CN103209692A - 多发性硬化(ms)的新疗法 - Google Patents
多发性硬化(ms)的新疗法 Download PDFInfo
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Abstract
本发明涉及下列通式(I)化合物的R-对映异构体或所述化合物的硝基变体的R-对映异构体和所述化合物的药物可接受的盐的R-对映异构体、优选他氟比尔(R-氟比洛芬)在治疗多发性硬化(MS)中的用途，
其中R1或R2是选自H、-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，或者R1或R2能够与另一个一起形成环丙基环、环丁基环、环戊基环或环己基环，R3是选自-COOH、-COOR6、-CONH2、-CONHR6、-CONR6R7、-CONHSO2R6、-COO-(CH2)3-CH2OH、-COO-(CH2)4-ONO2、-COO-PhOCH3-C2H2-COO-(CH2)4-ONO2、四唑基和-COOH生物电子等排体的基团，R4或R5是选自-Cl、-F、-Br、-I、-CF3、-OCF3、-SCF3、-OCH3、-OCH2CH3、-CN、-CH=CH2、-CH2OH和-NO2的基团，R6或R7是选自-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，并且m或n为选自0、1、2和3的整数。
Description
本发明涉及下列通式(I)化合物的R-对映异构体或所述化合物的硝基变体的R-对映异构体和所述化合物的药物可接受的盐的R-对映异构体、优选他氟比尔(Tarenflurbil)(R-氟比洛芬)在治疗多发性硬化(MS)中的用途，
其中R1或R2是选自H、-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，或者R1或R2能与另一个一起形成环丙基环、环丁基环、环戊基环或环己基环，R3是选自-COOH、-COOR6、-CONH2、-CONHR6、-CONR6R7、-CONHSO2R6、-COO-(CH2)3-CH2OH、-COO-(CH2)4-ONO2、-COO-PhOCH3-C2H2-COO-(CH2)4-ONO2、四唑基和-COOH生物电子等排体的基团，R4或R5是选自-Cl、-F、-Br、-I、-CF3、-OCF3、-SCF3、-OCH3、-OCH2CH3、-CN、-CH=CH2、-CH2OH和-NO2的基团，R6或R7是选自-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，并且m或n为选自0、1、2和3的整数。
MS是影响中枢神经***(CNS)的慢性炎性脱髓鞘疾病。最常见的初始病程是复发缓解亚型，其特征在于不可预知的发作(复发)，然后是没有新的疾病活性迹象的相对缓解期。
不同疗法用于经受急性发作的患者，用于具有复发缓解亚型的患者，用于具有进行性亚型的患者，以及用于处理MS的各种后果。疗法的主要目的是在发作后恢复功能、预防新的发作和预防残障。
在多发性硬化的情况下，能够使用下列疗法以治疗急性发作：干扰素β1a和1b、格拉替雷、米托蒽醌(mitoxantron)、那他珠单抗(针对整合素α4β1的单克隆抗体)和糖皮质激素。FTY-720(芬戈莫德，即鞘氨醇-1-磷酸盐类似物，其最近已被准许用于医疗用途)、克拉屈滨(免疫抑制)、特立氟胺(Teriflunomid)(免疫抑制)和氨吡啶(Fampridin)(4-氨基吡啶，钾通道抑制剂)正处于临床开发中。此外，在实验上研究了HMG-CoA还原酶抑制剂和某些***素的效能。
尽管使用药物芬戈莫德的研究和那他珠单抗用于治疗复发缓解MS的登记产生了许多有希望的结果，但不存在治愈发作，且最多是降低发作频率，由此延迟神经功能缺损。
