CN115181099B - 一种醌类化合物及其药学应用 - Google Patents
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Abstract
本发明公开一种醌类化合物及其药学应用,具有通式(I)所述的化学结构。本发明具有药用价值,具有独特止痛效果,抑制炎症,抑制肿瘤细胞的侵袭和生长。可用于制备镇痛,抗肿瘤,抗炎、治疗自身免疫性疾病等的药物。
Description
技术领域
本发明涉及医药化学领域,具体涉及一种新结构化合物,具有通式(I)所述的化学结构。
背景技术
吡咯喹啉醌(pyrroloquinoline quinone,PQQ),它是继黄素核苷酸(FAD)和烟酰胺核苷酸(NAD)之后在细菌脱氢酶中发现的第三种辅基,化学名称为4,5-二氢-4,5-二氧化-1-氢吡咯(2,3f)醌-2,7,9-三羧酸。结构式如下:
虽然自然条件下仅少数细菌能够合成PQQ,但在各种植物、动物以及人体内都发现含有微量PQQ,尤其在母乳中相对含量较高。PQQ作为一种普遍存在于动物和植物组织中的氧化还原酶辅基,含量非常低,但作用重要,不仅是一种新发现的线粒体呼吸链组分,参与催化生物体内氧化还原反应,还具有非常多样的生物活性,缺乏时会引起哺乳动物诸多障碍,被认为是一种新型维生素。
关于PQQ的研究可追溯到1959年,在研究非磷酸化细菌的葡萄糖代谢时(一般细菌代谢葡萄糖是通过葡萄糖-6-磷酸途径),观察到乙酸钙不动杆菌(Acinetobactercalcoaceticus)含有一种不依赖于NAD(P)和FAD的葡萄糖脱氢酶(glucose dehydrogenase,GDH)。随后Hauge通过这种酶得到一种可分离的辅基,并推断这个辅基可能是一种萘醌的衍生物[Hauge,J.G.,Glucose dehydrogenase of bacterium anitratum:an enzyme with anovel prosthetic group.J Biol Chem.1964Nov;239:3630-9]。
Duine等于1979年提出,该辅基是一个含两个N原子的醌型结构物质[Duine JA,Frank J,van Zeeland JK.Glucose dehydrogenase from Acinetobactercalcoaceticus:a'quinoprotein'.FEBS Lett.1979Dec 15;108(2):443-6..]。与此同时,Salisbury等通过X-射线晶体衍射技术对该辅基的结晶丙酮加成物分析后,确定此辅基为三羧基吡咯喹啉醌结构,其结构式是4,5-二氢-4,5二氧-1-氢吡咯并(2,3-f)喹啉-2,7,9-三羧酸[Salisbury SA,Forrest HS,Cruse WB,Kennard O.A novel coenzyme frombacterial primary alcohol dehydrogenases.Nature.1979Aug 30;280(5725):843-4]。
PQQ的发现是醌酶研究史上的一个重要事件。它不仅使人们认识了一个新辅基,而且意味着酶学将出现一个新的分支:醌酶,即以PQQ和其它醌类化合物作为辅基的氧化还原酶类。在发现PQQ之前,人们曾认为氧化还原酶只有NAD/NADP和FAD/FMN两类辅基。
PQQ功能广泛,简述如下:
1,PQQ具有广泛的营养滋养功能。
PQQ能够促进微生物和植物的生长,影响动物的生长与生殖。动物不能内源生成PQQ,是必不可少的营养因子。缺少PQQ可导致小鼠生长发育不良和生育能力下降:雌鼠时产仔数量仅为饮食含PQQ雌鼠的一半,且缺PQQ的雌鼠的后代半数活不过断奶期(4周)。
小鼠食物中PQQ低于200ng/g时,细胞增殖所需的细胞***素,尤其是促进淋巴细胞***增殖的IL-2减少,T细胞成熟、加工过程受阻,最终成熟的T细胞有缺陷,导致小鼠机体免疫反应力低下[Steinberg,F.M.et al.Dietary pyrroloquinoline quinone:growthand immune response in BALB/c mice.Journal of Nutrition,1994.124(5):p 744]。
妊娠期小鼠或新生幼鼠缺乏PQQ,将导致皮肤中赖氨酰氧化酶的含量显著减少(只有正常皮肤值的10%~30%),胶原蛋白溶解度翻倍,皮肤变得干燥、易脱落。说明PQQ对胶原蛋白交联和皮肤健康有重要价值[Nishigori et al,Preventive effect ofpyrroloquinoline quinone(PQQ)on biliverdin accumulation of the liver of chickembryo after glucocorticoid administration.Life Sciences,1993.52(3):p 305-12.]。
