CN113905732A - 用于预防或治疗脊髓损伤或椎管狭窄的药物组合物 - Google Patents
用于预防或治疗脊髓损伤或椎管狭窄的药物组合物 Download PDFInfo
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- CN113905732A CN113905732A CN202080040412.1A CN202080040412A CN113905732A CN 113905732 A CN113905732 A CN 113905732A CN 202080040412 A CN202080040412 A CN 202080040412A CN 113905732 A CN113905732 A CN 113905732A
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- cord injury
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- spinal stenosis
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/4015—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Neurology (AREA)
- Neurosurgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及用于预防或治疗脊髓损伤或椎管狭窄的包含3‑(4‑氯苯基)‑4‑(4‑氨基磺酰基‑苯基)‑1‑甲基‑1H‑吡咯‑2,5‑二酮或其药学上可接受的盐的药物组合物。本发明的发明人新发现,根据本发明的化合物通过抑制作为炎症介质的促炎细胞因子和PGE2的活性来抑制脊髓损伤或椎管狭窄引起的炎症或疼痛。由于根据本发明的化合物能够有效地抑制脊髓损伤或椎管狭窄引起的炎症或疼痛,因此,预期其将有效地用于预防或治疗脊髓损伤或椎管狭窄。
Description
技术领域
本发明涉及用于预防或治疗脊髓损伤或椎管狭窄的包含3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮或其药学上可接受的盐的药物组合物,更具体地,涉及通过抑制脊髓损伤或椎管狭窄的炎症介质来预防或治疗脊髓损伤或椎管狭窄的组合物。
背景技术
椎管狭窄(spinal stenosis)是指由骨和构成神经结构的软组织所包围的椎管变窄的医学病况,其引起间歇性跛行(intermittent claudication)、下肢疼痛、无法行走等。
作为椎管狭窄的治疗方法,通常最推荐的手术治疗选项是手术减压,但难以预测手术的成功可能性,并且由于椎板切除术而导致诸如肌纤维韧带等的解剖学支撑结构的破坏从而存在诱发肌肉萎缩的风险,因此,优选通过使用以与炎症或疼痛相关的生物材料作为目标的药物来治疗椎管狭窄的方法。
椎管狭窄的药物主要使用消炎剂、镇痛剂、肌肉松弛剂等,或者注射类固醇等。其中,类固醇是具有免疫抑制作用和强力的抗炎作用的肾上腺皮质激素,其被广泛地用作诸如多发性硬化症的中枢神经系统脱髓鞘疾病等的治疗剂,但是长期使用时存在类固醇所诱发的糖尿病、骨质疏松症、血压增加及电解质异常、体重增加、免疫力减弱及感染可能性增加、消化性溃疡、肌病症、骨坏死、白内障、皮肤变化、行动障碍等副作用。
脊髓损伤(Spinal cord injury)意味着暂时地或永久地改变脊髓的功能的损伤,其会引起位于受损部位下方的身体部位的感觉的丧失、肌肉功能的丧失和腰椎的疼痛等。
脊髓损伤的治疗大体上分为药物治疗和手术治疗,在药物治疗的情况下,虽然据报道,对于急性脊髓损伤而言,大量给予类固醇对恢复有效果,但此时也有与上述的对狭窄症使用类固醇时的副作用相同的副作用,因此存在使用上的缺点。
对此,作为治疗脊髓损伤或椎管狭窄的消炎剂,可以考虑塞来昔布和罗非昔布等昔布类药物,但在2004年,默克公司的罗非昔布等昔布类药物因其在长期使用时过度增加心脏病发作和中风的风险而被禁用。
此外,在一些研究中已经确认,与心血管系统相关的罗非昔布的副作用问题可能是与罗非昔布的新陈代谢(metabolism)相关的内在化学性质问题,因此,迫切地需要开发新的化合物结构,并且正在对此进行积极的研究(British Journal of Pharmacology(2012)165,Shin等人)。
发明内容
本发明的发明人为开发对脊髓损伤或椎管狭窄有效的化合物而进行了研究,其结果确认了包含本发明的化合物的组合物抑制引起炎症或疼痛的促炎介质的表达,从而完成了本发明。
据此,本发明的目的是提供用于预防或治疗由脊髓损伤或椎管狭窄引起的症状的药物组合物,其包含以下化学式(I)的化合物或其药学上可接受的盐。
【化学式I】
然而,本发明要解决的技术问题不限于上述技术问题,且本领域的技术人员将可以通过下面的描述清楚地理解未提及的其它问题。