对于原发性进行性MS，已知没有有效治疗。此外，所有可获得的基于药物的疗法(β-干扰素、格拉替雷、米托蒽醌、那他珠单抗)导致大量的毒性。
他氟比尔(R-氟比洛芬)(化学名称(R)-2-(2-氟-4-苯基苯基)丙酸)在2008年作为治疗阿尔兹海默病的潜在候选者而进行了测试。然而，在发现认知功能改善不足之后，对该适应症的进一步开发停止了。
R-氟比洛芬连同例如布洛芬和萘普生属于2-芳基丙酸组(洛芬类)。正如布洛芬一样，R-氟比洛芬是市售的外消旋氟比洛芬的副产物，所述氟比洛芬的活性剂被认为是S-对映异构体。氟比洛芬目前处于治疗转移性***癌的临床试验中。
Cardozo等人(在Cardozo LD,Stanton SL,Robinson H,Hole D.Evaluation of flurbiprofen in detrusor instability(氟比洛芬在逼尿肌不稳定中的评价).Br Med J.1980年2月2日；280(6210):281-2中)描述了***素合成酶抑制剂氟比洛芬和安慰剂对于患有逼尿肌不稳定的女性中的双盲交叉实验(27例为特发性多发性硬化且3例为继发性多发性硬化)。频发性、急迫性和欲望性尿失禁均由氟比洛芬显著降低(分别为P小于0.001、P小于0.025和P小于0.025)，在膀胱充盈期逼尿肌压力上升同样显著降低(P小于0.01)。然而，在摄取氟比洛芬时13位患者出现副作用，相比之下摄取安慰剂时5位患者出现副作用(P小于0.025)。在试验之后，19名患者希望继续采用氟比洛芬。氟比洛芬可用于治疗特发性逼尿肌不稳定，并且对于大部分患者是完全耐受的。
US2009-0162421描述了对映异构体纯的他氟比尔和/或其药物可耐受的盐或衍生物在制备用于治疗疼痛相关性神经病的药物中的用途。与US2009-0162421相比，本发明涉及R-氟比洛芬用于治疗多发性硬化的神经免疫病理学并由此预防运动功能损失和由免疫介导的脱髓鞘导致的神经退行性变性的发展的用途。预防由中枢神经***中成髓鞘细胞的自体免疫攻击而产生的脱髓鞘可能与其它神经学MS相关症状的减少相关，所述症状可以包括具有神经性疼痛样现象的伤害感受***的中枢介导的高敏感性。然而，由神经损伤(创伤、炎性、代谢性、缺血性、毒性等)诱发的并在US2009-0162421中描述的神经性疼痛主要由损伤性或继发性伤害感受神经元的过度兴奋而诱发。在啮齿动物模型中，某些形式与小神经胶质激活有关，然而其与多发性硬化中的全身性免疫激活和扩散性免疫激活在机制和位置方面完全不同。
此外，神经性疼痛不是自身免疫疾病，并且在US2009-0162421中描述的R-氟比洛芬用于治疗神经性疼痛的效能和用途与本文所述的免疫调节特征相比通过不同机制而介导。使用R-氟比洛芬减轻神经性疼痛大多归因于轴突损伤之后发生的不适应性神经元变化的预防，而其在多发性硬化中的效能大多归因于对T-细胞的免疫调节作用，由此预防自身免疫介导的神经元髓鞘破坏，即少突胶质细胞和施万细胞的破坏。如果该髓鞘破坏发生在丘脑皮质束中，即上行疼痛路径，则其可以诱发MS的中枢神经性疼痛的症状。意即，其次，R-氟比洛芬可以减轻该形式的神经性疼痛或其在MS患者中的进展。总之，然而，R-氟比洛芬在神经性疼痛(例如，主要由创伤、带状疱疹感染、糖尿病或局部缺血而诱发的)中的效能不允许其免疫调节作用的预测以及本文所述的MS中的免疫介导的髓鞘破坏和运动功能损失的预防。
因此，本发明基于R-氟比洛芬用于多发性硬化中的免疫调节和运动功能保持的新用途，所述多发性硬化是神经***的自身免疫疾病，从而涉及R-氟比洛芬在预防或逆转最频繁地由外周神经创伤、炎症、代谢功能障碍或局部缺血诱发的伤害感受神经元过度兴奋。
