CN101861301A - 二氧代蒽磺酸盐衍生物 - Google Patents
二氧代蒽磺酸盐衍生物 Download PDFInfo
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- CN101861301A CN101861301A CN200880116160A CN200880116160A CN101861301A CN 101861301 A CN101861301 A CN 101861301A CN 200880116160 A CN200880116160 A CN 200880116160A CN 200880116160 A CN200880116160 A CN 200880116160A CN 101861301 A CN101861301 A CN 101861301A
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Abstract
可具有抗炎症活性的化合物，其具有通式(I)：其中R1，R2，R3彼此独立地是H或C1-4烷基基团或C2-4酰基基团；R4和R5彼此独立地是H或式-SO3R6的基团，其中R6是H或C1-4烷基基团或C2-4酰基基团；条件是R4和R5中至少一个是式-SO3R6的基团，或其药物可接受的盐。
Description
本发明涉及特定的二氧代蒽磺酸盐衍生物，涉及其制备方法，并涉及该化合物作为药物，特别是在治疗由IL-1家族的促炎症细胞因子影响的病症，特别是炎症和自身免疫性疾病，例如关节炎疾病中的用途。
大黄酸，4，5-二羟基-9，10-二氧代-2-蒽羧酸，及其二酰基化的衍生物双醋瑞因，已在用于多种治疗应用。特别是大黄酸和双醋瑞因已知用于治疗关节炎疾病，特别是骨关节炎和类风湿性关节炎，例如如在US 4,244,968，GB 1578452，EP 544 880 B1，EP 636 602 B1和US 6,610,750中所述，和牛皮癣和相关病症，如在EP 1 248 608 B1中所述。大黄酸和双醋瑞因也被描述用于治疗不同的病症，例如炎症疾病、自身免疫性疾病、血管疾病、痛减轻、糖尿病性肾病。
细胞因子IL-1(α，β)和TNF-α被认为在炎症过程和软骨降解的介导中发挥实质性作用。IL-1和TNF-α也被认为涉及对内毒素和其它传染性刺激物的生物响应的介导。促炎症和抗炎症细胞因子的广泛综述由C.A.Dinarello，MD et L.L.Moldawer，PhD in the primer forclinicians“Proinflammatory and Anit-inflammatory Cytoklnesin Rheumatoid Arthritis”，2000，Amgen Inc提供。所述细胞因子IL-1和TNF-α涉及多种炎症和自身免疫性病症的机制，如骨关节炎，类风湿性关节炎，牛皮癣性关节炎，牛皮癣，Paget′s病，骨质疏松症，炎症性肠病，包括溃疡性结肠炎和克罗恩病，子宫内膜异位，Wegener′s肉芽肿病，神经机能障碍，如阿尔茨海默氏病和帕金森病，骨髓瘤，髓样白血病，骨转移，糖尿病性肾病，慢性心脏病，关节硬化，哮喘。
双醋瑞因及其活性代谢产物大黄酸已知抑制白细胞介素-1(IL-1)家族，特别是IL-1β的促炎症异化细胞因子的合成和活性。大黄酸和双醋瑞因显示抑制IL-6，IL-8和其它细胞因子的表达，所述其它细胞因子如组织坏死因子(TNF-α)。炎症细胞因子IL-1和TNF-α被大黄酸和双醋瑞因抑制描述于，例如，WO 02/058681，WO 01/051044，J.Martel-Pelletier et al.Journal of Rheumatology，1998，25(4)，753-762，E.Douni et al.Arthritis Res Ther，2004，6：R65-R72。
