CN116323614A - 用于治疗炎性和自身免疫性病症的rabeximod的硫羰酯衍生物 - Google Patents
用于治疗炎性和自身免疫性病症的rabeximod的硫羰酯衍生物 Download PDFInfo
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Abstract
化合物2‑(9‑氯‑2,3‑二甲基‑6H‑吲哚并[2,3‑b]喹喔啉‑6‑基)‑N‑(2‑(二甲基氨基)乙基)乙硫代酰胺,用于治疗炎症、炎性病症或自身免疫性病症。
Description
技术领域
本发明涉及化合物Rabeximod(2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙酰胺)的衍生物,用于治疗选自炎症、炎性病症和自身免疫性病症的病况。
背景技术
Rabeximod在作为WO 2005/123741 A1公布的国际专利申请号PCT/SE2005/000718中描述为具有自身免疫性病症,例如多发性硬化症(MS)和类风湿性关节炎(RA)的治疗活性。该化合物目前作为用于治疗RA的药物处于临床阶段,具有有前景的结果。然而,对于用于治疗各种自身免疫性病症(例如RA)的新药物,仍存在需要。
WO 2014/140321 A1描述了硫代Rabeximod,即2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺和其制备方法,以及该化合物作为抗病毒剂的用途。
发明内容
第一个方面是化合物2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,用于治疗选自炎症和炎性病症或自身免疫性病症的病况。
进一步的方面是2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐在制备用于治疗选自炎症和炎性病症或自身免疫性病症的病况的药物中的用途。
进一步的方面是2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐在治疗选自炎症和炎性病症或自身免疫性病症的病况中的用途。
进一步的方面是用于治疗选自炎症和炎性病症或自身免疫性病症的病况的方法,其通过向需要这种治疗的哺乳动物施用2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐。
进一步的方面是包含化合物2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐的药物组合物,用于治疗选自炎症和炎性病症或自身免疫性病症的病况。
进一步的方面是化合物2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,或包含所述化合物或盐和任选的药学上可接受的赋形剂的药物组合物,用于治疗类风湿性关节炎。
进一步的方面是化合物2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,或包含所述化合物或盐和任选的药学上可接受的赋形剂的药物组合物,用于治疗多发性硬化症。
进一步的方面是化合物2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,或包含所述化合物或盐和任选的药学上可接受的赋形剂的药物组合物,用于治疗其中活性氧物类(ROS)起病原作用的病况。
在下文描述了本发明的进一步方面和其实施方案。
附图说明
图1是显示在用30ng/ml的PMA激活的PBMC中以相对发光单位(RLU)测量的活性氧物类(ROS)产生的图,有或没有用不同浓度的本发明的化合物处理。结果表示为一式三份样品的平均值+/-SEM。
图2是显示在用30ng/ml的PMA激活的PBMC中以相对发光单位(RLU)测量的活性氧物类(ROS)产生的图,有或没有用不同浓度的Rabeximod处理。结果表示为一式三份样品的平均值+/-SEM。
图3是显示用500ng/ml的LPS刺激和用浓度范围为312.5nM-5000nM的本发明化合物(I)或Rabeximod(R)处理后全血中的TNF-α浓度的图。结果表示为一式两份样品的平均值+/-SEM。
图4是显示用500ng/ml的LPS刺激和用浓度范围为312.5nM-5000nM的本发明化合物(I)或Rabeximod(R)处理后全血中的IL-6浓度的图。结果表示为一式两份样品的平均值+/-SEM。
图5是显示用500ng/ml的LPS刺激和用浓度范围为312.5nM-5000nM的本发明化合物(I)或Rabeximod(R)处理后全血中的IL-1β浓度的图。结果表示为一式两份样品的平均值+/-SEM。
图6是代表在抗体注射后5、7、9、11、13和15天用5mg/kg、10mg/kg或20mg/kg的本发明化合物处理,或仅溶媒处理的胶原抗体诱导的关节炎(CAIA)小鼠模型中的平均关节炎严重程度的图,并使用小鼠四肢的宏观评分系统,其中最大关节炎评分是60(8只动物/组)。
图7是代表在抗体注射后5、7、9、11、13和15天用5mg/kg、10mg/kg或20mg/kg的Rabeximod处理,或仅溶媒处理的胶原抗体诱导的关节炎(CAIA)小鼠模型中的平均关节炎严重程度的图,并使用小鼠四肢的宏观评分系统,其中最大关节炎评分是60(8只动物/组)。
图8是代表用仅溶媒或用20mg/kg的本发明化合物或Rabeximod处理的CAIA模型中的小鼠前爪的免疫组织化学关节炎评分的图,其中最大关节炎评分是3。
图9是代表在疾病诱导后5、7、9、11、13和15天用20mg/kg的Rabeximod或本发明化合物处理,或仅溶媒处理的降植烷诱导的关节炎(PIA)大鼠模型中的平均关节炎严重程度的图,并使用小鼠四肢的宏观评分系统,其中最大关节炎评分是60(10只动物/组)。
具体实施方式