Barkhof等人(在Barkhof F,van Waesberghe JH,Uitdehaag BM,Polman CH.Ibuprofen does not suppress active multiple sclerosis lesionson gadolinium-enhanced MR images(布洛芬在钆增强MR图像上未抑制活性多发性硬化病变).Ann Neurol.1997年12月;42(6):982中)测试了布洛芬在MRT中对MS病变的数量和大小的影响。作者描述了共同给药的β-干扰素的作用基本不受联用药物的影响。
由此，对于开发新的且有效的针对MS、特别是针对原发性进行性MS的疗法存在着持续的需求。
在本发明的第一方面，本发明的该目的由用于治疗多发性硬化(MS)的通式(I)化合物的R-对映异构体或所述化合物的硝基变体的R-对映异构体(例如(R)-2-(2-氟-联苯-4-基)丙酸4-硝氧基丁酯)以及所述化合物的药物可接受的盐的R-对映异构体而解决，
其中R1或R2是选自H、-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，或者R1或R2能与另一个一起形成环丙基环、环丁基环、环戊基环或环己基环，R3是选自-COOH、-COOR6、-CONH2、-CONHR6、-CONR6R7、-CONHSO2R6、-COO-(CH2)3-CH2OH、-COO-(CH2)4-ONO2、-COO-PhOCH3-C2H2-COO-(CH2)4-ONO2、四唑基和-COOH生物电子等排体的基团，R4或R5是选自-Cl、-F、-Br、-I、-CF3、-OCF3、-SCF3、-OCH3、-OCH2CH3、-CN、-CH=CH2、-CH2OH和-NO2的基团，R6或R7是选自-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，并且m或n为选自0、1、2和3的整数。
优选地，R1选自H。还优选的是本发明的化合物的用途，所述化合物选自：
(R)-2-(2-氟-4-苯基苯基)丙酸，
(R)-2-(2-氟-4-联苯-4-基)丙酸4-硝氧基丁酯，
(R)-1,1'-联苯基-4-乙酸2-氟-α-甲基-4-羟基丁酯，
(R)-3-[4-(2-氟-α-甲基-[1,1'-联苯基]-4-乙酰氧基)-3-甲氧基苯基]-2-丙酸4-硝氧基丁酯，
(R)-2-甲基-2(2-氟-4’-三氟甲基联苯-4-基)丙酸，
(R)-2-甲基-2(2-氟-4’-环己基联苯-4-基)丙酸，
(R)-2-(2-氟-3’,5’-双(氯)联苯-4-基)丙酰胺，
(R)-2-(2-氟-4’-三氟甲基联苯-4-基)丙酸，
(R)-2-(2-氟-3’-三氟甲基联苯-4-基)丙酸，
(R)-2-(2-氟-3’,5’-双(三氟甲基)联苯-4-基)丙酸，
(R)-2-(4’-环己基-2-氟联苯-4-基)丙酸，
(R)-2-(2-氟-1,1’-联苯-4-基)-2-甲基丙酸，
和(R)-5-[1-(2-氟-联苯-4-基)-1-甲基-乙基]-2H-四唑。
还优选的是用于治疗多发性硬化(MS)的R-氟比洛芬或硝基-R-氟比洛芬。甚至还优选的是上述化合物、优选R-氟比洛芬或硝基-R-氟比洛芬在制备用于治疗多发性硬化(MS)的药物中的用途。本发明的另一方面涉及用于治疗多发性硬化(MS)的方法，其包括向有需要的患者给予治疗有效量的本发明化合物，并优选给予R-氟比洛芬或硝基-R-氟比洛芬。本发明疗法的主要目的是在发作后恢复功能、防止新的发作并防止残障。因此，本疗法优选涉及与疼痛相关的神经病的疗法不同的疗法，即优选不涉及疼痛相关的神经病的疗法。
在本发明的情况下，治疗应包括预防地和/或实际地治疗本文所述的MS的疾病症状，所述疾病症状能使用所述疗法而减轻和/或甚至完全消除。
本发明基于令人惊讶的发现，即洛芬化合物的R-对映异构体、即R-氟比洛芬在小鼠的多发性硬化的EAE模型(EAE：实验性自身免疫性脑脊髓炎)中降低/抑制瘫痪的发生，并且几乎完全阻断腰脊髓中MOG-诱导的小神经胶质激活和免疫细胞浸润。因此，由于人类情形与小鼠模型之间的相似性，期望他氟比尔(R-氟比洛芬)在人类患者中的有至少类似的作用。