为了达成如上所述的本发明的目的,本发明提供了用于预防或治疗由脊髓损伤或椎管狭窄引起的症状的药物组合物,其包含以下化学式(I)的化合物或其药学上可接受的盐。
【化学式I】
此外,本发明提供了药物组合物,其中,所述椎管狭窄为腰椎管狭窄(Lumbarspinal stenosis)。
此外,本发明提供了药物组合物,其中,所述组合物抑制间歇性跛行(intermittent claudication)、不全麻痹、感觉减退、感觉异常、感觉障碍、炎症或疼痛。
此外,本发明提供了预防或治疗由脊髓损伤或椎管狭窄引起的症状的治疗方法,该方法包括将所述组合物施用至个体。
此外,本发明提供了所述组合物用于预防或治疗脊髓损伤或椎管狭窄引起的症状的用途。
有利效果
本发明的发明人新发现,包含3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮或其药学上可接受的盐的化合物抑制脊髓损伤和椎管狭窄引起的炎症或疼痛,由于根据本发明的化合物能够有效地抑制脊髓损伤或椎管狭窄引起的炎症或疼痛,因此,预期其将有效地用于预防或治疗脊髓损伤或椎管狭窄。
附图说明
图1a示出目标腰椎部位,图1b示出用于制作动物模型的硅块,以及图1c示出硅块插入到目标腰椎部位的状态。
图2示出根据本发明的化合物对LPS诱导的PEG2生成的抑制作用。
图3a示出慢性机械性痛觉超敏诱导的动物模型和模拟对照组(假手术组)的旋转试验结果,图3b示出慢性机械性痛觉超敏诱导的动物模型和模拟对照组(假手术组)的缩足反应阈值(paw withdrawal threshold,PWT)的测量结果,以及图3c示出在慢性机械性痛觉超敏诱导的动物模型中,进行马尾(cauda equina)压迫之后,在压迫部位和非压迫部位观察ED-1阳性巨噬细胞的结果。
图4a示出在对慢性机械性痛觉超敏诱导的动物模型使用塞来昔布的情况下的PWT测量结果,图4b示出在对慢性机械性痛觉超敏诱导的动物模型使用根据本发明的化合物的情况下的PWT测量结果,图4c示出在对慢性机械性痛觉超敏诱导的动物模型使用塞来昔布和本发明的化合物的情况下的30分钟后的TNF-α、白细胞介素-1β(IL-1β)、IL-6和诱导型一氧化氮合酶(iNOS)mRNA的表达结果,图4d示出在对慢性机械性痛觉超敏诱导的动物模型使用塞来昔布和本发明的化合物的情况下的上述炎症介质的相对表达水平的测量结果,以及图4e示出在对慢性机械性痛觉超敏诱导的动物模型使用塞来昔布和本发明的化合物的情况下的PEG2表达水平的测量结果。
具体实施方式
以下,详细说明本发明。
本发明涉及用于治疗或预防脊髓损伤或椎管狭窄的药物组合物,其包含化学式(I)的化合物或其药学上可接受的盐。
【化学式I】
本发明的化合物是1-H-吡咯或呋喃-2,5-二酮的衍生物,将其命名为3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮。
如本文所用,术语“预防”是指通过根据本发明的药物组合物的给药来抑制或延迟脊髓损伤或椎管狭窄的发作的任何作用。
如本文所用,术语“治疗”是指通过本发明的药物组合物的给药,脊髓损伤或椎管狭窄的症状好转或发生有利变化的任何作用。
如本文所用,术语“盐”是由药学上可接受的游离酸(free acid)形成的酸加成盐。酸加成盐从诸如盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸或亚磷酸的无机酸类、以及诸如脂肪族单羧酸酯及二羧酸酯、苯基取代的链烷酸酯、羟基链烷酸酯及链烷二酸酯、芳香酸类、脂肪族及芳香族磺酸类的无毒性有机酸获得。这种药学上无毒的盐类包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐氯化物、溴化物、碘化物、氟化物、醋酸盐、丙酸盐、癸酸酯、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己烷-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、苯甲酸甲酯、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸酯、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯丁酸盐、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、苹果酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐或扁桃酸盐。
根据本发明的酸加成盐可以通过常规方法制备,例如,可以通过使上述化合物溶解于过量酸的水溶液,并使用水溶性有机溶剂例如甲醇、乙醇、丙酮或乙腈沉淀该盐来制备。也可以通过蒸发该混合物中的溶剂或过量的酸之后进行干燥,或者对析出的盐进行吸入过滤来制备。