术语“自身免疫性病症”是指由身体针对身体中正常存在的物质和组织(自身免疫性)的不合适的免疫反应产生的任何病症。这样的反应可能限于某些器官或涉及在不同位置的特定组织。示例性的自身免疫性病症是急性播散性脑脊髓炎(ADEM)、艾迪生病、无丙种球蛋白血症、斑秃、肌萎缩侧索硬化症、强直性脊柱炎、抗磷脂综合征、抗合成酶综合征、特应性过敏、特应性皮炎、自身免疫性再生障碍性贫血、自身免疫性心肌病、自身免疫性肠病、自身免疫性溶血性贫血、自身免疫性肝炎、自身免疫性内耳疾病、自身免疫性淋巴细胞增生综合征、自身免疫性周围神经病、自身免疫性胰腺炎、自身免疫性多内分泌综合征、自身免疫性孕酮皮炎、自身免疫性血小板减少性紫癜、自身免疫性荨麻疹、自身免疫性葡萄膜炎、巴洛病/巴洛同心性硬化、白塞病、伯杰氏病、Bickerstaff脑炎、布劳综合征、大疱性类天疱疮、卡斯尔曼病、乳糜泻、美洲锥虫病、慢性炎性脱髓鞘性多发性神经病、慢性复发性多灶性骨髓炎、慢性阻塞性肺病、丘格-施特劳斯综合征、瘢痕性类天疱疮、科根综合征、冷凝集素病、补体成分2缺乏、接触性皮炎、颅动脉炎、CREST综合征、克罗恩病(两种类型的特发性炎性肠病“IBD”之一)、库欣综合征、皮肤白细胞破碎性血管炎、德戈氏病、德尔肯氏病、疱疹样皮炎、皮肌炎、1型糖尿病、弥漫性皮肤系统性硬化症、德雷斯勒综合征、药物性狼疮、盘状红斑狼疮、湿疹、子宫内膜异位症、附着点炎相关关节炎、嗜酸细胞性筋膜炎、嗜酸细胞性胃肠炎、获得性大疱性表皮松解症、结节性红斑、胎儿成红细胞增多症、原发性混合性冷球蛋白血症、埃文综合征、进行性骨化性纤维发育不良、纤维化肺泡炎(或特发性肺纤维化)、胃炎、胃肠道类天疱疮、肾小球肾炎、肺出血肾炎综合征(Goodpasture's syndrome)、格雷夫氏病、吉兰-巴雷综合征(GBS)、桥本脑病、桥本甲状腺炎、过敏性紫癜、妊娠疱疹(又名妊娠类天疱疮)、化脓性汗腺炎、休斯-斯托文综合征、低丙种球蛋白血症、特发性炎性脱髓鞘病、特发性肺纤维化、特发性血小板减少性紫癜、IgA肾病、包涵体肌炎、慢性炎性脱髓鞘性多发性神经病、间质性膀胱炎、幼年特发性关节炎(又名幼年类风湿性关节炎)、川崎病、兰伯特-伊顿肌无力综合征、白细胞破碎性血管炎、扁平苔藓、硬化性苔藓、线性IgA病(LAD)、狼疮样肝炎(又名自身免疫性肝炎)、红斑狼疮、马吉德综合征、梅尼埃病、显微镜下多血管炎、混合性结缔组织病、硬斑病、穆卡-哈伯曼病(又名急性痘疮样苔藓样糠疹)、多发性硬化症、重症肌无力、肌炎、发作性睡病、视神经脊髓炎(又名德维克病)、神经肌强直、眼部瘢痕性类天疱疮、视性眼阵挛性肌阵挛综合征、奥德甲状腺炎(Ord's thyroiditis)、复发性风湿病、PANDAS(与链球菌相关的小儿自身免疫性神经精神病)、副肿瘤性小脑变性、阵发性睡眠性血红蛋白尿(PNH)、帕罗综合征、Parsonage-Turner综合征、扁平炎、寻常型天疱疮、恶性贫血、静脉周围脑脊髓炎、POEMS综合征、结节性多动脉炎、风湿性多肌痛、多发性肌炎、原发性胆汁性肝硬化、原发性硬化性胆管炎、进行性炎性神经病、银屑病、银屑病关节炎、坏疽性脓皮病、纯红细胞再生障碍、拉斯穆森脑炎、雷诺现象、复发性多软骨炎、赖特综合征、不宁腿综合征、腹膜后纤维化、类风湿性关节炎、风湿热、结节病、精神分裂症、施密特综合征(另一种形式的APS)、施尼茨勒综合征、巩膜炎、硬皮病、血清病、干燥综合征、脊柱关节病、僵人综合征、亚急性细菌性心内膜炎(SBE)、苏萨克综合征、斯维特综合征、交感性眼炎、系统性红斑狼疮、高安氏动脉炎、颞动脉炎(又名“巨细胞动脉炎”)、血小板减少症、托洛萨-亨特综合征、横贯性脊髓炎、溃疡性结肠炎(两种类型的特发性炎性肠病“IBD”之一)、不同于混合性结缔组织病的未分化结缔组织病、未分化脊柱关节病、荨麻疹性血管炎、血管炎、白癜风和韦格纳肉芽肿病。
本文使用的术语“炎症”可以指急性炎症(包括过度炎症)和慢性炎症。
慢性炎症可在无效的急性炎性反应之后,或没有临床上明显的急性期。慢性炎症由通常缺少基本的炎症迹象(发红、肿胀、疼痛和温度增加)而与急性炎症区别开来,并且具有足以允许组织表现免疫反应和修复的持续时间。慢性炎症通常伴随有广泛组织坏死和通过纤维化的组织修复。
术语“炎性病症”是指与炎症相关的病理状态,通常由白细胞浸润引起。炎性病症可以是急性或慢性的。示例性的炎性病症包括炎性皮肤疾病(包括但不限于银屑病和特应性皮炎)、系统性硬皮病和硬化症、与炎性肠病(IBD)(例如克罗恩病和溃疡性结肠炎)相关的反应、缺血性再灌注病症(包括手术组织再灌注损伤)、心肌缺血性病况(例如心肌梗死、心脏骤停、心脏手术后再灌注和经皮腔内冠状动脉成形术后收缩)、中风和腹主动脉瘤、继发于中风的脑水肿、颅外伤、低血容量性休克、窒息、成人呼吸窘迫综合征、急性肺损伤、白塞病、皮肌炎、多发性肌炎、多发性硬化症(MS)、皮炎、脑膜炎、脑炎、葡萄膜炎、骨关节炎、狼疮性肾炎、自身免疫性疾病(例如类风湿性关节炎(RA)、干燥综合征、血管炎)、涉及白细胞游出的疾病、中枢神经系统(CNS)炎性病症、继发于败血症或创伤的多器官损伤综合征、酒精性肝炎、细菌性肺炎、抗原-抗体复合物介导的疾病(包括肾小球肾炎)、脓毒病、结节病、对组织或器官移植的免疫病理反应、肺的炎症(包括胸膜炎、肺泡炎、血管炎、肺炎、慢性支气管炎、支气管扩张症、弥漫性泛细支气管炎、过敏性肺炎、特发性肺纤维化(IPF)和囊性纤维化)等。
术语炎性病症还指由过度炎症引起或与过度炎症相关的病症,例如过度炎症综合征。
术语“过度炎症综合征”包括选自免疫缺陷相关的过度炎症综合征、巨噬细胞活化综合征、感染相关综合征(例如与covid-19相关)、恶性肿瘤相关的过度炎症综合征的综合征。
"治疗有效量"意指当向受试者施用以治疗疾病状态时,对于疾病状态的治疗足以实现治疗效果的化合物的量。"治疗有效量"将根据化合物、治疗的疾病状态、治疗的疾病的严重程度、受试者的年龄和相对健康状况、施用途径和形式、主治医师或兽医执业医师的判断等改变。治疗效果可以客观(即,可通过一些检验或标记物测量)或主观(即,受试者提供效果指示和/或感觉效果)的方式观察。