与来自健康个体的软骨细胞相比，来自遭受这些病症的患者的软骨细胞表达高水平的TNF-α和IL-1，并且大黄酸作为IL-1抑制剂的该特异机制被认为至少部分地解释了大黄酸和双醋瑞因在治疗某些关节炎病症，例如，类风湿性关节炎、骨关节炎和牛皮癣性关节炎中的有效性。
然而存在于双醋瑞因中的代谢产物芦荟大黄素显示对结肠和肾细胞具有诱裂作用。芦荟大黄素的基因毒性，由彗星分析法测定(Cometassay)，记载于，例如，S.O.Müller等人，Mutation Research，371，(1996)，165-173中。
此外，大黄酸和双醋瑞因具有在水溶液中溶解差的缺点，使得可生物利用的治疗剂的药物剂型的制备困难。对于用于肠胃外给药的配制剂而言，大黄酸和双醋瑞因的溶解度低是值得注意的问题。
双醋瑞因，及其活性代谢产物大黄酸，已知在长期治疗的患者中具有产生轻泻药作用的倾向。认为，该轻泻药作用可至少部分地归因于大黄酸和双醋瑞因的非常低的溶解度。
对用于由IL-1家族的促炎症细胞因子影响和介导的病症的治疗和疗法的化合物的提供存在持续需求，所述病症特别是炎症和自身免疫性疾病，包括关节炎疾病。
进一步有利的是，提供具有抑制IL-1家族的促炎症细胞因子的活性的可替代的化合物，并且其允许克服大黄酸和/或双醋瑞因的某些缺陷。
还有利的是提供具有提高的抑制IL-1家族的促炎症细胞因子的活性的化合物。
现在提供新颖的式(I)的药物化合物：
其中R1、R2、R3彼此独立地是H或C1-4烷基基团或C2-4酰基基团；
R4和R5彼此独立地是H或式-SO3R6的基团，其中R6是H或C1-4烷基基团或C2-4酰基基团；
条件是R4和R5中的至少一个是式-SO3R6的基团。
根据本发明的具体实施方式，提供式(I)的化合物，其中R1、R2、R3和R4是H，且R5是-SO3H(式(III))。
发明人出人意料地发现，式(I)的化合物能够抑制IL-1家族的促炎症细胞因子的产生。式(I)的化合物，其中R4和/或R5是-SO3H，还展示了表现出有利的溶解度特性。
根据本发明的一个方面，提供制备式(I)的化合物的方法，其包括用硫酸处理相应的式(II)的化合物：
其中R1、R2和R3彼此独立地是H。
根据本发明的一个方面，提供包含式(I)的化合物与适宜的药物可接受的赋形剂的组合的药物组合物。
根据其它方面，本发明涉及用作为人类或兽医学施用的药物的式(I)的化合物，涉及用于治疗由IL-1家族的细胞因子介导或影响的病症，特别是用于治疗炎症或自身免疫性疾病的式(I)的化合物，涉及式(I)的化合物用于制备治疗由IL-1家族的细胞因子介导或影响的病症的药物的用途，所述病症特别是炎症或自身免疫性疾病，并涉及用于治疗由IL-1家族的细胞因子介导或影响的病症的方法，其包括给予受者治疗有效量的式(I)化合物。
本发明的其它目的和优点由权利要求和以下的具体描述、实施例和附图呈现。
图1(a)、1(b)和1(c)展示了根据本发明的化合物的1H-NMR图谱。
图2展示了根据本发明的同样的化合物的MS分析；
图3是展示了根据本发明的化合物抑制人软骨细胞中IL-1β细胞因子的生产的图解描述；且
图4是展示了根据本发明的化合物剂量依赖性抑制人软骨细胞中IL-1β细胞因子的生产的图解描述。
本发明提供式(I)化合物：
其中R1、R2、R3彼此独立地是H或C1-4烷基基团或C2-4酰基基团；
R4和R5彼此独立地是H或式-SO3R6的基团，其中R6是H或C1-4烷基基团或C2-4酰基基团；
条件是R4和R5中至少一个是式-SO3R6的基团。
根据本发明的一个实施方式，R1和R2独立地选自H、C1-4烷基基团或C2-4酰基基团；R3是H，且R4和R5可以是H或-SO3H，条件是，R4和R5中至少一个是-SO3H。在优选的实施方式中，R1和R2都是H或都是乙酰基基团，R3和R4都是H，且R5是-SO3H。
根据本发明的一个实施方式，R1、R2、R3是H，且R4和R5独立地是H或-SO3H，条件是，R4和R5中至少一个是-SO3H。