2,抗氧化功能
生物体内各种自由基的产生与清除应处于动态平衡,即机体内的自由基要始终保持一定水平。自由基过多或过少对机体都不利。过多时,会促进机体衰老引发各种疾病,包括癌症、心脏病等;过少时,也会影响健康甚至阻碍正常代谢或诱发另一类疾病。PQQ通过以下几方面机制防止机体氧化损伤。
动物细胞组织和体液中的游离态PQQ是以醌型、氢醌型和半醌型存在的,它可催化氧与O2-相互转化,从而帮助机体维持自由基平衡。
PQQ与超氧化物歧化酶(SOD)结合形成一个广谱的产生过氧化氢的氧化酶***从而抑制超氧阴离子自由基对细胞的伤害:SOD作为脱辅基酶蛋白,PQQ作为非共价结合的氧化还原辅基。
PQQ通过加速“NAD+→NADH”的反应,将被利用后的氧化型谷胱甘肽(GSSG)更快地转化为还原型谷胱甘肽(GSH)。
PQQ本身还具有很强的清除该自由基的能力,相当于抗坏血酸的50~100倍[Akaike T,Sato K,Maeda H,et al.PQQ as a Generator and a Scavenger of OxygenRadicals:Determination with ESR Spectroscopy using a Spin Trap Agent[M]//Enzymes Dependent on Pyridoxal Phosphate and Other Carbonyl Compounds AsCofactors.1991.]。
3,PQQ与疾病
由于PQQ具有营养和抗氧化的特点,其在多种实验室疾病模型中体现出一定预防与治疗效果。
(1)保护心脏免受氧化损伤
PQQ对心脏的保护作用与其清除自由基能力有关。PQQ能够清除由缺氧再灌注产生的活性氧(reactive oxygen species,ROS),显著降低心脏中乳酸脱氢酶的释放,在黄素还原酶催化作用下,其催化产物还能够降低血红蛋白过氧化状态,消除缺氧再灌注对心肌的损伤。研究显示,使用PQQ保护缺血-再灌注小鼠的心脏,显著缩小心肌梗死范围,增强左室压力和左室舒张压升降速率,减少心室纤维性颤动,降低心肌组织中丙二醛的水平。PQQ还能抑制过氧化氢诱导的大鼠心肌细胞ROS的产生,以及线粒体膜电位的降低,从而降低氧化应激、抑制线粒体功能的失活,保护大鼠心肌细胞[Zhu BQ,Zhou HZ,Teerlink JR,Karliner JS.Cardiovasc Drugs Ther.2004Nov;18(6):421-31;Xu X,Chen C,Lu WJ,SuYL,Shi JY,Liu YC,Wang L,Xiao CX,Wu X,Lu Q.Cardiovasc Diagn Ther.2020Jun;10(3):453-469.]。
(2)防治肝脏损伤
由四氯化碳(CCl)、半乳糖胺、硫化乙酰胺等毒素造成的大鼠试验性肝脏损伤,可采用预先在腹腔内注射一定剂量PQQ及其衍生物来预防。PQQ可以减少肝脏毒性物质引发的ROS生成,显著降低血清胆红素谷丙转氨酶(glutamic pyruvic transaminese,GPT)及乳酸脱氢酶的水平,阻断肝脏细胞坏死,还不影响大鼠的常规生化指标(如血糖、血尿氮等)。[Tsuchida,T.,et al.,The protective effect of pyrroloquinoline quinone and itsderivatives against carbon tetrachloride-induced liver injury of rats.JGastroenterol Hepatol,2010.8(4):p.342-347.]。
(3)促进神经生长,保护神经***
神经生长因子(nerve growth factor,NGF)是神经营养因子中最早被发现,研究也最透彻的,具有神经元营养和神经保护的双重生物学功能,对中枢及周围神经元的生长、发育、分化、再生及生物功能特异性表达都起到重要的调控作用。实验表明在体外,PQQ能够刺激L-M细胞、施旺细胞生成NGF[Urakami T,Tanaka A,Yamaguchi K,et al.Synthesis ofesters of coenzyme PQQ and IPQ,and stimulation of nerve growth factorproduction.[J].Biofactors,1995,5(3):139.]。
