CN115869294B - 托品酸及其衍生物在制备治疗银屑病药物中的用途 - Google Patents
托品酸及其衍生物在制备治疗银屑病药物中的用途 Download PDFInfo
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Abstract
本发明提供了一种托品酸及其衍生物在制备治疗银屑病药物中的用途。本发明发现了托品酸及其衍生物可以明显改善银屑病动物模型的皮肤损伤，其具有毒性低，起效快、疗程短、用量小、复发率低及使用方便，兼顾了外用、口服及注射等剂型，可适应不同疾病程度、不同类型的银屑病患者。本发明还发现经过结构修饰得到的化合物3和4具有比托品酸显著更佳的治疗效果。本发明所使用的小分子药物易于获取，价格低廉，性质稳定，便于保存和运输，具有广阔的应用前景。
Description
技术领域
本发明属于医药技术领域，尤其涉及托品酸及其衍生物在制备治疗银屑病药物中的用途和治疗银屑病的药物。
背景技术
银屑病是一种复杂的多因素慢性炎症性自身免疫性皮肤病，临床以边界清楚的红斑鳞屑为典型特征。银屑病患者皮肤组织病理学表现为角质形成细胞过度增殖、炎症细胞浸润和新生血管形成，临床表现为表皮过度增生、角化不全和真皮慢性炎症反应。银屑病复发率高，患者多需长期或反复用药，发病时可伴有全身表现，其中肘部、膝盖、手、骶尾骨区域及头皮为病理斑块的主要发生部位。根据银屑病的临床特征，可分为寻常型、关节病型、脓疱型及红皮病型，以寻常型最为常见。银屑病发病机制非常复杂且尚未完全明确，目前认为种族、遗传及环境等因素与该疾病的发生发展密切相关。根据银屑病流行病学调查资料，全球发病率约为2％，不同国家地区银屑病的患病率从0.09％～11.4％不等。银屑病可以发生在任何年龄段，成人患病率在0.51％～11.43％之间，儿童患病率在0％～1.37％之间。中国目前约有600多万银屑病患者。银屑病是系统性疾病，无传染性，主要累及皮肤及关节，20％～30％患者伴关节损害，中重度患者罹患代谢综合征和动脉粥样硬化性心血管疾病的风险增加，加之社会排斥及个人心理问题，严重影响患者的生活质量。
目前，治疗银屑病的药物较多，主要有单抗类药物、类固醇激素、免疫抑制剂、维A酸类、JAK/STAT信号通路抑制剂、非甾体抗炎药、抗肿瘤药、磷酸二酯酶抑制剂、其他外用药、物理疗法及中医疗法。单抗类药物包括IL-23抑制剂、IL-17A靶点药物、抗CD单克隆抗体药物、抗肿瘤坏死因子药物、IL-6抑制剂及IL-12/IL-23抑制剂等药物。其中IL-23抑制剂有古塞奇尤单抗(Guselkumab)、替曲吉珠单抗(Tildrakizumab)及瑞莎珠单抗(Risankizumab)等；IL-17A靶点的单抗类药物有司库奇尤单抗(Secukinumab)、艾克司单抗(Ixekizumab)、布罗达单抗(Brodalumab)及尼塔奇单抗(Netakimab)等；抗CD单克隆抗体药物主要有依法利珠单抗(Efalizumab)、阿法西普(Alefacept)及利妥昔单抗(Rituximab)等；抗肿瘤坏死因子药物包括依那西普(Etanercept)、阿达木单抗(Adalimumab)、英利昔单抗(Infxiimab)、赛妥珠单抗(Certolizumab pegol)、戈利木单抗(Golimumab)及奥那西普(Onercept)等；IL-6抑制剂如托珠单抗(Tocilizumab)，以及IL-12/IL-23抑制剂伏特克单抗(Ustekinumab)。本类药物主要用于中重度银屑病的系统治疗，有的刚刚上市处于临床试验阶段，需更多的循证依据；该类药物还存在诸多不良反应不利于银屑病患者长期或反复使用，如增加感染的风险、加重克罗恩病、以及肿瘤、狼疮、恶性肿瘤、感染和心力衰竭新发或恶化的风险，其他不良反应还有呼吸系统炎症、发热、皮疹、关节炎症及淋巴结肿大等，个别药物如依法利珠单抗和阿法西普因严重不良而退出市场。此外，因该类药物开发成本高，多售价较高，致患者难以承担。类固醇激素倍他米松及免疫抑制剂维生素D3衍生物钙泊三醇、他克莫司、阿巴西普(Abatacept)和环孢素用于治疗银屑病虽有效果，但存在严重的激素依赖以及免疫系统方面的副作用。维A酸类药物尤适用于脓疱型、红皮病型银屑病，其不良反应主要为对皮肤黏膜、生殖系统、骨骼与肌肉、肝功能和血脂的影响及皮肤刺激反应等。如他扎罗汀乳膏，是治疗局限性斑块状银屑病的一线药物，但因激性较强，不宜用于面部、眼周、外阴及皮肤皱褶部位。靶向外用剂JAK/STAT信号通路抑制剂托法替尼(Tofacitinib)可用于关节病型银屑病治疗，不良反应为增加带状疱疹感染率或引起血栓栓塞；JET-052软膏可能对银屑病的炎症皮损有效。非甾体抗炎药苯烯莫德(Benvitimod)是由我国自主研发，在动物实验还是临床试验都获得良好的疗效，但是也存在一些不良反应，且随着药物浓度的增加而显著，但整体不良反应较小，多为轻度皮肤刺激，如瘙痒、接触性皮炎、毛囊炎等。抗肿瘤药物甲氨蝶呤多适用于红皮病型银屑病、关节病型银屑病和广泛的慢性斑块状银屑病，在治疗过程中可引起严重不良反应，如肝脏毒性、骨髓抑制及肺纤维化等。磷酸二酯酶抑制剂阿普斯特(Apremilast)治疗关节病型银屑病表现出良好的效果和耐受性，常见腹泻，恶心和头痛等副作用。其他外用药治疗还包括润肤剂、角质促成剂、角质松解剂、地蒽酚及焦油类等。物理疗法有窄谱中波紫外线、A波段紫外线和308nm准分子激光、温泉浴及海水浴等。中医疗法包括内治和外治，主要为内服中药汤剂或复方、外用中药熏洗及针灸等，疗效显著，且不良反应少，但关于银屑病病因病机众医家说法不一，尚未形成统一的治疗方案，疗程长且易复发，一些疗法常因使用不便及药物气味颜色等感官不适而使患者难以接受。
