CN115040507A - 一类倍半萜聚酮化合物作为免疫调节剂在防治免疫性疾病的用途 - Google Patents
一类倍半萜聚酮化合物作为免疫调节剂在防治免疫性疾病的用途 Download PDFInfo
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Abstract
本发明涉及一类倍半萜聚酮化合物、药物组合物及其作为免疫调节剂和防治免疫性疾病的用途。生物活性实验显示本发明涉及的倍半萜聚酮类化合物，可作为免疫调节剂用于免疫相关疾病的预防和/或治疗。
Description
技术领域
本发明属于天然药物领域，具体涉及一类倍半萜聚酮化合物作为免疫调节剂在制备预防或治疗免疫相关疾病的药物中的用途。
背景技术
免疫系统平衡对身体健康至关重要，当其被打破时容易患免疫性疾病。肿瘤和感染与机体免疫低下相关。器官移植免疫排斥、过敏和自身免疫病与机体免疫反应过强相关[1]，其中，自身免疫病包括炎症性肠病(IBD)、多发性硬化症(MS)和类风湿性关节炎(RA)在内的100余种疾病，发病重，发病率高，发病周期长，无治愈方法，严重危害人类健康。免疫调节剂可通过调节机体的免疫反应(增强、抑制或双向调节作用)，用于治疗免疫功能紊乱所引起的免疫性疾病。对于肿瘤和感染等与免疫力低下相关的疾病，可采用增强机体免疫力的调节剂进行干预。而对于器官移植免疫排斥、过敏和自身免疫病等与机体免疫反应过强相关的疾病，目前主要使用免疫抑制剂来改善疾病症状和预后。
皮质激素、甲氨蝶呤、环孢素A等化学药物属于非特异性免疫抑制剂，长期使用毒副作用大；生物制剂价格昂贵，治疗效果个体差异大，且具有增加病人感染与患肿瘤的风险。因此，开发新型免疫抑制剂来防治与免疫反应过强相关的疾病仍受到全世界的重视。近年来，我们对免疫性疾病的致病机制的研究取得了重要进展。抑制致炎因子IL17表达、促进抑炎因子IL10表达以及抑制DC细胞产生促炎因子均已成为抑制与免疫反应过强相关的免疫性疾病的有效策略，这为研发新型免疫抑制剂提供了新思路。
IL10是一类具有免疫抑制特性和广泛抗炎特性的细胞因子。IL10能调节多种髓系或淋系来源细胞的活性，抑制其产生促炎因子，从而发挥抑制器官移植免疫排斥、过敏、炎症以及自身免疫病的作用[4]。I型调节性T细胞(Tr1)分泌大量的IL10，是一类具有免疫抑制作用的细胞，目前，转输Tr1细胞防治自身免疫性疾病或保护器官移植免疫排斥的临床实验已现疗效[5]。
因此抑制IL17和/或促进IL10的化合物可作为免疫调节剂防治器官移植免疫排斥、过敏、炎症和自身免疫病(炎症性肠病、Ⅰ型糖尿病、多发性硬化症、类风湿性关节炎、银屑病、系统性红斑狼疮、哮喘、干燥综合症和强直性脊柱炎、葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、扁平苔藓、多种呼吸道疾病、多种肝脏疾病以及多种心血管疾病等)。此外，抑制IL17和/或促进IL10的化合物还可作为免疫调节剂用于痤疮、椎间盘突出、腹腔疾病等与炎症相关的疾病的治疗。IL17还与肿瘤的发生密切相关，尤其是炎症相关的肿瘤。IL10对肿瘤的发生发展具有双向调节的作用。IL10可通过抑制促进肿瘤发生发展的炎性因子的产生以及通过活化肿瘤特异性CD8+T来发挥抗肿瘤作用[4]。因此抑制IL17和/或促进IL10的化合物还可作为免疫调节剂用于肿瘤治疗。
树突状细胞(Dendritic cell，DC)是一种抗原提呈细胞，DC细胞可将抗原呈递到T细胞为T细胞的活化提供第二信号，也可通过分泌细胞因子IL6、TNFα、IL12诱导T细胞的极化。然而，当DC细胞介导的免疫反应过度激活时，可促进炎症因子风暴甚至脓毒症的发生、也会介导器官移植排斥反应、炎症和自身免疫病等免疫性疾病[6]。因此，在抗原刺激下，抑制DC细胞分泌炎症因子如IL6、TNFα、IL12等的化合物可用于炎症和自身免疫病、脓毒症、器官移植排斥反应的治疗。对于抑制DC免疫反应药效学实验，常采用小鼠骨髓来源的树突状细胞(Bone Marrow-Derived Dendritic Cells，BMDC)。
Th2细胞主要分泌细胞因子IL4。IL4具有多种生物学功能，在体液免疫和获得性免疫中发挥重要作用[7]。IL4能诱导B细胞、T细胞活化以及B细胞向浆细胞分化。此外，IL4还能抑制淋巴细胞凋亡、促进巨噬细胞的抗原提呈能力和提高杀伤肿瘤细胞的功能。因此，促进IL4的化合物可作为免疫调节剂用于抗肿瘤、抗感染(尤其是抗寄生虫感染)相关的疾病。
发明内容
本发明的目的在于提供一类倍半萜聚酮化合物、药物组合物及其用途。具体地，发明人从一株漆斑属真菌中发现并分离鉴定了一类倍半萜聚酮化合物，经实验证明其具有免疫调节活性，可用于防治免疫性疾病，尤其是炎症性肠病、多发性硬化症、银屑病和脓毒症等自身免疫性疾病。
本发明的第一方面提供了一类倍半萜聚酮化合物或其药学上可接受的盐作为免疫调节剂的用途，所述倍半萜聚酮类化合物如式(I)所示：
其中，R1选自：羟基，乙酰氧基，或＝O；
R2选自：甲基，羟甲基，乙酰羟甲基，醛基，或二甲氧基甲基；
R3选自：甲基，羟甲基，乙酰羟甲基，或醛基；
或者R2，R3与苯环组成5元内酰胺环或内酯环；
R4，R5，R6，R7为碳原子，并且任一相邻基团间选自双键，其余基团间选自单键。
进一步的，所述药学上可接受的盐为式(I)化合物与有机碱或无机碱形成的盐。
更进一步的，所述形成的盐为钠盐、钾盐、钙盐、铁盐、镁盐、锌盐、铝盐、钡盐或铵盐。
优选的，所述倍半萜聚酮类化合物选自式Ⅱ-式Ⅻ的化合物，具体结构式如下：
本发明的第二方面提供了一种上述化合物的制备方法，包括：由产生如式(I)所示的倍半萜聚酮类化合物的微生物发酵后，再用色谱法分离后得到。
进一步的，所述微生物为漆斑属真菌。
进一步可选的，所述漆斑属真菌为ZLW0801-19，其保藏号为CGMCC No.19039。
本发明的第三方面提供了一种用于免疫调节的药物组合物，包括上述倍半萜聚酮类化合物或其药学上可接受的盐以及药学上可接受的载体。
进一步可选的，所述盐为钠盐、钾盐、钙盐、铁盐、镁盐、锌盐、铝盐、钡盐、铵盐中的任意一种。
进一步可选的，在一个实施方式中药物组合物中含有的活性成份(即本发明化合物)的量可以根据患者的病情、医生诊断的情况特定的加以应用，活性化合物的量或浓度在一个较宽的范围内调节，所述式(I)化合物或其药学上可接受的盐的含量为组合物重量的1-90％。
进一步可选的，药学上可接受的载体包括稀释剂、润滑剂、粘合剂、崩解剂、稳定剂、溶剂等。本发明所述稀释剂包括但不限于淀粉、微晶纤维素、蔗糖、糊精、乳糖、糖粉、葡萄糖等；所述润滑剂包括但不限于硬脂酸镁、硬脂酸、氯化钠、油酸钠、月桂醇硫酸钠、泊洛沙母等；所述粘合剂包括但不限于水、乙醇、淀粉浆、糖浆、羟丙基甲基纤维素、羧甲基纤维素钠、海藻酸钠、聚乙烯吡咯烷酮等；所述崩解剂包括但不限于淀粉泡腾混合物即碳酸氢钠和枸橼酸、酒石酸、低取代羟丙基纤维素等；所述稳定剂包括但不限于多糖如金合欢胶、琼脂、藻酸、纤维素醚和羧甲基甲壳酯等；所述溶剂包括但不限于水、平衡的盐溶液等。