此外,也可以使用碱来制备药学上可接受的金属盐。例如,通过将化合物溶解在过量的碱金属氢氧化物或碱土金属氢氧化物的溶液中,过滤未溶解的化合物盐,并对滤液进行蒸发干燥来获得碱金属或碱土金属盐。此时,以金属盐制备钠盐、钾盐或钙盐是适合制药的。与此对应的银盐通过使碱金属盐或碱土金属盐与合适的银盐(例如,硝酸银)反应而获得。
此外,本发明的化合物不仅包括药学上可接受的盐,还包括可通过常规方法制备的所有盐、异构体、水合物和溶剂化物。
本发明中作为对象的疾病,“脊髓损伤(spinal cord injury,SCI)”是指脊柱(脊柱内存在的中枢神经)由于事故或疾病而损伤的同时脊髓一起损伤,或者指脊髓由于疾病而损伤,并且其症状有因脑与身体之间不能正常地进行神经传递而产生的运动麻痹、感觉麻痹等,但不限于此。
此外,椎管是脊柱中间的管状空腔,由上下脊椎产生椎间孔,中间管的内部成为从脑到四肢神经(脊髓)经过的通道。管形状为椭圆形或三角形,其在颈椎部位(颈部侧)最大,在胸椎部位(胸部侧)变窄,在腰椎部(腰部侧)再次变大后越往下部变窄。“椎管狭窄(spinal stenosis)”是脊柱中央的椎管、神经根管或椎间孔变窄从而诱发腰部疼痛或在腿上引起多种复合性的神经症状的疾病。椎管狭窄主要发生在腰椎部,通常称椎管狭窄是指腰椎管狭窄,而本发明的椎管狭窄可以是腰椎管狭窄,但不限于此,且包括与椎管相关地发生的各种狭窄症。
此外,“腰椎管狭窄(lumbar spinal stenosis,LSS)”是指由腰椎部的骨和构成神经结构的软组织所包围的椎管变窄的疾病。上述椎管狭窄的原因有腰椎滑脱症(lumbarspondylolisthesis)、椎间盘突出(slipped disk)、韧带增厚(ligamentous thickening)及老化引起的脊柱退化。根据本发明的上述椎管狭窄的症状有间歇性跛行(intermittentclaudication)、下肢疼痛、无法行走、马尾神经纤维的压迫(compression)、过敏症(hypersensitivity)、中枢神经系统及周围神经系统的致敏(sensitization)诱导、由此引起的严重的神经性疼痛、不全麻痹、感觉减退、感觉异常、感觉障碍等,但不限于此。
此外,已知神经炎症反应对脊柱神经性疼痛的发展和维持起到重要作用。发生组织损伤后,免疫细胞移动到损伤部位并产出促炎细胞因子(pro-inflammatory cytokine),并且介导炎症反应。作为促炎细胞因子,有TNF-α、IL-1β、IL-6、iNOS和前列腺素E2(prostaglandin E2),其使神经细胞的疼痛传递变得敏感。
在本发明的一个实例中,将本发明的化合物施用至神经性疼痛诱导的大鼠,并观察到对疼痛的阈值与媒介物组相比显著增加,从而确认本发明的化合物有效地抑制椎管狭窄的疼痛(参照实验例4)。
此外,在高剂量给药本发明的化合物的情况下,观察到镇痛效果维持到给药后的3小时,从而确认本发明的化合物对压迫马尾而产生的慢性机械性痛觉超敏具有缓解效果(参照实验例4)。
在本发明的另一个实例中,通过RT-PCR观察使用作为消炎剂的塞来昔布或根据本发明的化合物给药的大鼠中炎症介质的生成是否得到抑制,并且通过ELISA观察促炎细胞因子和PGE2的生成是否得到抑制,结果,TNF-α、IL-1β、IL-6、iNOS mRNA的表达显著减少,并且马尾中的PGE2的生成显著减少,从而确认本发明的化合物对压迫马尾而产生的炎症具有预防或缓解效果(参照实验例5)。
上述结果证明了本发明的化合物能够缓解作为脊髓损伤或椎管狭窄的症状的慢性机械性痛觉超敏或炎症的有用性。
根据本发明的药物组合物包含3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮或其药学上可接受的盐作为活性成分,并且还可以包含药学上可接受的载体。
在上述药物的制备中,本发明的化合物或其药学上可接受的盐的含量根据药物的形态而不同,但浓度优选为0.01-100重量%。上述药学上可接受的载体是在配制时通常使用的,其包括盐水、无菌水、林格氏液、缓冲盐水、环糊精、葡萄糖溶液、麦芽糊精溶液、甘油、乙醇、脂质体等,但不限于此,且根据需要还可以包括抗氧化剂、缓冲液等其它常规的添加剂。此外,还可以附加地添加稀释剂、分散剂、表面活性剂、粘合剂、润滑剂等,从而制成水溶液、悬浮液、乳浊液等注射用剂型、丸剂、胶囊、颗粒或片剂。关于合适的药学上可接受的载体及制剂,可以利用雷明顿的文献中所公开的方法,根据各种成分优选地配制。本发明的药物组合物可以制剂成注射剂、吸入剂、皮肤外用剂或口服剂,但剂型不限于此。
本发明的药物组合物可以根据需要的方法口服给药或肠胃外给药(例如,适用于静脉内、皮下、皮肤、鼻腔、气道给药等),给药量根据患者的状态和体重、疾病的程度、剂型、给药途径和时间而不同,但可以由本领域技术人员适当地选择。