综上，银屑病患者群体庞大，治疗药物或方法种类虽然很多，但疗效有限，常需要长期、反复甚至终身接受治疗，有些药物虽取得一时的疗效，但短期复发率高。多数药物常常受其自身固有的毒性及选择性的制约，系统及局部的各种不良反应不可避免。另外，现有治疗剂多为外用药物，使用不便，口服药物较少。针对上述问题，目前迫切需要开发起效快、疗程短、用量小、不良反应小、复发率低、价格低及使用方便的治疗药物，同时应兼顾外用、口服及注射等药物剂型的开发，以适应不同疾病程度、不同类型银屑病的患者。本发明前期经大量的动物实验研究，筛选并明确了托品酸(DL-Tropic Acid，别名2-苯基-3-羟基丙酸)及其衍生物治疗银屑病的有效性。托品酸是合成阿托品的中间体，原料价格低廉，目前尚未见托品酸及其衍生物防治银屑病的报道。
发明内容
本发明一方面提供托品酸及其衍生物、其药学上可接受的盐、溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物在制备预防和/或治疗银屑病药物中的用途，所述托品酸及其衍生物具有以下式A所示的结构：
其中，R1-R5各自独立地选自-H、-OH或者C1-C6的烷氧基。
在一个实施方案中，R1-R5各自独立的选自-H或-OH。
在一个实施方案中，所述托品酸及其衍生物选自以下式I-式IV所示化合物：
其中，式I为托品酸(DL-Tropic Acid)，式II为4-羟基-α-(羟甲基)苯乙酸(4-Hydroxy-α-(hydroxymethyl)benzeneacetic acid)，式III为3,4-二羟基-α-(羟甲基)苯乙酸(3,4-Dihydroxy-α-(hydroxymethyl)benzeneacetic acid)和式IV为3,4,5-三羟基-α-(羟甲基)苯乙酸(3,4,5-Trihydroxy-α-(hydroxymethyl)benzeneacetic acid)。
本发明所述托品酸及其衍生物对咪喹莫特乳膏诱导的银屑病小鼠模型的皮肤组织形态学组织病理学具有明显改善作用。
在一个实施方案中，所述银屑病选自寻常型银屑病、关节型银屑病、红皮病型银屑病和脓疱型银屑病中的一种或几种。
本发明第二个方面提供一种银屑病预防和/或治疗药物，该银屑病治疗药物中含有托品酸及其衍生物、其药学上可接受的盐、溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物。
本发明所提供的预防和/或治疗银屑病的药物效果显著。
在一个实施方案中，所述托品酸及其衍生物、其药学上可接受的盐、溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物在本发明所述药物中作为活性成分。优选的，其作为主要活性成分；更优选的，其作为唯一活性成分。
上述用途和药物中，托品酸及其衍生物、其药学上可接受的盐、溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物可以与药学上可接受的载体或者辅料制备成药物剂型外用药、口服给药或注射给药。
因此，本发明中，所述药物可以是外用药、口服药或者注射药。
本发明中，所述药物可以包含药学上可接受的载体或者辅料。所述药物可制成各种常规的固体剂型、液体剂型或半固体剂型，固体剂型如颗粒剂、片剂或胶囊剂等，液体剂型如喷雾剂及注射剂，半固体剂型如乳膏等。在一个方面中，所述药物的剂型可以是：散剂、片剂、包衣片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、凝胶剂、贴剂等。
本发明中，术语“药学上可接受的载体或者辅料”包括任何和所有的溶剂、共溶剂、分散介质、包衣材料、表面活性剂、抗氧化剂、防腐剂(例如抗菌剂、抗真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物稳定剂、粘合剂、赋形剂、稀释剂、助流剂、造粒剂、崩解剂、增稠剂、增粘剂、润滑剂、防结块剂、保湿剂、湿润剂、螯合剂、塑化剂、染料、矫味剂等和其组合，这是本领域技术人员所熟知的(例如参见Remington’s Pharmaceutical Sciences,19thEd.Mack Printing Company,1995；上海医药工业研究院等编著，药用辅料应用技术(第二版)，中国医药科技出版社，2002年；各国药用辅料标准对比手册1～3册，国家药典委员会编著，中国医药科技出版社，2016年；药用辅料手册，R.C.罗(Raymond C Rowe)，P.J.舍斯基(Paul J Sheskey)，P.J.韦勒(Paul J Weller)编，郑俊民主译，化学工业出版社，2005年等)。除了与活性成分不相容的载体和辅料外，在治疗或药物组合物中考虑使用任何常规载体和辅料。