进一步可选的，所述药物组合物为口服制剂或注射剂；优选的，所述口服制剂包括但不限于普通片剂、分散片、肠溶片、颗粒、胶囊、滴丸、散剂、口服液或乳剂中的任意一种；优选的，所述注射剂选自小水针剂、输液剂或冻干粉针剂中的任意一种。
本发明的第四方面还提供了制备免疫调节剂的上述式(I)化合物或其药学上可接受的盐。
进一步的，所述免疫调节剂用于免疫相关疾病的预防和/或治疗。
更进一步的，所述免疫调节剂用于防治抑制IL17和/或促进IL10是有益的疾病或适应症。
优选的，所述疾病或适应症选自银屑病、炎症性肠病、I型糖尿病、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、哮喘、干燥综合症、强直性脊柱炎、器官移植免疫排斥、过敏、脓毒症、葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、自身免疫性肝病、扁平苔藓、痤疮、椎间盘突出、腹腔疾病。
更进一步的，所述免疫调节剂用于促进IL4是有益的疾病或适应症。
优选的，所述疾病或适应症为寄生虫感染相关。
更进一步的，所述免疫调节剂用于防治抑制DC免疫反应是有益的疾病或适应症。
优选的，所述疾病或适应症为炎症和自身免疫病、脓毒症、器官移植排斥反应。
有益效果
本发明所述的倍半萜聚酮类化合物是从微生物发酵来源，便于大量发酵和工业化制备；通过细胞和动物活性测试，首次发现该类化合物具有显著的免疫调节活性。
附图说明
图1所示为式(III)化合物显著抑制人IL17的表达。
图2所示为式(III)化合物抑制了LPS刺激的BMDC中IL12/IL23 p40+、IL6+和TNFα+细胞的比例。
图3所示为：式(III)化合物显著抑制了肠炎小鼠体重下降(图3A)、DAI评分增高(图3B)、结肠缩短(图3C)的现象；结肠组织病理分析显示，式(III)化合物显著抑制了结肠炎症、上皮损伤以及肠道结构病变的程度(图3D和3E)。
图4所示为：式(III)化合物显著降低了EAE模型小鼠的EAE评分(图4A)；脊髓组织病理分析显示，式(III)化合物处理显著抑制了脊髓炎性细胞浸润以及脱髓鞘程度(图4B)。
图5所示为：相对于模型组，式(III)化合物处理显著抑制类银屑病小鼠耳朵增厚的现象(图5A和5B)；耳朵组织病理分析结果显示，式(III)化合物处理显著抑制了类银屑病小鼠耳朵皮肤角化不全、角化过度、Munro小体形成、棘层肥厚、炎性细胞浸润和真皮血管扩张充血的病理损伤(图5C和5D)。
图6所示为式(III)化合物显著提高了LPS诱导的脓毒症小鼠的存活率。
图7所示为式(III)化合物显著抑制了肝损伤小鼠血清中ALT的水平。
具体实施方式
下面将进一步的来举例说明本发明。需要指出的是，所述实施例说明了一些制备或使用方法，然而，要理解的是，这些实施例不限制本发明。本发明的保护范围以所附权利要求书记载的内容为准。
下列实施例中，质谱仪为美国Finnigan公司生产的LCQ-Advantage质谱仪。超导核磁共振仪为Bruker AV-400。薄层色谱用硅胶GF254和柱色谱硅胶(200-300目)均为青岛海洋化工厂产品。反相ODS填料50μm为日本YMC公司产品。中低压液相色谱仪为上海利穗电子科技有限公司产品。液相分离所使用色谱柱为Phenomenex Gemini C18 column(10.0×250mm,5μm)。液相色谱用甲醇和乙腈为色谱纯，水为双重蒸馏水，其他试剂均为分析纯。
实施例中显示的体外细胞水平的实验数据以平均值±标准差(Mean±SD)表示，动物实验数据以平均值±标准误差(Mean±SEM)表示。对于比较两组数据间的差异，采用Two-tailed Student’s t test进行分析；比较多于2组的数据间的差异，采用One-way Anova进行分析；对于每个受试对象在不同的时间点进行了重复测量的数据(如体重测量、耳朵厚度测量)，采用Two-way Anova中的重复测量方差分析来比较组间差异。统计学差异采用以下标示：*代表P<0.05，**代表P<0.01，***代表P<0.001，****代表P<0.0001，ns代表差异不显著。采用Graphpad Prism 7.00和FlowJo V10(用于流式)分析获取的数据，所有病理切片由病理医生进行评估。
实施例1漆斑属真菌ZLW0801-19大量发酵及其样品前处理方法
(1)漆斑属真菌ZLW0801-19真菌菌株在25℃的马铃薯葡萄糖琼脂(PDA)斜面上培养5天。经PDA斜面活化后接种至4个含马铃薯葡萄糖(PDB)培养基的锥形瓶(250mL)中制备种子液，每个锥形瓶含有100mLPDB培养基，转速200rpm在25℃培养5天制备种子液。在24个锥形瓶(500mL)中进行发酵，每个锥形瓶中含有70g大米，首先向每个锥形瓶中加入蒸馏水(105mL)，将大米浸泡过夜，然后在120℃下高压灭菌30分钟。冷却至室温后，向每个锥形瓶接种5.0mL种子液，并在室温避光培养51天。
(2)将发酵物加入乙酸乙酯进行浸泡提取3次，将提取液减压浓缩至干，得到粗提物(81.7g)。
实施例2式(II)—式(XII)化合物的制备
实施例1中乙酸乙酯粗提物(81.7g)利用硅胶柱层析，依次采用环己烷-乙酸乙酯(100:0,98:2,95:5,90:10,80:20,70:30,50:50,0:100,v/v)、甲醇进行洗脱，每个梯度洗脱体积6L，得到7个馏分样品(F1-F7)。馏分F5经中低压液相ODS柱层析，依次采用甲醇-水(70:30,80:20,90:10,and 100:0,v/v)洗脱，每个梯度洗脱体积2.5L，得到9个馏分样品(F5.1-F5.9)。馏分F5.2经中低压液相ODS柱层析，依次采用甲醇-水(60:40,70:30,80:20,90:10,v/v)洗脱，每个梯度洗脱体积0.7L，得到5个馏分样品(F5.2.1-F5.2.5)。馏分F5.2.4(387mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的乙腈-水(50:50,v/v)进行洗脱，得到式(X)化合物(tR:53.6min,26.2mg)。将馏分F5.2.5(365mg)经反相制备级HPLC制备(Phenomenex,Packed C18 column)，使用流速为8mL/min的乙腈-水(55:45,v/v)进行洗脱，得到式(XII)化合物(tR:86.4min,7.0mg)。