根据本发明优选的实施方式，提供式(III)的化合物(6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸)：
本发明的化合物可以以其药物可接受的盐的形式。特别是考虑钠、钾或铵盐。
式(I)的化合物可以由根据本发明的方法制备，其包括用浓硫酸处理式(II)化合物，其中
R1、R2和R3是H，以制备相应的磺酸形式的式(I)的化合物。在进一步的步骤中，希望的C1-4烷基基团或C2-4酰基基团可以使用常规技术被选择性取代。例如，与C2-4酰卤，或相应的酰酐反应，以引入希望的C2-4酰氧基基团，与C1-4醇反应以形成相应的酯，或者例如与重氮甲烷(CH2N2)反应以引入C1烷基基团或者与C2-4烷基卤反应以引入相应的C2-4烷基基团。取决于希望的取代，视需要，可以引入已知的保护性基团，并使用常规方法解离。
可替代地，可以用焦硫酸代替硫酸。
与硫酸的反应优选在介于60和120℃的温度，优选在约100℃进行。
与酸的反应时间可以取决于例如反应温度、所使用的酸、所希望的产物(即二-或单-磺酸取代)等而变化。作为常规说明，反应时间设定为介于1小时和48小时，例如约24小时。反应过程可以有利地通过例如HPLC监控，并且所述反应在生成所希望的二磺酸根或单磺酸根取代的产物的反应完成时结束。
所述产物可以其相应的盐形式被分离，例如通过添加相应的金属卤化物(例如NaCl)，或相应的金属碱化试剂(如NaOH、KOH或NH3)。盐设定为包括任何药物可接受的盐，例如，钠、钾或铵盐。
由此获得的式(I)的化合物可以使用任何适合的常规纯化方法，例如，制备性HPLC或液-液分配来纯化。
根据本发明的式(I)的化合物展示了对IL-1家族的促炎症细胞因子的抑制活性。
在对人的软骨细胞的体外研究中，与大黄酸相比，式(I)的化合物出人意料地展示了表现出对白细胞介素-1(IL-1β)抑制的提高。
有利地，式(I)的化合物使得能够避免在双醋瑞因中存在的代谢产物芦荟大黄素。
考虑到其对IL-1家族的促炎症细胞因子的抑制活性，本发明的化合物被考虑用于治疗由异常高的或增加的IL-1水平表征的病症。
可以用本发明的化合物治疗的病症包括炎症和自身免疫性疾病。可以提及的病症包括类风湿性关节炎，骨关节炎，骨质疏松症，牛皮癣性关节炎，牛皮癣，动脉粥样硬化，Paget′s病，慢性心脏病，炎症性肠病，包括溃疡性结肠炎和克罗恩病，子宫内膜异位，Wegener′s肉芽肿病，神经机能障碍如阿尔茨海默氏病和帕金森病，骨髓瘤，髓样白血病，骨转移，糖尿病性肾病，肺气肿，哮喘。
相应地，本发明的一个方面涉及治疗由提高的IL-1水平(与健康个体相比)表征的病症的方法，其包括给予受者有效量的根据本发明的化合物或其药物可接受的盐。所述病症优选是炎症疾病或自身免疫性疾病。特别地，待治疗的病症包括关节的炎症疾病，特别是骨关节炎或类风湿性关节炎。还特别要提及的是牛皮癣性关节炎和牛皮癣。
很可能的是，本发明的化合物在上述很宽的炎症和自身免疫性疾病范围内具有临床用途，也归因于其与大黄酸相比改善的物理特性。
根据本发明的一个方面，提供包含式(I)的化合物与适宜的药物可接受的赋形剂的组合的药物组合物。根据本发明的药物组合物可以用于人类或兽医学用途。
根据本发明的药物组合物可以具有适合于通过任何途径给药的制剂，包括例如口服、肌肉内、静脉内、皮下、直肠、局部、经皮、鼻内、关节内、舌下和腹膜内给药。
口服给药的制剂可以包括例如，例如，片剂、硬或软明胶胶囊、锭剂、水或油混悬剂、分散性粉剂或重构颗粒剂、糖浆剂或乳液。
肠胃外给药的制剂可以以任何适合的药物形式，例如以无菌的可注射的缓冲水溶液或悬浮液的形式，呈在任何其它非毒性的肠胃外可接受的稀释剂或溶剂中的无菌的可注射的溶液或悬浮液，或以冻干形式用于在使用时重构。
本发明的组合物也可以以局部给药的制剂提供，例如以具有水性或油性的载体的乳霜、凝胶、软膏或乳剂的形式。