例如，作为固体剂型中，所述药学上可接受的载体或者辅料可以包括以下至少一种：(a)填充剂例如淀粉、玉米淀粉、变性淀粉、可压性淀粉、乳糖、一水乳糖、微晶纤维素、环糊精、山梨醇、甘露醇、磷酸钙、氨基酸等；(b)粘合剂，例如淀粉浆、胶化淀粉、羧甲基纤维素钠、羟丙基纤维素、羟丙甲纤维素、甲基纤维素、乙基纤维素、羟丙基甲基纤维素、低取代羟丙基纤维素、聚乙烯吡咯烷酮、明胶、海藻酸盐等；(c)保湿剂，例如甘油；(d)崩解剂，例如干淀粉、变性淀粉、羧甲淀粉纳、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、微晶纤维素、泡腾崩解剂、交联聚乙烯吡咯烷酮等；(e)溶液阻滞剂，例如石蜡；(f)吸收促进剂，例如季铵化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸收剂，例如高岭土和膨润土；(i)润滑剂，例如滑石、硬脂酸、硬脂酸镁或钙、微粉硅胶、氢化蓖麻油和固体聚乙二醇、聚乙二醇4000-20000、十二烷基硫酸镁等。
本发明中，所述药物适用对象可以为人或其他恒温动物。当适用对像为人时，托品酸及其衍生物的单一或混合用量优选为1mg/kg·d～50mg/kg·d，进一步优选为10mg/kg·d～20mg/kg·d。化合物、药物组合物的治疗有效量是取决于个体的物种、体重、年龄及个体情况、被治疗的疾病或其严重程度。具备常用技能的医师、临床医师或兽医可以容易决定预防、治疗或抑制疾病发展过程中所需各活性成分的有效量。
本发明还提供一种式A所示的化合物、其药学上可接受的盐、溶剂化合物、对映异构体、非对映异构体、互变异构体或其任意比例的混合物：
其中，R1-R5各自独立地选自-H或-OH；
条件是，R1-R5中至少有两个选自-OH。
在一个实施方案中，R1-R5中有两个或三个选自-OH。
在一个实施方案中，所述化合物选自以下式III-式IV所示化合物：
本发明化合物的药学上可接受的盐包括其碱加成盐和酸加成盐。优选地，所述碱加成盐选自钠盐、钾盐、钙盐、锂盐、镁盐、锌盐、铵盐、四甲基铵盐、四乙基铵盐、三乙胺盐、三甲基铵盐、乙胺盐、二乙醇胺盐、精氨酸盐或赖氨酸盐；所述酸加成盐，选自乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、柠檬酸盐、乙二磺酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡糖酸盐、葡糖醛酸盐、乳酸盐、苹果酸盐、三氟乙酸盐、马来酸盐等有机酸盐，以及盐酸盐、氢溴酸盐、硫酸氢盐、硝酸盐、磷酸盐等无机酸盐。游离形式的本发明化合物可以被转化为盐形式的相应化合物；并且反之亦然。游离形式或盐形式和溶剂化物形式的本发明化合物可以被转化为非溶剂化物形式的游离形式或盐形式的相应化合物；并且反之亦然。
本发明化合物还包含其溶剂化物形式，其是指一个或多个溶剂分子与本发明化合物所形成的缔合物。形成溶剂化物的溶剂包括，但并不限于，水，异丙醇，乙醇，甲醇，二甲亚砜，乙酸乙酯，乙酸，氨基乙醇。
本发明化合物可以以异构体以及其混合物的形式存在；例如互变异构体、光学异构体、对映异构体、非对映异构体。本发明化合物可以例如包含不对称碳原子，并因此可以对映异构体或非对映异构体及其混合物的形式存在，例如以外消旋物的形式。本发明化合物可以以(R)-、(S)-或(R，S)-构型存在，优选在化合物的特定位置上为(R)-或(S)-构型。
本发明相对于现有技术具有如下的优点及效果：
(1)本发明首次发现托品酸及其衍生物可以明显改善银屑病动物模型的皮肤损伤；
(2)与现有药物相比，托品酸及其衍生物作为治疗银屑病药物的主要成分，所制备的药物毒性低，起效快、疗程短、用量小、复发率低及使用方便，兼顾了外用、口服及注射等剂型，可适应不同疾病程度、不同类型的银屑病患者；
(3)经过结构修饰得到的化合物3和4具有比托品酸显著更佳的治疗效果；
(4)本发明所使用的小分子药物易于获取，价格低廉，性质稳定，便于保存和运输，具有广阔的应用前景。
附图说明
图1.式III化合物的1H-NMR谱图
图2.式III化合物的13C-NMR谱图
图3.式IV化合物的1H-NMR谱图
图4.式IV化合物的13C-NMR谱图
图5A-B.各组小鼠背部皮损(第7天)的比较照片；
图6.各组小鼠皮损面积严重指数(PASI)评分结果(n＝10)；
图7.各组小鼠皮损病理组织学HE染色照片(x200)；
图8.各组小鼠表皮厚度统计数据(n＝10)。
具体实施方式
以下结合附图对本发明的优选实施例进行说明，应当理解，此处所描述的优选实施例仅用于说明和解释本发明，并不用于限定本发明，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1：式III化合物(3,4-二羟基-α-(羟甲基)苯乙酸)的制备
1.合成工艺
冰水浴条件下，取3,4-二甲氧基苯乙酸1.96g(10mmol,1.0eq.)于100mL Schlenk瓶中，氮气保护条件下，加入无水DCM 20mL，保持低温条件下缓慢滴加二氯亚砜1.8mL(25mmol,2.5eq)，将体系转移至室温，搅拌2h。40℃减压除去溶剂及过量氯化亚砜。随后向体系中加入甲醇20mL室温搅拌过夜，减压蒸馏除去溶剂得3,4-二甲氧基苯乙酸甲酯1.50g。