与其S-异构体相比，R-氟比洛芬不抑制环氧化酶并对***素合成没有影响。甚至在高的每日剂量和长期疗法中，已知没有实质性毒性。因此，本发明的另一方面涉及用于治疗多发性硬化(MS)且不抑制环氧化酶且对***素合成没有影响的方法，其包括向有需要的患者给予治疗有效量的本发明化合物，并优选给予R-氟比洛芬或硝基-R-氟比洛芬。本发明的又一方面涉及通过防止和/或降低由抑制环氧化酶产生的所述治疗中涉及的毒性而治疗多发性硬化(MS)的改进的方法，其包括向有需要的患者给予治疗有效量的本发明化合物，并优选给予R-氟比洛芬或硝基-R-氟比洛芬。
作为阿尔茨海默病的潜在疗法测试了R-氟比洛芬，但其最终没有表现出任何显著的作用。此外，Barkhof等人(如上所示)排除了布洛芬对MS的单独作用，由此技术人员已经预期氟比洛芬或上述通式(I)所述的化合物还将对MS无效。
优选地，待治疗的MS是复发缓解型或进行型MS。
甚至在高的每日剂量和长期疗法中，已知R-氟比洛芬没有实质性毒性。因此，通常，能使用任何剂量的本发明化合物、优选R-氟比洛芬或硝基-R-氟比洛芬，其表现出对待治疗的MS症状的有利作用。能由技术人员和/或主治医师容易地确定各自的有效剂量。优选的是本发明化合物、优选本发明的R-氟比洛芬或硝基-R-氟比洛芬的用途，其中以每剂型50mg至300mg、优选100mg至1500mg、更优选300mg至1200mg的量来提供本发明的所述化合物、优选R-氟比洛芬或硝基-R-氟比洛芬。还优选的是用途，其中每天以待治疗的患者的5mg/kg体重至15mg/kg体重的剂量来提供本发明化合物、优选R-氟比洛芬或硝基-R-氟比洛芬。
通常，能以任何合适且有效的方式、例如口服、直肠或通过注射来向患者提供本发明的化合物、优选R-氟比洛芬或硝基-R-氟比洛芬。优选是口服。此外，能以任何合适且有效的药物可接受的形式，例如以片剂、胶囊、糖衣药丸、散剂、栓剂、凝胶和/或注射用溶液的形式来向患者提供本发明的化合物、优选R-氟比洛芬或硝基-R-氟比洛芬。
能够单独地或与可用于MS疗法和/或治疗的其它化合物和治疗组合地使用本发明的化合物、优选R-氟比洛芬或硝基-R-氟比洛芬。优选地，实现神经学症候。组合包括同时或分开使用化合物和治疗。组合还包括可用于MS疗法和/或治疗的化合物和治疗的任何协同作用。因此，本发明的另一方面为本发明化合物、优选R-氟比洛芬或硝基-R-氟比洛芬的用途，其中与至少一种另外的针对MS的治疗剂组合地提供本发明的化合物、优选R-氟比洛芬或硝基-R-氟比洛芬，所述另外的针对MS的治疗剂例如干扰素β1a或1b、格拉替雷、米托蒽醌、那他珠单抗、糖皮质激素、芬戈莫德、克拉屈滨、特立氟胺、氨吡啶、HMG-CoA还原酶抑制剂或***素。优选干扰素β1a或1b。
然后，本发明的另一方面涉及用于治疗、具体地减轻多发性硬化(MS)的症状、优选神经功能缺损的方法，其包括向有需要的患者给予治疗有效量的如本文所述的本发明化合物，优选R-氟比洛芬或硝基-R-氟比洛芬。
然后，本发明的又一方面涉及用于降低多发性硬化、例如复发缓解性MS的发作的频率、发生率和/或严重程度的方法，其包括向有需要的患者给予治疗有效量的如本文所述的本发明化合物，优选R-氟比洛芬或硝基-R-氟比洛芬。
在多发性硬化的EAE模型中，用R-氟比洛芬(在饮用水中为9mg/d)治疗的小鼠未表现出瘫痪，而同时用安慰剂治疗的对照动物发展出下肢轻瘫至四肢轻瘫并且根据终止准则必须被处死。在用R-氟比洛芬治疗的动物中，在远端脊髓(即，EAE的病理免疫学临床表现的主要位置)中几乎没有检测到白质的小神经胶质激活或T-细胞浸润。髓鞘的T-细胞介导的破坏和轴突的直接损坏是神经功能缺损的诱因。
R-氟比洛芬在EAE中的作用的生物学机制仅部分已知。R-氟比洛芬导致脂质信号分子的复合调节和转录因子(例如，NF-κB和PPAR)的调节，由此导致神经免疫通讯的免疫调节和改变。因此，适度调节作用阐明了化合物的有利作用/毒性谱。