(4)防止乙醛中毒
乙醛是酒精在动物体内的中间代谢产物,具有毒性,很多人乙醛脱氢酶基因突变、功能不全,导致饮酒后乙醛堆积,造成面红耳赤、头晕等轻微乙醛中毒反应。
采用啮齿动物进行实验发现,PQQ有助于代谢乙醛。将乙醇灌入鼠胃前,在其腹腔中注射PQQ(剂量为11.5mg/kg体重),试验发现,处理组鼠血液和肝脏中乙醇浓度与对照组没有明显差别,但前者乙醛浓度却比后者低得多。用其它醌衍生物如辅酶Q10替代PQQ,也有类似的作用[Hobara N,Watanab A,Kobayashi M,et al.Quinone derivatives lowerblood and liver acetaldehyde but not ethanol concentrations following ethanolloading to rats.[J].Pharmacology,1988,37(4):264-267.]。
(5)镇痛作用
神经病理性疼痛是由躯体感觉神经***的损害所导致的慢性疼痛,Gong等人发现,PQQ在大鼠CCI模型中具有镇痛作用,可能与PQQ的NMDA受体抑制作用有关[Gong D,GengC,Jiang L,Aoki Y,Nakano M,Zhong L.Effect of pyrroloquinoline quinone oneuropathic pain following chronic constriction injury of the sciatic nerve inrats.Eur J Pharmacol.2012Dec 15;697(1-3):53-8.]]。
美国于2009年批准了第一款PQQ膳食补充剂,由于PQQ微溶于水,该补充剂成分为PQQ钠盐(PQQ-2Na+),溶解性更佳;2018年,欧盟也批准PQQ-2Na+为健康食品,适宜人群为除孕妇、哺乳期妇女外的成人。市面上PQQ钠盐剂量≤20mg/天。PQQ口服主要在小肠被吸收(~60%),服用24小时后,80%经肾脏(尿液)***。大鼠的安全剂量如下表所示:
大鼠口服PQQ安全性动物实验
在人类对照双盲临床试验中,志愿者以60mg/天服用PQQ一月,未见不良反应,肾损伤标志物也无变化。FDA的安全剂量为:健康的60kg左右的成年人每天摄入240mg PQQ也鲜有不良事件。FDA,Generally Recognized as S afe(GRAS)notice of pyrroloquinolinequinone disodium salt as a food ingredient。
PQQ发现已经超过40年,作为保健品在美国上市10年,从来没有被作为药物开发应用。究其原因我们认为可能有以下三个:1,生物利用度不高,PQQ原型水溶性低,我们的研究发现PQQ在比格犬的生物利用度约12%;2,靶点尚未明确,分子机制不明;3,PQQ结构公开已经超过40年,没有结构保护,作为药物开发的商业价值受限。因此通过PQQ改构,获得生物利用度更高,作用靶点清晰,分子机制明确,药效显著,且得到专利保护的新结构,无论在科学上还是商业上均具有重要意义。
AMP依赖的蛋白激酶(AMPK)是生物能量代谢调节的关键分子,是研究糖尿病及其他代谢相关疾病的核心。它表达于各种代谢相关的器官中,能被机体多种刺激激活,包括细胞压力、运动和很多激素及能影响细胞代谢的物质。遗传学和药理学研究表明,AMPK是机体保持葡萄糖平衡所必需的。除了与代谢性疾病有关,AMPK还与神经退行性疾病[Curry DW,Stutz B,Andrews ZB,Elsworth JD.Targeting AMPK Signaling as a NeuroprotectiveStrategy in Parkinson's Disease.JParkinsons Dis.2018;8(2):161-181.]、心血管疾病[Feng Y,Zhang Y,Xiao H.AMPK and cardiac remodelling.Sci China LifeSci.2018Jan;61(1):14-23.]、肿瘤[Wang Z,Wang N,Liu P,Xie X.AMPK and Cancer.ExpSuppl.2016;107:203-226.]、病理性疼痛[Asiedu MN,Dussor G,Price TJ.TargetingAMPK for the Alleviation of Pathological Pain.Exp Suppl.2016;107:257-285.]