室温条件下，取化合物3,4-二甲氧基苯乙酸甲酯1.0g(4.76mmol,1.0eq.)于100mLSchlenk瓶中，加入多聚甲醛0.171g(5.71mmol,1.2eq.)，及DMSO 5mL，氮气保护条件下，向体系中加入催化量甲醇钠0.0257g(0.476mmol,10mol％)，体系保持室温搅拌过夜。后处理将反应转移至100mL水中，EtOAc萃取水层3×20mL，合并有机相后，再水洗干燥，减压浓缩后柱分离纯化，得3,4-二甲氧基-α-(羟甲基)苯乙酸甲酯0.90g。
取3,4-二甲氧基-α-(羟甲基)苯乙酸甲酯0.6g(2.5mmol,1.0eq.)于20mL Schlenk瓶中，室温条件下向体系中缓慢加入溴化氢溶液(40％)2mL，加热回流反应过夜。后处理将反应体系转移至50mL水中，DCM萃取水层3×20mL，合并有机相后，再水洗干燥，减压浓缩后柱分离纯化，得3,4-二羟基-α-(羟甲基)苯乙酸0.35g。
2.结构鉴定
3,4-二羟基-α-(羟甲基)苯乙酸为白色结晶性粉末，易溶于甲醇，可溶于水。1H-NMR(400MHz,CD3OD)见图1，δH(ppm)3.63(2H,m,CH2),3.99(1H,m,CH),6.50(1H,dd,J＝2.0,8.0Hz,Ph-H),7.04(1H,d,J＝8.0Hz,Ph-H),7.09(1H,d,J＝2.0Hz,Ph-H)；13C-NMR(400MHz,CD3OD)见图2，δC(ppm)55.9(CH),65.2(CH2),114.3(CH),116.4(CH),123.9(CH),127.2(C),145.3(C),146.0(C),176.2(C＝O)。
实施例2：式IV化合物(3,4,5-三羟基-α-(羟甲基)苯乙酸)的制备
1.合成工艺
冰水浴条件下，取3,4,5-三甲氧基苯乙酸2.26g(10mmol,1.0eq.)于100mLSchlenk瓶中，氮气保护条件下，加入无水DCM 20mL，保持低温条件下缓慢滴加二氯亚砜1.8mL(25mmol,2.5eq)，将体系转移至室温，搅拌2h。40℃减压除去溶剂及过量氯化亚砜。随后向体系中加入甲醇20mL室温搅拌过夜，减压蒸馏除去溶剂得3,4,5-三甲氧基苯乙酸甲酯1.65g。
室温条件下，取化合物3,4,5-三甲氧基苯乙酸甲酯1.5g(6.25mmol,1.0eq.)于100mL Schlenk瓶中，加入多聚甲醛0.224g(7.50mmol,1.2eq.)，及DMSO 5mL，氮气保护条件下，向体系中加入催化量甲醇钠0.0338g(0.625mmol,10mol％)，体系保持室温搅拌过夜。后处理将反应转移至100mL水中，EtOAc萃取水层3×20mL，合并有机相后，再水洗干燥，减压浓缩后柱分离纯化，得3,4,5-三甲氧基-α-(羟甲基)苯乙酸甲酯1.17g。
取3,4,5-三甲氧基-α-(羟甲基)苯乙酸甲酯1.0g(3.70mmol,1.0eq.)于20mLSchlenk瓶中，室温条件下向体系中缓慢加入溴化氢溶液(40％)2mL，加热回流反应过夜。后处理将反应体系转移至50mL水中，DCM萃取水层3×20mL，合并有机相后，再水洗干燥，减压浓缩后柱分离纯化，得3,4,5-三羟基-α-(羟甲基)苯乙酸0.69g。
2.结构鉴定
3,4,5-三羟基-α-(羟甲基)苯乙酸为白色结晶性粉末，易溶于甲醇，可溶于水。1H-NMR(400MHz,CD3OD)见图3，δH(ppm)3.63(2H,m,CH2),3.99(1H,m,CH),6.10(2H,s,Ph-H)；13C-NMR(400MHz,CD3OD)见图4，δC(ppm)55.9(CH),65.2(CH2),106.8(2×CH),131.0(C),131.3(C),146.2(2×C),176.2(C＝O)。
实施例3：托品酸及其衍生物对咪喹莫特诱导的小鼠银屑病的作用研究
1.动物造模、分组及给药
取110只雄性Balb/c小鼠(8～10周，20～25g/只)，以10％水合氯醛腹腔注射麻醉后，剃掉约2cm×4cm大小的背毛。小鼠随机分为11组，每组10只，分别为空白对照组、模型组、阳性药物组、托品酸高剂量组(A)、托品酸低剂量组(B)、4-羟基-α-(羟甲基)苯乙酸高剂量组(C)、4-羟基-α-(羟甲基)苯乙酸低剂量组(D)、3,4-二羟基-α-(羟甲基)苯乙酸高剂量组(E)、3,4-二羟基-α-(羟甲基)苯乙酸低剂量组(F)、3,4,5-三羟基-α-(羟甲基)苯乙酸高剂量组(G)和3,4,5-三羟基-α-(羟甲基)苯乙酸低剂量组(H)，除空白对照组小鼠不做任何处理外，其他各组均每天涂5％咪喹莫特乳膏50mg制备成银屑病小鼠模型，各组同时进行给药，每天给药2次，分组和给药方案详见表1。连续治疗6d。第7天拍照记录小鼠皮肤损伤情况后处死小鼠，取小鼠背部皮肤备用。
表1.动物分组及给药信息表(n＝10)
| 分组 | 每日给药方案 |
| 空白对照 | 灌胃0.2mL生理盐水 |
| 模型 | 5％咪喹莫特乳膏50mg+灌胃0.2mL生理盐水 |
| 阳性药物 | 5％咪喹莫特乳膏50mg+灌胃地塞米松5mg/kg.d |