相比大黄酸或双醋瑞因，由于磺酸根基团的存在，根据本发明的式(I)的化合物预期显示在水中较好的溶解度。例如，根据本发明的式(I)的化合物，其中R1，R2，R3是H且R4和R5独立地或者都是SO3H，已经展示了表现出在水溶液中特别好的溶解度。例如，式(III)的化合物具有在水中1.2mg/ml的溶解度，而大黄酸和双醋瑞因是实际上不溶于水的。
本发明的化合物的良好的溶解性使得该化合物可以有利地通过肠胃外的途径给予，例如通过注射或输注，特别是作为关节内、肌内、静脉内或皮下注射或输注。
所述药物组合物可以根据本领域已知的方法使用适宜的已知的药物赋形剂和/或添加剂制备。
根据所选择的给药途径，考虑任何适宜的常规的药物可接受的赋形剂，例如稀释剂，粘合剂，表面活性剂，润滑剂，防沉降剂，乳化剂，缓冲液，抗结块剂，水性或油性载体，崩解剂，防腐剂，调味剂，甜味剂，着色剂。
适宜的剂量方案尤其是取决于因素如治疗应用、病症的严重性以及就待治疗的患者而变化。典型的日剂量可以在每日约0.05mg至约150mg每kg患者体重的数量级变化。总之，可以设定每日约10mg至500mg的日剂量，如介于每日约10mg和约250mg。单位剂型的活性成分的量取决于以上因素以及所选择的给药途径，并通常在每单位剂型1mg至500mg活性成分的范围内。
本发明由以下的非限制性实施例进一步说明。
实施例
实施例1
制备6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸
将由纯双醋瑞因的脱乙酰作用制备的具有超过99％的纯度的大黄酸(1g)溶解于浓硫酸(100ml)中。将溶液于100℃加热并搅拌24小时。使用HPLC实时跟踪反应的进程至反应完成。然后使反应混合物冷却并在搅拌下浇至2升水中。然后将所得溶液于4℃过夜保存。将未反应的大黄酸盐化物质(salting material)通过离心机除去。化合物6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸通过添加110g的氯化钠而沉淀为其钠盐。将所获得的悬浮液于4℃下冷却1小时，然后离心以分离出固体产物并在真空下干燥。获得2.32g产物。
除去盐：
将以上获得的产物加至水(115ml)中，同时在4℃下混合30分钟。然后将悬浮液离心并倾析以除去带有残余的盐的上清液。该操作重复7次直至常数电导率(约330μS/cm)(用电导仪(辐射计CDM 206)测量)。然后将离心后的残余物在真空下干燥以获得480mg产物，通过HPLC测得纯度为95.6％。
实施例2
表征
1H-NMR分析：
实施例1中获得的产物的1H-NMR光谱分析在二甲亚砜(DMSO)中使用Bruker
光谱仪于400MHz进行。在图1(a)至1(c)中展示的所获得的光谱，显示与产物6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸一致。
所述1H-NMR光谱说明仅存在4个芳族的质子，两个在间位，两个在邻位。显示磺酸取代在环上发生，该环之前只具有一个羟基取代基。与计算的基于增量的化学位移相比，化学位移显示磺酸基团的取代在邻位。
MS分析：
对实施例1的产物用Agilent 1100LC-MS光谱仪进行质谱检查，同时在大气压下以负电喷雾模式离子化。在图2中展示的所获得的光谱显示在364的峰值，并因此与产物6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸，式(III)一致。
实施例3
制备6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸钠盐