、病原微生物(包括病毒)感染[Silwal P,Kim JK,Yuk JM,Jo EK.AMP-Activated ProteinKinase and Host Defense against Infection.Int J Mol Sci.2018Nov 6;19(11):3495.]等疾病相关。AMPK还是延缓衰老延长寿命研究的重要靶点[Burkewitz K,Zhang Y,Mair WB.AMPK at the nexus of energetics and aging.Cell Metab.2014Jul 1;20(1):10-25.]。Cheng等报道,在鱼藤酮诱发的帕金森氏病模型中,PQQ能够通过激活AMPK促进线粒体合成,具有疾病治疗作用[Cheng Q,Chen J,Guo H,Lu JL,Zhou J,Guo XY,Shi Y,Zhang Y,Yu S,Zhang Q,Ding F.Pyrroloquinoline quinone promotes mitochondrialbiogenesis in rotenone-induced Parkinson's disease model via AMPKactivation.Acta Pharmacol Sin.2020Aug 28]。我们在多种细胞中发现,100nM的PQQ及其改构化合物SP3101和SP3102能够显著上调AMPK的磷酸化水平(AMPK的激活状态)。
一般认为,PQQ通过激发体内的抗氧化信号通路发挥其一系列的生物学功效。PQQ在作为镇痛药物时,起效较慢,不适用于作为急性镇痛药物使用。
发明内容
本发明的目的在于通过对PQQ改构,获得了具有如结构式(I)所示的化合物,该化合物具有快速镇痛以及长效镇痛的特点。
一方面,本发明提供如式(I)所示的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药,
其中:
R1选自-OH、-OR、-OC(O)R、-NH2、-NHR、-SH或-SR;
R2选自H、C1~C3烷基、NH2、NHR或-COOH;
R3选自H、C1~C3烷基、OH、NH2、NHR、-COOH或SH;
R4选自H、C1~C3烷基或C6~C10芳基;
R5选自H、C1~C3烷基、OH、NH2、NHR、-COOH或SH;
R6选自H、C1~C3烷基、OH、NH2、NHR、-COOH或SH;
其中R为C1~C6烷基;在一些具体的实施例中,R为C1~C3的烷基。
在本发明的一些实施例中,本发明还提供一种如式(II)所示的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药,
其中:R1选自-OH、-OR、-OC(O)R、-NH2、-NHR、-SH或-SR;R为C1~C6烷基;在一些具体的实施例中,R为C1~C3的烷基。
本发明还提供一些如下结果所示的化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药:
本发明的另一方面,还提供如式(II)所示的化合物的制备方法:
本发明中的化合物可能形成的盐也是属于本发明的范围。除非另有说明,本发明中的化合物被理解为包括其盐类。例如,式(I)化合物与一定量如等当量的酸或碱反应,在介质中盐析出来,或在水溶液中冷冻干燥得来。
本发明中的化合物,依次通过制备、分离纯化获得的该化合物其重量含量等于或大于90%,例如,等于或大于95%,等于或大于99%(“非常纯”的化合物),在正文描述列出。此处这种“非常纯”本发明的化合物也作为本发明的一部分。
本文还提供一种药物组合物,其包括本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药,以及药学上可接受的载体。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药作为AMPK激动剂的应用。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药作为Cox-2酶的抑制剂的应用。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备镇痛药物中的应用。