如上所述，对于目前可用的药物，不能实现MS的治愈，而仅能实现发作的减少和进展的抑制。在一些针对原发性进行性(非复发缓解性)MS的情况下，没有可用的有效疗法。疾病导致瘫痪的增加并最终是致命的。此外，患者经受由于疼痛传导神经元或中枢中的痉挛和神经免疫损伤而引起的疼痛。
本发明化合物、优选R-氟比洛芬或硝基-R-氟比洛芬的主要优势是其低毒性，这对于R-氟比洛芬而言是充分证明的。甚至对于在老年患者中的长期治疗，没有发生显著的副作用。通常，温和的副作用不导致疗法的终止。
在用R-氟比洛芬治疗的动物中所发现的神经性症状和神经免疫性病理的减轻是显著的。因此，假设本发明的化合物、优选R-氟比洛芬或硝基-R-氟比洛芬还将减轻患有MS的患者的症候。
现在将参考附图在下列实施例中阐释本发明，但本发明不受其限制。对于本发明的目的，本文所引用的所有参考文献以其整体形式并入本文作为参考。在附图中，
图1示出R-氟比洛芬(9mg/kg/d口服)在C57BL6/J小鼠的多发性硬化EAE模型中的作用。通过皮下注射含100μg MOG35-55的200μlCFA、然后腹膜内注射200ng百日咳-毒素(PTX)诱导了实验性自身免疫性脑脊髓炎(EAE)。2日后重复PTX-注射。在饮用水中口服给予了R-氟比洛芬(225μg/4ml/天)(n=6)。对照组接受了安慰剂(n=9)。专门研究了在表现出运动功能障碍之前的伤害感受行为。测试了机械性痛觉过敏、热痛觉过敏(顶部，左边的y轴)和冷触摸痛(底部)。痛觉过敏是神经免疫激活的早期表现。基于标准计分***检测了肌肉运动功能：0.5分：尾部的远端轻瘫；1分：尾部的完全瘫痪；1.5分：尾部的轻瘫和后腿的中度轻瘫；2.0分：一只后腿的严重轻瘫；2.5分：后腿的中度下肢轻瘫；3.0分：两只后腿的完全瘫痪；3.5分：两只后腿的完全瘫痪以及一只前腿的轻瘫；4分：完全瘫痪(四肢瘫痪)、濒死状态或死亡。在3.5分开始处死动物。由未被告知治疗的观察者来进行所有实验。R-氟比洛芬减轻了在开始时可检测到的痛觉过敏并完全抑制了运动功能障碍的发展(P<0.05)。用R-氟比洛芬治疗的动物在观察期内未表现出脱髓鞘作用的迹象。在安慰剂组中，所有动物达到2.5至3.5分。
图2示出在用R-氟比洛芬(9mg/kg/d口服)或安慰剂治疗的C57BL/6小鼠中，在注射MOG35-55之后三周脊髓(腰部)中的小神经胶质激活。对于组织学检查，对小鼠心脏内灌注4%的多聚甲醛；制备组织，在PFA中后固定，并且通过在20%蔗糖中保存而保护为低温人工产品。将组织嵌入OCT并在低温切片机上切割(16μm)。使用一抗进行免疫染色，所述原发性抗体能特异性针对小神经胶质-标记物Iba-1。用抗NeuN检测神经元。在由荧光染料标记的二抗染色之后，使用Zeiss荧光显微镜采集图片。在R-氟比洛芬治疗的动物中，没有检测到小神经胶质细胞的激活。即，脊髓未显示任何病理学变化，并且与健康对照动物没有差异。相反，用安慰剂治疗的EAE动物表现出小神经胶质的大量激活和增殖。
图3示出当用R-氟比洛芬(9mg/kg/d口服)(图3A)或安慰剂(图3B)治疗时在注射MOG35-55之后三周时腰脊髓的背角中的T-细胞浸润。如上所述进行制备。使用抗CD3抗体检测了T-细胞。通过用R-氟比洛芬的治疗几乎完全抑制了向腹角和背角中白质区域的T-细胞浸润。
图4示出依赖于R-氟比洛芬治疗的开始的在多发性硬化EAE模型中的临床分数的时间进程。通过在C57BL6小鼠中注射MOG35-55肽和百日咳毒素诱导了EAE。在免疫日(第1天)或用MOG免疫之后5或8天时开始介质或R-氟比洛芬(9mg/kg/d口服)的治疗。如图1所述的那样评价了临床EAE分数。R-氟比洛芬治疗的动物当在第一天开始疗法时未发展EAE，并且当在MOG注射之后5或8天开始治疗时具有显著降低的EAE分数。分数×时间进程下面积由t-测验进行了统计学分析，P<0.05。
