CN114569615B - 甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途 - Google Patents
甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途 Download PDFInfo
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- CN114569615B CN114569615B CN202210254268.2A CN202210254268A CN114569615B CN 114569615 B CN114569615 B CN 114569615B CN 202210254268 A CN202210254268 A CN 202210254268A CN 114569615 B CN114569615 B CN 114569615B
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- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本申请公开了甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途。本发明甲氨蝶呤类似物不仅活性强毒副作用低，同时可靶向皮肤分布，可作为新一代抗银屑病或抗皮肤癌药物。
Description
技术领域
本文涉及但不限于医药技术，尤指但不限于甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途。
背景技术
银屑病，俗称“牛皮癣”，严重影响着患者的生活质量。银屑病属于一种慢性复发性炎症性皮肤病，病因不明，发病机制复杂，治疗方法众多，但目前尚无理想的根治方法。尤其泛发性脓疱性银屑病(GPP)及红皮病性银屑病(EP)这2种严重类型银屑病，病情凶险，可出现多种并发症，治疗困难，给患者带来极大的痛苦。GPP以躯干及四肢弥漫性红斑基础上黄白色潜在性的无菌小脓疱为特征，常伴高热和全身不适等症状。EP以全身皮肤泛发性红斑、肿胀及脱屑为主要表现，同时可伴发热、乏力及全身酸痛等系统症状。GPP和EP均属于严重类型银屑病，疾病进展过程中常并发肝、肾等器官损害，还可因肺部感染、血源感染及电解质紊乱等而危及生命。临床上治疗GPP及EP多采用阿维A、MTX、雷公藤、补骨脂素长波紫外线(PUVA)及糖皮质激素等。近年来肿瘤坏死因子(TNF)-α抑制剂也逐步应用到严重类型银屑病的治疗中。糖皮质激素起效快且疗效显著，但在糖皮质激素类减量或者撤药时，病情往往出现反复甚至加重；近年来，银屑病新药开发是国际研究的热点，生物制剂和小分子靶向药是两类代表性药物。
甲氨蝶呤(MTX)为抗叶酸类抗肿瘤药。它主要通过对二氢叶酸还原酶的抑制而达到阻碍肿瘤细胞的合成，而抑制肿瘤细胞的生长与繁殖。淋巴细胞在真皮的浸润以及表皮角质细胞的过度增生是银屑病的发病原因之一，MTX从抗表皮细胞过度增生及抗淋巴细胞浸润方面对银屑病发挥有效治疗作用。低剂量口服甲氨蝶呤在临床上也被用于银屑病的治疗。但因其毒副作用大而限制了其在银屑病临床治疗的广泛应用。MTX通过抑制二氢叶酸还原酶的作用，从而抑制DNA合成，阻止上皮增生，增强活化T细胞的凋亡和抑制中性粒细胞的趋化。此外，MTX还可降低TNF-α和白细胞介素(IL)-1等一系列促炎细胞因子的合成，因此MTX的抗炎效果可以起到治疗银屑病的作用。
尽管如上所述，本领域迫切需要开发合成一种能改善MTX治疗效果且降低毒性的药物，从而提高患者的耐受性和安全性。
发明内容
以下是对本文详细描述的主题的概述。本概述并非是为了限制本申请的保护范围。
本申请提供了甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途，所述甲氨蝶呤类似物如式(I)所示，或其互变异构体、或立体构体、或外消旋体、或药学上可接受的盐、或水合物：
在本申请的实施方式中，本申请提供的甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途，所述的炎症性皮肤疾病为银屑病。
在本申请的实施方式中，本申请提供的甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途，所述的甲氨蝶呤类似物如式(Ia)所示，或其互变异构体、或药学上可接受的盐、或水合物：