馏分F5.3经凝胶柱LH-20柱层析，采用甲醇洗脱得到7个馏分(F5.3.1–F5.3.7)。馏分F5.3.7(144mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的甲醇-水(75:25,v/v)进行洗脱，得到式(II)化合物(tR:63.7min,17.0mg)和式(V)化合物(tR:69.9min,17.5mg)。将馏分F5.5(1550mg)经反相制备级HPLC制备(Phenomenex,Packed C18column)，使用流速为8mL/min的甲醇-水(75:25,v/v)进行洗脱，得到式(IV)化合物(tR:73.5min,507.0mg)。馏分F5.7经硅胶柱层析，依次采用环己烷-乙酸乙酯(90:10,85:15,80:20,75:25,70:30,60:40,50:50,0:100,v/v)洗脱，每个梯度洗脱体积1.0L，得到8个馏分样品(F5.7.1-F5.7.8)。馏分F5.7.4(62.1mg)经反相制备级HPLC制备(Cosmosil Packed C18column)，使用流速为3mL/min的甲醇-水(82:18,v/v)进行洗脱，得到式(VI)化合物(tR:21.3min,12.1mg)。馏分F6经中低压液相ODS柱层析，依次采用甲醇-水(60:40,70:30,80:20,90:10,100:0,v/v)洗脱，每个梯度洗脱体积2.5L，得到7个馏分样品(F6.1-F6.7)。馏分F6.3经硅胶柱层析，依次采用环己烷-乙酸乙酯(75:25,70:30,60:40,50:50,0:100v/v)洗脱，每个梯度洗脱体积0.3L，得到6个馏分样品(F6.3.1-F6.3.6)。馏分F6.3.6(349.7mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的乙腈-水(40:60,v/v)进行洗脱，得到式(IX)化合物(tR:17.5min,7.7mg)。馏分F6.4经中低压液相ODS柱层析，采用甲醇-水(70:30,v/v)洗脱，洗脱体积0.7L，得到5个馏分样品(F6.4.1-F6.4.5)。将馏分F6.4.2(1630mg)经反相制备级HPLC制备(Phenomenex,Packed C18 column)，使用流速为8mL/min的甲醇-水(70:30,v/v)进行洗脱，得到式(III)化合物(tR:35.2min,820mg)和式(XI)化合物(tR:25.4min,4.0mg)。馏分F6.4.3(212.9mg)经反相制备级HPLC制备(Cosmosil Packed C18 column)，使用流速为3mL/min的乙腈-水(55:45,v/v)进行洗脱，得到式(VII)化合物(tR:63.3min,10.3mg)和式(VIII)化合物(tR:25.0min,10.1mg)。
理化常数如下：
式(II)化合物：无色片状晶体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.31),225(4.28),221(4.10),300(4.27)nm；ECD(c 3.4×10–4MCH3OH)λmax(Δε)221(+1.86),245(+1.71),334(–0.55),306(–0.74)；IR(KBr)νmax3399,3137,2974,2929,2864,1616,1430,1293,1262,1117,1045cm–1；ESI-MS(positive)m/z 373[M+H]+,395[M+Na]+；ESI-MS(negative)m/z 371[M–H]–,743[2M–H]–；HR-ESI-MS(positive)m/z 373.2379[M+H]+(calcd.for C23H33O4,373.2379)，确定化合物分子式为C23H32O4；1H和13C NMR见表1。
式(III)化合物：淡黄色固体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.43),225(4.35),240(4.18),299(4.31)nm；IR(KBr)νmax 3146,2969,2929,2881,1621,1625,1448,1258cm-1；ESI-MS(positive)m/z 389[M+H]+,411[M+Na]+；ESI-MS(negative)m/z 387[M–H]–,775[2M–H]–；HR-ESI-MS(positive)m/z 389.2331[M+H]+(calcd.for C23H33O5,389.2328)，确定化合物分子式为C23H32O5；1H和13C NMR见表1。
式(IV)化合物：淡黄色针状晶体；
(c 1.0,CH3OH)；(CH3OH)λmax(logε)205(4.27),223(4.23),240(4.09),299(4.27)nm；IR(KBr)νmax 3399,3160,2973,2838,2868,1708,1619,1435,1268,1002cm–1；ESI-MS(positive)m/z 453[M+Na]+,883[2M+Na]+；ESI-MS(negative)m/z 429[M–H]–,859[2M–H]–；HR-ESI-MS(positive)m/z 453.2261[M+Na]+(calcd.for C25H34O6Na,453.2253)，确定化合物分子式为C25H34O6；1H和13C NMR见表1。
式(V)化合物：淡黄色固体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.47),226(4.43),242(4.31),300(4.44)nm；IR(KBr)νmax 3430,2961,2931,2868,1719,1622,1435,1265,1039cm–1；ESI-MS(positive)m/z 453[M+Na]+,883[2M+Na]+；ESI-MS(negative)m/z 429[M–H]–,859[2M–H]–；HR-ESI-MS(positive)m/z 431.2433[M+H]+(calcd.for C25H35O6,431.2434)，确定化合物分子式为C25H34O6；1H和13C NMR见表1。
式(VI)化合物：淡黄色油状；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.52),226(4.47),242(4.31),298(4.45)nm；IR(KBr)νmax 3279,2934,2867,1708,1618,1434,1267,1032cm–1；ESI-MS(positive)m/z 495[M+Na]+,967[2M+Na]+；ESI-MS(negative)m/z 471[M–H]–,943[2M–H]–；HR-ESI-MS(positive)m/z 495.2368[M+Na]+(calcd.forC27H36O7Na,495.2359)，确定化合物分子式为C27H36O7；1H和13C NMR见表2。