| A | 5％咪喹莫特乳膏50mg+灌胃托品酸6mg/kg.d |
| B | 5％咪喹莫特乳膏50mg+灌胃托品酸3mg/kg.d |
| C | 5％咪喹莫特乳膏50mg+灌胃4-羟基-α-(羟甲基)苯乙酸6mg/kg.d |
| D | 5％咪喹莫特乳膏50mg+灌胃4-羟基-α-(羟甲基)苯乙酸3mg/kg.d |
| E | 5％咪喹莫特乳膏50mg+灌胃3,4-二羟基-α-(羟甲基)苯乙酸6mg/kg.d |
| F | 5％咪喹莫特乳膏50mg+灌胃3,4-二羟基-α-(羟甲基)苯乙酸3mg/kg.d |
| G | 5％咪喹莫特乳膏50mg+灌胃3,4,5-三羟基-α-(羟甲基)苯乙酸6mg/kg.d |
| H | 5％咪喹莫特乳膏50mg+灌胃3,4,5-三羟基-α-(羟甲基)苯乙酸3mg/kg.d |
2.指标检测观察
组织形态学观察：从造模第一天开始，根据PASI评分标准，每天对小鼠背部的红斑、鳞屑、炎性浸润增厚程度进行评分，PAIS评分标准如下：0无；1轻度；2中度；3重度；4极重度。皮损伤程度越高，评分越高。将三项积分相加得PASI总分。对各组小鼠积分取平均值后绘制趋势线，观察各组小鼠皮损的变化情况。采用数码照相对各组小鼠第7天背部皮损情况进行拍照，观察比较。
组织病理学检测：造模第7日处死小鼠，并剪取各组小鼠背部皮肤，在4％多聚甲醛浸泡固定24h，石蜡包埋，切4μm厚的切片，常规HE染色，封片，光镜下观察组织病理学改变情况，并利用cellSens standard的标尺功能测量表皮厚度。
3.实验结果与讨论
组织形态学观察：每日观察小鼠背部皮肤的变化，空白对照组小鼠的皮肤平整无损伤，根据PASI评分，与空白对照组相比，模型组小鼠皮肤在第2天开始出现明显的损伤，第4-6天小鼠的皮损程度急剧加重(P<0.01)，小鼠皮肤红斑明显，压之有实质感，皮损处覆盖着较厚的黄白色鳞屑，皮肤存在明显炎性浸润增厚。在给予托品酸及其衍生物治疗过程中，高、低剂量组小鼠的皮损程度明显减轻，各项评分显著改善，其中高剂量组3-6天改善最为明显(P<0.01)，如图5A和5B。观察第7天的各组小鼠，与模型组相比，各托品酸及其衍生物治疗组小鼠的皮肤鳞屑减少，皮肤较平整，皮服损伤程度明显减轻，说明托品酸及其衍生物治疗能够改善咪喹莫特诱导的小鼠银屑病样皮肤损伤，如图6。
组织病理学检测：HE染色结果显示，与对照组比较，模型组小鼠皮肤组织的棘层厚度明显增加，细胞间隙增宽，表明存在细胞间水肿的现象；表皮最外层的角质层观察到大量未完全角化的细胞，表现出的组织病理学特征与人类银屑病相似。与模型组比较，阳性药物组和各托品酸及其衍生物治疗组的棘层厚度明显降低，皮肤角化不全的情况明显改善，其中以高剂量改善更为显著，如图7。对表皮层的厚度进行测量，结果显示，与对照组比较，模型组小鼠的表皮厚度显著增加(P<0.01)；与模型组比较，各托品酸及其衍生物治疗组小鼠的表皮厚度明显降低，各托品酸及其衍生物高剂量组小鼠的表皮厚度降低更为显著(P<0.01)，如图8。
综上结果表明，托品酸及其衍生物对咪喹莫特够诱导的银屑病小鼠模型背部皮肤损伤具有明显的治疗作用，化合物3和4具有最佳治疗效果。
实施例4：托品酸及其衍生物片剂的制备
处方见表2。按处方1取原料药(托品酸)及辅料(乳糖、微晶纤维素、聚乙烯吡咯烷酮、交联羧甲基纤维素钠、微粉硅胶、硬脂酸镁和纯化水)，将托品酸、乳糖、微晶纤维素和聚乙烯吡咯烷酮加入到湿法制粒机中，用纯化水作为润湿剂进行湿法制粒，经过湿整粒、干燥和干整粒后得到干颗粒，将交联羧甲基纤维素钠、微粉硅胶和硬脂酸镁加入到干颗粒中混合均匀后，用压片机将混合均匀的物料进行压片，即得到托品酸片。分别取处方2、3和4原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸片、3,4-二羟基-α-(羟甲基)苯乙酸片和3,4,5-三羟基-α-(羟甲基)苯乙酸片。
表2.托品酸及其衍生物片剂处方
| 物料名称 | 处方1(g) | 处方2(g) | 处方3(g) | 处方4(g) |
| 托品酸 | 200 | — | — | — |
| 4-羟基-α-(羟甲基)苯乙酸 | — | 200 | — | — |
| 3,4-二羟基-α-(羟甲基)苯乙酸 | — | — | 200 | — |
| 3,4,5-三羟基-α-(羟甲基)苯乙酸 | — | — | — | 200 |
| 乳糖 | 980 | 980 | 980 | 980 |
| 微晶纤维素 | 700 | 700 | 700 | 700 |
| 聚乙烯吡咯烷酮 | 160 | 160 | 160 | 160 |
| 交联羧甲基纤维素钠 | 80 | 80 | 80 | 80 |
| 微粉硅胶 | 20 | 20 | 20 | 20 |
| 硬脂酸镁 | 20 | 20 | 20 | 20 |
| 纯化水 | 340 | 340 | 340 | 340 |
实施例5：托品酸及其衍生物包衣片剂的制备