本发明的组合物以药学有效量给药。在本发明中,“药学有效量”意味着能够以适用于医学治疗的合理的获益/风险比足以治疗疾病的量,且有效剂量水平可以根据包括患者的疾病种类、严重程度、药物的活性、对药物的敏感度、给药时间、给药途径及排出比例、治疗时间、同时使用的药物等的要素以及其它医学领域中公知的要素来确定。本发明的组合物可以作为单独的治疗剂给药,或者与其它治疗剂一起给药,且可以与现有的治疗剂依次或同时给药,且可以单次或多次给药。重要的是考虑上述所有因素,以不会有副作用的最小的量并且是能够获得最大效果的量给药,这可以由本领域技术人员容易地确定。
具体地,根据本发明的组合物的有效量可以根据患者的年龄、性别、体重而变化,通常可以以每kg体重0.001~150mg、优选0.01~100mg的量每日或隔日给药,或者分1日1次~3次给药。但是,由于给药量可以根据给药途径、脊髓损伤或椎管狭窄的严重程度、性别、体重、年龄等而增减,因此,上述给药量并非旨在以任何方式限定本发明的范围。
此外,根据本发明的另一个方面,本发明提供了预防、控制或治疗脊髓损伤或椎管狭窄的方法,其包括将上述药物组合物施用至个体。
在本发明中,“个体”是指需要疾病的预防、控制或治疗方法的对象,更具体地,是指人类或非人类灵长类、小鼠(mouse)、大鼠(rat)、狗、猫、马和牛等哺乳类。
以下,为了有助于理解本发明,提供优选的实施例。但是,下述实施例仅用于更容易地理解本发明,而本发明的内容并不限于下述实施例。
【实施例】
实施例1:实验准备及实验方法
1-1.1HNMR光谱和13CNMR光谱
在本实验中,用于1HNMR光谱和13CNMR光谱的仪器是Bruker Avance DXR400(400MHz)光谱计。
此外,化学位移(δ)以ppm表示,将四甲基硅烷(TMS)用作内部基准物质,耦合常数(J)以赫兹(Hz)表示,以及信号多重性(signal multiplicities)以s(singlet,单峰)、d(doublet,双峰)、t(triplet,三重峰)、q(quartet,四重峰)、br(broad,宽)、m(multiplet,多重峰)、dd(doulet of doublet,双重双重峰)表示。
此外,低分辨率和高分辨率质谱(FABMS,FAB+能量;6kev,发射电流:5mA,加速电压:10kV)利用了JMS-700质谱仪(JEOL,JAPAN)。
此外,TLC使用了涂布有硅胶(E.Merck Kiesegel 60F254,层厚0.25mm)的玻璃板,为了确认TLC上的有机化合物,将254mm和365mm的紫外线或磷钼酸(PMA)5%乙醇溶液、对甲氧基苯甲醛5%乙醇溶液或茚三酮5%乙醇溶液用作显色剂。
此外,用于分离有机混合物的快速柱色谱(flash column chromatography)的硅胶使用了Merck Kiesegel 60Art 9385(230~400目)。
最后,反应中所需的试剂主要从Sigma-Aldroch、TCI、Acros或Fluka等公司购买,且需要提纯的溶剂通过公知的方法提纯后使用。
1-2.动物和伦理声明(ethics statement)
为了进行关于本发明的实验,使用了共167只Spraque-Dawley雄性大鼠(250g~270g,Samtako,Osan,Korea)。动物以可自由地接近水和食物的方式在12小时光照/黑暗循环(07:30-19:30h光照)、室温(23±1℃)和湿度(60±10%)的环境中保管。在垫有白杨刨花垫的笼子(410×282×153mm,透明聚碳酸脂)中单独饲养大鼠,并提供商业饮食疗法(5L79,PMI Nutrition International,St Louis,MO)和商业标准饮食(Lab Diet 5L791 PurinaMills,Richmond,IN)。所有的动物实验都按照韩国庆熙大学的动物保护委员会准则(许可号:KHUASP(SE)-15-006)执行,并遵守了用于疼痛研究的国际协会的伦理问题。
1-3.手术和马尾压迫
马尾压迫基于先前的报告而实施[PLoS One(2013)e56580,Ma等人]。
大鼠的手术过程如图1所示。更具体地,通过以腹腔内注射方式给药水合氯醛(500mg/kg)来麻醉大鼠,并剃掉背部区域,暴露L4-S2椎板。
接着,去除L4与L5之间的黄韧带(ligamenta flava),将梯形的硅块(1.00mm长×1.2mm至1.3mm宽×1.00mm高)插入到硬膜外腔从而放置于L5和L6椎板,并破坏硬膜囊(dural sac)。
另一方面,在模拟对照组(假手术组)的情况下,仅执行了后开孔和穿孔,而没有在大鼠中插入硅块。
在手术过程中,用加热垫(Biomed S.L.,Alicante,Spain)将大鼠的体温维持在37±0.5℃。在上述损伤后封上肌肉和皮肤,然后将大鼠置于温湿度调节室中过夜。
对经手术的大鼠在5天内用皮下补充输液(5ml,乳酸林格)和抗生素(庆大霉素,5mg/kg,腹腔内注射)每日一次地进行给药。对于所有的动物模型,每天早晨记录了体重以及剩余食物和水量。
1-4.行为评估(behavior assessment)
使用旋转棒系统(rotarod system,Rota ROD-R V2.0,B.S.Technolab.Inc)测量了自主活动。