在本申请的实施方式中，本发明所述的药学上可接受的盐包括无机酸盐或有机酸盐，包括与有机和无机的酸或碱生成的盐；这里，所述药学上可接受的酸成盐选自与以下酸一种或多种而形成的盐：盐酸、氢溴酸、硫酸、柠檬酸、酒石酸、磷酸、乳酸、丙酮酸、醋酸、三氟醋酸、丁二酸、乙二酸、富马酸、马来酸、丁酮二酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸和羟乙磺酸。药学上可接受的碱盐选自铵盐、碱金属盐(例如钠盐和钾盐)、碱土金属盐(例如钙盐和镁盐)以及有机碱(例如二环己基胺和N-甲基-D-葡糖胺)盐中的一种或多种。
在本申请的实施方式中，本申请提供的甲氨蝶呤类似物用于治疗炎症性皮肤疾病的用途，所述的甲氨蝶呤类似物是药物组合物的形式对有相应需要的患者进行施用。所述的药物组合物包含治疗上有效量的甲氨蝶呤类似物如式(I)所示或如式(Ia)所示，或其互变异构体、或药学上可接受的盐、或水合物，以及药学上可接受的载体或赋形剂。这里，所述有效剂量可以单位剂量5mg-200mg。
在本申请的实施方式中，对有相应需要的患者施用所述的药物组合物可根据本领域公知的方法制备不同的非肠道给药剂型，适于人或动物使用。例如，将本发明化合物制成注射用制剂，如溶液剂、混悬剂溶液剂、乳剂、冻干粉针剂，这种制剂可以是含水或非水的，可含一种和多种药效学上可接受的载体、稀释剂、防腐剂、表面活性剂、助溶剂、缓冲剂、pH调节剂。这些辅料都是本领域常用的。为达到用药目的，增强治疗效果，本发明药物或药物组合物可用任何公知的给药方法给药；可以采用每日1-6次进行施用。
在本申请的实施方案中，本发明的甲氨蝶呤类似物或其药物组合物可单独服用，或与其他治疗药物或对症药物合并使用，当本发明的甲氨蝶呤类似物与其他治疗药物存在协同作用时，本领域技术人可根据实际情况调整它的剂量。
在本申请的实施方式中，本申请提供的甲氨蝶呤类似物或者其药物组合物用于治疗炎症性皮肤疾病的用途，这里，所述炎症性皮肤疾病包括但不限于银屑病，或皮肤癌。
在本申请的实施方案中，本申请提供了上述甲氨蝶呤类似物的制备方法，所述的制备方法包括如下步骤：
甲氨蝶呤类似物MTX-1的按以下反应式经甲氨蝶呤7位羟基化合成得到。
有益技术效果：
本发明提供的甲氨蝶呤类似物(MTX-1)可以是甲氨蝶呤的体内代谢产物，相对原型药物，其毒性显著降低。实验结果也表明，本发明提供的甲氨蝶呤类似物在动物体内可明显靶向皮肤分布，对全身毒性尤其是肝脏毒性明显降低，而且抗银屑病的药效显著地优于同等剂量的甲氨蝶呤，因而MTX-1可以制成更低毒和有效的抗银屑病药物。
本申请的其它特征和优点将在随后的说明书中阐述，并且，部分地从说明书中变得显而易见，或者通过实施本申请而了解。本申请的其他优点可通过在说明书以及附图中所描述的方案来实现和获得。
附图说明
附图用来提供对本申请技术方案的理解，并且构成说明书的一部分，与本申请的实施例一起用于解释本申请的技术方案，并不构成对本申请技术方案的限制。
图1为本申请实施例化合物MTX-1的合成1H-NMR谱图；
图2为本申请实施例化合物MTX-1的合成(-)ESI-MS谱图；
图3为动物实验前(左)和动物实验后(右)的小鼠体重；
图4为银屑病样皮损面积和疾病严重程度PASI评分对比结果；其中，图4中中A三者积分相加得到总分；B，小鼠皮损处红斑(erythema)，C，鳞屑(scales)，及D浸润增厚程度(thickness)；
图5银屑病皮肤组织病理评分对比结果；其中，图5中A，角质层；B，表皮层；C，真皮层；D，总和评分；
图6为对甲氨蝶呤MTX和甲氨蝶呤类似物MTX-1的成像图。
具体实施方式
为使本申请的目的、技术方案和优点更加清楚明白，下文中将对本发明的实施例进行详细说明。需要说明的是，在不冲突的情况下，本申请中的实施例及实施例中的特征可以相互任意组合。
实施例1：化合物MTX-1的合成。
试剂：甲氨蝶呤；甲醇；BF3-OEt3:三氟化硼乙醚；DEPC：氰基磷酸二乙酯；TEA：三乙胺；NMP：N-甲基吡咯烷酮；THF：四氢呋喃。
化合物MTX-1的按以下反应式经甲氨蝶呤7位羟基化合成得到。具体操作如下：精密称取甲氨蝶呤1g，加入10ml甲醇溶解，加入适量BF3-OEt3室温搅拌过夜，获得甲氨蝶呤二甲酯，抽干后用水清洗过滤；过滤后的固体中加入去离子水、NMP、DEPC和TEA各10ml，室温搅拌过夜，获得7腈基甲氨蝶呤二甲酯；在反应液中加入10ml 10mM的NaOH水溶液,室温搅拌过夜，用THF萃取后，蒸干，制备液相分离纯化，获得化合物甲氨蝶呤类似物MTX-1。