术语“赋形剂”是指药学上可接受的化学品,例如制药领域的普通技术人员已知有助于施用药剂的化学品。其是可用于制备药物组合物、一般安全的、无毒的以及在生物学和其它方面均无不合乎期望的化合物,并且包括对于兽医使用以及人类制药用途可接受的赋形剂。示例性的赋形剂包括粘合剂、表面活性剂、稀释剂、崩解剂、抗粘剂和润滑剂。
“药学上可接受的”意指可用于制备一般安全的、无毒的并且包括可用于兽医使用以及人类制药用途的药物组合物。
根据本发明使用的化合物,即2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺,在本文中亦称为“本发明的化合物”或“本发明化合物”。该化合物由结构式(I)表示:
本发明化合物可用于治疗上文定义的病况。在一些实施方案中,所述病况是炎症或炎性病症,例如慢性炎症或慢性炎性病症。在一些实施方案中,所述病况是炎症,例如慢性炎症。在一些实施方案中,所述病况是急性炎症。在一些实施方案中,所述病况是过度炎症。在一些实施方案中,所述病况是炎性病症,例如慢性炎性病症。在一些实施方案中,所述病况是过度炎性综合征,例如感染相关的过度炎性综合征,例如与呼吸疾病(例如肺炎或covid-19,特别是covid-19)有关的过度炎性综合征。在一些实施方案中,所述病况是自身免疫性病症。在一些具体的实施方案中,所述病况是类风湿性关节炎。在一些进一步具体的实施方案中,所述病况是多发性硬化症。
应注意,类风湿性关节炎和多发性硬化症可各自分类为炎性病症和自身免疫性病症二者。
因此,本发明的一个方面是药物组合物,其包含治疗有效量的2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,和任选的药学上可接受的赋形剂,用于治疗本文提及的病况。
预期的药学用途是用于治疗哺乳动物,优选人,以及动物例如宠物,例如狗或猫,或家畜或实验动物,或例如马。在一些实施方案中,所述哺乳动物是人,例如患有类风湿性关节炎的人。在一些实施方案中,所述哺乳动物是患有多发性硬化症的人。在一些其它实施方案中,所述哺乳动物是宠物,例如狗(在狗中的炎性或自身免疫性病症可以是例如类风湿性关节炎、肉芽肿性脑膜脑脊髓炎或退行性脊髓病)。因此,在一些实施方案中,所述哺乳动物是患有类风湿性关节炎的狗。在一些其它实施方案中,所述哺乳动物是患有肉芽肿性脑膜脑脊髓炎的狗。
在一些进一步的实施方案中,所述哺乳动物是马,例如患有类风湿性关节炎的马。在其中哺乳动物是一种动物的实施方案中,表述例如“药学上可接受的”等应理解为是指对于相应的兽医使用等是可接受的。
在本文中,表述“本发明的化合物”或“发明的化合物”或“本发明化合物”应解释为是指2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺,而且是指所述化合物的药学上可接受的盐,除非另外指示或从上下文显而易见。在一些实施方案中,所述化合物以“游离碱”的形式,即非盐形式使用。
在一些实施方案中,本发明的化合物可以药学上可接受的盐的形式提供。本发明化合物的酸加成盐可呈本身已知使用碱性试剂例如碱或通过离子交换转化为游离碱的形式。得到的游离碱也可与有机或无机酸形成盐。本发明化合物的碱加成盐可呈本身已知通过使用酸性试剂例如酸或通过离子交换转化为游离酸的形式。得到的游离酸也可与有机或无机碱形成盐。
在酸或碱加成盐的制备中,优选地使用合适形成治疗上可接受的盐的这样的酸或碱。这样的酸的实例是氢卤酸,硫酸,磷酸,硝酸,脂肪族、脂环族、芳香族或杂环羧酸或磺酸,例如甲酸、乙酸、丙酸、琥珀酸、乙醇酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟马来酸、丙酮酸、对羟基苯甲酸、扑酸、甲磺酸、乙磺酸、羟基乙磺酸、卤苯磺酸、甲苯磺酸或萘磺酸。碱加成盐包括从无机碱衍生的那些,例如铵或碱金属或碱土金属氢氧化物、碳酸盐、碳酸氢盐等,以及从有机碱衍生的那些,例如醇盐、烷基酰胺、烷基和芳基胺等。可用于制备本发明的盐的碱的实例包括氢氧化钠、氢氧化钾、氢氧化铵、碳酸钾等。
可通过组合活性物质与常规的药用赋形剂来制备药物制剂,所述活性物质在本情况下为本发明的化合物或其药学上可接受的盐。可通过已知的方法,例如制粒、压制、微囊化、喷雾包衣等,进一步制备制剂。可通过常规方法以片剂、胶囊剂、颗粒剂、散剂、糖浆剂、混悬剂、栓剂或注射剂的剂型制备制剂。可通过在水或其它合适的溶媒中溶解或悬浮活性物质来制备液体制剂。片剂和颗粒剂可以常规方式包衣。
对于临床使用,本发明的化合物被配制成用于口服、直肠、肠胃外或其它施用方式的药物制剂。这些用于预期用途的药物制剂是本发明的进一步目的。
通常,活性化合物的有效量在制剂的0.1-95重量%之间,对于肠胃外用途,优选在制剂的0.2-20重量%之间,对于口服施用,优选在制剂的1-50重量%之间。
本发明化合物的剂量水平和剂量频率将根据多种因素而变化,包括所用本发明化合物的效力,该化合物的代谢稳定性和作用时间长短,患者的年龄、体重、一般健康状况、性别、饮食、施用方式和时间、排泄速率、药物组合、要治疗的病况的严重程度以及患者正经历的疗法。日剂量范围可以是例如,每千克体重约0.001mg至约100mg,其以单剂量或多剂量施用,例如每次从约0.01mg至约25mg。通常,这种剂量是口服的,但也可以选择肠胃外施用。
在以口服施用的剂量单位形式制备含有本发明的化合物的药物制剂时,所述化合物可以与固体粉末状成分,例如乳糖、蔗糖、山梨醇、甘露醇、淀粉、支链淀粉、纤维素衍生物、明胶或其它合适的成分混合,以及与崩解剂和润滑剂例如硬脂酸镁、硬脂酸钙、硬脂酰富马酸钠和聚乙二醇蜡混合。然后将混合物加工成颗粒剂或压制成片剂。
软明胶胶囊可以用含有本发明活性化合物、植物油、脂肪或其它合适用于软明胶胶囊的溶媒的混合物的胶囊制备。硬明胶胶囊可含有活性化合物的颗粒。硬明胶胶囊还可能含有本发明化合物与固体粉末状成分的组合,所述固体粉末状成分例如乳糖、蔗糖、山梨醇、甘露醇、马铃薯淀粉、玉米淀粉、支链淀粉、纤维素衍生物或明胶。
用于直肠施用的剂量单位可以如下制备:(i)以含有与中性脂肪基质混合的活性物质的栓剂的形式;(ii)以含有活性物质与植物油、石蜡油或其它适合用于明胶直肠胶囊的溶媒的混合物的明胶直肠胶囊的形式;(iii)以现成的微灌肠剂的形式;或(iv)以仅在施用前在合适的溶剂中复原的干的微灌肠制剂的形式。