本发明所述的镇痛药物,所作用的疼痛可以为任何的身体损伤、病患或不良的外部刺激所引起的不舒服的感觉,例如手术、炎症、肿瘤、心肌梗塞损伤、细菌感染、病毒感染、神经性疾病等多种因素所引起的各种疼痛;神经性疾病导致的疼痛例如包括但不限于神经退化、神经变化导致的疼痛,或者癫痫、偏头疼等带来的疼痛,或者多种肝损伤、心肌梗塞损伤等带来的疼痛。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗炎症疾病药物中的应用;本发明所述的炎症疾病可以为细菌或病毒感染引起的炎症反应,例如包括但不限于细菌或病毒感染引起的肺部炎症等呼吸道炎症、病毒性心肌炎、细菌或病毒引起的肝炎或肝功能衰退;也可以为肿瘤免疫治疗引发的过度炎症反应,也可以为自身免疫性疾病、异体器官和组织移植的排斥引起的炎症反应。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备抗肿瘤药物中的应用。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗细胞毒素进行肿瘤的化学治疗、化学物质或药物以及慢性肝炎引发的多种肝损伤、肝功能衰退以及预防和治疗心肌梗塞损伤、病毒性心肌炎药物中的应用。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗神经退化、变化疾病及癫痫、偏头痛药物中的应用。
本发明还提供本发明所述化合物或其药学上可接受的盐、酯、立体异构体、溶剂化合物或前药在制备预防和治疗病毒感染、病毒感染引发的炎症风暴药物中的应用。
本发明术语若无特别说明定义如下:
术语“C1-C3烷基”、“C1-C6烷基”、“C2-C6烷基”和“C3-C6烷基”是指分别具有一个到三个、一个到六个、两个到六个或三个到六个碳原子的饱和的直链或分支链一价烃基。实例包含(但不限于)甲基、乙基、1-丙基、异丙基、1-丁基、异丁基、仲丁基、叔丁基、2-甲基-2-丙基、戊基、新戊基和己基。烷基可以是取代的或未取代的。当被取代时,取代基优选为一个或多个,更优选为一个、两个或三个,进而更优选为一个或两个,独立地选自由低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、酰基、硫代酰基、O-氨基甲酰基、N-氨基甲酰基等。
术语“芳基”表示1至12个碳原子的全碳单环或稠合多环基团,具有完全共轭的π电子***。芳基的非限制性实例有苯基、萘基和蒽基。芳基可以是取代的或未取代的。当被取代时,取代基优选为一个或多个,更优选为一个、两个或三个,进而更优选为一个或两个,独立地选自由低级烷基、三卤烷基、卤素、羟基、低级烷氧基、巯基、(低级烷基)硫基、氰基、酰基、硫代酰基、O-氨基甲酰基、N-氨基甲酰基、O-硫代氨基甲酰基、N-硫代氨基甲酰基、C-酰氨基、N-酰氨基、硝基、N-磺酰氨基、S-磺酰氨基等。优选地,芳基可选地被一个或两个取代基取代,取代基独立地选自卤素、低级烷基、三卤烷基、羟基、巯基、氰基、N-酰氨基、单或二烷基胺基、羧基或N-磺酰氨基。
与现有技术相比,本发明的有益效果为:
本发明所述的化合物成盐后水溶性较好,生物利用率也较高。生物学上,这些新结构除了同样具有AMPK激活作用,而且意外地获得了Cox-2酶的抑制作用,具有独特的抗炎、镇痛效果。在采用完全弗氏佐剂建立的炎性痛觉模型中,单剂量的SP3101、SP3102、SP3103镇痛起效迅速,口服给药1.5小时镇痛明显,并且能够持续72小时。有趣的是,如果在给药前半小时,通过大鼠尾静脉注射AMPK抑制剂,不影响这些镇痛剂的短时镇痛效果,但24小时后镇痛效果完全消除,说明其长期镇痛效果依赖AMPK的激活。也说明,这类药物镇痛作用至少通过两种靶点发挥作用,即短时(1.5小时)镇痛和长时(24-72小时)镇痛作用的靶点是不一样的。
附图说明
图1为大鼠单次口服20mg/kg的SP3101后镇痛效果图;
图2为大鼠连续口服25mg/kg布洛芬镇痛效果图;
图3为大鼠连续三天口服20mg/kg/daySP330(PQQ)镇痛效果图;
图4为AMPK抑制剂compound c抑制SP3101的长效镇痛作用;
图5为SP3101系列分子作用的分子机制;
图6为SP3101抑制cox-2活性;
图7为SP3101抑制鼠肝炎病毒(MHV)诱发的小鼠肺部炎症;
图8为小鼠单次口服40mg/kg的SP3101后,对坐骨神经慢性压榨(CCI)模型镇痛效果图。
具体实施方式
以下的实施例便于更好地理解本发明,但并不限定本发明。下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的试验材料,如无特殊说明,均为自常规生化试剂商店购买得到的。
1、仪器与试剂:ALMEMO2490数据采集器:德国AHLBORN公司;
2、PQQ二钠盐购自海正药业;
3、MHV-A59病毒株购自苏州西山生物技术有限公司,PFU/毫升为1.4X107;