式(VII)化合物：淡黄色油状；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)205(4.37),225(4.35),239(4.18),300(4.35)nm；ECD(c 3.2×10–4MCH3OH)λmax(Δε)201(+1.34),235(+2.04),274(–0.80),324(+0.46)；IR(KBr)νmax3411,2929,2858,1618,1434,1386,1267,1240,1125,1050cm–1；ESI-MS(positive)m/z 387[M+H]+,409[M+Na]+；ESI-MS(negative)m/z 385[M–H]–,771[2M–H]–；HR-ESI-MS(positive)m/z 409.2009[M+Na]+(calcd.for C23H30O5Na,409.2015)，确定化合物分子式为C23H30O5；1H和13C NMR见表2。
式(VIII)化合物：淡黄色固体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.36),226(4.30),240(4.16),299(4.33)nm；ECD(c 5.8×10–4MCH3OH)λmax(Δε)224(+0.99),249(+3.46),302(–0.76),361(–1.02)；IR(KBr)νmax3399,2934,2850,1617,1386,1267,1245,1125,1050,988cm–1；ESI-MS(positive)m/z 455[M+Na]+,895[2M+Na]+；ESI-MS(negative)m/z 431[M–H]–,863[2M–H]–；HR-ESI-MS(positive)m/z 455.2415[M+Na]+(calcd.for C25H36O6Na,455.2410)，确定化合物分子式为C25H36O6；1H和13C NMR见表2。
式(IX)化合物：淡绿色固体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)215(4.57),262(4.06),305(3.27)nm；IR(KBr)νmax 3385,2929,2863,1675,1452,1386,1262cm–1；ESI-MS(positive)m/z 386[M+H]+,793[2M+Na]+；ESI-MS(negative)m/z 769[2M–H]–；HR-ESI-MS(positive)m/z 386.2340[M+H]+(calcd.for C23H32NO4,386.2331)，确定化合物分子式为C23H31NO4；1H和13C NMR见表2。
式(X)化合物：淡绿色固本；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.44),223(4.46),240(4.42),298(4.33)nm；ECD(c 6.0×10–4MCH3OH)λmax(Δε)204(+7.00),247(+18.5),330(+1.81)；IR(KBr)νmax 3283,2970,2925,2867,1621,1618,1430,1267,1005cm–1；ESI-MS(positive)m/z 409[M+Na]+,795[2M+Na]+；ESI-MS(negative)m/z385[M–H]–,771[2M–H]–；HR-ESI-MS(positive)m/z 387.2176[M+H]+(calcd.for C23H31O5,387.2176)，确定化合物分子式为C23H30O5；1H和13C NMR见表3。
式(XI)化合物：白色固体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.39),226(4.06),289(3.69)nm；ECD(c 6.4×10–4M CH3OH)λmax(Δε)220(+3.81),236(+3.09),246(+3.74),323(–0.54)；IR(KBr)νmax 3301,2961,2872,1628,1462,1284,1125,1076cm–1；ESI-MS(positive)m/z 389[M+H]+,411[M+Na]+；ESI-MS(negative)m/z 387[M–H]–,775[2M–H]–；HR-ESI-MS(positive)m/z389.2329[M+H]+(calcd.for C23H33O5,389.2328)，确定化合物分子式为C23H32O5；1H和13C NMR见表3。
式(XII)化合物：白色固体；
(c 1.0,CH3OH)；UV(CH3OH)λmax(logε)206(4.41),227(4.09),290(3.76)nm；ECD(c 2.9×10–4M CH3OH)λmax(Δε)220(+5.47),235(+4.19),246(+5.58),320(–1.30)；IR(KBr)νmax 3479,29743,2881,1740,1623,1489,1270,1045cm–1；ESI-MS(positive)m/z 453[M+Na]+；ESI-MS(negative)m/z 429[M–H]–,HR-ESI-MS(positive)m/z 453.2246[M+Na]+(calcd.for C25H34O6Na,453.2353)，确定化合物分子式为C25H34O6；1H和13C NMR见表3。
表1式(II)—式(V)化合物的13C NMR及1H NMR数据和归属
aThe data recorded in DMSO-d6(1H NMR for 300MHz,13C NMR for 75MHz)
bThe data recorded in DMSO-d6(1H NMR for 400MHz,13C NMR for 100MHz)
表2式(VI)—式(IX)化合物的13C NMR及1H NMR数据和归属
a The data recorded in DMSO-d6(1H NMR for 300 MHz,13C NMR for 75 MHz)
bThe data recorded in DMSO-d6(1H NMR for 400MHz,13C NMR for 100MHz)