将由纯双醋瑞因的脱乙酰作用制备的具有超过99％的纯度的大黄酸(1g)，溶解于浓硫酸(100ml)中。将溶液于100℃加热并搅拌24小时。使用HPLC实时跟踪反应的进程至反应完成。然后使反应混合物冷却并在搅拌下浇至2升水中。然后将所得溶液于4℃过夜保存。将未反应的大黄酸盐化物质通过离心机除去。将上清液(surnatant)的pH用1M的NaOH调节至7.0。然后通过制备型HPLC使用反相C18硅胶柱和甲醇/水/H3PO4洗脱剂从溶液中分离并纯化出产物6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸，以其钠盐的形式。分离出1g产物并通过如实施例2中的NMR和MS表征为6-磺基-4，5-二羟基-9，10-二氧代-2-蒽羧酸钠盐。
实施例4
对人软骨细胞的IL-1β抑制的体外研究
通过人的正常的和骨关节炎(OA)的软骨细胞，研究了实施例1的化合物和大黄酸抑制脂多糖(LPS)刺激产生IL-1β细胞因子的活性。
材料和方法：
在由于正常的受者或OA患者中的外伤性骨折而全髋关节置换的整形外科手术期间获得人软骨。患有OA的患者基于以下的标准进行选择(1)双-侧OA，(2)中度的OA诊断(等级I-III，Kellgren-Laurence)，由放射学和病理学支持。
经分离的软骨细胞悬浮液制备自源于四位OA患者和9位正常受者的软骨样本。样本是在无菌条件下获得并维持在无菌条件下。将所述软骨切成小片并用1mg/ml梭菌属胶原酶(clostridialcollagenase)在碳酸盐/碳酸氢盐缓冲液中于37℃下温育48小时。一旦从软骨基质分离，就将软骨细胞以1500RPM离心5分钟。将经分离的软骨细胞悬浮于培养基(DMEM补充有10％SCF)中，用于实验。细胞生存力通过锥虫蓝分离术来评估。
用细菌内毒素(LPS)体外刺激软骨细胞如下进行IL-1β的生产：
将在培养基中1x106个细胞/ml的等份接种于15ml Falcon管中并在转动摇床上(100RPM)保持摇动。
将软骨细胞在MPS(10μg/ml)的存在下用20mg/ml大黄酸或者用递增浓度(1，5，10，20和30μg/ml)的测试化合物(实施例1的化合物)培养48小时。对于用大黄酸的样品，将溶液经5分钟的超声处理从而将与大黄酸的疏水性有关的溶解度问题最小化。对于测试化合物来说，由于其良好的溶解度，该问题并不存在。
在培养基中在不同的样品培养物中通过ELISA试剂盒进行分析软骨细胞IL-1β的生产。
图3展示了用大黄酸以及实施例1的化合物对在LPS-刺激的正常的和OA软骨细胞中的IL-1β生产所获得的结果，如通过ELISA评估。图4展示了测试化合物(实施例1的化合物)对正常软骨细胞的IL-1β生产的剂量依赖性抑制。在图3中说明的结果展示了与大黄酸相比本发明的化合物显示显著提高的IL-1β抑制活性。图4展示了根据本发明的化合物提供对IL-1β生产的显著抑制，最大抑制介于10和20mg/ml。
Claims (17)
1.式(I)化合物：
其中R1、R2、R3彼此独立地是H或C1-4烷基基团或C2-4酰基基团；
R4和R5彼此独立地是H或式-SO3R6的基团，其中R6是H或C1-4烷基基团或C2-4酰基基团；
条件是R4和R5中至少一个是式-SO3R6的基团，
或其药物可接受的盐。
2.根据权利要求1的化合物，其中R1、R2独立地是H或C1-4烷基基团或C2-4酰基基团，R3和R4是H，且R5是-SO3H。
3.根据权利要求1或2的化合物，其具有式(III)：
4.根据权利要求1至3任一项的化合物，其用作药物。
5.根据权利要求1至3任一项的化合物，其用于治疗由IL-1家族的促炎症细胞因子介导或影响的病症。
6.根据权利要求1至3任一项的化合物，其作为用于治疗炎症或自身免疫性病症的药物使用。
7.根据权利要求1至3任一项的化合物，其用于治疗选自下组的病症：类风湿性关节炎，骨关节炎，骨质疏松症，牛皮癣性关节炎，牛皮癣，动脉粥样硬化，Paget′s病，慢性心脏病，炎症性肠病包括溃疡性结肠炎和克罗恩病，子宫内膜异位，Wegener′s肉芽肿病，神经机能障碍如阿尔茨海默氏病和帕金森病，骨髓瘤，髓样白血病，骨转移，糖尿病性肾病，肺气肿，哮喘。
8.根据权利要求7的化合物，其中所述病症选自骨关节炎，类风湿性关节炎，牛皮癣性关节炎和牛皮癣。