化合物MTX-1的鉴定和含量检测：
1H NMR(DMSO-d6):(核磁共振波谱仪，WNMR-1，400M，中科牛津波谱)δ1.76-2.02(m,2H,CH2CH2CO),2.13-2.37(m,2H,CH2CH2CO),3.32(m,6H,NCH3,-NH2),4.22-4.24(m,lH,NCHRCO),4.53(S,2H,HetCH2N),6.81(d,J＝8.0Hz,2H,3',5'-PhH),7.61(d,J＝8.0Hz,2H,2',6'-PhH).(见图1)
液质检测(高效液相质谱联用仪，LCMS-IT-TOF岛津，ESI负)：MTX-1，7-羟基氨甲喋呤分子量：470(见图2)，[M-H]-,m/z 469。
试验例1药理试验
试验分组及造模方法：
小鼠随机分为5组，分别为阴性对照组(n＝6)，模型组(n＝7)，阳性对照药(甲氨蝶呤)组MTX 1.5mg/kg口服给药组(n＝6)，甲氨蝶呤类似物MTX-1 1.5mg/kg口服给药组(n＝6)，甲氨蝶呤类似物MTX-1 1.5mg/kg腹腔注射给药组(n＝6)。
用宠物电推剪及脱毛膏给小鼠背部去毛，面积约为1.5×2cm。除了阴性对照组动物外，每组动物均用咪喹莫特乳膏(0.1g:2g)进行造模，即每天给予小鼠背部去毛部位的皮肤涂抹50mg的咪喹莫特乳膏，每天涂抹1次，连续7天。
给药方式及PASI评分：
第0天造模结束后即开始灌胃或腹腔注射给药，每天1次，连续7天。
1)阴性对照组(control)：每日灌胃给予蒸馏水。
2)模型组(IMQ Model)：每日灌胃给予蒸馏水。
3)阳性对照药组：MTX，1.5mg/kg，每日灌胃给药。
4)MTX-1-po-1.5mg/kg组：每日灌胃给药。
5)MTX-1-ip-1.5mg/kg组：每日腹腔注射给药。
首次造模次日开始每天对动物进行银屑病样皮损面积和疾病严重程度—PASI(psoriasis area and severity index)评分。依据PASI评分标准，给予小鼠皮损处红斑(erythema)，鳞屑(scales)，及浸润增厚程度(thickness)给予0-4的积分，将三者积分相加得到总分。
PASI评分标准：0，无；1，轻度；2，中度；3，重度；4，极重度。
实验过程中每天记录动物体重和观察动物状态。
表1.皮肤组织病理评分标准
试验结果：
实验动物造模和在给药期间，除空白对照组外，其他各组小鼠体重均有不同程度的降低，且具有统计学意义(图3)。且根据PASI评分，空白对照组(control)皮肤正常，PASI评分为0；造模组(IMQ-model)平均得分为9，与空白对照组相比具有显著统计学差异，造模成功(图4、5)，且皮肤组织病理结果表明，角质层、表皮层、真皮层等均出现显著病理改变，皮肤组织病理评分总分具有显著差异。MTX给药组(MTX-po-1.5mg/kg)第6天死一只，第7天死两只，其他各组动物正常存活，表明MTX组毒性大，MTX-1组毒性显著降低。
与模型对照组比较，MTX-po 1.5mg/kg、MTX-1-po 1.5mg/kg、MTX-1-ip1.5mg/kg剂量组对小鼠皮肤损伤均有显著改善；MTX-1无论是口服还是静脉注射，均优于MTX组。
试验结论：
口服或腹腔注射甲氨蝶呤类似物MTX-1 1.5mg/kg均可显著减轻小鼠银屑病模型的皮损症状，且优于同等剂量的阳性对照药MTX治疗组；MTX给药组2只动物死亡，甲氨蝶呤类似物MTX-1组动物活动正常，表明甲氨蝶呤类似物MTX-1经结构修饰后毒性显著降低。
试验例2药物体内分布试验
试验方法：
Balb/C小鼠24只，体重20g左右，随机分为两组(MTX和MTX-1给药组)，尾静脉注射给药，给药剂量1.5mg/kg，分别在给药后0.5、1、2、4hCO2处死，每个时间点各3只，处死后固定在2.5％羧甲基纤维素钠凝胶溶液中，并于-80℃冷冻保存。采用CM1860 XP型冷冻切片机制作25μm矢状面的整体动物切片，暴露脑、心、肝、脾、肺、肾等主要脏器。切片冷冻干燥后，扫描获得切片光学照片，采用质谱成像分析获得MTX和MTX-1在整体动物体内的分布情况。