处方见表3。按处方5取原料药(托品酸)及辅料(乳糖、微晶纤维素、羟丙甲纤维素、十二烷基硫酸钠、羧甲淀粉钠、微粉硅胶、硬脂酸镁、薄膜包衣预混剂和纯化水)，将十二烷基硫酸钠加入到纯化水中搅拌使其溶解，将托品酸、乳糖、微晶纤维素和羟丙甲纤维素加入到湿法制粒机中，用十二烷基硫酸钠的水溶液作为润湿剂进行湿法制粒，经过湿整粒、干燥和干整粒后得到干颗粒，将羧甲淀粉钠、微粉硅胶和硬脂酸镁加入到干颗粒中混合均匀后，用压片机将混合均匀的物料进行压片，即得到托品酸的素片。将薄膜包衣机预混剂加入到纯化水中，持续搅拌1小时以上，制得薄膜包衣液，然后在包衣机中对制得的素片进行包衣，即得到托品酸包衣片。分别取处方6、7和8原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸包衣片、3,4-二羟基-α-(羟甲基)苯乙酸包衣片和3,4,5-三羟基-α-(羟甲基)苯乙酸包衣片。
表3.托品酸及其衍生物包衣片剂处方
实施例6：托品酸及其衍生物喷雾剂I的制备
处方见表4。按处方9取原料药(托品酸)及辅料(聚乙烯吡咯烷酮K30、丙二醇单辛酸酯、羟苯乙酯、泊洛沙姆、二叔丁基对甲酚(BHT)、1N氢氧化钠溶液、乙醇和水)，将原料药、聚乙烯吡咯烷酮K30、丙二醇单辛酸酯、羟苯乙酯、BHT加入到乙醇中，搅拌使其完全溶解；将泊洛沙姆加入到适量水中溶解；然后将泊洛沙姆水溶液加入到上述混合物料的醇溶液中，用1N氢氧化钠溶液调节pH值至3～8的范围内；用水加至200ml，即得喷雾剂溶液；将溶液灌装至喷雾瓶中，即得到托品酸喷雾剂I。分别取处方10、11和12原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸喷雾剂I、3,4-二羟基-α-(羟甲基)苯乙酸喷雾剂I和3,4,5-三羟基-α-(羟甲基)苯乙酸喷雾剂I。
表4.托品酸及其衍生物喷雾剂I处方
| 物料名称 | 处方9 | 处方10 | 处方11 | 处方12 |
| 托品酸 | 4.0g | — | — | — |
| 4-羟基-α-(羟甲基)苯乙酸 | — | 4.0g | — | — |
| 3,4-二羟基-α-(羟甲基)苯乙酸 | — | — | 4.0g | — |
| 3,4,5-三羟基-α-(羟甲基)苯乙酸 | — | — | — | 4.0g |
| 聚乙烯吡咯烷酮K30 | 8.0g | 8.0g | 8.0g | 8.0g |
| 丙二醇单辛酸酯 | 15.0g | 15.0g | 15.0g | 15.0g |
| 羟苯乙酯 | 0.2g | 0.2g | 0.2g | 0.2g |
| 泊洛沙姆 | 1.0g | 1.0g | 1.0g | 1.0g |
| 二叔丁基对甲酚(BHT) | 0.5g | 0.5g | 0.5g | 0.5g |
| 1N氢氧化钠溶液 | 适量 | 适量 | 适量 | 适量 |
| 乙醇 | 80g | 80g | 80g | 80g |
| 水 | 加至200ml | 加至200ml | 加至200ml | 加至200ml |
实施例7：托品酸及其衍生物喷雾剂II的制备
处方见表5。按处方13取原料药(托品酸)及辅料(羟丙基纤维素、丙二醇单辛酸酯、羟苯乙酯、乙醇、水)，将原料药、羟丙基纤维素、丙二醇单辛酸酯、羟苯乙酯加入到乙醇中，搅拌使其完全溶解，用水加至200ml，即得喷雾剂溶液；将溶液灌装至喷雾瓶中，即得到托品酸喷雾剂II。分别取处方14、15和16原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸喷雾剂II、3,4-二羟基-α-(羟甲基)苯乙酸喷雾剂II和3,4,5-三羟基-α-(羟甲基)苯乙酸喷雾剂II。
表5.托品酸及其衍生物喷雾剂II处方
实施例8：托品酸及其衍生物注射剂I的制备
处方见表6。按处方17取原料药(托品酸)及辅料(氯化钠、磷酸氢二钠、磷酸二氢钠、泊洛沙姆、亚硫酸氢钠和注射用水)，将原料药和泊洛沙姆加入到注射用水中溶解，然后将氯化钠、磷酸氢二钠、磷酸二氢钠和亚硫酸氢钠加入到上述溶液中溶解，最后用水加至100mL，即得注射剂溶液；将上述注射剂溶液灌装至相应容积的安瓿瓶或西林瓶中，即得到托品酸注射剂I。分别取处方18、19和20原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸注射剂I、3,4-二羟基-α-(羟甲基)苯乙酸注射剂I和3,4,5-三羟基-α-(羟甲基)苯乙酸注射剂I。
表6.托品酸及其衍生物注射剂I处方
| 物料名称 | 处方17 | 处方18 | 处方19 | 处方20 |
| 托品酸 | 1.0g | — | — | — |
| 4-羟基-α-(羟甲基)苯乙酸 | — | 1.0g | — | — |
| 3,4-二羟基-α-(羟甲基)苯乙酸 | — | — | 1.0g | — |
| 3,4,5-三羟基-α-(羟甲基)苯乙酸 | — | — | — | 1.0g |
| 氯化钠 | 0.85g | 0.85g | 0.85g | 0.85g |
| 磷酸氢二钠 | 0.21g | 0.21g | 0.21g | 0.21g |
| 磷酸二氢钠 | 1.6mg | 1.6mg | 1.6mg | 1.6mg |
| 泊洛沙姆 | 0.5g | 0.5g | 0.5g | 0.5g |
| 亚硫酸氢钠 | 0.1g | 0.1g | 0.1g | 0.1g |