用于口服施用的液体制剂可以以糖浆或混悬液的形式制备,例如含有0.2重量%至20重量%活性成分和由糖或糖醇以及乙醇、水、甘油、丙二醇和聚乙二醇的混合物组成的其余部分的溶液或混悬液。如果需要,这种液体制剂可含有着色剂、调味剂、糖精和羧甲基纤维素或其它增稠剂。用于口服施用的液体制剂也可以以在使用前用合适的溶剂复原的干粉的形式制备。
用于肠胃外,例如静脉内施用的溶液,可以制备为本发明化合物在药学上可接受的溶剂中的溶液,优选浓度为0.1重量%至10重量%。这些溶液还可以含有稳定成分和/或缓冲成分,并以安瓿或小瓶的形式分配成单位剂量。用于肠胃外施用的溶液也可以制备为在使用前临时用合适的溶剂复原的干燥制剂。
本发明包括药物组合物,其包含治疗有效量的用于治疗本文定义的病况的本发明化合物,以及至少一种药学上可接受的赋形剂,例如载体,和任选的其它治疗和/或预防成分。
根据本发明的药物组合物可以用于局部(topical)(局部(local))或全身施用,例如用于肠内施用,例如直肠或口服施用,或用于肠胃外施用至哺乳动物(特别是人),并且包含治疗有效量的根据本发明的化合物或其药学上可接受的盐作为活性成分,其与药学上可接受的赋形剂(例如药学上可接受的载体)结合。活性成分的治疗有效量如上文所定义,并且取决于例如哺乳动物的种类、体重、年龄、个体状况、个体药代动力学数据、要治疗的疾病和施用方式。
对于肠内,例如口服施用,本发明化合物可以以多种剂型配制。药学上可接受的载体可以是固体或液体。固体形式制剂包括散剂、片剂、丸剂、锭剂、胶囊剂、扁囊剂、栓剂和可分散颗粒剂。固体载体可以是一种或多种物质,其还可以用作稀释剂、调味剂、增溶剂、润滑剂、悬浮剂、粘合剂、防腐剂、片剂崩解剂或包封材料。在散剂中,载体通常是极细的固体,它是与极细的活性组分的混合物。在片剂中,活性组分通常以适当的比例与具有必要结合能力的载体混合,并按所需的形状和尺寸压实。合适的载体包括但不限于碳酸镁、硬脂酸镁、滑石粉、糖、乳糖、果胶、糊精、淀粉、明胶、黄蓍胶、甲基纤维素、羧甲基纤维素钠、低熔点蜡、可可脂等。活性化合物的制剂可包含包封材料作为载体,提供胶囊,其中活性组分(有或没有载体)被与其结合的载体包围。
适合口服施用的其它形式包括液体形式制剂,其包括乳剂、糖浆剂、酏剂、水溶液剂、水混悬剂或预期在使用前不久转化为液体形式制剂的固体形式制剂。乳剂可以在溶液中,例如在丙二醇水溶液中制备,或者可以含有乳化剂,例如卵磷脂、脱水山梨糖醇单油酸酯或阿拉伯胶。可通过将活性组分溶解在水中并加入合适的着色剂、调味剂、稳定剂和增稠剂来制备水溶液。水混悬剂可以通过将极细的活性组分与粘性材料(例如天然或合成树胶、树脂、甲基纤维素、羧甲基纤维素钠和其它公知的悬浮剂)分散在水中来制备。固体形式制剂包括溶液剂、混悬剂和乳剂,并且除活性组分外,还可以含有着色剂、调味剂、稳定剂、缓冲剂、人工和天然甜味剂、分散剂、增稠剂、增溶剂等。
用于直肠施用的示例性组合物包括栓剂,其可含有例如合适的非刺激性赋形剂,例如可可脂、合成甘油酯或聚乙二醇,它们在常温下是固体,但在直肠腔中液化和/或溶解以释放药物。
本发明的化合物也可以肠胃外施用,例如通过吸入、注射或输注,例如通过静脉内、动脉内、骨内、肌肉内、脑内、脑室内、滑膜内、胸骨内、鞘内、病灶内、颅内、皮内和皮下注射或输注。
因此,对于肠胃外施用,本发明的药物组合物可以是无菌可注射或可输注制剂的形式,例如作为无菌水性或油性混悬液。这种混悬液可以根据本领域已知的技术配制,使用合适的分散剂或润湿剂(例如80)和悬浮剂。所述无菌可注射或可输注制剂也可以是在无毒的肠胃外可接受的稀释剂或溶剂中的无菌可注射或可输注溶液或混悬液。例如,所述药物组合物可以是在1,3-丁二醇中的溶液。可用于本发明的组合物的可接受的溶媒和溶剂的其它例子包括但不限于甘露醇、水、林格氏溶液和等渗氯化钠溶液。此外,无菌固定油通常用作溶剂或悬浮介质。为此,可以使用任何温和的固定油,包括合成甘油单酯或甘油二酯。脂肪酸,例如油酸及其甘油酯衍生物可用于制备注射剂,作为天然药学上可接受的油,例如橄榄油或蓖麻油,特别是以它们的聚氧乙基化形式。这些油溶液或混悬液还可以含有长链醇稀释剂或分散剂。
用于肠胃外使用的溶液还可以含有合适的稳定剂,并在必要时含有缓冲物质。合适的稳定剂包括抗氧化剂,例如硫酸氢钠、亚硫酸钠或抗坏血酸(单独或组合),柠檬酸及其盐和EDTA钠。肠胃外溶液还可含有防腐剂,例如苯扎氯铵、对羟基苯甲酸甲酯或丙酯和氯丁醇。
对于吸入或鼻腔施用,合适的药物制剂为颗粒剂、气溶胶、散剂、雾或液滴,例如平均尺寸为约10μm直径或更小。例如,用于吸入的组合物可以制备为盐溶液,采用苯甲醇或其它合适的防腐剂、提高生物利用度的吸收促进剂、碳氟化合物和/或本领域已知的其它增溶剂或分散剂。
本发明的药物组合物也可以局部施用,例如施用于皮肤或粘膜。对于局部应用,所述药物组合物可以是例如洗剂、凝胶、糊剂、酊剂、透皮贴剂、用于经粘膜递送的凝胶。
组合物可以用含有悬浮或溶解在载体中的活性组分的合适软膏配制。用于局部施用本发明化合物的载体包括但不限于矿物油、液体石油、白石油、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡和水。或者,药物组合物可以配制成含有悬浮或溶解在载体中的活性化合物的合适洗剂或乳膏。合适的载体包括但不限于矿物油、脱水山梨糖醇单硬脂酸酯、聚山梨醇酯60、鲸蜡基酯蜡、鲸蜡硬脂醇(cetaryl alcohol)、2-辛基十二烷醇、苯甲醇和水。本发明的药物组合物也可以通过直肠栓剂制剂或合适的灌肠制剂局部施用于下肠道。
合适的药用赋形剂,例如载体和制备药物剂型的方法在Remington'sPharmaceutical Sciences,Mack Publishing Company中描述,这是药物制剂领域的标准参考文本。
