肝毒性与姜黄素差别很小,然而其稳定性相比姜黄素却有很大程度的提高[图3]。在确保化合物有良好的体外活性和安全性之后,我们对小鼠进行了在高浓度的LPS(15mg/kg)刺激下的生存率实验,实验观察期为七天。空白组在第三天就全部死亡,而加药组(10mg/kg)的生存率达到了50%[图4],再次证明了此化合物具有良好抗炎活性和安全性。
本发明所述抗炎化合物可以应用于制备抗炎药物及其与炎症相关疾病的治疗药物中,所述疾病的病因至少部分是由炎症引起,所述疾病包括但不限于以 下疾病:
各类炎症疾病,主要是缓解类风湿关节炎、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;
一种用于治疗炎性疾病的药物组合物,其含有效量的作为活性成分的S1的任何一种或多种或其可药用盐及其药用辅料。“药物组合物”指由本发明所述化合物S1的任何一种或多种或其可药用盐与现已在临床使用的抗炎药物联合使用,制备防治炎症疾病类药物的组合物,已在临床使用的抗炎药物包括各种甾体类抗炎药物和非甾体类抗炎药物。
本文中所用“药用辅料”指药学领域常规的药物载体,例如:稀释剂、赋形剂如水等,填充剂如淀粉、蔗糖等;粘合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解剂如琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季铵化合物;表面活性剂如十六烷醇;吸附载体如高岭土和皂粘土;润滑剂如滑石粉、硬脂酸钙/镁、聚乙二醇等。另外还可以在组合物中加入其它辅剂如香味剂、甜味剂等。
本发明药物组合物的各种剂型可以按照药学领域的常规生产方法制备。例如使活性成分与一种或多种载体混合,然后将其制成所需的剂型。所述药物的制剂形式包括注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释或缓释剂或纳米制剂。本发明可以组合物的形式通过口服,鼻吸入、直肠或者肠胃外给药的方式施用于需要这种治疗的患者。用于口服时,可将其制成常规的固体制剂如片剂、粉剂、粒剂、胶囊等,制成液体制剂如水或油悬浮剂 或其它液体制剂如糖浆、酏剂等;用于肠胃外给药时,可将其制成注射用的溶液、水或油性悬浮剂等。
下面将结合实施例及说明书附图详细说明本发明
附图说明:
图1化合物S1对LPS刺激RAW264.7巨噬细胞释放炎症因子TNF-α的剂量依赖性抑制。
图2化合物S1抑制LPS刺激RAW264.7巨噬细胞释放炎症因子IL-6的剂量依赖性抑制。
图3化合物S1对人体正常的肝细胞HL-7702的毒性及其化合物的稳定性测试
图4化合物S1对LPS刺激小鼠的生存率改善实验
具体实施方式:
本发明在以下的实施例中进一步说明。这些实施例只是为了说明的目的,而不是用来限制本发明的范围。
实施例1
化合物S1的合成
室温下,将10mmol香草醛溶于12mL乙醇中,接着向其中加入5mmol哌啶酮,室温下反应半个小时后,向其中通入HCl气体,直至TLC检测原料点消失。然后将反应混合物倒入25mL冰水中,有黄色沉淀产生。过滤,残留的 固体用水洗涤后未进行进一步的纯化,直接进行下一步反应。将残留的固体溶于10mL四氢呋喃中,加入3mL三乙胺,搅动半小时后,再向其中加入相应10mmol的丙酰氯,反应完全后,浓缩,过硅胶柱得到纯度均大于98%的化合物S1目标化合物。
[(1E,1′E)-(4-Oxo-1-propionylpiperidine-3,5-diylidene)bis(methanylylidene)]bis(2-methoxy-4,1-phenylene)dipropionate(S1):Yellow powder,18.4%yield,mp146.6-148.5℃.1H-NMR(CDCl3)δ:7.580(s,2H,β-H×2),7.134-7.212(m,4H,H-3×2,H-5×2),6.910(d,J=8.4Hz,2H,H-6×2),3.824(t,J=5.4Hz,10H,2-OCH3×2,2’CH2,6’CH2),2.607(q,J=7.8Hz,6H,-CH2 CH3×3),1.125-1.163(t,J=7.8Hz,9H,-CH3×3).ESI-MS m/z:536.8(M+1)+,calcd for C30H34NO3:535.2.
实施例2
化合物S1对LPS刺激巨噬细胞释放炎症因子(TNF-α和IL-6)的抑制
采用化合物对LPS刺激巨噬细胞释放炎症因子抑制的方法,详细步骤如下:1.2×106个RAW264.7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(其终浓度为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TNF-α和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TNF-α和IL-6含量定标为100;每个化合物重复测试3次,计算平均值和误差值。测试时用阳性药物姜黄素(curcumin,cur)做对照。化合物S1对IL-6和TNF-α释放的抑制活性分别见图1。
同进,我们还进一步测试了化合物S1抑制LPS刺激RAW264.7巨噬细胞 释放TNF-α和IL-6的量效关系,方法同上。化合物的浓度梯度为1、2.5、5.0μM。实验数据见图2。这三个化合物均呈现出较好的量效关系,对TNF-α和IL-6抑制活性的IC50均达到了5.0μM的较好水平,见图2。
实施例3
化合物S1对人体正常的肝细胞HL-7702的毒性及其化合物的稳定性测试
用10μM的化合物S1处理24小时后,用MTT(噻唑蓝)检测人体正常肝细胞细胞HL-7702的细胞存活率,用于表征化合物对肝细胞HL-7702的活性(图3A);将化合物S1溶于DMSO中,配制成10μM的溶液。在250-600nm的波长范围内分别检测0,5,10,15,20,25min时化合物的吸光度。因为吸光度的强度与溶液中化合物的含量或者浓度成正比,所以用此参数表征化合物稳定性程度(图3B)。
实施例4
化合物S1对LPS刺激小鼠的生存率改善实验
小鼠服用10mg/kg化合物S115min,注射致命量的15mg/kg的LPS。每两天注射一次,观察7天内老鼠的生存率情况,每天观察一次。与不加药的空白组进行对比实验,每组分别取9只老鼠进行实验。实验结果如图4所示。
Claims (5)
1.含哌啶酮结构的姜黄素类似物S1在制备抗炎药物中的应用,所述化合物S1的化学结构如下:
S1的分子式为C30H33NO8,化学名称为:[(1E,1′E)-(4-Oxo-1-propionylpiperidine-3,5-diylidene)bismethanylylidene)]bis(2-me thoxy-4,1-phenylene)dipropionate。
2.根据权利要求1所述的应用,其中所述抗炎药物针对的炎症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。
3.根据权利要求1所述的应用,所述抗炎药物针对的炎症包括: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。
4.一种用于治疗炎症的药物组合物,其特征在于,所述药物组合物含有权利要求1所述的哌啶酮结构的姜黄素类似物S1。
5.根据权利要求书4所述的药物组合物,其特征是:所述药物组合物的制剂形式包括注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂。
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