4、RAW264.7购自北京协和细胞中心。
实施例1化合物SP3101(中文命名:4,5-二氧-4,5-二氢-1氢-吡咯[2,3-f]喹啉-7-羟基-9-羧酸)的制备与鉴定
将PQQ样品溶于1M的NaOH水溶液中,浓度100mg/ml,装入多个反应瓶中,微波250度反应1小时,取出,用LCMS检测,降解主产物分子量为258,将样品过滤,用Prep-LC高压多次制备,制备条件如下:高压C18-乙腈/2mM醋酸铵,梯度:2%-30%。将制备完的样品旋去有机相后,冻干,并将冻干后的样品在烘箱内105度烘干2小时,称重。
质谱电喷雾正离子模式下检测到m/z=259.2(M+1)+,证明化合物的游离态分子量为258。
核磁共振波谱如表1所示。
表1氢谱和碳谱归属
编号 | 1HNMR | 13CNMR |
1 | 6.24d,1H,j=2.4 | 105.4 |
2 | 6.91d,1H,j=2.4 | 126.7 |
3 | / | 124.4 |
4 | / | 184.9 |
5 | / | 159.9 |
6 | / | 136.2 |
7 | / | 165.9 |
8 | 8.15,1H,s | 128.4 |
9 | / | 147.1 |
10 | / | 133.1 |
11 | / | 149.7 |
12 | / | 167.0 |
注:样品溶解于DMSO-d6
经核磁数据比对与解析,再往样品中加入马来酸做氢谱,可明显显示出两个NH4+的信号,表明化合物为二胺盐。
经TGA失重分析结果表明,样品在150度下失重5.97%,结合之前样品在105度烘干过及核磁推测,样品中含有一分子的结合水。
通过对纯化后杂质UPLC-MS,核磁波谱的解析及TGA失重分析,可以确认为以下结构,命名为SP3101的二铵盐,通过常规处理,可以为SP3101形式。
实施例2化合物SP3102(中文命名:7-乙酰氧基-4,5-二氧-4,5-二氢-1氢-吡咯【2,3-f】喹啉-9-羧酸)的制备与鉴定
把原料SP3101(3.1克,0.01摩尔)溶解于干燥的吡啶(6毫升)中,然后加入乙酸酐(6毫升),反应于室温搅拌20小时。反应结束后把溶剂旋干,得到的固体用柱层析分离,即化合物SP3102。
质谱电喷雾正离子模式下检测到m/z=300.1(M+1)+,证明化合物SP3102的游离态分子量为300。其核磁共振波谱如表2所示。
表2氢谱和碳谱归属
编号 | 1H NMR | 13C NMR |
1 | 2.28,3H,s | 20.3 |
2 | 5.0,1H,s | / |
3 | 6.40d,1H,j=7.5 | 104.4 |
4 | 6.95d,1H,j=7.5 | 118.3 |
5 | 7.82,1H,s | 112.9 |
6 | 11.0,1H,s | / |
7 | / | 122.7 |
8 | / | 125.2 |
9 | / | 126.4 |
10 | / | 137.2 |
11 | / | 144.8 |
12 | / | 156.4 |
13 | / | 167.7 |
14 | / | 172.6 |
15 | / | 173.5 |
16 | / | 176.7 |
样品溶解于DMSO-d6
实施例3化合物SP3103(中文命名:7-甲氧基-4,5-二氧-4,5-二氢-1氢-吡咯【2,3-f】喹啉-9-羧酸)的制备与鉴定
在反应瓶中,先加入硫酸二甲酯(1.26克,0.01摩尔),升温至80℃,再分批加入原料SP3101(3.1克,0.01摩尔),TLC监控原料反应完全后,在零度下向反应液中加入一定量的水,再缓慢滴加氨水溶液,滴加碳酸氢钠溶液使反应液pH达到4左右,抽滤得到产物SP3103。
质谱电喷雾正离子模式下检测到m/z=273.1(M+1)+,证明化合物的游离态分子量为272。其核磁共振波谱如表3所示。
表3氢谱和碳谱归属
编号 | 1H NMR | 13C NMR |
1 | 3.80,3H,s | 54.1 |
2 | 5.0,1H,s | / |
3 | 6.40d,1H,j=7.5 | 104.4 |
4 | 6.95d,1H,j=7.5 | 118.3 |
5 | 7.82,1H,s | 112.9 |
6 | 11.0,1H,s | / |
7 | / | 115.0 |
8 | / | 122.7 |
9 | / | 125.2 |
10 | / | 135.7 |
11 | / | 144.2 |
12 | / | 162.4 |
13 | / | 167.7 |
14 | / | 173.5 |
15 | / | 176.7 |