更具体地,将大鼠置于速度从4rpm增加到40rpm的棒(rod)上(以每5秒1rpm加速)。对于每个动物,测量了3次大鼠从棒上掉下之前的步行时间。在上述测量之前,以4rpm的恒定速度使大鼠适应棒3分钟。实验之间的间隔为20分钟。为了进行统计分析,计算了3次临床实验的平均值。
机械性痛觉超敏是对经校正的冯弗雷(von Frey)灯丝刺激所引起的反应进行探测(probing)而获得,并且通过缩足反应阈值(paw withdrawal threshold,PWT)进行评价。疼痛行为检查由不知道实验条件的熟练的技术人员执行。
1-5.药物施用
在进行马尾压迫后的第28天,仅将诱导慢性机械性痛觉超敏(2.5-4.0g)的350~380g的大鼠选为实验组。将上述大鼠随机地分为用媒介物、塞来昔布和本发明的化合物处理的实验组。
将塞来昔布(Sigma,St.Louis,MO)或根据本发明的化合物溶解在甲基吡咯烷酮:吐温-80:盐水(1:1:8,100μl)中,并以腹腔内注射的方式以2、5或10mg/kg的剂量给药。媒介物组在相应的时间点等量地注入1-甲基-2-吡咯烷酮(1-甲基-2-吡咯烷酮:吐温-80:盐水(1:1:8))。
1-6.组织准备
在峰值效应(药物注射后30分钟)时,通过注射水合氯醛(500mg/kg)麻醉大鼠并灌注0.1M PBS(pH 7.4),之后灌注含有4%多聚甲醛的PBS溶液。
为了制备冻结切片,将切片嵌入OCT中,并利用低温恒温器(CM1850;Leica,Wetzlar,Germany)在10℃下切成切片。
为了进行分子水平的分析,用0.1M PBS对大鼠进行灌注,分离损伤部位位于中心的20mm的马尾切片,并在-80℃下冷冻直至使用。
1-7.免疫组织化学(immunohistochemistry)
用针对ED-1的抗体(CD68,1:200,Serotec,Raleigh,NC)和针对COX-2的抗体(1:100,Abcam,MA)对冷冻切片进行免疫组织化学处理。荧光信号通过荧光显微镜(BX51,Olympus,Japan)检测,且信号共定位测量(measurement of signal colocalization)使用MetaMorph软件(Molecular devaices,Sunnyvale,CA)进行。
1-8.蛋白质印迹(Western blot)
准备了来自包括压迫部位的马尾部分的总蛋白质,并进行了蛋白质印迹分析,而用于蛋白质印迹的一抗如下:COX-2(1:1000,Abcam)和β-tublin(1:3000,Sigma)。
使用AlphaImager软件(Alpha Innotech Coperation,San Leandro,CA)对条带进行量化。
1-9.RNA分离和实时RT-PCR
进行了tnf-α、il-1β、il-6、inos和gapdh的RT-PCR。各序列的引物如下表1所示(5'->3')。
【表1】
1-10.PGE2水平测量
马尾纤维中的PEG2水平使用PEG2 ELISA试剂盒(Monoclonal,Cayman ChemicalAnn Arbor,MI)根据制造商的说明进行分析。
1-11.统计分析
数据用平均值±SD或SEM表示。
在实验组之间的比较中,使用非配对学生t检验(unpaired student t test)来评价统计学显著性。组之间的多重比较通过单向方差分析(one-way ANOVA)来进行。
部分行为评估分数通过重复测量方差分析(ANOVA)进行分析。在Dunnett的情况下,比较用于事后分析(Post hoc anlaysis)。
组的大小由各组的动物数表示。统计学显著性被接受为p<0.05。所有的统计分析使用SPSS 15.0(SPSS science,Chicago,IL)进行。
实施例2:本发明的化合物3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡
咯-2,5-二酮的制备
2-1.2-(4-(氯磺酰基)苯基)乙酸的制备
在冰浴中冷却ClSO3(20ml)。向其中缓慢加入苯乙酸(5.00g,36.72mmol),然后移除冰浴,并将溶液的温度升至室温并搅拌12小时。反应完成后,将溶液缓慢滴入冰水中从而去除残留的ClSO3H。对此进行过滤得到白色的固体产物2-(4-(氯磺酰基)苯基)乙酸(7.84g,91%)。
1H-NMR(400MHz,DMSO-d6)δ:11.6(1H,s),7.56(2H,d,J=8.4Hz),7.23(2H,d,J=8.4Hz),3.58(2H,s)。
2-2.2-(4-氨磺酰基苯基)乙酸的制备
在冰浴中,将在实施例2-1中得到的2-(4-(氯磺酰基)苯基)乙酸(2.00g,8.55mmol)溶解于无水MeOH并冷却。向其中滴加过量的NH4OH(25%),然后移除冰浴,并将溶液的温度升至室温并搅拌12小时。当反应结束时,加入HCl酸化,并在减压条件下搅拌12小时。反应结束后,加入HCl酸化,并减压去除溶剂。利用EtOAc进行萃取并用无水MgSO4干燥有机层,然后减压去除溶剂。利用ACN和DCN对从有机层得到的反应混合物进行结晶,由此得到白色的固体产物2-(4-氨磺酰基苯基)乙酸(1.03g,56%)。