表3式(X)—式(XII)化合物的13C NMR及1H NMR数据和归属
aThe data recorded in DMSO-d6(1H NMR for 300MHz,13C NMR for 75MHz)
实施例3倍半萜聚酮类化合物式(II)—式(XII)对IL17表达的影响
T细胞分化后产生特定细胞因子，如Th17产生细胞因子IL17，Th2产生细胞因子IL4，Tr1产生细胞因子IL10。IL17-GFP小鼠、IL4-eGFP小鼠和IL10-eGFP小鼠(均引自JAX公司)是带有绿色荧光报告基因(GFP)的转基因小鼠，其在T细胞分化后产生的特定细胞因子的基因下游连接上GFP荧光蛋白编码序列。因此可用荧光探测系统检测GFP的表达量来衡量细胞因子的表达水平。
提取荧光报告小鼠IL17-GFP小鼠的原代脾脏淋巴细胞，在Th17分化条件下与化合物共培养，通过流式细胞术检测IL17-GFP水平来评价化合物对IL17表达的影响(此方法使用原代淋巴细胞更好模拟复杂的生理过程；使用GFP小鼠和流式细胞术使实验简便，重复性好且结果可靠)。具体实验步骤如下：
Anti-mouse CD3 Ab(antibody，抗体)包板：在96孔板中加入IMDM培养基稀释的终浓度为10μg/mL的anti-mouse CD3 Ab，37℃孵育2小时。
制备单细胞悬液：无特定病原体(SPF)环境下饲养的IL17-GFP小鼠，颈椎脱臼处死，取脾脏置于IMDM培养基中，用灭菌的病理玻片在超净台中磨碎脾脏，磨碎后的细胞悬液用40μm cell strainer滤网过滤至离心管；后离心(4℃，1400rpm，7分钟)，弃上清，加红细胞裂解液，混匀，室温静置5分钟，后加IMDM终止裂解红细胞；40μm cell strainer滤网过滤后再离心(4℃，1400rpm，7分钟)，弃上清，用含10％FBS的IMDM重悬细胞；细胞稀释100倍，显微镜下细胞计数，根据计数结果，配成1×106个/mL(终浓度)的细胞悬液。
加入Th17细胞分化诱导因子：anti-mouse CD28 Ab(1μg/mL)，rhTGFb1.2(0.25ng/mL)，rmIL6(40ng/mL)，anti-mouse IL4(5μg/mL)，anti-mouse IFNγ(5μg/mL)(此处细胞因子均为终浓度)。
待检测样本稀释：用含10％FBS的IMDM将化合物稀释成10μM(终浓度)；将抑制IL17的阳性化合物SR2211稀释成1μM(终浓度)。
铺板：将包板的抗体吸去，用IMDM洗一遍，每孔加入100μL细胞悬液和100μL终浓度样本溶液共培养(如100μL 4×106个/mL浓度的细胞悬液和100μL20μM化合物共培养，培养体系中细胞终浓度为2×106个/mL，化合物浓度为10μM)。
细胞培养：样本溶液和细胞置于37℃，5％的CO2的湿润培养箱中共培养72小时。
细胞表面染色和流式检测：收取培养的细胞于流式管，加入3mL预冷的PBS，离心(4℃，1400rpm，7分钟)，弃上清，后在50μL细胞悬液中加入0.25μL APC anti-mouse CD4抗体表面染色，4℃避光放置20分钟。后用1mL预冷的PBS重悬细胞，补2mL PBS，再离心(4℃，1400rpm，7分钟)，弃上清，每管加200μL PBS，流式检测分析GFP+的细胞占CD4+细胞的比率。
其中IMDM培养基和胎牛血清(FBS)购自Gibco公司；anti-mouse CD28 Ab，anti-mouse CD3 Ab，anti-mouse IL4，anti-mouse IFNγ，APC anti-mouse CD4购自Sungene公司；rmIL6购自Peprotech公司；rhTGFb1.2购自R&D公司；红细胞裂解液购自Tiangen公司；PBS购自Solarbio公司。
采用公式：(DMSO组GFP+占CD4+的比率-化合物组GFP+占CD4+的比率)/DMSO组GFP+占CD4+的比率×100％来计算化合物对IL17的相对抑制活性(Relative InhibitionActivity)。
结果如表4所示：脾脏淋巴细胞向Th17细胞分化条件下，本发明化合物式(II)、式(III)、式(V)、式(XI)和式(XII)对IL17的相对抑制活性显著增强。这表明，本发明化合物式(II)、式(III)、式(V)、式(XI)和式(XII)具有抑制IL17表达的效果，可用于防治免疫相关疾病尤其是IL17介导的免疫性疾病。
表4式(II)—式(XII)化合物对IL17表达影响(10μM)
实施例4倍半萜聚酮类化合物式(II)—式(XII)对IL4表达的影响
提取荧光报告小鼠IL4-eGFP小鼠的原代脾脏淋巴细胞，在Th2分化条件下与化合物共培养，通过流式细胞术检测IL4-GFP水平来评价化合物对IL4表达的影响。Th2使用的培养基为RPMI-1640；细胞密度为2×106个/mL；使用的分化条件为：anti-mouse CD28 Ab(1μg/mL)，rmIL2(2ng/mL)，rmIL4(40ng/mL)，Anti-mouse IFNγ(10μg/mL)。其他Th2分化的实验步骤同实施例3中的Th17分化一致。
其中rmIL4，rmIL2购自Peprotech公司；RPMI-1640培养基购自Sigma公司。
在评价化合物对IL4表达的影响时，采用公式：化合物组GFP+占CD4+的比率/DMSO组GFP+占CD4+的比率×100％来计算化合物对IL4的相对活性(Relative Activity)。
具体结果如表5所示：脾脏淋巴细胞向Th2细胞分化条件下，本发明化合物式(II)、式(III)、式(X)、式(XI)和式(XII)对IL4的相对活性显著增强。这表明本发明化合物式(II)、式(III)、式(X)、式(XI)和式(XII)具有促进IL4表达的效果，可用于抗寄生虫感染。
表5式(II)—式(XII)化合物对IL4表达影响(10μM)
| Compounds | Relative Activity(％)(10μM) | P-value |
| 式II | 169.77±4.65 | **** |
| 式III | 165.12±33.48 | ** |
| 式IV | 97.91±7.68 | ns |
| 式V | 101.63±5.82 | ns |
| 式VI | 89.77±2.79 | ns |
| 式VII | 88.61±2.56 | ns |
| 式VIII | 87.68±1.63 | ns |
| 式IX | 87.68±2.56 | ns |
| 式X | 247.21±1.16 | **** |
| 式XI | 216.75±3.26 | **** |
| 式XII | 346.98±2.33 | **** |