所述药物组合物可包含约1%至约95%、优选约20%至约90%的本发明化合物,以及至少一种药学上可接受的赋形剂。一般而言,本发明的化合物将通过用于类似效用的药剂的任何可接受的施用模式以治疗有效量施用。合适的日剂量范围通常为1至1000mg,例如每天1-500mg,或每天1-50mg,取决于许多因素,例如要治疗的疾病的严重程度、患者的年龄和相对健康状况、所用化合物的效力、施用途径和形式以及施用所针对的适应症等。治疗此类疾病的本领域的普通技术人员将能够在不进行不当实验的情况下,依靠个人知识和本申请的公开,确定本发明化合物对给定疾病的治疗有效量。本发明的化合物可以作为药物制剂施用,包括那些适合于肠内或肠胃外施用的药物制剂。优选的施用方式通常是口服,使用方便的日剂量方案,其可以例如根据痛苦程度进行调整。
本发明的化合物也可以与一种或多种额外的治疗活性剂组合使用或施用。所述组分可以在同一制剂中或在分开的制剂中同时或依次施用。
因此,在本发明的进一步的方面,提供了一种组合产品,其包含:
(A)本发明的化合物,用于治疗本文定义的病况;以及
(B)另一种治疗剂;其中(A)和(B)与药学上可接受的赋形剂混合配制。
这种组合产品提供了将本发明化合物与其它治疗剂联合施用,并且因此可以作为分开的制剂呈现,其中这些制剂中的至少一种包含本发明化合物,并且至少一种包含另一种治疗剂,或者可以作为组合制剂呈现(即配制)(即作为包括本发明化合物和另一种治疗剂的单一制剂呈现)。
因此,进一步提供了:
(1)药物制剂,其包括用于治疗本文定义的病况的本发明化合物、另一种治疗剂和药学上可接受的赋形剂,例如辅助剂、稀释剂或载体;或者
(2)成套试剂盒(kit of parts),其包含以下作为组分:
(a)药物制剂,其包括与药学上可接受的赋形剂,例如辅助剂、稀释剂或载体混合的用于治疗本文定义的病况的本发明化合物;和
(b)药物制剂,其包括与药学上可接受的赋形剂,例如辅助剂、稀释剂或载体混合的另一种治疗活性剂,所述组分(a)和(b)各自以适合彼此结合施用的形式提供。
在一些实施方案中,本发明化合物与另外的治疗上有用的化合物组合用于治疗炎症或炎性病症。例如,在一些实施方案中,本发明化合物与具有对于相同炎性病症的确定活性的另外的药剂组合用于治疗炎性病症。
在一些实施方案中,本发明化合物与另外的治疗上有用的化合物组合用于治疗自身免疫性病症。例如,在一些实施方案中,本发明化合物与具有对于相同自身免疫性病症的确定活性的另外的药剂组合用于治疗自身免疫性病症。
在一些实施方案中,进一步提供了:
(1)药物制剂,其包括用于治疗前文定义的病况的本发明化合物、另外的治疗活性剂和药学上可接受的赋形剂,例如辅助剂、稀释剂或载体;或者
(2)成套试剂盒,其包含以下作为组分:
(a)药物制剂,其包括与药学上可接受的赋形剂,例如辅助剂、稀释剂或载体混合的用于治疗本文定义的病况的本发明化合物;和
(b)药物制剂,其包括与药学上可接受的赋形剂,例如辅助剂、稀释剂或载体混合的另外的治疗剂,所述组分(a)和(b)各自以适合彼此结合施用的形式提供。
在一些实施方案中,所述病况是类风湿性关节炎,并且在这样的实施方案中,另外的化合物例如可选自用于治疗类风湿性关节炎的其它药剂,疾病改进的抗风湿药物(DMARD),例如甲氨蝶呤、来氟米特、羟氯喹或柳氮磺吡啶;生物治疗剂,例如依那西普或英夫利昔单抗;JAK抑制剂,例如托伐替尼或巴瑞替尼。在一些实施方案中,另外的化合物也可以是镇痛药,例如扑热息痛;非类固醇抗炎药(NSAID),例如布洛芬、萘普生或双氯芬酸;或类固醇,例如泼尼松龙。
在任何以上的成套试剂盒中的组分(a)和(b)可同时、依次或彼此分开施用。
如本文示出,本发明化合物具有对活性氧物类的抗氧化作用,其可助于治疗各种涉及细胞内活性氧物类的病症的治疗效果,所述病症例如各种炎性或自身免疫性病症,例如类风湿性关节炎和多发性硬化症。因此,在一些实施方案中,在治疗涉及细胞内活性氧物类或其中细胞内活性氧物类在发病中起作用的病症(例如类风湿性关节炎或多发性硬化症)中提供本发明化合物。
本发明化合物进一步具有抗细胞因子作用,这在治疗其中细胞因子可具有病理作用的病症中赋予有用性。因此,在一些实施方案中,提供本发明化合物用于抗细胞因子疗法,因为其可用于治疗其中细胞因子,例如TNF-α、IL1β和IL-6具有病原作用的病症,例如炎性和/或自身免疫性病症,例如类风湿性关节炎和多发性硬化症。
用于治疗本文提及的病症的本发明化合物8可根据以下通用反应方案,通过在硫代剂的存在下Rabeximod 3的硫代来制备:
该反应包括通过使用任何合适的硫代剂,例如P2S5·2C5H5N或Lawesson试剂(CAS号19172-47-5),将Rabeximod的氧代官能转化为硫代官能(用硫原子替换氧原子)。然而优选地,P2S5·2C5H5N用作硫代剂。硫代Rabeximod因此可在多步方法中制备,包括9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉的阴离子与α-卤代(例如α-溴代或α-氯代)乙酸甲酯或乙酸乙酯反应,接着得到的酯与过量的N1,N1-二甲基乙烷-1,2-二胺缩合,以及使用合适的硫代剂,例如P2S5·2C5H5N,优选在包含环丁砜的液体反应介质中(例如在环丁砜中)将得到的产物硫代。9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉的阴离子可例如通过使所述喹喔啉与大量过量的强碱(例如碳酸钾)在溶剂介质(例如丙酮)中接触来制备。例如,Rabeximod可在如反应方案1中所示的反应中制备。
在反应方案1所示的反应中,在丙酮中用大量过量的碳酸钾将9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉(4)转化为其阴离子,并用氯乙酸甲酯烷基化以得到酯6。最后加热(110℃,1h)6与2-二甲基-氨基乙基胺,以高收率得到Rabeximod 3。用于制备化合物8的多步方法包括在酸性介质(例如乙酸)中加热5-氯靛红和4,5-二甲基苯二胺合适的时间段,例如8h,从而获得2,3-二甲基-9-氯-6H-吲哚并[2,3-b]喹喔啉,该化合物随后如上文所述用于获得Rabeximod,接着将Rabeximod硫代。因此,在一些情况下,该多步方法包括在如反应方案2所示的反应中制备2,3-二甲基-9-氯-6H-吲哚并[2,3-b]喹喔啉,其用作起始材料4。