图5示出在多发性硬化的EAE模型中的神经炎症的成像。在通过注射MOG35-55肽和百日咳毒素诱导EAE之后3天开始的、用介质或R-氟比洛芬(9mg/kg/d口服)治疗的C57BL6小鼠中静脉注射ProSense680之后3天进行了近红外成像(Maestro成像平台)。ProSense680是组织蛋白酶的荧光底物并允许进行炎症分析。A：未注射ProSense的对照小鼠。B：介质治疗。C：用R-氟比洛芬治疗。
图6示出在多发性硬化的EAE模型中的脊髓中CD4+/CD25+T-细胞的流式细胞仪分析。在通过注射MOG35-55肽和百日咳毒素而诱导EAE之后3天开始用介质或R-氟比洛芬(9mg/kg/d口服)治疗了C57BL6小鼠。当动物达到1.5至2的临床分数时，由腰脊髓段制备了单细胞悬浮液。在具有针对细胞表面标记物蛋白的特异性抗体的流式细胞仪(BD FACS Conto II)上进行了T-细胞分析。T-细胞由CD3来鉴别并随后根据CD标记物表达针对T-细胞亚型进行画门。R-氟比洛芬治疗的动物表现出更高数量的CD4+/CD25+T-细胞，表明更高数量的在EAE中具有保护功能的调节T-细胞。
图7示出在多发性硬化的EAE模型中的IL10+和FoxP3+T-细胞的流式细胞仪分析。在通过注射MOG35-55肽和百日咳毒素而诱导EAE之后3天开始用介质或R-氟比洛芬(9mg/kg/d口服)治疗了C57BL6小鼠。当动物达到1.5至2的临床分数时，由脾脏制备了单细胞悬浮液。在具有针对细胞表面标记物蛋白的特异性抗体的流式细胞仪(BD FACS Conto II)上进行了T-细胞分析。T-细胞由CD3鉴别并随后针对T-细胞亚型进行画门。对于细胞内细胞因子的分析，在37°C下用50ng/ml PMA+500ng/ml离子霉素刺激了来自用介质或R-氟比洛芬治疗的EAE小鼠中的脾细胞2小时，然后在37°C下用布雷菲德菌素A10μg/ml刺激2小时，从而防止细胞因子释放。R-氟比洛芬治疗的小鼠表现出更高分数的CD4+/CD25+/FoxP3+调节T-细胞以及增加的抗炎性IL-10产生。
图8示出在多发性硬化的EAE模型中，在视神经中的脱髓鞘的免疫荧光分析。在通过注射MOG35-55肽和百日咳毒素而诱导EAE之后5天开始用介质或R-氟比洛芬(9mg/kg/d口服)治疗了C57BL6小鼠。当动物达到1.5至2的临床分数时，对小鼠心脏内灌注磷酸盐缓冲盐水，然后用PFA4%固定。移除视神经，后固定，在20%蔗糖中过夜低温保护并在低温切片机上切割。用针对髓鞘碱性蛋白的抗体来孵育切片，并且用神经元标记物抗体NeuN复染色。用荧光显微镜(ZeissAxiovert)完成了分析。图像表明与介质治疗的小鼠相比，R-氟比洛芬治疗显著降低了神经元纤维周围的髓鞘的破坏。
Claims (8)
1.用于治疗多发性硬化(MS)的下列通式(I)化合物的R-对映异构体或所述化合物的硝基变体的R-对映异构体以及所述化合物的药物可接受的盐的R-对映异构体，
其中
R1或R2是选自H、-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，或者R1或R2能够与另一个一起形成环丙基环、环丁基环、环戊基环或环己基环，
R3是选自-COOH、-COOR6、-CONH2、-CONHR6、-CONR6R7、-CONHSO2R6、-COO-(CH2)3-CH2OH、-COO-(CH2)4-ONO2、-COO-PhOCH3-C2H2-COO-(CH2)4-ONO2、四唑基和-COOH生物电子等排体的基团，
R4或R5是选自-Cl、-F、-Br、-I、-CF3、-OCF3、-SCF3、-OCH3、-OCH2CH3、-CN、-CH=CH2、-CH2OH和-NO2的基团，
R6或R7是选自-CH3、-CH2CH3、-CH2CH2CH3和-CH2CH2CH2CH3的基团，