样品溶解于DMSO-d6
活性实验1:炎性痛模型及药物镇痛研究
200-250克SD大鼠,4只左足底注射生理盐水作为空白对照(NC),18只炎性痛造模,即左足底注射100微升完全弗氏佐剂,24小时后ALMEMO2490数据采集器检测左足机械疼痛阈值,舍弃疼痛阈值超过15克的2只大鼠,其余16只大鼠随机分成4组,每组4只,分别灌胃水(PC),SP3101(20mg/kg),PQQ(20mg/kg)和布洛芬(25mg/kg/d)。
结果如图1~图3所示:
其中图1为大鼠单次口服20mg/kg的SP3101后镇痛效果图。单次口服1.5小时具有明显的镇痛效果,并且效果持续72小时(1-4天),5-7天,镇痛效果降低,但与模型组(PC)比较,依然具有显著性差异(*表示p<0.05,**表示p<0.01,***表示p<0.001,下同)。
图2为大鼠连续口服25mg/kg布洛芬镇痛效果图。布洛芬剂量25毫克每公斤体重,每天一次,连续口服给药3天,每次给药后1.5小时检查痛阈。与SP3101类似,布洛芬起效迅速,口服1.5小时后即能够明显镇痛,1/2/3天连续给药后均能显著镇痛,给药前没有镇痛效果(数据未显示),第四天未给药,无任何镇痛效果。
图3为大鼠连续三天口服20mg/kg/daySP330(即PQQ)镇痛效果图。第一天口服给药1.5小时后无镇痛效果,2/3/4/5/6/7天均有明显的镇痛效果。
结果表明,本发明所述的化合物SP3101具有快速镇痛和长效镇痛的效果。且发明人发现化合物SP3102和化合物SP3103也具有类似效果。
活性实验2:长效镇痛作用机理研究
如活性实验1中的造模方法:200-250克SD大鼠左足底注射100微升完全弗氏佐剂,24小时后ALMEMO2490数据采集器检测左足机械疼痛阈值,舍弃疼痛阈值超过15克的大鼠。造模第二天每只大鼠尾静脉注射AMPK抑制剂compound c(Dorsomorphin,CAS No.866405-64-3,CC,0.4mg/ml)100微升,半小时后口服给药SP3101(20mg/kg),分别于1.5小时和24小时后检测痛阈。
结果如图4所示,抑制AMPK不影响SP3101的短效(1.5小时)镇痛作用,但消除其长效(24小时)镇痛作用。
活性实验3:AMPK的激动剂
RAW264.7细胞接种至两块六孔板,生长至密度约为90%,分别加入不同浓度的SP3101和SP3102。24小时后RIPA裂解细胞,蛋白杂交检测蛋白表达。
AMPK127位丝氨酸磷酸化是激活的标志,结果如图5所示,0.1uM浓度的SP3101和SP3102即能够显著激活AMPK(p-AMPK表达增加),同时抗氧化转录因子Nrf2呈剂量依赖性的表达增加,自噬相关蛋白LC3B表达也增加。可见,SP3101和SP3102代表的本发明所述的化合物是AMPK的激动剂。
活性实验4:Cox-2抑制剂
1、样品制备
(1)复苏RAW264.7,细胞长密度约为100%,用PBS清洗两遍;
(2)用无血清含1ug/ml的LPS DMEM培养基培养3小时后换成2%血清含1ug/ml的LPS DMEM培养基培养21h;
(3)配置1110ul细胞裂解液,对准细胞吹打,冰浴摇床摇晃15min,打开离心机降温;
(4)用枪头刮大皿,吸取处理液分于两个EP管中,12000r,15min,4℃,后于冰上保存。
2、COX活性检测
环氧酶COX活性检测采用abcam试剂盒(ab204699cox activity assay kit,fluorometric),依据说明书操作,最后Ex/Em=535/587nm荧光检测。
结果如图6所示,结果表明,SP3101与阳性对照塞来昔布类似的抑制cox-2活性的作用。
活性试验5:SP3101抑制炎症
C57BL/B6小鼠经鼻腔滴注MHV-A59病毒可以引发病毒性肺炎,通过该模型研究SP3101抑制病毒引发小鼠肺部炎症的能力。
MHV-A59病毒株购至苏州西山生物技术有限公司,PFU/毫升为1.4X107。
六周龄小鼠分3组,每组8只。小鼠麻醉后空对照组经鼻给生理盐水,另两组病毒性肺炎造模如下:经鼻给MHV,PFU=1.4×105,每只10ul,左右鼻各给5ul,约3-6h小鼠苏醒。模型治疗组SP3101水溶液灌胃,SP3101组剂量为20毫克/公斤体重/天(mg/kg/d)。
连续给药5天,最后一次给药后4小时,小鼠麻醉,解剖,取肺脏多聚甲醛固定保存用于HE切片染色。病理切片见图7,SP3101具有显著的抑制病毒诱发的肺部炎症的作用。
活性试验6:神经病理痛及药物镇痛作用研究