| 注射用水 | 加至100mL | 加至100mL | 加至100mL | 加至100mL |
实施例9：托品酸及其衍生物注射剂II的制备
处方见表7。按处方21取原料药(托品酸)及辅料(氯化钠、磷酸氢二钠、磷酸二氢钠、吐温80、注射用水)，将原料药和吐温80加入到注射用水中溶解，然后将氯化钠、磷酸氢二钠和磷酸二氢钠加入到上述溶液中溶解，最后用水加至100mL，即得注射剂溶液；将上述注射剂溶液灌装至相应容积的安瓿瓶或西林瓶中，即得到托品酸注射剂II。分别取处方22、23和24原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸注射剂II、3,4-二羟基-α-(羟甲基)苯乙酸注射剂II和3,4,5-三羟基-α-(羟甲基)苯乙酸注射剂II。
表7.托品酸及其衍生物注射剂II处方
实施例10：托品酸及其衍生物乳膏I的制备
处方见表8。按处方25取原料药(托品酸)及辅料(白凡士林、十六醇、吐温80、二乙二醇单乙醚、羟苯乙酯、BHT、丙二醇、柠檬酸/柠檬酸钠和水)，制备工艺如下：(1)原料药溶解：称取丙二醇，加入原料药，40～50℃搅拌溶解：(2)油相制备：称取白凡士林、十六醇、羟苯乙酯和BHT，升温至60～80℃，搅拌溶解，将溶解的原料药缓慢加入，继续搅拌，混合均匀，备用；(3)水相制备：称取纯化水，加入吐温80和二乙二醇单乙醚，升温至60～80℃，柠檬酸/柠檬酸钠调节pH值，搅拌溶解备用；(4)乳化：将水相缓慢加入油相中，保持70℃，均质、继续搅拌30min以上；(5)成膏：降温，停止加热，继续搅拌，逐步降至室温并冷却成膏，灌装。即得托品酸乳膏I。分别取处方26、27和28原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸乳膏I、3,4-二羟基-α-(羟甲基)苯乙酸乳膏I和3,4,5-三羟基-α-(羟甲基)苯乙酸乳膏I。
表8.托品酸及其衍生物乳膏I处方
| 物料名称 | 处方25 | 处方26 | 处方27 | 处方28 |
| 托品酸 | 4g | — | — | — |
| 4-羟基-α-(羟甲基)苯乙酸 | — | 4g | — | — |
| 3,4-二羟基-α-(羟甲基)苯乙酸 | — | — | 4g | — |
| 3,4,5-三羟基-α-(羟甲基)苯乙酸 | — | — | — | 4g |
| 白凡士林 | 20g | 20g | 20g | 20g |
| 十六醇 | 40g | 40g | 40g | 40g |
| 吐温80 | 10g | 10g | 10g | 10g |
| 二乙二醇单乙醚 | 20g | 20g | 20g | 20g |
| 羟苯乙酯 | 0.4g | 0.4g | 0.4g | 0.4g |
| BHT | 0.4g | 0.4g | 0.4g | 0.4g |
| 丙二醇 | 20g | 20g | 20g | 20g |
| 柠檬酸/柠檬酸钠 | 适量 | 适量 | 适量 | 适量 |
| 水 | 加至200g |
实施例11：托品酸及其衍生物乳膏II的制备
处方见表9。按处方29取原料药(托品酸)及辅料(白凡士林、十六醇、泊洛沙姆407、丙二醇单辛酸酯、苯甲酸钠、BHA、丙二醇、冰醋酸/醋酸钠和水)，制备工艺如下：(1)原料药溶解：称取丙二醇，加入原料药，40～50℃搅拌溶解；(2)油相制备：称取白凡士林、十六醇、丙二醇单辛酸酯和BHA，升温至60～80℃，搅拌溶解，将溶解的原料药缓慢加入，继续搅拌，混合均匀，备用；(3)水相制备：称取纯化水，加入泊洛沙姆407和苯甲酸钠，升温至60～80℃，冰醋酸/醋酸钠调节pH值，搅拌溶解备用；(4)乳化：将水相缓慢加入油相中，保持70℃，均质、继续搅拌30min以上；(5)成膏：降温，停止加热，继续搅拌，逐步降至室温并冷却成膏，灌装。即得托品酸乳膏II。分别取处方30、31和32原料药和辅料，按照与上述相同工艺方法，分别制备得到4-羟基-α-(羟甲基)苯乙酸乳膏I、3,4-二羟基-α-(羟甲基)苯乙酸乳膏I和3,4,5-三羟基-α-(羟甲基)苯乙酸乳膏II。
表9.托品酸及其衍生物乳膏II处方
| 物料名称 | 处方29 | 处方30 | 处方31 | 处方32 |
| 托品酸 | 8g | — | — | — |
| 4-羟基-α-(羟甲基)苯乙酸 | — | 8g | — | — |
| 3,4-二羟基-α-(羟甲基)苯乙酸 | — | — | 8g | — |
| 3,4,5-三羟基-α-(羟甲基)苯乙酸 | — | — | — | 8g |
| 白凡士林 | 20g | 20g | 20g | 20g |
| 十六醇 | 40g | 40g | 40g | 40g |
| 泊洛沙姆407 | 10g | 10g | 10g | 10g |
| 丙二醇单辛酸酯 | 20g | 20g | 20g | 20g |
| 苯甲酸钠 | 1g | 1g | 1g | 1g |
| BHA | 0.4g | 0.4g | 0.4g | 0.4g |
| 丙二醇 | 20g | 20g | 20g | 20g |
| 冰醋酸/醋酸钠 | 适量 | 适量 | 适量 | 适量 |