实施例5倍半萜聚酮类化合物式(II)—式(XII)对IL10表达的影响
提取分选荧光报告小鼠IL10-eGFP小鼠的原代脾脏淋巴细胞，在Tr1分化条件下与化合物共培养，通过流式细胞术检测IL10-eGFP水平来评价化合物对IL10表达的影响。Tr1使用的培养基为RPMI-1640；细胞密度为1×106个/mL；使用的分化条件为：anti-mouseCD28 Ab(1μg/mL)，rmIL27(50ng/mL)，rhTGFb1.2(0.5ng/mL)。其他Tr1分化的实验步骤同实施例3中的Th17分化一致。
其中rmIL27购自Biolegend公司；RPMI-1640培养基购自Sigma公司。
在评价化合物对IL10的影响时，采用公式：化合物组GFP+占CD4+的比率/DMSO组GFP+占CD4+的比率×100％来计算化合物对IL10的相对活性(Relative Activity)。
具体结果如表6所示：脾脏淋巴细胞向Tr1细胞分化条件下，本发明化合物式(II)、式(III)、式(IV)、式(VI)、式(VII)、式(VIII)、式(IX)、式(X)、式(XI)和式(XII)对IL10的相对活性显著增强。这表明上述化合物具有促进IL10表达的效果，可发挥广谱的抗炎作用，用于抗炎和自身免疫疾病。
表6式(II)—式(XII)化合物对IL10表达影响(20μM)
| Compounds | Relative Activity(％)(20μM) | P-value |
| 式II | 265.43±7.25 | **** |
| 式III | 285.40±9.68 | **** |
| 式IV | 118.74±1.09 | ** |
| 式V | 112.78±4.28 | ns |
| 式VI | 117.79±5.93 | * |
| 式VII | 114.74±1.95 | * |
| 式VIII | 115.47±3.49 | * |
| 式IX | 116.12±5.19 | * |
| 式X | 274.15±4.40 | **** |
| 式XI | 236.75±10.91 | **** |
| 式XII | 332.97±3.83 | **** |
综合上述实施例3、4和5的结果可知：倍半萜聚酮类化合物具有抑制IL17、促进IL4和促进IL10表达的活性，可用于免疫性疾病的防治。
实施例6式(III)化合物抑制人IL17表达
从健康人外周血液样本中分离出人外周血单核细胞(PBMC)，采用EasySepTM Human
CD4+T Cell Isolation Kit II试剂盒(购自Stem cell)从人的PBMC中分离出人的naive CD4+T细胞，用于后续人的Th17分化。
用含10％FBS的IMDM将分选的人的naive CD4+T细胞稀释到5×105个/mL，加入anti-human CD28 Ab(1μg/mL)；rhIL6(40ng/mL)；rhTGFβ1.2(0.5ng/mL)；anti-human IL4(10μg/mL)；anti-human IFNγ(10μg/mL)；在上述细胞悬液中分别加入DMSO和2.5μM式(III)化合物，接种于anti-human CD3 Ab(5μg/mL)包板2小时的培养板，放入细胞培养箱中培养；在第三天补加rhIL6，第五天洗去anti-human CD23 Ab和anti-human CD28 Ab，用含rhIL6，rhTGFβ1.2，anti-human IL4，anti-human IFNγ的新的培养基转孔，继续培养2天；用含rhIL6，rhTGFβ1.2，anti-human IL4，anti-human IFNγ的新的培养基分孔，再培养2天。
人的Th17分化好后，用50ng/mL PMA、1μg/mL Ionomycin和Golgi-Plug刺激5小时。加入流式抗体BV421 anti-human IL17A和BV500 anti-human CD4，按照胞内染色试剂盒的实验步骤进行染色。
其中anti-human CD3，anti-human CD28，anti-human IFNγ，anti-human IL4购自Tonbo Biosciences公司；rhIL6购自Peprotech公司；BV421 anti-human IL17A购自BioLegend公司，BV500 anti-human CD4购自BD公司。
实验结果如图1所示：人的naive CD4+T细胞向人的Th17分化的条件下，式(III)化合物显著抑制了人的CD4+T细胞中IL17+细胞的比例。这说明，式(III)化合物具有抑制人的IL17表达的效果。
实施例7式(III)化合物抑制BMDC分泌炎性细胞因子
从C57BL/6小鼠腿骨提取骨髓来源的细胞，在骨髓来源的树突状细胞(BMDC)培养液(含50ng/mL GM-CSF、20ng/mL IL4预温的10％FBS的1640培养基)中培养2天，转移上清到新的皿并补加BMDC培养液继续培养2天，半换液继续培养2天；收集细胞，磁珠富集BMDC后将细胞稀释到2×105/mL，每管1mL接种于流式管，培养过夜；在培养过夜的BMDC中分别加入DMSO和5μM式(III)化合物，在LPS(100ng/mL)刺激下培养18小时后加入Golgi-Plug处理6小时；加入Purified Rat Anti-Mouse CD16/CD32封闭15分钟，加入流式抗体Percepcy5.5anti-mouse CD11c、eF450 anti-mouse MHCⅡ、FITC anti-mouse TNFα、PE anti-mouseIL6和APC anti-mouse IL12/IL23 p40，按照胞内染色试剂盒的实验步骤进行染色。
其中Percepcy5.5 anti-mouse CD11c、FITC anti-mouse TNFα、PE anti-mouseIL6和APC anti-mouse IL12/IL23 p40购自Biolegend公司；eF450 anti-mouse MHCⅡ购自Invitrogen公司；Purified Rat Anti-Mouse CD16/CD32购自BD公司。
实验结果如图2所示：式(III)化合物抑制了LPS刺激的BMDC(CD11c+MHCII+细胞)中IL12/IL23 p40+、IL6+和TNFα+细胞的比例。这说明式(III)化合物具有抑制BMDC产生炎性细胞因子IL12/IL23、IL6和TNFα的效果。
实施例8式(III)化合物具有抑制DSS诱导的急性肠炎的效果
硫酸葡聚糖钠(DSS)诱导的小鼠肠炎是经典的炎性肠病(IBD)模型。建模步骤如下：第0到第4天，C57BL/6小鼠自由饮用3％DSS(购自MP公司)；第5天将3％DSS撤离换成水，继续饲养3天。