1H-NMR(400MHz,DMSO-d6)δ:7.75(2H,d,J=8.4Hz),7.44(2H,d,J=8.4Hz),7.34(2H,s),3.68(2H,s)。
2-3.2-(4-甲基苯基)-2-氧代乙酸乙酯的制备
在无水条件下,将氯苯(2.00g,17.77mmol)溶解于无水DCM,并利用低温反应器冷却至-5℃。向其中缓慢滴加无水AlCl3(2.1g,16.28mmol)和乙基乙二酰氯酯(ethylchlorooxoacetate,0.6ml,5.43mmol)。在0℃下搅拌4小时,然后向冰中加入产物从而使反应终止。用DCM进行萃取,然后用蒸馏水洗涤有机层。接着,用无水MgSO4进行干燥之后减压过滤。再次减压去除溶剂,从而得到淡黄色的液体产物2-(4-甲基苯基)-2-氧代乙酸乙酯(3.01g,80%)。
1H-NMR(400MHz,CDCL3-d)δ:7.99(2H,d,J=8.4Hz),7.49(2H,d,J=8.4Hz),4.45(2H,q,J=7.2Hz),1.43(3H,t,J=7.2Hz)。
2-4.2-(4-氯苯基)-2-氧代乙酸的制备
将在实施例2-3中得到的2-(4-甲基苯基)-2-氧代乙酸乙酯(0.26g,1.23mmol)溶解于DCM,并向其中加入过量的2N NaOH,然后在室温下搅拌3小时。反应结束后,加入HCl酸化,并用DCM进行萃取。用无水MgSO4干燥有机层,然后减压去除溶剂。利用DCM和己烷对从有机层得到的反应混合物进行结晶,由此得到白色的固体产物2-(4-氯苯基)-2-氧代乙酸(0.14g,60%)。
1H-NMR(400MHz,CDCL3-d)δ:8.31(2H,d,J=8.8Hz),7.53(2H,d,J=8.8Hz)。
2-5.3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮的制备
将在实施例2-2中得到的2-(4-氨磺酰基苯基)乙酸(0.10g,0.46mmol)和在实施例2-4中得到的2-(4-氯苯基)-2-氧代乙酸(0.09g,0.46mmol)溶解于Ac2O,然后在85℃回流下搅拌8小时。反应完成后,在高温下减压去除溶剂。将反应混合物溶解于EtOH,然后向其中加入过量的CH3NH2(33%)(0.38ml,3.74mmol)并搅拌18小时。反应完成后,减压去除溶剂,并用EtOAc进行萃取。用无水MgSO4干燥有机层并减压去除溶剂。利用IPE对通过柱层析得到的产物进行结晶,得到浅黄色的固体产物3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮(0.05g,28%)。
1H-NMR(400MHz,DMSO-d6)δ:7.86(2H,d,J=8.4Hz),7.56(2H,d,J=8.4Hz),7.53(2H,d,J=8.4Hz),7.45(2H,br),7.41(2H,d,J=8.4Hz),3.04(3H,s)。
13C-NMR(100MHz,丙酮-d6)δ:171.35,171.29,145.82,138.13,137.06,136.39,133.39,132.58,131.36,129.64,128.37,127.05,23.35。
下表2示出了最终产物3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮以及用于制备其的实施例2的各步骤中的产物的结构和1H-NMR结果。
【表2】
实验例1:3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮的
生物学评价
生理活性的检测
根据实施例2制备的3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮的生理活性效果用IC50表示,IC50是当该酶的活性降低50%时的浓度。此外,关于本发明的化合物的细胞毒性,使用MTT分析法测量了细胞活力值(viability)IC50。
1-1.巨噬细胞系的LPS-诱导的PGE2生成抑制检测
RAW 264.7(小鼠巨噬细胞系)从韩国细胞系库(KCLB)购得使用,并且在包含10%胎牛血清(FBS:Foetal Bovine Serum)、青霉素(100单位/mL)、硫酸链霉素(100μg/mL)的DMEM(达尔伯克改良伊格尔培养基,Dulbecco's modified Eagle's medium)培养基中,在37℃、5%CO2的潮湿环境下进行培养。