实验结果：如图6所示，在给药0.5h的成像图中，甲氨蝶呤MTX(绿色)主要分布在肝脏和肠道的上部，随着时间延长，主要分布到肠道的下端部位，说明MTX主要在肝脏富集，并可能经胆汁排泄进入肠道。而MTX-1(红色)主要分布在胃腔和皮肤上，随着时间延长，MTX-1进一步在皮层组织中富集，且在4小时后进一步明显在皮肤中高表达。
实验结论：MTX经过结构修饰为MTX-1后，靶向器官从肝脏转为皮肤。因而，MTX-1对皮肤具有显著靶向性，且为降低MTX肝毒性，提高治疗指数提供有效的实验数据支撑。
本申请描述了多个实施例，但是该描述是示例性的，而不是限制性的，并且对于本领域的普通技术人员来说显而易见的是，在本申请所描述的实施例包含的范围内可以有更多的实施例和实现方案。
Claims (7)
1.甲氨蝶呤类似物作为唯一活性成分在制备治疗炎症性皮肤疾病的药物中的用途，其中，所述炎症性皮肤疾病为银屑病；所述甲氨蝶呤类似物如式(I)所示，或其立体异构体、或外消旋体、或药学上可接受的盐：
2.根据权利要求1所述的用途，其中，所述甲氨蝶呤类似物如式(Ia)所示，或其药学上可接受的盐：
3.根据权利要求1或2所述用途，其中，所述甲氨蝶呤类似物是以药物组合物的形式对有相应需要的患者进行施用；所述药物组合物包含治疗上有效量的如式(I)所示或如式(Ia)所示的甲氨蝶呤类似物，或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
4.根据权利要求1所述的用途，其中所述甲氨蝶呤类似物或其立体异构体、或外消旋体、或药学上可接受的盐通过口服或注射施用。
5.根据权利要求4所述的用途，其中所述甲氨蝶呤类似物或其立体异构体、或外消旋体、或药学上可接受的盐通过静脉注射施用。
6.根据权利要求1所述的用途，其中所述甲氨蝶呤类似物或其立体异构体、或外消旋体、或药学上可接受的盐每日施用1-6次。
7.根据权利要求1所述的用途，其中所述甲氨喋呤类似物或其立体异构体、或外消旋体、或药学上可接受的盐以单位剂量施用，所述单位剂量为5mg-200mg。
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| WO2003007961A1 (en) * | 2001-07-20 | 2003-01-30 | Iomed, Inc. | Methods for treating neoplastic, angiogenic, fibroplastic, and/or immunosuppresive ocular irregularities via administration of methotrexate based medicaments, and ocular iontophoretic devices for delivering methotrexate based medicaments |
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| WO2011133748A1 (en) * | 2010-04-21 | 2011-10-27 | University Of Medicine And Dentistry Of New Jersey | Treatments for cellular proliferative disorders and identification thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2003007961A1 (en) * | 2001-07-20 | 2003-01-30 | Iomed, Inc. | Methods for treating neoplastic, angiogenic, fibroplastic, and/or immunosuppresive ocular irregularities via administration of methotrexate based medicaments, and ocular iontophoretic devices for delivering methotrexate based medicaments |
| WO2007017512A1 (en) * | 2005-08-09 | 2007-02-15 | Cellzome Ag | Treatment of inflammatory diseases |
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