Rabeximod 3的硫代可如反应方案3中所示,通过在溶剂(例如环丁砜)中在110℃下使用P2S5·2C5H5N作为硫代剂7进行,以获得化合物8。
以上所示的多步方法的反应在下文中更详细地描述。
除非另有说明,否则所有反应均在空气气氛下进行。所有市售试剂均按收到的使用,无需进一步纯化。在Bruker Avance/500(1H:500MHz,13C:125MHz,25℃)上记录1H NMR和13N NMR波谱。熔点在Mettler Toledo DSC上测量。FT-IR光谱在Thermo Nicolet Nexus470FTIR光谱仪上记录。通过高效液相色谱(HPLC)(Waters,对称屏蔽RP8,流动相A:95%乙腈,5%水,0.1%甲酸,流动相A:5%乙腈,95%水,0.1%甲酸)监测反应。元素分析由Mikroanalytisches Laboratorium Kolbe,D-46047Oberhausen进行。
2,3-二甲基-9-氯-6H-吲哚并[2,3-b]喹喔啉4
将4,5-二甲基苯二胺(7.42g,0.053mol)在乙酸(50mL)中的溶液加入至5-氯靛红(10.0g,0.053mol)在乙酸(150mL)中的溶液。当用于合成4的两种组分在热乙酸中混合时,在几分钟内形成沉淀物5,其缓慢转变为4。在回流下处理由此形成的浆液,直到完全转变,如通过1H NMR(8h)测定的。将混合物冷却,并收集形成的固体,用乙醇洗涤和干燥。将粗材料从N-甲基吡咯烷酮重结晶。收率53%(7.9g),mp390-393℃。IR 3030,1621,1594,1460,1446,1325,1285,1211,1164,806,772,680cm-1。1H NMR(DMSO-d6)δ12.08(br.s,1H),8.30(dd,J=2.2,0.4Hz,1H),8.02(s,1H),7.86(s,1H),7.69(dd,J=8.6,2.2Hz,1H),7.58(dd,J=8.6,0.4Hz,1H),2.50(s,6H).13C NMR(DMSO-d6)δ145.8(s),139.6(s),139.2(s),137.7(s),137.5(s),136.2(s),130.4(d),128.0(d),126.6(d),124.7(s),121.1(d),120.5(s),113.5(d),20.0(q),19.7(q).M/Z+1:281.8。
甲基酯6
将氯乙酸甲酯(4.1g,37.1mmol)加入至4(10g,33.7mmol)和K2CO3(46.5g,333mmol)在丙酮(200mL)中的浆液。在回流温度下处理混合物,直到根据HPLC完全转变(~8h)。将浆液冷却至室温,并倾入水中。收集由此形成的黄色固体,用水洗涤和干燥。粗产物用于下一步骤。将少量样品从四氢呋喃重结晶。收率98%(11.9g),mp271-274℃。IR 2942,1736,1588,1463,1450,1270,1208,877,808,798,684cm-1。1H NMR(DMSO-d6)δ8.36(d,J=2.0Hz,1H),8.05(s,1H),7.91(s,1H),7.84(d,J=8.7Hz,1H),7.78(dd,J=8.7,2.1Hz,1H),5.41(s,2H),3.71(s,3H),2.51(s,6H).13C NMR(DMSO-d6)δ168.7(s),144.9(s),142.3(s),140.3(s),138.8(s),138.1(s),137.3(s),136.8(s),130.5(d),128.1(d),126.7(d),125.7(s),121.1(d),120.2(s),112.3(d),52.3(q),42.5(t),20.0(q),19.7(q).M/Z+1:354.0。
Rabeximod 3
将酯6(0.5g,1.4mol)加入至N,N-二甲基氨基乙基胺(4mL,17.4mmol)。在回流温度下一段时间后,将反应混合物浓缩,并加入水。收集形成的固体,并用热乙醇洗涤,用乙醇再次洗涤并干燥。收率:80%(0.45g),mp 219-224℃。IR 3263,2939,2768,1673,1584,1472,1461,1273,1210,868,820,798,681cm-1。1H NMRδ8.30(d,2.2Hz,1H),8.24(t,J=5.6Hz,1H),7.99(s,1H),7.84(s,1H),7.71(dd,J=8.7,2.2Hz,1H),7.62(d,J=8.7Hz,1H),5.108s,2H),3.16(q,J=6.7Hz,2H),2.48(br.s,6H),2.28(t,J=6.7Hz,2H),2.13(s,6H).13CNMRδ19.6(q),20.0(q),34.3(t),42.6(q),43.9(t),55.6(t),112.2(d),120.2(s),12.8(d),125.3(s),126.4(d),127.9(d),130.1(d),136.2(s),137.2(s),137.8(s),138.6(s),139.7(s),142.5(s),144.9(s),167.5(s).M/Z+1:409.9。
2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺(硫代Rabeximod)