利用DMEM培养基将RAW 264.7以5×105个细胞/mL的量在24孔中每孔接种1ml,并放置过一夜,然后更换培养基,之后以适量的浓度处理药物。孵育1小时之后,LPS以1μg/ml进行处理,并孵育24小时(或适当的时间)。取上清液并稀释5倍。将150μl的分析缓冲液加入非特异性结合(NSB:Non Specific Binding)孔中,并将100μl的分析缓冲液加入空白标准(B0)孔中。在剩下的孔中加入100μl的标准样品,并加入50μl的PGE2偶联物(不包括NSB)。加入50μl的PGE2抗体溶液并振荡2小时。对各个孔进行抽吸(suction)并用洗涤缓冲液洗涤5次。将200μl的磷酸对硝基苯酯(pNPP:para-Nitrophenyl phosphate)底物加入所有的孔中,并在室温下(在工作台中)储存1小时,然后加入50μl的终止溶液,并在405nm下测量吸光度。利用测量的吸光度值和标准曲线对PGE2生成量进行量化,并与单独用LPS处理的组比较从而求出抑制50%的浓度IC50。其结果如下表3所示。此外,如图2所示,确认了测量对于PGE2生成抑制的IC50值的结果为5.95nM(阳性对照组为NS-398,3μM)。这意味着3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮在8.70nM(IC50)下抑制由LPS诱导的PEG2生物合成的效果。
1-2.对巨噬细胞的细胞毒性测量
在包含10%FBS、青霉素(100单位/ml)和硫酸链霉素(100μg/ml)的DMEM培养基中、在37℃、5%CO2的环境下培养RAW 264.7(小鼠巨噬细胞系)。细胞用离心机和刮刀收集,并以1×105/孔的量加入到96孔板中,该96孔板包含100μl的含有10%FBS的RPMI(RoswellPark Memorial Institute)1640培养基。将3β,4β-环氧-8a-异丁酰氧基-1(10),11,(13)-二烯-12.6a-内酯溶解于甲基亚砜(DMSO)溶剂,而在所有实验中DMSO的浓度均未超过0.1%。过一夜后,加入样品和LPS(1μg/ml)并对板进行24小时的培养。对细胞进行一次洗涤之后,加入50μl的含有5mg/ml MTT[3-(4,5-二甲基噻唑-2-基)-2,5-二苯基溴化四唑]的无FBS的培养基,并在37℃下培养4小时,然后去除培养基,将细胞内形成的甲瓒蓝(formazanblue)溶解于100μl的DMSO,然后在540nm下测量吸光度,并以IC50值求出细胞毒性效果。IC50意味着与未用化合物处理时相比显示细胞数减少50%的效果的浓度。
在下表3中示出了3-(4-氯苯基)-4-(4-氨基磺酰基-苯基)-1-甲基-1H-吡咯-2,5-二酮的细胞毒性。
【表3】
*参考文献:Bioorg,Med,Chem.Lett.(2012),Kaur,J.等人
实验例2:利用硅块确认慢性机械性痛觉超敏的诱导
首先,使用实施例1-3的手术后的大鼠来检查在马尾压迫之后是否发生慢性神经性疼痛。运动和感觉检查在手术前和手术后的1至28天的特定时间点进行。
其结果,如图3a所示,所有动物模型在手术前都能在旋转棒(rotarod)上行走289±15秒,但在马尾压迫后的第一天,跌落旋转棒的等待时间显著减少到48.2±16秒。此外,由于自然恢复,在马尾压迫之后第28天的步行效率(walking efficiency)略增加到75.2±14秒。
此外,如图3b所示,在对无害的机械刺激的反应中,机械性缩足反应阈值(PWT)从马尾压迫后的第3天开始逐渐减小,并且出现显著的触觉痛觉超敏(tactile allodynia)直至第28天(PWT 3.22±0.6)。
此外,在模拟对照组(假手术组)中,旋转棒上的步行时间和触觉退缩阈值(tactile withdrawal threshold)没有发生变化。
实验例3:马尾压迫引起的巨噬细胞浸润的确认
炎症细胞的浸润是对神经系统损伤的反应,其不仅诱导常驻的免疫细胞的活化,还诱导包括促炎细胞因子和PGE2的各种炎症介质的生成和分泌。上述炎症介质可促进神经免疫力的活化,并且可使初级传入神经细胞变得敏感,从而引起痛觉过敏。
因此,为了确认炎症介质是否在出现巨噬细胞的浸润的部位表达,执行了对出现巨噬细胞的浸润的部位进行观察的实验。
此外,在马尾压迫后的第28天,执行了通过ED-1抗体的免疫染色用于观察在脊髓和马尾以外的区域中浸润的巨噬细胞的空间模式(spatial pattern)的实验。
其结果如图3c所示,在马尾压迫后的第14天确认了巨噬细胞在脊髓组织和马尾神经纤维中的浸润。
更具体地,可以在马尾压迫部位鉴定出ED-1阳性巨噬细胞,并且也可以在非压迫部位和与病变中心(lesion epicenter)相隔30mm的脊髓的背部上神经纤维束(背索,dorsal funiculus)进一步确认浸润的巨噬细胞。
实验例4:根据本发明的化合物对腰椎管狭窄诱导的慢性机械性痛觉超敏的缓解
的确认
为了研究本发明的化合物在慢性机械性痛觉超敏中的效果,将抗炎药塞来昔布(2、5、10mg/kg,腹腔内注射)施用至损伤后第28天的慢性机械性痛觉超敏诱导的大鼠。
其结果如图4a所示,确认了与媒介物组相比,在注射塞来昔布(10mg/kg)后经过30分钟和60分钟时,对机械性疼痛的缩足反应阈值(PWT)显著增加。
此外,将根据本发明的化合物(2、5、10mg/kg,腹腔内注射)施用至慢性机械性痛觉超敏诱导的大鼠。