将10周龄雄性C57BL/6小鼠分为4组，每组8只，各组处理如下：空白对照组(Control+Vehicle)：自由饮用纯水，每天腹腔注射溶剂2次；DSS模型组(DSS+Vehicle)：自由饮用3％DSS，每天腹腔注射溶剂2次；高剂量组(DSS+Formula III(H))：自由饮用3％DSS，每天腹腔注射40mg/kg式(III)化合物2次；低剂量组(DSS+Formula III(L))：自由饮用3％DSS，每天腹腔注射20mg/kg式(III)化合物2次。Vehicle指溶解式(III)化合物的溶剂，由5％DMSO+5％Solutol HS 15(聚乙二醇-15羟基硬脂酸酯，购自巴斯夫公司)+90％注射用水组成。
实验期间每天称量小鼠体重，监测小鼠粪便成型程度以及便隐血情况，按照发病严重程度打分(每项0-4分)。临床疾病活动指数(DAI)是临床上用于评价疾病活动程度的一项指标，DAI分数＝(体重下降评分+大便成型评分+便血评分)/3。
实验第8天处死小鼠，取出完整结肠测量小鼠结肠长度。PBS冲洗结肠，解剖远端结肠用于病理分析。
实验结果发现：式(III)化合物显著抑制了肠炎小鼠体重下降(图3A)、DAI评分增高(图3B)、结肠缩短(图3C)的现象(n＝8)；病理分析的结果显示式(III)化合物显著抑制了结肠炎症、上皮损伤以及肠道结构病变的程度(图3D和3E)(n＝8)。这些结果说明式(III)化合物具有抑制DSS诱导的急性肠炎的效果，可用作炎症性肠病治疗。
实施例9式(III)化合物具有治疗小鼠EAE的效果
MOG35-55诱导的实验性自身免疫性脑膜炎(EAE)是经典的模拟人类多发性硬化症(MS)的小鼠模型。建模步骤如下：取MOG35-55(上海吉尔生化公司)，调整浓度为2mg/mL；取不完全弗氏佐剂(Sigma公司)，加入灭活的结核杆菌H37 RA(DIFCO公司)，调整浓度为5mg/mL；按照体积比1:1将MOG35-55溶液与弗氏佐剂混合，冰上乳化2小时至油包水状态；小鼠麻醉后，在小鼠双耳后侧及股侧皮下进行免疫，每个部位注射50μL，共200μL/只，此时设为第0天；在免疫的第0天及第2天，每只小鼠每次腹腔注射300ng百日咳毒素(List labs公司)。该实验免疫小鼠为10周龄雌性C57BL/6小鼠。
EAE评分是用于评价EAE疾病活动程度的一项指标，按照疾病严重程度可评分0-5分：0分-无明显异常；0.5分-尾尖无力，运动能力未见异常；1分-整条尾巴无力，运动能力未见异常；1.5分-整条尾巴无力，两条后肢可分开，运动偶有踩空；2分-整条尾巴无力，两条后肢合在一起，运动常见踩空；2.5分-一条后肢拖行；3分-两条后肢拖行，仰面放置后可自行翻身；3.5分-两条后肢拖行，仰面放置后不能自行翻身，前肢可正常抓取笼架金属条；4分-小鼠两条后肢拖行，仰面放置后不能自行翻身，一条前肢无力，不能正常抓取笼架金属条；4.5分-小鼠四肢瘫痪；5分-小鼠死亡或连续2天超过4分。
建模10天后，将23只已初步发病(EAE评分0.5-1分)的小鼠随机分为2组，各组处理如下：EAE模型组(EAE+Vehicle)：每天腹腔注射溶剂2次，连续5天，n＝11；式(III)化合物处理组(EAE+Formula III)：每天腹腔注射40mg/kg式(III)化合物2次，连续5天，n＝12。
实验期间每天对小鼠的EAE评分进行打分。在式(III)化合物进行干预的第5天，处死小鼠，取脊髓膨大区组织用于病理分析。
实验结果发现：式(III)化合物显著降低了EAE模型小鼠的EAE评分(图4A)；脊髓病理分析结果显示，式(III)化合物处理显著抑制了脊髓炎性细胞浸润以及脱髓鞘程度(图4B)。这些结果说明式(III)化合物具有治疗小鼠EAE的效果，可用作多发性硬化症的治疗。
实施例10式(III)化合物具有治疗小鼠类银屑病的效果
局部涂抹咪喹莫特(IMQ)诱导的小鼠类银屑病在表型和组织学特征上与人类银屑病非常相似。建模步骤如下：实验第0天到第7天小鼠耳朵每天涂抹25mg IMQ(四川明欣利迪公司)，第7天发病达高峰期；之后间隔一天涂抹IMQ维持病情。
将8周龄雄性Babl/c小鼠分为3组，各组处理如下：空白对照组(Control+Vehicle)：实验全程不涂IMQ，第7天后每天腹腔注射溶剂2次，n＝6；模型组(IMQ+Vehicle)：连续7天涂抹IMQ，之后间隔一天涂抹IMQ维持病情，第7天后每天腹腔注射溶剂2次，n＝6；式(III)化合物处理组(EAE+Formula III)：连续7天涂抹IMQ，之后间隔一天涂抹IMQ维持病情，第7天后每天腹腔注射20mg/kg式(III)化合物，n＝8。
实验期间每天测量耳朵厚度。实验第21天处死小鼠，对小鼠耳朵拍照，取耳朵组织用于病理分析。
实验结果发现：相对于模型组，式(III)化合物处理显著抑制类银屑病小鼠耳朵增厚的现象(图5A和5B)；耳朵病理切片H&E染色评分显示，式(III)化合物处理显著抑制了类银屑病小鼠耳朵皮肤角化不全、角化过度(鳞状上皮增生)、Munro小体形成、棘层肥厚、炎性细胞浸润和真皮血管扩张充血(图5C和5D)。这些结果说明式(III)化合物具有治疗小鼠类银屑病的效果，可用作银屑病的治疗。
实施例11式(III)化合物对LPS诱导的小鼠脓毒症具有保护作用
脂多糖(LPS)诱导的小鼠脓毒症模型是经典的脓毒症动物模型。实验采用腹腔注射致死剂量的35mg/kg LPS(购自Sigma公司)诱导脓毒症。
将雄性C57BL/6小鼠分为2组，各组处理如下：模型组(LPS+Vehicle)：腹腔单次注射溶剂，n＝11；式(III)化合物处理组(LPS+Formula III)：腹腔单次注射20mg/kg式(III)化合物，n＝13。小鼠给与溶剂或式(III)化合物预处理2小时后，腹腔注射致死剂量的35mg/kg LPS诱导脓毒症。
观察小鼠存活情况，同时记录小鼠死亡时间，直到第6天。
使用Graphpad 7.0绘制生存曲线，进行显著性分析。具体结果如图6所示：式(III)化合物显著提高了小鼠的存活率。这些结果说明式(III)化合物对LPS诱导的小鼠脓毒症具有保护作用，可用于脓毒症的防治。
实施例12式(III)化合物对APAP诱导的肝损伤具有保护作用
对乙酰氨基酚(APAP)诱导的肝损伤模拟了临床的药物性肝损伤。实验前一天小鼠禁食不禁水，实验采用腹腔注射250mg/kg APAP(购自sigma公司)诱导小鼠药物性肝损伤。
将雄性C57BL/6小鼠分为2组，各组处理如下：模型组(APAP+Vehicle)：腹腔单次注射溶剂，n＝6；式(III)化合物处理组(APAP+Formula III)：腹腔单次注射20mg/kg式(III)化合物，n＝6。小鼠给与溶剂或式(III)化合物预处理0.5小时后，腹腔注射250mg/kg APAP诱导小鼠药物性肝损伤。