将Rabeximod(5.6g,13.7mmol)和试剂7(5.2g,13.7mmol)和环丁砜(45mL)在110℃下处理,直到完全转变(~0.5h)。将溶液冷却至室温,并倾入水(150mL)中。收集形成的固体,并用水(50mL)、稀氢氧化铵(1.25%,100mL)和水(50mL)洗涤和干燥。纯度:97%(根据HPLC)。收率92%,5.52g,mp 184-188℃。IR 3232,2944,1586,1452,1270,1207,1167,880,799,685cm-1。1H NMR(DMSO-d6)δ10.17(br.s,1H),8.31(br.s,1H),8.31(d,J=8.7,2.1Hz,1H),8.02(s,1H),7.85(s,1H),7.72(dd,J=8.7,2.1Hz,1H),7.57(d,J=8.7,1H),5.46(s,2H),3.66(m,2H),2.50(m,2H),2.50(s,6H),2.21(s,6H).13C NMR(DMSO-d6)δ196.1(s),145.3(s),139.8(s),138.8(s),138.0(s),137.6(s),130.2(d),128.0(s),126.6(d),125.4(s),120.9(d),120.4(s),112.3(d),55.8(t),50.8(t),44.8(q),42.9(t),20.0(q),19.6(q).M/Z+1:426.0。
体外测定
异鲁米诺测定
氧代谢在类风湿性关节炎和多发性硬化症二者的发病中具有重要作用。在细胞氧化磷酸化过程中和在氧化爆发期间通过激活的吞噬细胞产生的活性氧物类(ROS)超过生理缓冲能力,并导致氧化应激。ROS的过度产生可破坏蛋白质、脂质、核酸和基质组分。ROS还用作重要的细胞内信号传导分子,其放大滑膜炎性-增殖性反应。氧化应激已表明在RA中通过影响蛋白质和蛋白酶体降解诱导T细胞低反应性。最后,抗氧化剂已表明在动物模型中改善关节炎。该测定表明测试的化合物减少ROS的能力。
LPS测定
炎症可通过用LPS刺激体外诱导,表现为释放各种细胞因子。该测定表明本发明化合物在人全血中LPS诱导的细胞因子释放的体外抗炎功效。TNF-α、IL1β和IL-6是在RA和MS的发病中重要的细胞因子,因此在该测定中被选择。
材料和方法
异鲁米诺测定
将使用Ficoll通过梯度离心从人血液(Blodcentralen,Lund,Sweden)中分离的冷冻的PBMC快速融化,用30ng/ml的PMA激活并用范围从12.5μg/ml(经8个步骤,1:2剂量滴定)的不同浓度的Rabeximod或本发明化合物处理。包括的对照是DMSO对照、30ng/ml的PMA和0μg/ml的测试物。将异鲁米诺缓冲液加入至板(异鲁米诺0,175mg/ml和HRP级分II 1,75U/ml,在HBSS中)。使用Scepter细胞计数器(Millipore Merck,MA,USA)测定细胞浓度,并当加入至测定板时以2x106个细胞/ml稀释。经25分钟测量发光信号。
LPS测定
从成人志愿者收集全血到肝素管中。LPS刺激在抽取血液的60分钟内开始。用RPMI稀释血液,然后用LPS刺激和用不同浓度的Rabeximod或本发明化合物孵育。将样品离心和收获血浆,并在Luminex上分析以测量细胞因子。
图表和统计学
使用用于Mac OS X的Prism 8(GraphPad Software,San Diego,CA,USA)作图。如果没有另外说明,结果表示为平均值±SEM。
结果
异鲁米诺测定
研究用范围从12.5μg/ml(经8个步骤,1:2剂量滴定)的不同浓度的本发明化合物或Rabeximod处理后的ROS产生。经25分钟测量发光信号。
根据图1和2的结果,两种化合物均以剂量依赖性方式抑制ROS产生。本发明化合物从6.25μg/ml开始完全抑制ROS产生,而Rabeximod需要12.5μg/ml以完全抑制ROS产生。
LPS测定
在用LPS刺激并用本发明化合物或Rabeximod处理全血后,研究细胞因子和趋化因子的释放。
与5000nM的Rabeximod相比,用本发明化合物处理的样品中,TNF-α、IL1β和IL-6的水平显著更低,对于更低浓度也具有细胞因子水平的降低趋势,见图3-5。
体内实验
CAIA小鼠模型
小鼠中胶原抗体诱导的关节炎(CAIA)是一种不依赖于B和T细胞二者的模型。CAIA是关节炎的急性模型,并且该疾病用II型胶原的抗体诱导。所述抗体结合软骨,导致免疫系统激活,接着募集巨噬细胞和粒细胞至关节。在第5天LPS加强后,疾病发展开始并在第15天附近达到最大。
材料和方法
CAIA模型:小鼠(DBA/1,8-10周龄)在第-1天称重,以确定在实验中的动物平均体重和构成各组。各组在笼内混合,以避免笼影响。在第0天,小鼠经i.v.注射II型胶原的四(4)种单克隆抗体的混合物(2mg/小鼠)。第5天,小鼠用LPS(50μg/小鼠)i.p.注射,以加强疾病。每日在玉米油中进行测试物的剂量制备。使用范围从0至15的四肢宏观评分系统(对于每处肿胀或红足尖为1分,对于肿胀或红中足趾或趾关节为1分,对于肿胀踝关节为5分),从第3天开始每日盲法评价疾病,导致对于每只小鼠的最大总评分为60。由于伦理限制,评分超过45的动物从实验中除去。
免疫组织化学:在溶媒、Rabeximod(20mg/kg)和本发明化合物(20mg/kg)组中,在动物终点时收集动物的前爪。将爪直接转移到含4%甲醛的小瓶中,用于浸入固定。将组织固定24小时,然后转移到70%EtOH中,并储存在+4℃直至染色。将爪脱钙,石蜡包埋,切片以及苏木精和伊红(H&E)染色。所得载玻片以高分辨率拍摄。图像用于形态学分析,以研究关节中软骨的破坏和炎性细胞的浸润。对整个爪的总体评价进行评分(0-3),包括滑膜炎症、滑膜血管翳形成和骨破坏的评估。
统计学
图表和统计学分析使用用于Mac OS X的Prism 8(GraphPad Software,SanDiego,CA,USA)进行。如果没有另行说明,结果表示为平均值±SEM。使用双尾非参数Mann-Whitney检验计算统计数据,其中p<0.05被认为是显著的。*表示p值<0.05,**表示p值<0.01和***表示p值<0.001。
结果