| 水 | 加至200g | 加至200g | 加至200g | 加至200g |
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (5)
1.托品酸衍生物、其药学上可接受的盐作为唯一活性成分在制备预防和/或治疗银屑病药物中的用途，所述托品酸衍生物选自以下式III-式IV所示化合物：
。
2.根据权利要求1所述的用途，其特征在于，所述药物是外用药、口服药或者注射药。
3.根据权利要求1所述的用途，其特征在于，所述药物还包含药学上可接受的载体或者辅料。
4.根据权利要求1所述的用途，其特征在于，所述药物为固体剂型、液体剂型或半固体剂型。
5.根据权利要求1所述的用途，其特征在于，所述药物的剂型是：散剂、片剂、颗粒剂、胶囊剂、溶液剂、乳剂、混悬剂、注射剂、喷雾剂、气雾剂、粉雾剂、洗剂、搽剂、软膏剂、硬膏剂、糊剂、凝胶剂、贴剂。
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| CA2644311C (en) * | 2006-03-01 | 2012-07-10 | Tristrata, Inc. | Composition and method for topical treatment of tar-responsive dermatological disorders |
| CN115869294B (zh) * | 2022-10-25 | 2023-10-20 | 广东药科大学 | 托品酸及其衍生物在制备治疗银屑病药物中的用途 |
| CN116440110B (zh) * | 2023-03-08 | 2024-01-09 | 广东药科大学 | 托品酸及其衍生物在制备免疫与炎症相关疾病治疗药物中的医药用途 |
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2022
- 2022-10-25 CN CN202211309894.3A patent/CN115869294B/zh active Active
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2023
- 2023-10-20 WO PCT/CN2023/125517 patent/WO2024088153A1/zh unknown
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| US4363815A (en) * | 1975-07-23 | 1982-12-14 | Yu Ruey J | Alpha hydroxyacids, alpha ketoacids and their use in treating skin conditions |
| US5091171A (en) * | 1986-12-23 | 1992-02-25 | Yu Ruey J | Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use |
| US5389677A (en) * | 1986-12-23 | 1995-02-14 | Tristrata Inc | Method of treating wrinkles using glycalic acid |
| US5091171B1 (en) * | 1986-12-23 | 1995-09-26 | Ruey J Yu | Amphoteric compositions and polymeric forms of alpha hydroxyacids, and their therapeutic use |
| US5091171B2 (en) * | 1986-12-23 | 1997-07-15 | Tristrata Inc | Amphoteric compositions and polymeric forms of alpha hydroxyacids and their therapeutic use |
| US5389677B1 (en) * | 1986-12-23 | 1997-07-15 | Tristrata Inc | Method of treating wrinkles using glycalic acid |
| CN101128117A (zh) * | 2005-01-03 | 2008-02-20 | 吕伊·J·于 | 包含氨基糖类和氨基酸的o-乙酰水杨基衍生物的组合物 |
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| Publication number | Publication date |
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| CN115869294A (zh) | 2023-03-31 |
| WO2024088153A1 (zh) | 2024-05-02 |
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