其结果如图4b所示,确认了与媒介物组相比,在注射根据本发明的化合物后经过30分钟时,对机械疼痛的缩足反应阈值(PWT)以依赖剂量的方式显著增加。
此外,在高剂量给药根据本发明的化合物的情况下的镇痛效果在给药后维持3小时。根据这些结果确认了根据本发明的化合物可以缓解在马尾压迫后产生的慢性机械性痛觉超敏。
实验例5:根据本发明的化合物对炎症介质表达的抑制作用确认
使用以塞来昔布和根据本发明的化合物给药的大鼠,通过RT-PCR进行实验以确认炎症介质的生成是否受到抑制,并通过ELISA进行实验以确认PGE2的生成是否受到抑制。
其结果如图4c和4d所示,确认了用塞来昔布或本发明的化合物处理慢性机械性痛觉超敏诱导的大鼠后经过30分钟时,TNF-α、IL-1β、IL-6和iNOS mRNA的表达显著减少。
此外,如图4e所示,与模拟对照组(假手术组)相比,慢性机械性痛觉超敏诱导的大鼠的马尾中PEG2生成水平由于马尾压迫而显著增加。
此外,确认了与媒介物组相比,在将塞来昔布或根据本发明的化合物施用至慢性机械性痛觉超敏诱导的大鼠的情况下,显著地减少了PGE2的生成。
以上所述的本发明的描述是为了说明,且本发明所属技术领域的普通技术人员将可以理解,在不改变本发明的技术思想或必要特征的情况下,能够容易地变形为其它具体的形态。因此,应理解,上述实施例在所有方面都是示例性的,而不是限制性的。
【工业实用性】
本发明是开发用于通过抑制促炎细胞因子和PGE2来预防或治疗脊髓损伤或椎管狭窄的组合物的技术,能够提供克服现有的外科手术和类固醇的使用所具有的缺点的新的炎症及疼痛缓解组合物,因此根据本发明的技术将可以广泛地应用于针对脊髓损伤和椎管狭窄的预防或治疗剂开发领域。
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US20070167403A1 (en) * | 2003-04-03 | 2007-07-19 | Yoshifumi Takenobu | Remedy for spinal canal stenosis |
WO2008071736A1 (en) * | 2006-12-15 | 2008-06-19 | Glaxo Group Limited | Benzamide derivatives as ep4 receptor agonists |
CN101594861A (zh) * | 2006-11-30 | 2009-12-02 | 亨特-弗莱明有限公司 | 前列腺素/环加氧酶代谢途径的调节 |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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US20060046961A1 (en) * | 2004-09-02 | 2006-03-02 | Mckay William F | Controlled and directed local delivery of anti-inflammatory compositions |
CN101594861A (zh) * | 2006-11-30 | 2009-12-02 | 亨特-弗莱明有限公司 | 前列腺素/环加氧酶代谢途径的调节 |
WO2008071736A1 (en) * | 2006-12-15 | 2008-06-19 | Glaxo Group Limited | Benzamide derivatives as ep4 receptor agonists |
Non-Patent Citations (3)
Title |
---|
KYUNG JU KIM: "Synthesis, biological evaluation, and docking analysis of a novel family of 1-methyl-1H-pyrrole-2, 5-diones as highly potent and selective cyclooxygenase-2 (COX-2) inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 24, no. 8, 15 April 2014 (2014-04-15), pages 1, XP028841750, DOI: 10.1016/j.bmcl.2014.02.074 * |
周慎: "《实用神经精神科手册》", vol. 2002, 31 January 2002, 湖南科学技术出版社, pages: 439 - 440 * |
周跃, 梅芳瑞, 廖维宏: "炎症介质与脊神经根损伤", 中国脊柱脊髓杂志, no. 04, 28 August 1998 (1998-08-28) * |
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