用CIA-MAB-50免疫和用溶媒(第5、7、9、11、13和15天)、本发明化合物(5、10和20mg/kg,第5、7、9、11、13和15天)和Rabeximod(5、10和20mg/kg,第5、7、9、11、13和15天)处理小鼠中关节炎发展。在目前的CAIA研究中,CAIA诱导的溶媒处理的小鼠发展为中度至重度疾病,发病率为100%。评估本发明化合物和Rabeximod分别在三种不同剂量下的功效,从第5天开始每隔一天s.c.给药一次,共六次施用。与溶媒相比,10和20mg/kg的本发明化合物(图6)和所有三个剂量的Rabeximod(图7)均观察到疾病严重程度略有降低,但并不显著。在用测试的任何剂量的本发明化合物或Rabeximod处理的动物中,未观察到处理的不良作用。数据表明,与用Rabeximod处理的动物相比,用本发明化合物处理的小鼠有明确的剂量反应。
IHC分析的结果使用范围为0到3的评分系统进行评分,其中0代表没有炎症的健康组织,3代表大量发炎的组织。在研究结束时,与溶媒处理的动物相比,20mg/kg剂量的本发明化合物的组织学评分显著更低。溶媒与Rabeximod处理的小鼠之间未观察到显著差异(图8)。
PIA大鼠模型
大鼠中降植烷诱导的关节炎(PIA)是一种模仿用于类风湿性关节炎(RA)诊断的标准的动物模型。PIA是RA中重现性最强的模型之一,发病率高,并且严重程度变化小。疾病的特征是明显的T细胞依赖性炎性反应,导致外周关节炎症。单次注射降植烷诱导该疾病,并在第8-12天之间具有高度可重复的关节炎发作。关节炎最严重的阶段通常在诱导后第15-25天之间,实验可在25-30天后终止。
材料和方法
对于疾病诱导,大鼠用兽用IsoFlo(3%)和氧气麻醉。尾巴的根部用EtOH清洁,并在距离尾巴根部约0.5cm处皮下(s.c.)注射降植烷(体积200μl)。注射后对注射部位施加轻微压力10秒,以防止漏油。将大鼠从麻醉剂中取出并监测呼吸,直到确保恢复。对于接受Rabeximod、本发明化合物或仅溶媒的所有处理组,从第5天开始每隔一天s.c.施用测试物,共6次施用(即第5、7、9、11、13和15天)。将化合物配制在玉米油中,施用体积为200μl,浓度为20mg/ml。使用范围从0至15的四肢宏观评分系统(对于每处肿胀或红足尖为1分,对于肿胀或红中足趾或趾关节为1分,对于肿胀踝关节为5分),从第10天开始每周盲法评估疾病3次,导致对于每只大鼠的最大总评分为60。
统计学
图表和统计学分析使用用于Mac OS X的Prism 8(GraphPad Software,SanDiego,CA,USA)进行。如果没有另行说明,结果表示为平均值±SEM。
结果
用本发明化合物处理的大鼠在所有测量的研究时间点均显示出略低的RA评分(图9)。在关节炎最严重的阶段期间,本发明化合物比Rabeximod功效更好。
Claims (20)
1.化合物2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,用于治疗选自炎症、炎性病症和自身免疫性病症的病况。
2.根据权利要求1使用的化合物或药学上可接受的盐,其中所述病况是炎症或炎性病症。
3.根据权利要求1使用的化合物或药学上可接受的盐,其中所述病况是自身免疫性病症。
4.根据权利要求1-3中任一项使用的化合物或其药学上可接受的盐,其中所述病况是类风湿性关节炎。
5.根据权利要求1-3中任一项使用的化合物或其药学上可接受的盐,其中所述病况是多发性硬化症。
6.药物组合物,其包含2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐,和任选的药学上可接受的赋形剂,用于治疗选自炎症、炎性病症和自身免疫性病症的病况。
7.根据权利要求6的组合物,其中所述病况是炎症或炎性病症。
8.根据权利要求6的组合物,其中所述病况是自身免疫性病症。
9.根据权利要求6-8中任一项的组合物,其中所述病况是类风湿性关节炎。
10.根据权利要求6-8中任一项的组合物,其中所述病况是多发性硬化症。
11.2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐在制备用于治疗选自炎症、炎性病症和自身免疫性病症的病况的药物中的用途。
12.根据权利要求11的用途,其中所述病况是炎症或炎性病症。
13.根据权利要求11的用途,其中所述病况是自身免疫性病症。
14.根据权利要求11-13中任一项的用途,其中所述病况是类风湿性关节炎。
15.根据权利要求11-13中任一项的用途,其中所述病况是多发性硬化症。
16.用于治疗选自炎症、炎性病症和自身免疫性病症的病况的方法,其通过向需要这种治疗的哺乳动物施用2-(9-氯-2,3-二甲基-6H-吲哚并[2,3-b]喹喔啉-6-基)-N-(2-(二甲基氨基)乙基)乙硫代酰胺或其药学上可接受的盐。
17.根据权利要求16的方法,其中所述病况是炎症或炎性病症。
18.根据权利要求16的方法,其中所述病况是自身免疫性病症。
19.根据权利要求16-18中任一项的方法,其中所述病况是类风湿性关节炎。
20.根据权利要求16-18中任一项的方法,其中所述病况是多发性硬化症。
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- 2021-09-21 WO PCT/EP2021/075944 patent/WO2022058614A1/en active Application Filing
Also Published As
Publication number | Publication date |
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EP4213850A1 (en) | 2023-07-26 |
JP2023543089A (ja) | 2023-10-12 |
WO2022058614A1 (en) | 2022-03-24 |
US20230381174A1 (en) | 2023-11-30 |
CA3191963A1 (en) | 2022-03-24 |
AU2021344650A1 (en) | 2023-05-18 |
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