9.药物组合物，其包含根据权利要求1至3任一项的化合物或其药物可接受的盐作为活性成分。
10.根据权利要求9的药物组合物，其中所述组合物用于肠胃外给药。
11.根据权利要求9的药物组合物，其中所述组合物用于口服给药。
12.根据权利要求9的药物组合物，其中所述组合物用于局部给药。
13.治疗由IL-1家族的促炎症细胞因子介导或影响的病症的方法，其包括给予受者治疗有效量的根据权利要求1至3任一项的化合物或其药物可接受的盐。
14.治疗炎症或自身免疫性疾病的方法，其包括给予受者治疗有效量的根据权利要求1至3任一项的化合物或其药物可接受的盐。
15.根据权利要求13的方法，其中所述疾病选自骨关节炎、类风湿性关节炎、牛皮癣性关节炎和牛皮癣。
16.根据权利要求1至3任一项的化合物用于制备治疗由IL-1家族的炎症细胞因子介导或影响的病症的药物的用途。
17.制备式(I)的化合物或其药物可接受的盐的方法：
其中R1、R2、R3彼此独立地是H或C1-4烷基基团或C2-4酰基基团；
R4和R5彼此独立地是H或式-SO3R6的基团，其中R6是H或C1-4烷基基团或C2-4酰基基团；
条件是R4和R5中至少一个是式-SO3R6的基团，
包括将式(II)化合物用浓硫酸处理，
其中R1，R2，R3是H。
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| WO2012099216A1 (ja) | 2011-01-19 | 2012-07-26 | 国立大学法人弘前大学 | プロテオグリカンの大量調製法 |
| CN104507484B (zh) * | 2012-07-25 | 2019-08-30 | 国立大学法人弘前大学 | 变形性关节病预防或治疗用组合物 |
| US20160252954A1 (en) * | 2015-02-27 | 2016-09-01 | Microsoft Technology Licensing, Llc | Control apparatus |
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| MY153945A (en) | 2015-04-15 |
| ES2400028T3 (es) | 2013-04-05 |
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| AU2008322341B2 (en) | 2013-02-21 |
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| RU2482109C2 (ru) | 2013-05-20 |
| HK1147738A1 (en) | 2011-08-19 |
| US8754128B2 (en) | 2014-06-17 |
| CN101861301B (zh) | 2013-05-29 |
| KR20100097162A (ko) | 2010-09-02 |
| CA2704630C (en) | 2016-01-19 |
| PT2220036E (pt) | 2013-03-05 |
| CL2008003378A1 (es) | 2011-04-01 |
| CA2704630A1 (en) | 2009-05-22 |
| KR101527620B1 (ko) | 2015-06-09 |
| UA99745C2 (en) | 2012-09-25 |
| MX2010004800A (es) | 2010-05-20 |
| WO2009063427A1 (en) | 2009-05-22 |
| US20150011636A1 (en) | 2015-01-08 |
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