神经病理痛采用坐骨神经慢性压榨(CCI)模型。6-8周龄B6小鼠麻醉,小鼠左腿根部到尾根骨水平线向上约1-2mm处剃毛,水平切小口,止血钳钝性分离肌肉,找出坐骨神经,用弯头捏挑出,用另一只弯头镊挑出提前浸泡好的无菌生理盐水中的4-0含铬羊肠线,三根穿过坐骨神经,上中下间隔1毫米结扎,强度以周围肌肉产生小的短暂的抽搐为宜。然后在肌肉下放好坐骨神经,伤口缝针。用碘酒消毒伤口,观察。
术后7天,Von Frey纤维丝检测小鼠机械痛,将小鼠先放在透明有机玻璃足底测试平台中适应20min,使用一系列Von Frey垂直刺激小鼠造模一侧(即右后脚)足前掌,首先从低一级强度开始刺激,如果该强度不能引起阳性反应时,则使用强一级开始刺激,出现快速缩足为阳性反应,则再次使用邻近小一级的强度再次刺激,纪录出现第一次阳性和阴性反应的强度区间。以阳性反应低于0.4克为造模成功。
试验小鼠共分三组,未造模组,造模溶媒组,造模给药组,溶媒为0.5%甲基纤维素,药物为SP3101,按照体重40mg/kg单次给药,给药后1.5,24,48,72小时检测痛域。结果见图8,SP3101小鼠灌胃后1.5,24,48小时具有显著的镇痛效果(**p<0.01)。
Claims (9)
1.式(II)所示的化合物或其药学上可接受的盐,
其中:R1选自-OH、-OR或-OC(O)R;R为C1~C3的烷基。
2.如下所示的化合物或其药学上可接受的盐:
3.权利要求1式(II)所示的化合物的制备方法:
其中:R1定义如权利要求1中所述。
4.一种药物组合物,其包括权利要求1或2所述化合物或其药学上可接受的盐,以及药学上可接受的载体。
5.权利要求1或2所述的化合物或其药学上可接受的盐在制备AMPK激动剂中的应用。
6.权利要求1或2所述的化合物或其药学上可接受的盐在制备Cox-2酶抑制剂中的应用。
7.权利要求1或2所述的化合物或其药学上可接受的盐在制备镇痛药物中的应用。
8.权利要求1或2所述的化合物或其药学上可接受的盐在制备预防和治疗肺炎药物中的应用。
9.化合物在制备治疗坐骨神经痛药物中的应用,所述化合物选自
。
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- 2022-03-28 WO PCT/CN2022/083261 patent/WO2022206654A1/zh active Application Filing
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106110321A (zh) * | 2008-03-04 | 2016-11-16 | 莱布瑞斯生物公司 | 治疗炎性疼痛的方法 |
CN101851234A (zh) * | 2009-04-03 | 2010-10-06 | 上海日馨生物科技有限公司 | 吡咯喹啉醌锂盐衍生物及其制备方法 |
CN101885725A (zh) * | 2009-05-12 | 2010-11-17 | 江苏道琪生物科技有限公司 | 吡咯喹啉醌钠盐衍生物及其制备方法 |
Non-Patent Citations (3)
Title |
---|
Kazuhiro Saihara et al.."Pyrroloquinoline Quinone, a Redox-Active o‑Quinone, Stimulates Mitochondrial Biogenesis by Activating the SIRT1/PGC-1α Signaling Pathway".《Biochemistry》.2017,第56卷第6615-6625页. * |
Qiong Cheng et al.."Pyrroloquinoline quinone promotes mitochondrial biogenesis in rotenone-induced Parkinson’s disease model via AMPK activation".《Acta Pharmacologica Sinica》.2020,第42卷第665-678页. * |
孙静娴等."吡咯喹啉醌生理医学功效研究进展".《生物学杂志》.2012,第29卷第80-83页. * |
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US20240199601A1 (en) | 2024-06-20 |
EP4317158A1 (en) | 2024-02-07 |
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