并且m或n为选自0、1、2和3的整数。
2.如权利要求1所述的化合物，其中所述化合物选自R-氟比洛芬(他氟比尔)或硝基-R-氟比洛芬。
3.如权利要求1或2所述的化合物，其中所述MS是复发缓解性或进行性MS。
4.如权利要求1至3中任一权利要求所述的化合物，其中以50mg至3000mg、优选100mg至1500mg的量提供所述化合物。
5.如权利要求1至3中任一权利要求所述的化合物，其中以每天5mg/kg体重至15mg/kg体重的剂量来提供所述化合物。
6.如权利要求1至5中任一权利要求所述的化合物，其中所述化合物口服给药、直肠给药或通过注射给药。
7.如权利要求1至6中任一权利要求所述的化合物，其中以片剂、胶囊、糖衣药丸、散剂、栓剂、凝胶或注射用溶液的形式提供所述化合物。
8.如权利要求1至7中任一权利要求所述的化合物，其中将所述化合物与至少一种另外的针对MS的治疗剂组合地提供，所述另外的针对MS的治疗剂例如干扰素β1a或1b、格拉替雷、米托蒽醌、那他珠单抗、糖皮质激素、芬戈莫德、克拉屈滨、特立氟胺、氨吡啶、HMG-CoA还原酶抑制剂或***素。
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| WO2008034244A1 (en) * | 2006-09-21 | 2008-03-27 | Waratah Pharmaceuticals Inc. | The combination of a cyclohexanehexol and a nsaid for the treatment of neurodegenerative diseases |
| WO2009083115A1 (de) * | 2007-12-21 | 2009-07-09 | Paz Arzneimittel-Entwicklungsgesellschaft Mbh | Arzneimittel sowie deren herstellung und verwendung bei der behandlung von schmerzhaften neuropathien |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022089598A1 (zh) * | 2020-10-30 | 2022-05-05 | 杭州拉林智能科技有限公司 | 黄酮苷-有机胺类神经激动剂复盐化合物及其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| RU2595861C2 (ru) | 2016-08-27 |
| US20130309199A1 (en) | 2013-11-21 |
| CA2816911C (en) | 2018-09-25 |
| BR112013010883A2 (pt) | 2016-09-13 |
| JP5903438B2 (ja) | 2016-04-13 |
| RU2013125470A (ru) | 2014-12-10 |
| GB2485169A (en) | 2012-05-09 |
| EP2635271A1 (en) | 2013-09-11 |
| CA2816911A1 (en) | 2012-05-10 |
| JP2014505015A (ja) | 2014-02-27 |
| KR20140017494A (ko) | 2014-02-11 |
| KR101877587B1 (ko) | 2018-07-11 |
| GB201018519D0 (en) | 2010-12-15 |
| WO2012059541A1 (en) | 2012-05-10 |
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