分别于APAP注射前以及注射后3小时，6小时，12小时，24小时从小鼠眼框采集血样，肝素钠抗凝。血液样本采集后使用ALT试剂盒(购自上海荣盛生物药业有限公司)检测小鼠血清中谷丙转氨酶(ALT)水平。
具体结果如图7所示：式(III)化合物显著抑制了肝损伤小鼠血清中ALT的水平。这些结果说明式(III)化合物对APAP诱导的肝损伤具有保护作用，可用于药物性肝损伤的防治。
本发明内容仅仅举例说明了要求保护的一些具体实施方案，其中一个或更多个技术方案中所记载的技术特征可以与任意的一个或多个技术方案相组合，这些经组合而得到的技术方案也在本申请保护范围内，就像这些经组合而得到的技术方案已经在本发明公开内容中具体记载一样。
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Claims (18)
1.一类倍半萜聚酮化合物或其药学上可接受的盐作为免疫调节剂的用途，其特征在于，所述倍半萜聚酮化合物如式(I)所示：
其中，R1选自：羟基，乙酰氧基，或＝O；
R2选自：甲基，羟甲基，乙酰羟甲基，醛基，或二甲氧基甲基；
R3选自：甲基，羟甲基，乙酰羟甲基，或醛基；
或者R2，R3与苯环组成5元内酰胺环或内酯环；
R4，R5，R6，R7为碳原子，并且任一相邻基团间选自双键，其余基团间选自单键。
2.根据权利要求1所述的用途，其特征在于，所述药学上可接受的盐为所述倍半萜聚酮化合物与有机碱或无机碱形成的盐。
3.根据权利要求2所述的倍半萜聚酮类化合物或其药学上可接受的盐，其特征在于，所述形成的盐为钠盐、钾盐、钙盐、铁盐、镁盐、锌盐、铝盐、钡盐或铵盐。
4.一类倍半萜聚酮化合物或其药学上可接受的盐，其特征在于所述化合物为：
5.根据权利要求1-4中任一项所述倍半萜聚酮化合物或其药学上可接受的盐的制备方法，其特征在于，包括：由产生如式(I)所示的倍半萜聚酮类化合物的微生物，经发酵后再用色谱法分离后得到。
6.根据权利要求5所述的制备方法，其特征在于，所述微生物为漆斑属真菌。
7.根据权利要求6所述的制备方法，其特征在于，所述漆斑属真菌为ZLW0801-19，其保藏号为CGMCC No.19039。
8.根据权利要求1所述的用途，其特征在于，所述免疫调节剂用于免疫相关疾病的预防和/或治疗。
9.根据权利要求8所述的用途，其特征在于，所述的免疫相关疾病的预防和/或治疗是防治抑制IL17和/或促进IL10是有益的疾病或适应症。
10.根据权利要求9所述的用途，其特征在于，所述疾病或适应症选自银屑病、炎症性肠病、I型糖尿病、多发性硬化症、类风湿性关节炎、系统性红斑狼疮、哮喘、干燥综合症、强直性脊柱炎、器官移植免疫排斥、过敏、脓毒症、葡萄膜炎、自身免疫性肾炎、自身免疫甲状腺炎、白塞氏病、自身免疫性肝病、药物性肝损伤、扁平苔藓、痤疮、椎间盘突出、腹腔疾病。
11.根据权利要求8所述的用途，其特征在于，所述的免疫相关疾病的预防和/或治疗是防治促进IL4是有益的疾病或适应症。
12.根据权利要求11所述的用途，其特征在于，所述疾病或适应症为寄生虫感染相关。
13.根据权利要求8所述的用途，其特征在于，所述的免疫相关疾病的预防和/或治疗是防治抑制DC免疫反应是有益的疾病或适应症。
14.根据权利要求13所述的用途，其特征在于，所述疾病或适应症为炎症和自身免疫病、脓毒症、器官移植排斥反应。
15.一种用于免疫调节的药物组合物，其特征在于，包括权利要求1-4中任意一项所述倍半萜聚酮化合物或其药学上可接受的盐以及药学上可接受的载体。
16.根据权利要求15所述的药物组合物，其特征在于，所述倍半萜聚酮化合物或其药学上可接受的盐的含量为组合物重量的1-90％。
17.根据权利要求15-16所述的药物组合物，其特征在于，所述药物组合物为口服制剂或注射剂。
18.根据权利要求17所述的药物组合物，其特征在于，所述口服制剂选自普通片剂、分散片、肠溶片、颗粒、胶囊、滴丸、散剂、口服液或乳剂，所述注射剂为小水针剂、输液剂或冻干粉针。
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| WO2023232126A1 (zh) * | 2022-06-02 | 2023-12-07 | 暨南大学 | 一个倍半萜聚酮化合物用于防治肺动脉高压的用途 |
| WO2023232123A1 (zh) * | 2022-06-02 | 2023-12-07 | 暨南大学 | 一类倍半萜聚酮化合物作为免疫调节剂在防治免疫性疾病的用途 |
| WO2023232125A1 (zh) * | 2022-06-02 | 2023-12-07 | 暨南大学 | 一类倍半萜聚酮化合物、药物组合物及其用途 |
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| CN114956974B (zh) * | 2022-06-02 | 2023-10-31 | 暨南大学 | 一类倍半萜聚酮化合物、药物组合物及其用途 |
| CN114796171A (zh) * | 2022-06-02 | 2022-07-29 | 暨南大学 | 一个倍半萜聚酮化合物用于防治肺动脉高压的用途 |
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| US20170209519A1 (en) * | 2016-01-26 | 2017-07-27 | Industrial Technology Research Institute | Pharmaceutical composition for treating or alleviating autoimmune-related diseases and method for treating or alleviating autoimmune-related diseases |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2023232126A1 (zh) * | 2022-06-02 | 2023-12-07 | 暨南大学 | 一个倍半萜聚酮化合物用于防治肺动脉高压的用途 |
| WO2023232123A1 (zh) * | 2022-06-02 | 2023-12-07 | 暨南大学 | 一类倍半萜聚酮化合物作为免疫调节剂在防治免疫性疾病的用途 |
| WO2023232125A1 (zh) * | 2022-06-02 | 2023-12-07 | 暨南大学 | 一类倍半萜聚酮化合物、药物组合物及其用途 |
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